Vol 35, No.

2, 2013
Medicographia
115
A Ser vier publication

Osteoarthritis: a story of
close relationship between
bone and cartilage
E DITORIAL
139 Osteoarthritis: new approaches
Arthrose : nouvelles approches
M. C. Hochberg, USA

T HEMED ARTICLES
145 Epidemiology of osteoarthritis
C. Cooper, E. Dennison, M. Edwards, A. Litwic, United Kingdom

152 Osteoarthritis and comorbidities

L. I. Alekseeva, E. L. Nasonov, Russia

158 Osteoarthritis pathophysiology: similarities and dissimilarities with other

rheumatological diseases and the role of subchondral bone
J. A. Roman-Blas, G. Herrero-Beaumont, Spain

164 Role of imaging in osteoarthritis: diagnosis, prognosis, and follow-up

A. Guermazi, F. W. Roemer, H. K. Genant, USA and Germany

172 Osteoarthritis treatments: where do we stand at the moment?

C. Roubille, J. Martel-Pelletier, J. P. Pelletier, Canada

181 Knee replacement for osteoarthritis: facts, hopes, and fears

L. S. Lohmander, Sweden and Denmark

189 Disease-modifying osteoarthritis drugs (DMOADs): what are they and

what can we expect from them?
A. J. Barr, P. G. Conaghan, United Kingdom

197 The economic weight of osteoarthritis in Europe

M. Hiligsmann, J. Y. Reginster, The Netherlands and Belgium

Contents continued on next page

Vol 35, No. 2, 2013
Medicographia
115
A Ser vier publication

C ONTROVERSIAL QUESTION
203 Can normal age-related changes in cartilage be distinguished from early
osteoarthritic changes?

Kingdom - S. Blkba i, Turkey - O. P. Bortkevych, Ukraine - P. Hork,

L. A. Alekseeva, Russia - J. P. A. Arokoski, Finland - F. N. Birrell, United

Czech Republic - A. El Maghraoui, Morocco - A. Mahmoud Ali Elsayed,

Egypt - A. Migliore, Italy - T. Pap, Germany - J. del Pino-Montes, Spain -
C. A. F. Zerbini, Brazil

I NTERVIEW
216 Nonpharmacological treatments in osteoarthritis
E. Kon, Italy

F OCUS
221 Long overlooked: the role of subchondral bone in osteoarthritis
pathophysiology and pain
D. M. Findlay, Australia

U PDATE
228 Clinical research in osteoarthritis: whats new?
X. Chevalier, F. Eymard, France

A TOUCH OF F RANCE
237 Cinema, science, and medicine in France
C. Rgnier, France

246 Children of the Cinmathque

I. Spaak, France
 EDITORIAL
In early phases of OA, there
are anabolic changes in both ar-
ticular cartilage and subchondral
bone. In the former, there is in-
creased synthesis of matrix mole-
cules while, in the latter, there is
activation of the bone remodel-
ing cycle. With progression of OA,
catabolic changes dominate in the
articular cartilage with increased
synthesis of tissue-destructive en-
zymes including matrix metallopro-
teases (MMPs), and disintegrins
and MMPs with thrombospondin
motifs.
Marc C. HOCHBERG, MD, MPH
Professor of Medicine and
Epidemiology and Public Health
University of Maryland School
of Medicine, Baltimore
Maryland, USA
Address for correspondence:
Professor Marc C. Hochberg,
MD, MPH, c/o Division of
Rheumatology, University of Maryland
School of Medicine, 10 S. Pine St.,
MSTF 8-34, Baltimore, Maryland
21201, USA (e-mail: mhochber@
medicine.umaryland.edu)
Medicographia. 2013;35:139-144.
www.medicographia.com
Osteoarthritis: new approaches Hochberg
Osteoarthritis:
new approaches
by M. C. Hochberg, USA
steoarthritis (OA) is a disease of the total joint, not just the articular car-
O tilage. The Osteoarthritis Research Society International Disease State
Working Group defined OA as a progressive disease representing the
failed repair of joint damage that, in the preponderance of cases, has
been triggered by abnormal intra-articular stress.1 They noted that all tissues of the
joint are involved, including not only the articular cartilage, but also the subchondral
bone, ligaments, periarticular structures, and menisci, when present. The results of
the OA process are cartilage degradation and bone remodeling; these features are
associated with the development of symptoms of pain, stiffness, and functional dis-
ability. In this current concept of OA, the structural changes represent the disease
while the symptoms of aching, discomfort, pain, and stiffness represent the illness
for which patients seek medical care. This concept has profound implications for
treatment: while there are drugs currently approved for treating the illness of OA,
there are none currently approved for slowing the structural progression of OA.
Osteoarthritis (OA) is the most common form of arthritis, and is a major cause of
morbidity, activity limitation, physical disability, excess health care utilization and re-
duced health-related quality of life, especially in people aged 45 and above in de-
veloped countries.2 The incidence (risk of developing the disease) and prevalence
(proportion of persons with the disease) of OA increase with advancing age in both
sexes. In general, women have a higher incidence and prevalence of symptomatic
radiographic OA, particularly in the hands and knees. There are ethnic and racial
differences in the occurrence of OA that may be due to genetic and/or lifestyle fac-
tors; these include the lower prevalence of hand and hip OA in Chinese and the
higher prevalence of hip and knee OA in African Americans compared with whites.3
It is now recognized that OA is not only a cause of pain and physical dysfunction,
but is also associated with excess mortality.4,5 Losina and colleagues reported that
the presence of knee OA, especially when combined with the presence of obesi-
ty, was associated with the loss of 3 to 4 quality-adjusted years of life.4 Neusch
and colleagues, in analyzing data from a 15-year prospective cohort study in the
United Kingdom, reported that persons with symptomatic hip and/or knee OA had
a 50% increase in all-cause mortality compared with that expected based on their
age and gender distribution.5 Risk factors for all-cause mortality included not only
the presence of comorbid conditions such as cardiovascular disease, cancer, and
diabetes, but also the presence of walking disability. This suggests that an approach
to reducing walking disability in patients with symptomatic lower limb OA might not
only improve quality of life, but also prolong survival.
MEDICOGRAPHIA, Vol 35, No. 2, 2013 139
EDITORIAL
Much research has focused on the role of obesity, joint injury,
and genetic predisposition as risk factors for the development
of OA.6-8 Metabolic syndromethe phenotype characterized
by abdominal obesity, dyslipidemia, hypertension, and type 2
diabetes mellitus due to insulin resistanceis associated with
OA; this association may be mediated by the production of
circulating adipokines and accumulation of age-related gly-
cation end products in articular cartilage.6 While the heritability
of OA has been recognized for over 60 years, only in the past
decade, with the development of commercially available geno-
typing platforms, have scientists been able to perform genome-
wide association studies examining the association of sin-
gle nucleotide polymorphisms (SNPs) with OA.8 The largest
consortium to investigate the association of SNPs with radio-
graphic and clinical OA is Translational Research in Europe
Applied Technologies for OsteoArthritis (TreatOA); indeed, the
TreatOA website (http://www.treatoa.eu/publications.html)
currently lists more than 50 peer-reviewed articles on the re-
sults of genetic studies in OA.
The interplay between the articular cartilage and subchondral
bone in the pathophysiology of OA has been increasingly rec-
ognized over the past decade and is a major focus for current
research into the development and progression of OA.9-11 In
early phases of OA, there are anabolic changes in both artic-
ular cartilage and subchondral bone. In the former, there is in-
creased synthesis of matrix molecules while, in the latter, there
is activation of the bone remodeling cycle. With progression
of OA, catabolic changes dominate in the articular cartilage
with increased synthesis of tissue-destructive enzymes in-
cluding matrix metalloproteases (MMPs), and disintegrins and
MMPs with thrombospondin motifs. Accompanying changes
in the subchondral bone include trabecular thinning leading to
relative osteopenia below areas of sclerosis due to thickening
of the cortical plate. These changes are mediated, in part, by
the diffusion of small molecules between bone and cartilage,
including cytokines, angiogenic growth factors, and MMPs.
Another component of the OA process that has received in-
creasing recognition is the role of synovitis.12,13 Studies have
demonstrated increased expression of genes that encode cy-
tokines (such as interleukin-1 and 15), chemokines, and MMPs
in synovial fibroblasts. Synovitis, as measured on magnetic res-
onance imaging (MRI) and/or ultrasound, is associated with
both pain and structural progression; it is not known, howev-
er, whether specific anti-inflammatory therapy is more effica-
cious in patients with synovitis than in those without it.
Synovitis is but one feature of OA that is associated with pain;
others include the presence of moderate-to-large bone mar-
row lesions and joint effusions. Studies of the mechanisms of
pain in OA have increasingly explored the nature of OA pain
and the role of peripheral and central sensitization superim-
posed on peripheral nociception.14,15 Peripheral sensitization
has a spinal component with signal amplification in neurons
140 MEDICOGRAPHIA, Vol 35, No. 2, 2013
of the spinal cord underlying both primary and secondary hy-
peralgesia. In addition, there is central sensitization, manifest-
ed by lower pressure pain thresholds and higher pain sum-
mation scores. The mechanisms of central sensitization in OA
may be due to spinal hyperexcitability coupled with defective
descending inhibitory noxious control pathways. Functional
MRI studies in patients with chronic OA pain have demon-
strated atrophy in the thalamus and gray matter of pain-re-
lated cortical areas, which is partially reversible after total joint
arthroplasty.
The management of patients with OA continues to evolve with
more evidence supporting the efficacy of nonpharmacologic
modalities as well as the approval and study of newer phar-
macological modalities, including biologic agents.16 The Amer-
ican College of Rheumatology published new recommenda-
tions for the medical management of OA of the hand, hip, and
knee in 2012.17 Nonsteroidal anti-inflammatory drugs (NSAIDs)
remain the cornerstone of oral therapy for pain in patients with
OA, despite their association with potential serious adverse
events including gastrointestinal bleeding from complicated
ulcers and small and large bowel lesions, and cardiovascular
thrombotic events, especially myocardial infarction. Patients
who have an inadequate response to or are unable to toler-
ate oral NSAIDs may be treated with intra-articular agents
such as glucocorticoids and hyaluronates and/or centrally act-
ing analgesics such as tramadol, duloxetine, and opioids. The
efficacy of duloxetinea serotonin norepinephrine reuptake
inhibitor that can be used either alone or as an adjunct to acet-
aminophen or NSAIDssupports the observations summa-
rized above that demonstrate the role of central sensitization
in chronic OA pain due to loss of diffuse inhibitory noxious
control.
There remains an unmet need for both more efficacious treat-
ments for pain and agents that are capable of modifying the
rate of structural progression in OA. Tanezumab, a monoclon-
al antibody directed against nerve growth factor, has demon-
strated efficacy in patients with hip and knee OA with mod-
erate-to-severe pain.18 However, the development of this agent,
and of other compounds in its class, has been placed under
clinical hold by the US Food and Drug Administration (FDA)
because of reports of osteonecrosis adverse events that were
eventually adjudicated to be rapidly destructive OA involving
not only index joints such as the hip and knee, but also non-
index joints such as the shoulder. Further studies of the mech-
SELECTED ABBREVIATIONS AND ACRONYMS
MMP matrix metalloprotease
MRI magnetic resonance imaging
NSAID nonsteroidal anti-inflammatory drug
OA osteoarthritis
SNP single nucleotide polymorphism
Osteoarthritis: new approaches Hochberg

anism underlying these joint-related serious adverse events
are needed to assess the risk-benefit relationship of this prom-
ising treatment for pain in patients with OA.
There have been many studies involving potential disease-
modifying OA drugs (DMOADs); however, there are no agents
that are approved at this time by either the FDA or European
Medicines Agency (EMA) for this indication. Recent data sug-
gest that oral strontium ranelate, at doses of either 1 or 2 g
per day, significantly reduced the rate of decline in joint space
References
1. Lane N, Brandt K, Hawker G, et al. OARSI-FDA initiative: defining the disease
state of osteoarthritis. Osteoarthritis Cartilage. 2011;19:478-482.
2. Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of
arthritis and other rheumatic conditions in the United States. Arthritis Rheum.
2008;58:26-35.
3. Jordan JM: Impact of race/ethnicity in OA treatment. HSS J. 2012;8:39-41.
4. Losina E, Walensky RP, Reichmann WM, et al. Impact of obesity and knee
osteoarthritis on morbidity and mortality in older Americans. Ann Intern Med.
2011;154:217-226.
5. Nuesch E, Dieppe P, Reichenbach S, Williams S, Iff S, Juni P. All cause and dis-
ease specific mortality in patients with knee osteoarthritis: population based
cohort study. BMJ. 2011;342:d1165.
6. Zhuo Q, Yang W, Chen J, Wang Y. Metabolic syndrome meets osteoarthritis.
Nat Rev Rheumatol. 2012;8:729-737.
7. Muthuri SG, McWilliams DF, Doherty M, Zhang W. History of knee injuries and
knee osteoarthritis: a meta-analysis of observational studies. Osteoarthritis
Cartilage. 2011;19:1286-1293.
8. Hochberg MC, Yerges-Armstrong L, Mitchell BM. Osteoarthritis susceptibility
genes continue trickling in. Lancet. 2012;380:785-787.
9. Lories RJ, Luyten FP. The bone-cartilage unit in osteoarthritis. Nat Rev Rheu-
matol. 2011;7:43-49.
10. Goldring MB. Articular cartilage degradation in osteoarthritis. HSS J. 2012;8:7-9.
11. Weinans H. Periarticular bone changes in osteoarthritis. HSS J. 2012;8:10-12.
12. Sellam J, Berenbaum F. The role of synovitis in pathophysiology and clinical
Keywords: osteoarthritis, pathophysiology, risk factors, treatment
Osteoarthritis: new approaches Hochberg
EDITORIAL
width compared with placebo in subjects with knee OA fol-
lowed for a mean of 30 months.19 Similar results were noted
when subjects were classified as progressors based on a
decline in joint space width of at least 0.5 mm.20 Another ap-
proach to disease modification is the application of principles
of regenerative medicine with endogenous stem cells.21 It is
hoped that the results of basic biomedical, clinical, and trans-
lational research will provide new approaches to the manage-
ment of patients with OA during the remaining years of this
and future decades. I
symptoms of osteoarthritis. Nat Rev Rheumatol. 2010;6:625-635.
13. Scanzello CR. Pathologic and pathogenic processes in osteoarthritis: the ef-
fects of synovitis. HSS J. 2012;8:20-22.
14. Mease PJ, Hanna S, Frakes EP, Altman RD. Pain mechanisms in osteoarthritis:
understanding the role of central pain and current approaches to its treatment.
J Rheumatol. 2011;38:1546-1551.
15. Schaible HG. Mechanisms of chronic pain in osteoarthritis. Curr Rheumatol
Rep. 2012; 14:549-556.
16. Hochberg MC. Osteoarthritis year 2012 in review: clinical. Osteoarthritis Carti-
lage. 2012. 20:1465-1469.
17. Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology
2012 recommendations for the use of nonpharmacologic and pharmacologic
therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res. 2012;
64:455-474.
18. Lane NE, Schnitzer TJ, Birbara CA, et al. Tanezumab for the treatment of pain
from osteoarthritis of the knee. N Engl J Med. 2010;363:1521-1531.
19. Reginster JY, Chapurlat R, Christiansen C, et al. Structure modifying effects of
strontium ranelate in knee osteoarthritis. Osteoporos Int. 2012;23(suppl 2):
S58-S59.
20. Reginster JY, Chapurlat R, Christiansen C, et al. Strontium ranelate reduces the
number of radiological or radioclinical progressors in patients with primary knee
osteoarthritis. Osteoporos Int. 2012;23(suppl 2):S366-S367.
21. Marini JC, Forlino A. Replenishing cartilage from endogenous stem cells. N Engl
J Med. 2012;366:2522-2524.
MEDICOGRAPHIA, Vol 35, No. 2, 2013 141
 DITORIAL

Dans les phases prcoces de

larthrose, des changements ana-
boliques interviennent aussi bien
dans le cartilage articulaire que
dans los sous-chondral. Dans le
premier type de tissu se produit
une augmentation de la synthse
Arthrose :
des molcules de la matrice tandis
que dans le second se droule une
nouvelles approches
activation du cycle du remodelage
osseux. Au fur et mesure de la
progression de larthrose, les chan-
gements cataboliques dominent
dans le cartilage articulaire, avec
une augmentation de la synthse
denzymes destructrices des tis-
sus.
par M. C. Hochberg, tats-Unis

L
arthose est une maladie qui affecte la totalit de larticulation, et non pas
seulement le cartilage articulaire. Le Groupe de travail de lOARSI (Osteoar-
thritis Research Society International, la Socit internationale de recherche
sur larthrose) a dfini larthrose de la faon suivante : maladie progres-
sive correspondant une incapacit de rparation des lsions articulaires qui, dans
la majorit des cas, ont t dclenches par des stress intra-articulaires anormaux .1
Il a t observ que tous les tissus de larticulation sont touchs, non seulement le
cartilage articulaire, mais galement los sous-chondral, les ligaments, les structures
priarticulaires et les mnisques lorsquils sont prsents. Le processus arthrosique
conduit une dgradation du cartilage et un remodelage osseux ; ces caract-
ristiques sont associes au dveloppement de symptmes douloureux, de raideur
et dincapacit fonctionnelle. Dans ce concept actuel de larthrose, les altrations
structurelles reprsentent la maladie, tandis que les symptmes type de douleur
sourde, gne, douleur et raideur constituent la pathologie pour laquelle les patients
consultent un mdecin. Ce concept a dimportantes rpercussions sur le traitement :
alors que certains mdicaments sont actuellement autoriss pour le traitement de
la pathologie de larthrose, il nexiste actuellement aucun traitement approuv ra-
lentissant la progression structurelle de larthrose.

Larthrose, la forme la plus frquente darthropathie, est une cause importante de

morbidit, de limitation des activits, dincapacit physique, de surutilisation des soins
de sant et de rduction de la qualit de vie lie la sant, et ce plus particulire-
ment chez les personnes ges de 45 ans et plus dans les pays dvelopps.2 Lin-
cidence (le risque de dvelopper la maladie) et la prvalence (proportion de personnes
atteintes de la maladie) de larthrose augmentent avec lge dans les deux sexes.
Dune manire gnrale, les femmes prsentent une incidence et une prvalence
suprieures darthrose symptomatique radiographique, en particulier au niveau des
mains et des genoux. Il existe des diffrences ethniques et raciales dans la surve-
nue de larthrose, principalement lies des facteurs gntiques et/ou relatifs au
style de vie ; notamment une prvalence plus faible de larthrose des mains et de
la hanche chez les Chinois, et une prvalence suprieure de larthrose de la hanche
et du genou chez les Afro-Amricains par rapport aux blancs.3

Il est dsormais tabli que larthrose provoque non seulement une douleur et un dys-
fonctionnement physique, mais quelle est galement associe un excs de mor-
talit.4,5 Losina et coll. ont indiqu que la prsence dune arthrose du genou, en
particulier en cas dobsit concomitante, tait associe une perte de 3 4 an-
nes de vie ajustes sur la qualit de vie.4 Neusch et coll., qui ont analys les don-

142 MEDICOGRAPHIA, Vol 35, No. 2, 2013 Arthrose : nouvelles approches Hochberg

nes dune tude de cohorte prospective de 15 ans mene
au Royaume-Uni, ont montr que les personnes prsentant
une arthrose symptomatique de la hanche et/ou du genou
prsentaient une augmentation de 50 % de la mortalit de
toute cause par rapport celle prvue sur la base dune dis-
tribution par tranche dge et sexe.5 Les facteurs de risque
de mortalit de toute cause comprennent la prsence de co-
morbidits, notamment les maladies cardio-vasculaires, le can-
cer et le diabte, mais galement la prsence dune incapa-
cit la marche. Cela suggre quune approche permettant
de rduire lincapacit la marche chez les patients atteints
darthrose symptomatique des membres infrieurs pourrait
non seulement amliorer leur qualit de vie, mais galement
prolonger leur dure de vie.
Un grand nombre de recherches ont port sur le rle de lob-
sit, des lsions articulaires et de la prdisposition gntique
comme facteurs de risque du dveloppement de larthrose.6-8
Le syndrome mtabolique un phnotype caractris par une
obsit abdominale, une dyslipidmie, une hypertension et un
diabte de type 2 d une insulinorsistance est associ
larthrose ; cette association pourrait tre due la produc-
tion dadipokines circulantes et laccumulation de produits ter-
minaux de glycation lis lge dans le cartilage articulaire.6
Si la transmission hrditaire de larthrose est reconnue de-
puis plus de 60 ans, ce nest quau cours de la dernire d-
cennie que les scientifiques, grce la disponibilit dans le
commerce de plates-formes de gnotypage, ont t en me-
sure deffectuer de larges tudes dassociation sur lensemble
du gnome, en examinant lassociation des polymorphismes
nuclotidiques (single nucleotide polymorphisms, SNP) avec
larthrose.8 Le plus large consortium ayant explor lassocia-
tion des SNP avec les preuves radiographiques et cliniques
darthrose est TreatOA (Translational Research in Europe Ap-
plied Technologies for OsteoArthritis) ; en effet, le site Internet
de TreatOA (http://www.treatoa.eu/publications.html) com-
porte actuellement une liste de plus de 50 articles valus par
des pairs sur les rsultats dtudes gntiques dans larthrose.
Linterconnexion entre le cartilage articulaire et los sous-chon-
dral dans la physiopathologie de larthrose a t confirme au
cours de la dernire dcennie, et constitue lun des sujets ma-
jeurs des recherches actuelles sur le dveloppement et la pro-
gression de larthrose.9-11 Dans les phases prcoces de lar-
throse, des changements anaboliques interviennent aussi bien
dans le cartilage articulaire que dans los sous-chondral. Dans
ABRVIATIONS ET ACRONYMES
MMP matrix metalloprotease (mtalloprotinases de la matrice)
IRM Imagerie par rsonance magntique
AINS Anti-inflammatoires non strodiens
SNP single nucleotide polymorphism (polymorphisme nuclo-
tidique)
Arthrose : nouvelles approches Hochberg
DITORIAL
le premier type de tissu se produit une augmentation de la
synthse des molcules de la matrice tandis que dans le se-
cond se droule une activation du cycle du remodelage os-
seux. Au fur et mesure de la progression de larthrose, les
changements cataboliques dominent dans le cartilage articu-
laire, avec une augmentation de la synthse denzymes des-
tructrices des tissus, notamment les mtalloprotinases de la
matrice (MMP), ainsi que des dsintgrines et des MMP mu-
nies de motifs thrombospondines. Les changements conco-
mitants dans los sous-chondral comprennent un amincisse-
ment trabculaire provoquant une ostopnie relative sous
les zones de sclrose, lie lpaississement de la plaque cor-
ticale. Ces changements sont assurs en partie par la diffu-
sion de petites molcules entre los et le cartilage, notamment
des cytokines, des facteurs de croissance angiogniques et
des MMP.
Un autre composant du processus arthrosique de mieux en
mieux identifi est le rle de la synovite.12,13 Des tudes ont
dmontr une augmentation de lexpression des gnes co-
dant pour les cytokines (notamment les interleukines 1 et 15),
les chimiokines et les MMP dans les fibroblastes synoviaux.
La synovite, mesure par imagerie par rsonance magntique
(IRM) et/ou chographie, est associe la fois la prsence
de douleurs et une progression structurelle ; il na cepen-
dant pas t tabli si un traitement anti-inflammatoire sp-
cifique tait plus efficace chez les patients atteints de syno-
vite que chez ceux qui ne ltaient pas.
La synovite est lune des caractristiques de larthrose as-
socie la douleur ; les autres comprennent la prsence de
lsions modres importantes de la moelle osseuse et
dpanchements articulaires. Les tudes des mcanismes de
la douleur dans larthrose explorent de plus en plus souvent
la nature de la douleur arthrosique et le rle de la sensibilisa-
tion priphrique et centrale associe la nociception pri-
phrique.14,15 La sensibilisation priphrique a une compo-
sante rachidienne saccompagnant dune amplification des
signaux dans les neurones de la moelle pinire, qui sous-tend
une hyperalgie primitive et secondaire. En outre, il existe une
sensibilisation centrale, qui se manifeste par labaissement
des seuils de douleur la pression et une augmentation des
scores totaux de douleur. Les mcanismes de la sensibilisa-
tion centrale dans larthrose peuvent tre dus une hyperex-
citabilit rachidienne couple un dficit des voies de contrle
descendantes inhibitrices des stimuli nociceptifs. Des tudes
dIRM fonctionnelle menes chez des patients prsentant une
douleur arthrosique chronique ont mis en vidence latrophie
des zones corticales lies la douleur dans le thalamus et la
substance grise, partiellement rversible aprs une arthroplas-
tie articulaire totale.
La prise en charge des patients atteints darthrose ne cesse
dvoluer au fur et mesure que les preuves confirmant lef-
ficacit des modalits non pharmacopidmiologiques sac-
MEDICOGRAPHIA, Vol 35, No. 2, 2013 143
DITORIAL
cumulent, mais galement avec lautorisation de nouvelles mo-
dalits pharmacologiques, notamment les agents biologiques,
et les tudes qui sont menes dessus.16 L Acadmie amri-
caine de rhumatologie (American College of Rheumatology)
a publi en 2012 de nouvelles recommandations sur la prise
en charge mdicale de larthrose de la main, de la hanche et
du genou.17 Les anti-inflammatoires non strodiens (AINS)
restent la base du traitement oral de la douleur chez les pa-
tients arthrosiques, malgr leur association des effets ind-
sirables potentiellement graves, notamment des hmorragies
gastro-intestinales provenant dulcres compliqus et de l-
sions de lintestin grle et du gros intestin, ainsi que des v-
nements cardio-vasculaires thrombotiques, en particulier lin-
farctus du myocarde. Les patients prsentant une rponse
inadquate ou ntant pas en mesure de tolrer les AINS
oraux peuvent tre traits par des agents intra-articulaires,
notamment les glucocorticodes et les hyaluronates et/ou des
analgsiques centraux, par exemple le tramadol, la dulox-
tine et les opiacs. Lefficacit de la duloxtine un inhibiteur
de la recapture de la srotonine et de la noradrnaline pou-
vant tre utilis seul ou en complment du paractamol ou
des AINS confirme les observations rsumes ci-dessus,
dmontrant le rle de la sensibilisation centrale dans la dou-
leur arthrosique chronique provoque par la perte du contrle
inhibiteur diffus induit par la nociception.
Il reste sur ce plan un besoin non satisfait de traitements plus
efficaces de la douleur et dagents capables de modifier la vi-
tesse de progression structurelle de larthrose. Le tanzumab,
un anticorps monoclonal dirig contre le facteur de croissance
nerveuse, a dmontr son efficacit chez les patients atteints
darthrose de la hanche et du genou prsentant une douleur
144 MEDICOGRAPHIA, Vol 35, No. 2, 2013
modre svre.18 Cependant, le dveloppement de cet
agent et des autres composs de sa classe a fait lobjet dune
suspension clinique de la part de la Food and Drug Adminis-
tration (FDA), cause dvnements indsirables type dos-
toncrose finalement confirms comme constituant une ar-
throse rapidement destructrice affectant non seulement les
articulations de rfrence comme la hanche et le genou, mais
galement dautres articulations, notamment lpaule. Dau-
tres tudes sur le mcanisme li ces vnements indsi-
rables articulaires graves sont ncessaires pour valuer le
rapport bnfice-risque de ces traitements prometteurs de
la douleur chez les patients atteints darthrose.
De nombreuses tudes ont t menes sur les traitements de
fond de larthrose ; cependant, aucun mdicament na jusqu
prsent t approuv par la FDA ou lAgence europenne
des mdicaments (EMA) dans cette indication. De rcentes
donnes suggrent que le ranlate de strontium par voie orale,
des posologies de 1 ou 2 g par jour, rduit de manire signi-
ficative le taux de dclin de lpaisseur de linterligne articu-
laire par rapport un placebo chez des sujets prsentant une
arthrose du genou suivis pendant une dure moyenne de 30
mois.19 Des rsultats similaires ont t recueillis lorsque les su-
jets ont t classs comme progresseurs sur la base dune
diminution de linterligne articulaire dau moins 0,5 mm.20 Une
autre approche de lvolution de la maladie est lapplication
des principes de la mdecine rgnrative avec des cellules
souches endognes.21 Les rsultats de recherches biom-
dicales fondamentales, cliniques et translationnelles suscitent
lespoir de fournir de nouvelles approches pour la prise en
charge des patients atteints darthrose vers la fin de cette d-
cennie et dans les dcennies venir. I
Arthrose : nouvelles approches Hochberg
 OSTEOARTHRITIS: A STORY OF CLOSE R E L AT I O N S H I P

BETWEEN BONE AND CARTILAGE

A systematic review and

meta-analysis of the risk factors
for the onset of knee osteoarthri-
tis in older adults has shown that
there is a consistent strong asso-
ciation between increased bone
Epidemiology of
mineral density and the onset of
knee osteoarthritis Although a
definite molecular basis and com-
osteoarthritis
mon pathophysiology have not
been identified to explain the in-
verse relationship between osteo-
arthritis and osteoporosis, a shared
genetic component may explain
why they seldom coexist.

b y C . C o o p e r, E . D e n n i s o n , M . E d wa rd s ,
and A. Litwic, United Kingdom

O
steoarthritis is a global degenerative joint disease involving the car-
tilage and many of its surrounding tissues. Prevalence and incidence
estimates of osteoarthritis in different populations may vary consid-
erably due to different diagnostic classifications; in general, radiographic case
definition produces the highest estimates, with self-reported and symptomatic
osteoarthritis definitions producing similar estimates. The World Health Orga-
nizations Scientific Group on Rheumatic Diseases estimates that 10% of the
worlds population aged 60 years or older have significant clinical problems
that could be attributed to osteoarthritis. The highest osteoarthritis prevalence
estimates are found in the hand joints, with women more commonly affected
L
than men.
Cyrus COOPER,a,b MA, DM,
FRCP, FFPH, FMedSci Medicographia. 2013;35:145-151 (see French abstract on page 151)
Elaine DENNISON,b MB BChir,
MA, MSc, FRCP, PhD
Mark EDWARDS,b BSc, MBChB,
MRCP
Definition and classification
steoarthritis (OA) is a degenerative joint disease involving the cartilage and

O
Anna LITWICb
a
IHR Musculoskeletal Biomedical many of its surrounding tissues. In addition to damage and loss of articu-
Research Unit lar cartilage, there is remodeling of subarticular bone, osteophyte formation,
University of Oxford, UK
b
ligamentous laxity, weakening of periarticular muscles, and, in some cases, synovial
MRC Lifecourse Epidemiology
inflammation.1 These changes may occur as a result of an imbalance in the equilib-
Unit, (University of Southampton)
Southampton General Hospital rium between the breakdown and repair of joint tissue. Primary symptoms of OA in-
Southampton, UK clude joint pain, stiffness, and limitation of movement. Disease progression is usually
slow but can ultimately lead to joint failure with pain and disability.

Address for correspondence:
Professor Cyrus Cooper, Director
and Professor of Rheumatology,
MRC Lifecourse Epidemiology Unit,
(University of Southampton),
Southampton General Hospital,
Southampton SO16 6YD, UK
(e-mail: cc@mrc.soton.ac.uk)
www.medicographia.com
There have been many attempts to accurately identify and grade radiographic dis-
ease in OA. Of these, the classification by Kellgren and Lawrence (K&L) is the most
widely accepted and used. Overall, grades of severity are determined from 0 to 4
and are related to the presumed sequential appearance of osteophytes, joint space
loss, sclerosis, and cysts.2 The World Health Organization (WHO) adopted these
criteria as the standard for epidemiological studies on OA. Cross-sectional imaging
methods, such as magnetic resonance imaging (MRI), can visualize joint structures
in more detail and continue to undergo evaluation to determine if they will provide
a means by which the definition of OA can be refined.
Many studies now report the prevalence of self-reported or symptomatic OA; these
differing approaches may go some way toward explaining part of the heterogeneity
in OA estimates.3 A recent systematic review3 attempted to understand the differ-
ences in prevalence and incidence of OA according to case definition in knee, hip,

Epidemiology of osteoarthritis Cooper and others MEDICOGRAPHIA, Vol 35, No. 2, 2013 145
OSTEOARTHRITIS: A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE

SELECTED ABBREVIATIONS AND ACRONYMS

Self-reported
OA BMI body mass index
COPCORD Community Oriented Program for the Control of
Rheumatic Disorders
DIP distal interphalangeal
Symptomatic
NHANES National Health And Nutrition Examination Survey
OA
OA osteoarthritis
WHO World Health Organization

Radiographic OA
age of 50 years. A leveling off or decline occurs at all joint sites
around the age of 80 years. For example, the age- and sex-
standardized incidence rate from the Fallon Community Health
Plan in Massachusetts (USA) was highest for knee OA (240/
100 000 person-years), with intermediate rates for hand OA
(100/100 000 person-years), and lowest observed rates for
hip OA (88/100 000 person-years) (Figure 3).6 The incidence
rates found by the Dutch Institute for Public Health (RIVM)
Figure 1. Relationships between osteoarthritis (OA) classifications.
After reference 3: Pereira et al. 2011;19:1270-1285. 2011, Elsevier Ltd.
in 2000 were similar. For hip OA, the reported prevalence was
0.9 and 1.6 per 1000 per year in men and women, respec-
and hand joints and concluded that radiographic case defi- tively, and for knee OA the corresponding figures were 1.18
nition afforded the highest estimates, while self-reported and and 2.8 per 1000 per year in men and women, respectively
symptomatic OA definitions presented similar estimates. The (Figure 4).7
interrelationship between the different classifications used is
shown in Figure 1. N Hand OA
The prevalence of radiographic hand OA varies greatly and
Epidemiology has been reported to range from 27% to over 80%.8,9 In a
OA may develop in any joint, but most commonly affects the study from the Netherlands, 75% of women aged between
knee, hip, hand, spine, and foot. In 2005, it was estimated that 60 and 70 years had evidence of OA in the distal interpha-
over 26 million people in the USA had some form of OA.4 langeal (DIP) joints, and 10% to 20% of subjects aged below
Self-reported physician-diagnosed OA data from the 2004- 40 years were reported to have OA radiological changes in
2005 Australian National Health Survey is shown in Figure 2.5 their hands or feet.7 In a rural sample from the former Soviet
The incidence of hand, hip, and knee OA increases with age, Republic of Turkmenia,10 all males over the age of 65 years had
and women have higher rates than men, especially after the at least one affected hand joint. Symptomatic hand OA, as
defined by the American College of Rheuma-
tology (ACR) criteria, is, however, far less com-
35% mon. Its prevalence was found to be 8% in
the US National Health and Nutrition Exam-
30% Males
Females ination Survey (NHANES III).11 Data from the
25% Framingham cohort demonstrated a preva-
lence of 13.2% in men and 26.2% in women
20%
aged 70 years, with at least one hand joint
15% with symptomatic OA.8 A study from Teheran
10% showed that the prevalence of hand OA in
people aged 40 to 50 years was 2.2%, ris-
5%
ing with age to 22.5% in people aged >70
0% years.12 As with many studies, including the
0-14 15-24 25-34 35-44 45-54 55-64 65-74 75+ Framingham cohort, differentiation by sex in
Age group (years) this population showed that women were
more frequently affected than men.12 Interest-
Figure 2. Age-specific prevalence of osteoarthritis in Australia in 2004-2005 (Aus- ingly, data from China based on thirteen sur-
tralian Institute of Health and Welfare analysis of the Australian Bureau of Statistics veys involving 29 621 adults demonstrated
2004-2005 National Health Survey).
After reference 5: Australian Institute of Health and Welfare. 2007. Arthritis series no 5. Cat no. PHE
that symptomatic OA of the hand was rarely
93. Canberra: AIHW. 2007, Australian Institute of Health and Welfare. observed, irrespective of age or sex.13

146 MEDICOGRAPHIA, Vol 35, No. 2, 2013 Epidemiology of osteoarthritis Cooper and others
 OSTEOARTHRITIS: A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE

Men Women
1200 1200 Figure 3.
Incidence of
Incidence (per 10 5 patient-years)

1000 1000 clinical osteo-

Knee
arthritis of
800 800 the hand,
knee, and
600 600 Hip hip among
Knee participants
400 400
Hand
in the Fallon
Hip
Health Plan.
200 200 After reference
Hand 6: Oliveria SA
et al. Arthritis
0 0
Rheum. 1995;
20 30 40 50 60 70 80 20 30 40 50 60 70 80
38:1134-1141.
Age (years) Age (years) 1995, Ameri-
can College of
Rheumatology.

Men Women
80 80
DIP Figure 4.
Prevalence
Prevalence of osteoarthritis (%)

of clinical
60 60
osteoarthritis
of the hand,
DIP
knee, and hip
40 40
in a Dutch
Knee
Knee population.
Reproduced
20 20 with permission
Hip from reference
Hip
7: van Saase
0 0 JL et al. Ann
20 30 40 50 60 70 80 20 30 40 50 60 70 80 Rheum Dis.
1989;48:271-
Age (years) Age (years) 280. 1989,
BMJ Publishing
Group Ltd.

N Knee OA could not be fully explained by increasing obesity. According

Knee involvement occurs less frequently than hand OA, al-
though, similarly, it is more common in women, with female-
to-male ratios varying between 1.5:1 and 4:1. Prevalence rates
for knee OA, based on population studies in the USA, are com-
parable to those in Europe. These studies report that severe
radiographic changes affect 1% of people aged between 25
and 34 years and this figure increases to nearly 50% in those
75 years and above.14 Few studies have reported secular trends
in knee pain; a recent report from the Framingham Study
found that the age- and BMI-adjusted prevalence of knee
pain and symptomatic knee OA approximately doubled in
women and tripled in men over 20 years (Figure 5, page 148);
no such trend was observed in the prevalence of radiographic
knee OA.15 Similarly, using questionnaire data enquiring about
pain in and around the knee, the same researchers found
that the age- and BMI-adjusted prevalence of knee pain in-
creased by about 65% in NHANES from 1974 to 1994 among
non-Hispanic white and Mexican American men and women
and among African American women.15 These secular trends
to data produced by the Dutch Institute for Public Health,
the prevalence of knee OA in those aged 55 and above was
15.6% in men and 30.5% in women.7
Geographical variation in OA epidemiology also exists. Stud-
ies from China, which used similar methods and definitions
to those used in the Framingham Study, found that the preva-
lence of bilateral knee OA and lateral compartment disease
were two to three times higher in Chinese cohorts compared
with estimates from the Framingham OA Study.16 Data on clin-
ically diagnosed knee OA in the Community Oriented Program
for the Control of Rheumatic Disorders studies (COPCORD) in
Asia showed that the prevalence within this area ranged from
1.4% in urban Filipinos to 19.3% in rural communities in Iran.17
Part of the reason for this difference may be explained by the
physical and socioeconomic environment. The COPCORD
studies conducted in India, Bangladesh, and Pakistan looked
specifically into differences between rural and urban popula-
tions. In India, it showed a significantly higher prevalence of

Epidemiology of osteoarthritis Cooper and others MEDICOGRAPHIA, Vol 35, No. 2, 2013 147
OSTEOARTHRITIS: A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE

Figure 5. Varying prevalence of radiographic

and symptomatic knee osteoarthritis over
50
a 20-year period among participants in the
Framingham Osteoarthritis Study.
Radiographic knee OA
radiographic and symptomatic knee OA (%)

41.9 Abbreviations: BMI, body mass index; OA, osteoarthritis.

39.7 Reproduced with permission from reference 15:
Age- and BMI-adjusted prevalence of

40
Nguyen US et al. Ann Intern Med. 2011;155:725-732.
35.1 2011, American College of Physicians.
36.5 35.4
32.5
30
fect the forces applied to the joint. Risk
Women factors are discussed individually below;
Men the varying prevalence of some, such as
20 obesity and nutritional factors, may part-
16.7
ly explain the differing rates of OA seen
11.8 16.1 in different populations.
10.4
10
7.8 Symptomatic knee OA N Age
5.7
The prevalence and incidence of radi-
0 ographic and symptomatic OA consid-
1983-1985 1992-1995 2002-2005 erably increase with age. The relation-
Original Original Offspring and ship between age and the risk of OA is
community
Examination period likely multifactorial and is probably the
consequence of numerous individual fac-
tors that may include oxidative damage,
knee pain in rural (13.0%) than in urban (8.1%) communities.17 thinning of cartilage, muscle weakening, and a reduction in
Furthermore, in China, men aged 60 years and above from a proprioception. Furthermore, the basic cellular mechanisms
rural community had approximately double the prevalence of that maintain tissue homeostasis decline with age, leading to
symptomatic knee OA than their urban counterparts.16 an inadequate response to stress or joint injury and resultant
joint tissue destruction and loss.
N Hip OA
Hip OA is less common than either hand or knee OA. The N Sex
mean prevalence of primary radiographic hip OA in studies The incidence of knee, hip, and hand OA is higher in women
from Asia and Africa is 1.4% and 2.8%, respectively.17 These than men and in women it increases dramatically around the
levels are much lower than those seen in Europe and North time of menopause. The latter finding has led investigators to
America. In the Study of Osteoporotic Fractures, the preva- hypothesize that hormonal factors may play a role in the de-
lence of radiographic hip OA was analyzed in women over the velopment of OA, but the results of clinical and epidemiolog-
age of 65, using eleven different definitions. Excluding the def- ic studies have not universally corroborated this.20-22 A recent
inition of minimum joint space of less than 2.5 mm, the preva- systematic review of 17 studies found that there was no clear
lence ranged from 1.0% to 6.2%, depending on the defini- association between sex hormones and hand, knee, or hip
tion used.18 OA in women, although single analysis of the studies was not
possible due to study heterogeneity.23
Risk factors
OA is referred to as primary in the absence of an extrinsic N Ethnicity and race
cause. The proportion of individuals with primary OA within a The prevalence of OA and patterns of joint involvement vary
specific OA population varies greatly. As age increases, the among different racial and ethnic groups. Both hip and hand
likelihood of an individual having primary OA increases. There OA were much less frequent among Chinese in the Beijing
are also differences by sex; in the Queensland Aboriginal com- Osteoarthritis Study than in whites in the Framingham Study,
munities it was found that 88% of women had primary OA, but interestingly, Chinese women had a higher prevalence of
whereas 82% of men had secondary OA.19 knee OA, which may be explained by excessive knee loading
from squatting.24 Indeed, prolonged squatting and kneeling
The risk of developing OA is determined by both systemic and has been associated with an increased risk of moderate to se-
local factors. Several systemic factors have been identified; vere radiographic knee OA.24 Results from the Johnston Coun-
these may act by increasing the susceptibility of the joints to ty Osteoarthritis Project have shown that the prevalence of
injury, by direct damage to joint tissues, or by impairing the hip OA in African American women was similar to that in white
process of repair in damaged joint tissue. Local factors are women, but that the prevalence was slightly higher in African
most commonly biomechanical in nature and adversely af- American men (21%) than in white men (17%).25

148 MEDICOGRAPHIA, Vol 35, No. 2, 2013 Epidemiology of osteoarthritis Cooper and others
 OSTEOARTHRITIS:
N Genetics
Strong evidence from family clustering and twin studies indi-
cates that the risk of OA has an inherited component. Classic
twin studies have shown that the influence of genetic factors
is between 39% and 65% in radiographic OA of the hand
and knee in women, about 60% in OA of the hip, and about
70% in OA of the spine.26 Although specific genes have been
identified, the individual effects are relatively small; for exam-
ple, Kerkhof et al27 reported a genome-wide association study
showing that the C allele of rs3815148 on chromosome 7q22
was associated with a 1.14-fold increased prevalence of knee
and/or hand OA and also with a 30% increased risk of knee
OA progression.
N Nutrition (including vitamin D)
Dietary factors are the subject of considerable interest in
OA.28,29 Protection against knee OA progression has been re-
ported in older men and women with high dietary vitamin D
intakes, and for those with high serum levels of vitamin D.28
The Rotterdam Study reported that low vitamin D intake in-
creased the risk of progression of knee OA.30 The Osteoporot-
ic Fractures in Men study found that men with vitamin D de-
ficiency were twice as likely to have prevalent radiographic
OA,31 but a recent longitudinal study of Finnish participants
failed to find associations between low vitamin D status and
risk of incident hip or knee OA.32 Although the results are in-
consistent, a biologically plausible mechanism for the effect of
vitamin D on OA could be postulated, through its important
role in bone metabolism, which may modulate periarticular
bone responses to excess loading and joint damage. The
results of further studies are awaited.
Low vitamin C dietary intake has also been associated with an
increased risk of OA progression among participants in the
Framingham Study.33 A role for selenium has also been pos-
tulated.34
N Osteoporosis
Osteoporosis is, like OA, a common age-related skeletal dis-
order. While early results indicated that reduced bone miner-
al density might be protective against OA, further studies have
been inconsistent with this finding. A systematic review and
meta-analysis of the risk factors for the onset of knee OA in
older adults has shown that there is a consistent strong as-
sociation between increased bone mineral density and the
onset of knee OA in the three studies that investigated this risk
factor in women.35 Although a definite molecular basis and com-
mon pathophysiology have not been identified to explain the
inverse relationship between OA and osteoporosis, a shared
genetic component may explain why they seldom coexist.
N Smoking
There have been conflicting reports on the role of smoking in
OA. Some studies have reported a protective association be-
tween smoking and OA, but others in contrast, report that
Epidemiology of osteoarthritis Cooper and others
A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE
smoking may be associated with a greater risk of both car-
tilage loss and knee pain in OA. A recent meta-analysis of
observational studies concluded that the observed protective
effect of smoking in OA is likely to be false.35 It may be caused
by selection bias, as many studies have been conducted in a
hospital setting where control subjects have smoking-relat-
ed conditions, and subjects were recruited as part of studies
that were not primarily designed to investigate smoking.36
N Obesity and metabolic disease
Obesity is one of the strongest and best-established risk fac-
tors of OA. The current literature suggests that, although both
show significant associations, the relationship between obe-
sity and hip OA is weaker than with knee OA.37 Recent data
suggest that OA is associated with the metabolic syndrome,
suggesting a possible common pathogenic mechanism in-
volving metabolic abnormalities and systemic inflammation.38
Studies have specifically suggested significant associations
between OA and cardiovascular risk factors, such as hyper-
tension and hypercholesterolemia. However, clinical evidence
of an association between diabetes and OA is inconsistent.
Several studies did find an association between diabetes and
OA39 and fascinating hypotheses explaining this association
have been suggested, including that high glucose concentra-
tions produce reactive oxygen species (ROS) and advanced
glycation end products, which induce cartilage degeneration
and degradation. Other studies have failed to confirm the as-
sociation and further research is required.
N Sarcopenia
Muscle weakness may be an important risk factor for knee OA.
Men and women with pre-existing radiographic evidence of
knee OA have been identified as having weaker quadriceps
than those without OA, particularly when the joints are symp-
tomatic.40 One consequence of quadriceps weakness is that
the knee becomes less stable during physical activity. Quadri-
ceps exercises may therefore offer some protective advan-
tage to patients involved in activities that are known to be as-
sociated with a high risk of OA development. Greater muscle
strength is not, however, always protective as it corresponds
to higher forces and thus increased joint loading during ac-
tivity. It has been shown that higher grip strength in men is
associated with a greater risk of developing OA in the prox-
imal interphalangeal, metacarpophalangeal, and first carpo-
metacarpal jointsthe joints subjected to the largest forces
during grip.41
N Local mechanical risk factors
A traumatic knee injury is one of the strongest risk factors for
the development of knee OA. Acute injuries, including menis-
cal and cruciate tears, fractures, and dislocations, can result
in an increased risk of OA development and musculoskeletal
symptoms. In addition to the direct trauma-induced damage
to local tissues, disruption of normal biomechanics and altered
load distribution within the joint also contribute to the subse-
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OSTEOARTHRITIS: A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE
quent increased OA risk. This risk is greater still if the sub-
ject has OA in another joint. The repetitive and excessive joint
loading that accompanies specific physical activities increas-
es the risk of developing OA in the involved joints. Workers
whose jobs require repeated pincer grip have an increased
risk of hand OA, particularly in the DIP joint.42 Similarly, pro-
longed squatting and kneeling stresses the larger joints and
is consequently associated with increased risk of moderate
to severe radiographic knee OA.
There have been conflicting results in studies examining the
relationship between sporting activities and subsequent OA.
There is some evidence that elite long-distance runners are
at high risk of developing knee and hip OA.43 Other studies
suggest that in the absence of joint injury, moderate recreation-
al running and sports participation do not appear to increase
the risk of hip or knee OA.44 The mechanical alignment of the
knee influences load distribution across the articular surfaces.
In a normally aligned knee, 60% to 70% of the weight-bearing
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prevalence of radiographic tibiofemoral knee osteoarthritis: The Beijing Osteo-
arthritis Study. Arthritis Rheum. 2004;50:1187-1192.
25. Nelson E, Braga L, Benner J, et al. Characterization of individual radiographic
features of hip osteoarthritis in African American and White women and men:
the Johnston County Osteoarthritis Project. Arthritis Care Res. 2010;62:190-197.
26. Spector TD, MacGregor AJ Risk factors for osteoarthritis: genetics. Osteoar-
thritis Cartilage. 2004;12:S39-S44.
27. Kerkhof HJ, Lories RJ, Meulenbelt I, et al. A genome-wide association study
identifies an osteoarthritis susceptibility locus on chromosome 7q22. Arthri-
tis Rheum. 2010;62:499-510.
28. McAlindon TE, Felson DT, Zhang Y, et al. Relation of dietary intake and serum
levels of vitamin D to progression of osteoarthritis of the knee among partici-
pants in the Framingham Study. Ann Intern Med. 1996;125:353-359.
29. Felson DT, Niu J, Clancy M, et al. Low levels of vitamin D and worsening of knee
osteoarthritis: results of two longitudinal studies. Arthritis Rheum. 2007;56:
129-136.
30. Bergink AP, Uitterlinden AG, Van Leeuwen JP, et al. Vitamin D status, bone min-
eral density, and the development of radiographic osteoarthritis of the knee:
the Rotterdam Study. J Clin Rheumatol. 2009;15:230-237.
31. Chganti RK, Parimi N, Cawthon P, Dam TL, Nevitt MC, Lane NE. Association of
25-hydroxyvitamin D with prevalent osteoarthritis of the hip in elderly men: the
Epidemiology of osteoarthritis Cooper and others
 OSTEOARTHRITIS: A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE

osteoporotic fractures in men study. Arthritis Rheum. 2010;62:511-514. 2009;121:9-20.

32. Konstari S, Paananen M, Heliovaara M, et al. Association of 25-hydroxyvita-
min D with the incidence of knee and hip osteoarthritis: a 22-year follow-up study.
Scand J Rheumatol. 2012;41:124-131.
33. McAlindon TE, Jacques P, Zhang Y, et al. Do antioxidant micronutrients pro-
tect against the development and progression of knee osteoarthritis? Arthri-
tis Rheum. 1996;39:648-656.
34. Jordan JM, Fang F, Arab L, et al. Low selenium levels are associated with in-
creased risk for osteoarthritis of the knee. Arthritis Rheum. 2005;52:s455.
35. Blagojevic M, Jinks C, Jeffery A, Jordan KP. Risk factors for onset of osteoarthri-
tis of the knee in older adults: a systematic review and meta-analysis. Osteo-
arthritis Cartilage. 2010;18:24-33.
36. Hui M, Doherty M, Zhang W. Does smoking protect against osteoarthritis?
Meta-analysis of observational studies Ann Rheum Dis. 2011;70:1231-1237.
37. Grotle M, Hagen KB, Natvig B, et al. Obesity and osteoarthritis in knee, hip and/
or hand: An epidemiological study in the general population with 10 years fol-
low-up. BMC Musculoskelet Disord. 2008;9:132.
38. Puenpatom RA, Victor TW. Increased prevalence of metabolic syndrome in
individuals with osteoarthritis: an analysis of NHANES III data. Postgrad Med.
39. Frey MI, Barrett-Conner E, Sledge PA, et al. The effect of noninsulin dependent
diabetes on the prevalence of clinical osteoarthritis. A population based study.
J Rheumatol. 1996;23:716-722.
40. Slemenda C, Brandt KD, Heilman DK, et al. Quadriceps weakness and os-
teoarthritis of the knee. Ann Intern Med. 1997;127:97-104.
41. Chaisson CE, Zhang Y, Sharma L, Kannel W, Felson DT. Grip strength and the
risk of developing radiographic hand osteoarthritis: results from the Framingham
Study. Arthritis Rheum. 1999;42:33-38.
42. Hadler NM, Gillings DB, Imbus HR, et al. Hand structure and function in an
industrial setting. Arthritis Rheum. 1978;21:210-220.
43. Buckwalter JA, Lane NE. Athletics and osteoarthritis. Am J Sports Med. 1997;
25:873-881.
44. Spector TD, Harris PA, Hart DJ, et al. Risk of osteoarthritis associated with long-
term weight-bearing sports: a radiologic survey of the hips and knees in female
ex-athletes and population controls. Arthritis Rheum. 1996;39:988-995.
45. Tanamas S, Hanna FS, Cicuttini FM, Wluka AE, Berry P, Urquhart DM. Does
knee malalignment increase the risk of development and progression of knee
osteoarthritis? A systematic review. Arthritis Rheum. 2009;61:459-467.

Keywords: burden; epidemiology; osteoarthritis; risk factor

EPIDMIOLOGIE DE LARTHROSE
Larthrose est une maladie dgnrative articulaire mondiale touchant le cartilage et la plupart des tissus environ-
nants. Sa prvalence et son incidence varient considrablement dune population lautre selon les classifications
diagnostiques utilises pour les estimer; la dfinition radiologique de larthrose donne gnralement les estimations
les plus leves, tandis que les dfinitions symptomatiques et auto-rapportes donnent des estimations peu prs
quivalentes entre elles. Daprs le groupe scientifique des maladies rhumatologiques de lOMS, 10% des gens gs
de 60 ans ou plus ont des problmes cliniques significatifs pouvant tre attribus larthrose. Larthrose a une plus
forte prvalence au niveau des articulations de la main, et touche plus volontiers les femmes que les hommes.

Epidemiology of osteoarthritis Cooper and others MEDICOGRAPHIA, Vol 35, No. 2, 2013 151
 OSTEOARTHRITIS: A STORY OF CLOSE R E L AT I O N S H I P

BETWEEN BONE AND CARTILAGE

Adipose tissue is an active

metabolic and endocrine organ
producing hormones and bioac-
tive substances, such as adipo-
kines (also known as adipocyto-
kines), that have various biological
Osteoarthritis
effects and underlie the associa-
tion of obesity with concomitant
diseases Adipokines, including
and comorbidities
leptin, are involved in the local
modulation of articular cartilage
metabolism. Patients with OA were
found to have elevated levels of
leptin in both synovial fluid and
subchondral bone.

b y L . I . A l e k s e e va
a n d E . L . N a s o n ov, R u s s i a

L
Eugeny L. NASONOV, MD, PhD
Director, National Scientific
Research Institute of Rheumatology
(Russian Academy of Medical
Sciences), Moscow
RUSSIA
Lyudmila I. ALEKSEEVA,
MD, FACPh
Research Institute of Rheumatology
(Russian Academy of Medical
Sciences), Chief of Department
Department of Metabolic Disorders
of the Musculoskeletal System and
Osteoarthritis and Osteoporosis
Laboratories, Moscow
RUSSIA
O
steoarthritis (OA) is the most common disorder of the musculoskele-
tal system and the leading cause of functional incapacity and disabil-
ity in adults. A significant number of studies have demonstrated that
patients with OA are at significantly higher risk of developing comorbid con-
ditions than people without the disease. OA is most commonly associated with
cardiovascular diseases, including arterial hypertension, as well as obesity,
diabetes mellitus, and pulmonary diseases. The combination of various chron-
ic diseases with diseases of the musculoskeletal system, especially with OA,
will be observed more and more frequently, and will affect not only health care
systems, but also the quality of life. The relation between OA and comorbid dis-
orders may be explained, to some extent, by common etiologic and patho-
genetic mechanisms, or may be related to the biological processes of aging,
which can lead not only to the development, but possibly also to the mainte-
nance of comorbidities. The data presented in this article suggest that OA is
a disease that is pathogenetically related to cardiovascular diseases, obesity,
and other metabolic conditions. As a consequence, the examination of OA
patients should not be limited to the assessment of their articular disorder, but
rather should be comprehensive, with particular attention paid to the state of
their cardiovascular system. This article highlights the importance of using
an integrated approach when considering treatment options.
Medicographia. 2013;35:152-157 (see French abstract on page 157)
steoarthritis (OA) is the most common disorder of the musculoskeletal

Address for correspondence:
Professor Eugeny L. Nasonov,
Institute of Rheumatology, Russian
Academy of Medical Sciences,
34 A Kashirskoye shosse,
115522 Moscow, Russia
(e-mail: nasonov@irramn.ru)
www.medicographia.com
O system: about 15% of the world population suffers from OA and 65% of
them are aged 60 years and over. Osteoarthritis is the leading cause of func-
tional incapacity and disability in adults1 and reduces the quality of life of patients.
Moreover, patients with OA were found to have higher all-cause mortality rates than
the general population.2 The analysis of 617 lethal outcomes in osteoarthritic pa-
tients, compared with a population of similar age and sex, has shown that almost
40% of deaths were caused by atherosclerotic coronary artery disease (CAD) and
gastrointestinal tract disorders.3
In 1990, in a study of 2384 people aged 55 to 74 years, Lawrence et al showed that
patients with radiographic evidence of knee OA had higher mortality rates than sub-
jects without radiographic abnormalities (38.9% vs 31.6% in men; 30% vs 17.7%
in women, respectively).4 Haara et al found an association between the presence
of OA in any finger joint and increased cardiovascular mortality, and in women the

152 MEDICOGRAPHIA, Vol 35, No. 2, 2013 Osteoarthritis and comorbidities Alekseeva and Nasonov
 OSTEOARTHRITIS:
risk of death was higher in the presence of radiographic evi-
dence of OA of the distal interphalangeal joints of both hands.5
Although there is a discrepancy between the presence of pain
and the radiographic signs of OA, which are observed togeth-
er in 15% to 76% of cases,6 higher mortality rates are found
both in patients with symptomatic OA and in those with only
radiographic evidence of the disease.5 This suggests that OA
is not only the most common disease of the joints, but also
the most urgent problem in general practice. Osteoarthritis
along with cardiovascular diseases (CVD), degenerative dis-
eases of the nervous system, and osteoporosisis an age-
related disorder. Moreover, joint dysfunction and pain and the
resulting reduction in physical activity are destabilizing factors
in the course of various somatic disorders. In patients with un-
derestimated concomitant somatic diseases, OA is associ-
ated with a high rate of drug-related complications, especially
when nonsteroidal anti-inflammatory drugs (NSAIDs) are used.7
Many studies have demonstrated that patients with OA are
at significantly higher risk of developing comorbid conditions
than people without the disease. In their 18-month follow-up
study of 1026 patients with OA, Kadam et al revealed a clear
correlation between the number of concomitant conditions
(morbidity count) and a patients physical function. Almost
half of the patients with OA (49%) were diagnosed with more
than 5 conditions other than OA (high morbidity count), 28%
had 3 or 4 conditions (medium morbidity count), 25% had 1
or 2 conditions (low morbidity count), and only 3.7% of the
patients had OA alone.8 In osteoarthritic patients, high mor-
bidity counts were associated with reduced physical function
(after adjusting for age, sex, and socioeconomic parameters).
Osteoarthritis and cardiovascular disease
OA is most commonly associated with CVD, including arteri-
al hypertension (AH), as well as obesity, diabetes mellitus, and
pulmonary diseases.8-10 An analysis of publications in Medline
SELECTED ABBREVIATIONS AND ACRONYMS
AGE advanced glycation end-product
AH arterial hypertension
AMICA Atrial fibrillation Management In Congestive heart
failure with Ablation
BMI body mass index
CAD coronary artery disease
CVD cardiovascular diseases
ICAM-1 intracellular adhesion molecule-1
IGF-1 insulin-like growth factor
IL interleukin
MMP matrix metalloproteinase
NSAID nonsteroidal anti-inflammatory drug
OA osteoarthritis
PAI plasminogen activator inhibitor
TGF-1 transforming growth factor-1
Osteoarthritis and comorbidities Alekseeva and Nasonov
A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE
in the period from 1966 to July 2004 revealed that hyperten-
sion is present in 48% to 65% of patients with OA and in more
than 65% of patients over 80 years of age with OA requiring
knee arthroplasty.11 Rosemann et al showed that osteoarthrit-
ic patients of both sexes have similar rates of hypertension
(53%), high cholesterol (36%), heart failure (19%), diabetes
mellitus (17%), and CAD (13%).12 Women with OA were found
to have a lower quality of life and lower mood (P<0.01), a high-
er degree of disability (P<0.01), and to feel more pain (P<0.01).
In the large-scale AMICA study (Atrial Fibrillation Management
in Congestive Heart Failure With Ablation) in Italy, which in-
volved 3080 physicians and 29132 patients with OA, hyper-
tension was found in 53% of study participants, type 2 dia-
betes in 15%, and history of myocardial infarction or angina in
6%. The degree of hypertension correlated with pain inten-
sity, joint dysfunction, and worsening quality of life.9 Danish
researchers found CVD in 54% patients with hip OA aged be-
tween 50 and 85 years.1 In Russia, a 1-year study of the rates
of concomitant diseases associated with knee OA in an out-
patient clinic also revealed twice higher rates of CAD, AH, and
obesity, compared with patients without OA from the same
clinic.13
The increase in life expectancy has resulted in an aging popu-
lation. Therefore, the combination of various chronic diseases
with diseases of the musculoskeletal system, especially with
OA, will be observed more and more frequently, and will affect
not only health care systems, but also the quality of life. The re-
lation between OA and comorbid disorders may be explained,
to some extent, by common etiologic and pathogenetic mech-
anisms, or may be related to the biological processes of ag-
ing, which become more prevalent with age (such as cartilage
degeneration, insulin resistance, weight gain, dyslipidemia, etc),
and lead not only to the development, but possibly also to the
maintenance of comorbidities.
OA and CVD are both considered to be age-related diseases.
With aging, various human tissues accumulate advanced gly-
cation end-products (AGEs), which play an important role in
the pathogenesis of both atherosclerosis and OA.14-16 The for-
mation of AGEs on the basement membrane of vascular walls
leads to wall thickening, a narrowing of the lumen of capillar-
ies, and reduced vascular wall elasticity, which can accelerate
the development of the atherosclerotic process. AGEs also
accumulate in human cartilage tissue,16 where they bind with
long-lived proteinsmainly collagenand subsequently dam-
age and deteriorate their functional properties. AGEs are sup-
posed to adversely affect the metabolic activity of chondro-
cytes and can stimulate the formation of proinflammatory
cytokines.17,18
Metabolic disturbances and nonspecific inflammation also play
an important role in the pathogenesis of atherosclerosis and
OA. Traditionally, OA has been considered to be a degenera-
MEDICOGRAPHIA, Vol 35, No. 2, 2013 153
OSTEOARTHRITIS: A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE
tive disease of the joints, but accumulating evidence suggests
that nonspecific inflammation is also important in its patho-
genesis.19,20 In OA, there are no classical macroscopic signs
of inflammation and no severe infiltration by inflammatory cells
in joint tissues. However, elevated levels of proinflammatory
cytokines, interleukins (IL)-1, and tumor necrosis factor
(TNF-) are observed in the synovial fluid of osteoarthritic pa-
tients. IL-1 stimulates the chondrocytes, thereby increasing
the production of matrix metalloproteinases (MMPs)prote-
olytic enzymes that degrade collagen and cartilage proteo-
glycans. Increased levels of MMP-3 were found in the syn-
ovial fluid and blood of patients with OA of the knee and hip
joints. Moreover, serum levels of MMP-3 and MMP-9 were
significantly higher in patients with hip OA compared with
those with less severe OA.21 Therefore, MMP-3 and MMP-9
levels can serve as diagnostic markers of rapidly progressive
OA. In addition, the chondrocytes of osteoarthritic individuals
overexpress COX-2; this induces the synthesis of proinflam-
matory prostaglandins and the inducible form of nitric oxide
synthase (iNOS), an enzyme that regulates the formation of
nitric oxide and exerts a toxic action on the cartilage.
Epidemiological and immunopathological data suggest that
inflammation is the major manifestation of atherosclerosis and
is associated with dyslipidemia and chronic immune dysreg-
ulation.22,23 Proinflammatory cytokines and cell adhesion mol-
ecules expressed by vascular and blood cells play an impor-
tant role in the pathophysiology of atherosclerosis. Prospective
epidemiological studies have shown an association between
the clinical manifestations of atherothrombotic disease and
systemic markers of inflammation, including white blood cell
count and various hemostatic proteins that reflect acute in-
flammation, such as fibrinogen, plasminogen activator inhibitor
(PAI), and von Willebrand factor.20,24 C-reactive protein is di-
rectly involved in the pathogenesis of atherothrombosis and
stimulates the production of tissue factor by the macrophages.
Tissue factor is the main inductor of coagulation in vivo and
its local concentration in the arterial wall is associated with
the development of events resulting in coronary thrombosis.25
In patients with a high risk of vascular complications, elevated
levels of other markers of inflammation, such as IL-6, intracel-
lular adhesion molecule-1 (ICAM-1), macrophage inhibitory
cytokine-1 (MIC-1), and soluble CD40 ligand are also ob-
served. Experimental studies have shown that the vascular
endothelium and the smooth muscle cells of the arteries pro-
duce IL-6. At the same time, the IL-6 gene is expressed in
areas of atherosclerotic lesions in man; therefore, IL-6 may
also have procoagulant properties.25,26 Metalloproteinases
take part in the remodeling of blood vessels and increase the
rigidity of the arteries with age.27 Matrix metalloproteinase-3
(MMP-3) has been associated with lipid structures in arte-
riosclerotic plaques and MMP-3 genotype may be an impor-
tant determinant of age-related vascular remodeling and ar-
terial stiffness.27 MMP-9 is involved in the rupture of the fibrous
154 MEDICOGRAPHIA, Vol 35, No. 2, 2013
capsule of atherosclerotic plaques, and elevated levels of
inhibitor of plasminogen activator-1 (PAI-1) are implicated in
the process of thrombogenesis.28
Another aspect of the association of vascular disease with OA
relates to changes in the blood vessels of subchondral bone.
The occurrence of OA and its subsequent progression are
thought to be a consequence of atheromatous disease in
these vessels.29,30 Bone is a highly vascularized tissue, and its
vasculature is involved in all aspects of the growth, recovery,
and metabolism of bone tissue. It is possible that in the con-
text of vascular disease, episodic circulatory disorders take
place in the subchondral bone, resulting in the development
of OA. Subchondral bone ischemia, on the one hand, may
lead to impaired nutrition and gas exchange in the articular
cartilage, and thus trigger degenerative changes; on the other
hand, it may promote osteocyte apoptosis in the subchon-
dral bone, thereby inducing osteoclastic resorption.31,32
The association of OA with CVD is probably determined not
only by common pathogenetic mechanisms, but also by oth-
er external factors. Thus, the limitation of physical activity in
patients with OA is a significant aggravating factor for car-
diovascular disease. By inducing a neuroendocrine response,
chronic pain is often the cause of complications in CVD pa-
tients. Pincus and Sokka have found that reduction in life ex-
pectancy in older people is determined, to a great extent, by
the severity of pain.33 They assessed the survival rates of 1525
patients, of which 24% (370 patients) had OA, 16% (246 pa-
tients) had CVD, and 7.1% (109 patients) had OA and CVD.
The results showed that the relative risk of death among pa-
tients with OA and a pain intensity of more than 40 mm on the
visual analog scale (VAS) was higher than in patients with a
pain intensity of less than 40 mm, without any significant dif-
ferences according to age or sex.
Osteoarthritis and obesity
Obesity is among the most urgent health care and social
problems of contemporary society. It is a risk factor not only
for OA, but also for many other diseases associated with meta-
bolic disturbances. OA, in turn, through the dysfunction and
limitation of physical activity leads to an increase in body mass
index (BMI) that can result in the development of CVD and
diabetes. The risk of developing these conditions increases
progressively with increasing BMI. In overweight patients with
a 40% excess in body mass, the risk of premature death is
twice that of people of average weight. In Russia, a study of
298 patients with overt OA of the knee and hip joints showed
a marked increase in the prevalence of CVD and diabetes
with increasing BMI.34
Many studies have demonstrated an association between
obesity (BMI >30) and OA of the knee, for both symptomatic
and radiographic OA.35,36 Moreover, the risk of OA of the knee
increases progressively with increasing BMI. Prospective stud-
Osteoarthritis and comorbidities Alekseeva and Nasonov
 OSTEOARTHRITIS:
ies have revealed that excess body mass contributes to the
progression of the radiographic manifestations of knee OA.37
In a prospective cohort study, Wang et al found that both
central obesity and the amount of fat mass represent risk
factors for arthroplasty of the knee and hip joints.38 Interest-
ingly, not only is increased body weight associated with an
increased risk of OA, but it was also shown that weight loss
causes a decrease in the risk of OA. A 2-kg/m2 decrease in
BMI was shown to reduce the risk of OA development by more
than 50% at 10 years.39
There is also some evidence of an association between obe-
sity and OA of the joints of the hand. A study in female twins
has shown that obesity is an important risk factor for the
development of OA of the knee and carpometacarpal joints,
with a significant 9% to 13% increase in the risk of OA per
each additional kilogram of body weight.40 A recently pub-
lished systematic review confirms the existence of a posi-
tive association between body weight and OA development
in the hands.41
There is some controversy in the data published on the rela-
tionship between obesity and OA of the hip. Some researchers
identified a clear correlation between BMI and the risk of hip
OA,42 while others did not find any correlation at all.43
However, a majority of studies have demonstrated an asso-
ciation between OA and obesity. Excess weight increases the
load on the skeleton and causes lesions in bone and mus-
cle tissue. Pressure-sensitive mechanoreceptors capable of
triggering a signaling cascade were found on the surface of
chondrocytes.17 Activation of these mechanoreceptors can
lead to the expression of cytokines, metalloproteinases, pros-
taglandins, and nitric oxide.19 Experimental data show that,
under certain conditions, overload can trigger the inhibition
of matrix synthesis and degradation of cartilage.44 Obesity can
potentially induce cartilage damage through activation of the
mechanoreceptors.
Available data not only suggest an effect of overweight on
the development of OA in the knee joints, but also confirm
the existence of other mechanisms related to obesity that can
change the metabolism of cartilage and bone tissue and lead
to the development of OA. Adipose tissue is an active meta-
bolic and endocrine organ producing hormones and bioac-
tive substances, such as adipokines (also known as adipo-
cytokines), that have various biological effects and underlie
the association of obesity with concomitant diseases. Thus,
leptin and adiponectin can have an influence on cartilage,
bone tissue, and vascular walls. Adipokines, including lep-
tin, are involved in the local modulation of articular cartilage
metabolism.45 Elevated levels of leptin were found in both the
synovial fluid and subchondral bone of osteoarthritic patients.
Mainard et al demonstrated the importance of leptin in the
pathogenesis of OA by showing its impact on the synthesis
Osteoarthritis and comorbidities Alekseeva and Nasonov
A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE
of insulin-like growth factor (IGF-1) and transforming growth
factor-1 (TGF-1).46 Leptin, IGF-1, and TGF-1 can be found
in the cartilage of osteoarthritic patients (in osteophytes), but
not in the cartilage of disease-free patients.47 Moreover, os-
teophytes are associated with increased TGF1 expression.
TGF1 induces fibrotic changes in the synovial membrane,
bone sclerosis, and the differentiation of stem cells from the
periosteal layer, resulting in the formation of osteophytes.48
An experimental study showed that injections of leptin into
the joints of healthy rats caused symptoms of OA.45 In addi-
tion, Miller et al showed that a decrease in serum leptin levels
may be one of the mechanisms by which weight loss slows
down the progression of OA.49
Treatment of OA
The data presented above suggest that we can consider OA
as a disease that is pathogenetically related to cardiovascular
diseases, obesity, and other metabolic conditions. As a result,
the examination of OA patients should not be limited to the
assessment of their articular disorder, but rather should be
comprehensive, with particular attention paid to the state of
their cardiovascular system. This highlights the importance of
having an integrated approach when choosing a treatment,
which should ideally combine nonpharmacological and phar-
macological therapy. Patients should be informed about their
condition, its main symptoms, and what may cause its pro-
gression. Patient education is, therefore, required in order to
teach patients to follow an exercise regimen at work and at
home and to perform regular aerobic exercise. Physical ex-
ercise regimens should be individualized, taking into account
the presence of comorbidities and their severity. Patients should
clearly understand that overweight, especially of the viscer-
al type, is a confounding factor for the disease and, there-
fore, the target is not only to prevent weight gain, but also to
reduce it. In addition, information should be provided on the
use of orthopedic devices that facilitate the reduction of the
load applied to the joints.
The main goals of pharmacological therapy in OA are effec-
tive pain relief, suppression of inflammation in the joint, im-
provement in functional capacity, and prevention of disease
progression. When treating the clinical manifestations of OA
in patients with obesity and other metabolic diseases (AH,
CAD, etc)or who are at high risk of their development
doctors should thoroughly think through their choice of ther-
apy. In the presence of comorbidities, the excessive and un-
reasonable prescribing of drugs without first considering the
particularities of their interactions can lead to a sharp increase
in the risk of adverse effects and a worsening of the disease.
NSAIDs are commonly used to relieve pain in osteoarthritic
patients, in accordance with the European League Against
Rheumatism (EULAR), Osteoarthritis Research International
(OARSI), and American College of Rheumatology (ACR) treat-
ment guidelines. However, despite their being the most com-
MEDICOGRAPHIA, Vol 35, No. 2, 2013 155
OSTEOARTHRITIS: A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE
monly prescribed drugs for the treatment of OA, NSAIDs were
shown to cause a significant proportion of side effects in phar-
maco-epidemiological studies, especially due to their improp-
er use in elderly patients with comorbidities. Both selective
and nonselective NSAIDs have pronounced anti-inflammato-
ry and analgesic effects, but in patients with OA and metabol-
ic diseases (obesity, AH, CAD, etc), or at high risk of develop-
ing them, they may cause a number of side effects that can
aggravate the course of cardiovascular conditions. An in-
creased risk of cardiovascular accidents (myocardial infarc-
tion, stroke, and sudden cardiac death) can be considered to
be a class-specific side effect for all NSAIDs.50 NSAIDs can
cause the destabilization of AH and progression of heart fail-
ure and it was found that NSAID treatment in patients with a
history of heart disease increases the likelihood of hospitaliza-
tion due to heart failure by 10 times (odds ratio=10.5), com-
pared with patients not taking NSAIDs (odds ratio=1.6).51 Fi-
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13. Khitrov NA. Structure of osteoarthritis diseases and the problem of concomitant
diseases [Russian]. Ther Arkh. 2005;12:59-64.
14. Saudek DM, Kay J. Advanced Glycation End-products and Osteoarthritis. Curr
Rheumat Reports. 2003;5:33-40.
15. Garnero P, Peterfy C, Zaim S, Schoenharting M. Bone marrow abnormalities on
magnetic resonance imaging are associated with type II collagen degradation in
knee osteoarthritis: a three-month longitudinal study. Arthr Rheum. 2005;52:
2822-2929.
16. Szekanecz Z, Koch AE. Review: Vascular involvement in rheumatic diseases:
'vascular rheumatology.' Arthr Res Ther. 2008;10:224-230.
17. Millward-Sadler SJ, Salter DM. Integrin-dependent signal cascades in chondro-
cyte mechanotransduction. Ann Biomed Eng. 2004;32:435-446.
18. Steenvoorden MM, Huizinga TW, Verzijl N, et al. Activation of receptor for ad-
vanced glycation end products in osteoarthritis leads to increased stimulation
of chondrocytes and synoviocytes. Arthritis Rheum. 2006;54:14-18.
19. Guilak F, Fermor B, Keefe FJ, et al. The role of biomechanics and inflammation
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156 MEDICOGRAPHIA, Vol 35, No. 2, 2013
nally, it should also be borne in mind that NSAIDs can reduce
the efficacy of drugs used in the conventional therapy of CVD
(-blockers, diuretics, angiotensin-converting enzyme inhib-
itors, and, to a lesser extent, calcium channel blockers).
Conclusion
Current data suggest that OA is a disease that is pathogenet-
ically related to cardiovascular diseases and other metabol-
ic conditions. The problem of comorbidity in patients with OA
has clear prognostic significance. Early recognition of the
comorbid conditions associated with OA and their compre-
hensive treatment with well-evidenced therapies will substan-
tially reduce cardiovascular risks and improve patient prog-
nosis. I
Acknowledgements. Professor Eugeny L. Nasonov is chief editor of
Scientific-Practical Rheumatology (Russia) and on the editorial board of
Clinical Rheumatology (EULAR).
20. Patel P, Carington D, Strachan DP, et al. Fibrinogen; a link between chronic in-
fection and coronary heart disease. Lancet. 1994;343:1634-1635.
21. Garnero P. Biochemical markers of osteoarthritis. In: Sharma L, Berenbaum F.
Osteoarthritis: A companion to rheumatology. Philadelphia, PA: Mosby Elsevier;
2007:113-128.
22. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Na-
ture. 1993;362:801-809.
23. Solomon DH, Karlson EW, Rimm EB, et al. Cardiovascular morbidity and mor-
tality in women diagnosed with rheumatoid arthritis. Circulation. 2003;107:1303-
1307.
24. Van der Wall AC, Becker AC, van der Loos CM. Site of intimal rupture or ero-
sion of thrombosed coronary atherosclerotic plaques is characterized by an in-
flammatory process irrespective of the dominant plaque morphology. Circula-
tion. 1994;89:36-44.
25. Tracy RP, Lematre RN, Psaty BM, et al. Relationship of C-reactive protein to risk
of cardiovascular disease in the elderly. Arterioscler Thromb Vasc Biol. 1997;17:
1121-1127.
26. De Vries HE, Buchner B, Van Berkel TJ, Kuiper J. Specific interaction of oxidized
low-density lipoprotein with macrophage-derived foam cells isolated from rab-
bit atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 1999;19:638-645.
27. Page-McCaw A, Ewald AJ, Werb Z. Matrix metalloproteinases and the regu-
lation of tissue remodelling. Nat Rev Molec Cell Biol. 2007;8:221-233.
28. Rybakowski JK. Matrix metalloproteinase-9 (MMP9)a mediating enzyme in
cardiovascular disease, cancer, and neuropsychiatric disorders. Cardiovasc
Psychiat Neurol. 2009;9:1-7.
29. Conaghan PG, Vanharanta H, Dieppe PA. Is progressive osteoarthritis an athero-
matous vascular disease? Ann Rheum Dis. 2005;64:1539-1541.
30. Findlay DM. Review: Vascular pathology and osteoarthritis. J Rheumatol. 2007;
46:1763-1768.
31. Zanetti M, Bruder E, Romero J, Hodler J. Bone marrow edema pattern in os-
teoarthritic knees: correlation between MR imaging and histologic findings. Ra-
diology. 2000;215:835-840.
32. Zhou S, Cui Z, Sniekers Y, Urban JJ. Subchondral supply is a critical determi-
nant of the oxygen concentration profile across cartilage; in vitro measurement
and modeling. Osteoarthritis Cartilage. 2003;11(suppl A):20.
33. Pincus T, Sokka T. Mortality in rheumatic diseases. Clin Exp Rheum. 2008;26
(suppl 51):S1-S4.
34. Denisov LN, Nasonova VA, Koreshkov EG, Kashevarova NG. Obesity in the de-
velopment of osteoarthritis and concomitant diseases. Ther Arch. 2010;10:
34-37.
35. Gelber AC, Hochberg MC, Mead LA, et al. Body mass index in young men and
the risk of subsequent knee and hip osteoarthritis. Am J Med. 1999;107:542-
548.
36. Manek Nisha J, Hart D, Spector TD, MacGregor AJ. The association of body
mass index and osteoarthritis of the knee joint: an examination of genetic and
environmental influences. Arthritis Rheum. 2003;48:4:1024-1029
37. Reijman M, Pols HA, Bergink AP, et al. Body mass index associated with onset
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 OSTEOARTHRITIS: A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE

and progression of osteoarthritis of the knee but not of the hip. The Rotterdam
Study. Ann Rheum Dis. 2007;66:158-162
38. Wang Y, Simpson JA, Wluka AE, et al. Relationship between body adiposity
measures and risk of primary knee and hip replacement for osteoarthritis: a
prospective cohort study. Arthritis Res Ther. 2009;11:R31.
39. Christensen R, Bartels EM, Astrup A, Bliddal H. Effect of weight reduction in
obese patients diagnosed with knee osteoarthritis: a systematic review and
meta-analysis. Ann Rheum Dis. 2007;66:4:433-439.
40. Cicuttini FM, Baker JR, Spector TD. The association of obesity with osteoarthri-
tis of the hand and knee in women: a twin study. J Rheumatol. 1996;23:1221-
1226.
41. Yusuf E, Nelissen RG, Ioan-Facsinay A, et al. Association between weight or
body mass index and hand osteoarthritis: a systematic review. Ann Rheum Dis.
2010;69:761-765
42. Liu B, Balkwil A, Cooper C, et al; Million Women Study Collaborators. Reproduc-
tive history, hormonal factors and the incidence of hip and knee replacement for
osteoarthritis in middle-aged women. Ann Rheumat Dis. 2009;68:1165-1170.
43. Tepper S, Hochberg MC. Factors associated with hip osteoarthritis: data from
the First National Health and Nutrition Examination Survey (NHANES-I). Am J
Epidemiol. 1993;137:1081-1088.
44. Pottie P, Presle N, Terlain B, et al. Obesity and osteoarthritis: more complex than
predicted. Ann Rheum Dis. 2006;65:1403-1405.
45. Dumond H, Presle N, Terlain B, et al. Evidence for a key role of leptin in os-
teoarthritis. Arthrit Rheumat. 2003;48:11:3118-3129.
46. Mainard D, Dumont H, Presle N, et al. Role of leptin in the pathogenesis of os-
teoarthritis: a clinical and experimental study. J Bone Joint Surg Br Proc. 2008;
90:254-255.
47. Lajeunesse D, Delalandre A, Fernandes JC. Subchondral osteoblasts from os-
teoarthritic patients show abnormal expression and production of leptin: Pos-
sible role in cartilage degradation. J Bone Min Res. 2004;19(suppl 1):S149.
48. Chevalier X, Tyler JA. Production of binding proteins and role of the insulin-
like growth factor I binding protein 3 in human articular cartilage explants. Br J
Rheumatol. 1996;35:6:515-522.
49. Miller GD, Nicklas BJ, Loeser RF. Inflammatory biomarkers and physical func-
tion in older, obese adults with knee pain and self-reported osteoarthritis after
intensive weight-loss therapy. J Am Geriatr Soc. 2008;56:644-651.
50. Antman EM, Bennett JS, Daugherty A, et al. Use of nonsteroidal antiinflamma-
tory drugs: an update for clinicians: A scientific statement from the American
Heart Association. Circulation. 2007;115:1634-1642.
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Med. 2000;160:777-784.

Keywords: arterial hypertension; cardiovascular system; comorbidity; metabolic disorder; obesity; osteoarthritis; pathogen-
esis; treatment goal

ARTHROSE ET COMORBIDITS
Larthrose est la pathologie la plus courante du systme musculosquelettique et la cause principale de handicap et
dincapacit fonctionnelle chez ladulte. Daprs un nombre significatif dtudes, les patients arthrosiques ont un
risque nettement plus important de dvelopper des comorbidits que ceux qui nont pas darthrose. Larthrose se re-
trouve le plus souvent associe aux maladies cardiovasculaires, dont lhypertension artrielle, lobsit, au diabte
et aux maladies pulmonaires. Lassociation de diverses maladies chroniques avec des pathologies du systme mus-
culosquelettique, en particulier larthrose, va devenir de plus en plus frquente et cela aura des consquences non
seulement sur les systmes de soins de sant, mais aussi sur la qualit de vie. Les liens entre larthrose et les trou-
bles comorbides peuvent sexpliquer, en partie, par des mcanismes tiologiques et pathogntiques communs, ou
peuvent tre lis aux processus biologiques du vieillissement, qui peuvent conduire non seulement au dveloppe-
ment, mais peut-tre aussi au maintien des comorbidits. Les donnes prsentes dans cet article suggrent que
larthrose est lie pathogntiquement aux maladies cardiovasculaires, lobsit et dautres troubles mtabo-
liques. Ainsi, lexamen des patients arthrosiques ne devrait pas se limiter lvaluation de leur pathologie articulaire,
mais devrait tre plus complet, en faisant particulirement attention leur systme cardiovasculaire. Ceci souligne
limportance de lusage dune approche globale lors du choix des traitements dans larthrose.

Osteoarthritis and comorbidities Alekseeva and Nasonov MEDICOGRAPHIA, Vol 35, No. 2, 2013 157

A complex and paradoxical
relationship seems to exist be-
tween osteoarthritis and osteo-
porosis, although there is increas-
ing evidence to support a close
biomolecular and mechanical as-
sociation between subchondral
bone and cartilage. Indeed, micro-
array profiles have identified a
number of genes differentially ex-
pressed in osteoarthritic bone that
are key players in the structure and
function of both bone and carti-
lage.
L
Gabriel HERRERO-BEAUMONT, MD
Jorge A. ROMAN-BLAS, MD
Bone and Joint Research Unit
Rheumatology Service
IIS Fundacin Jimnez Daz also potentially progression of joint damage.
Universidad Autnoma
Madrid, SPAIN
Address for correspondence:
Professor Gabriel Herrero-Beaumont,
Bone and Joint Research Unit,
Fundacin Jimnez Daz,
Avenida Reyes Catlicos, 2,
28040 Madrid, Spain
(e-mail: gherrero@fjd.es)
www.medicographia.com
158 MEDICOGRAPHIA, Vol 35, No. 2, 2013
OSTEOARTHRITIS: A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE
Osteoarthritis pathophysiology:
similarities and dissimilarities with
other rheumatological diseases
and the role of subchondral bone
by J. A. Roman-Blas
a n d G . H e r re ro - B e a u m o n t , S p a i n
O
steoarthritis (OA) is a disease not only of the cartilage, but also of the
whole joint. In osteoarthritis and chronic inflammatory arthritides, the
intensity of the inflammatory response of the joint determines juxta-
articular bone loss. Thus, in rheumatoid arthritis, the intense synovial and car-
tilage inflammation, pannus formation, and systemic bone loss induce in-
creased subchondral bone turnover with subsequent juxta-articular bone loss.
By contrast, the mild and patchy synovitis seen in osteoarthritis results in low-
er subchondral bone turnover and less subsequent bone loss than in rheuma-
toid arthritislike conditions. Angiogenesis and sensory nerve growth also
contribute to joint damage to different extents in these arthropathies. How-
ever, the main underlying pathogenic mechanisms may be common among
these joint diseases. A better understanding of the biological events involved
in inflammation-induced bone loss in these diseases could lead to the iden-
tification of novel therapeutic strategies for the prevention of bone loss and
Medicographia. 2013;35:158-163 (see French abstract on page 163)
steoarthritis (OA) is a multifactorial disease that affects not only articular
O cartilage, but also the whole joint. The involvement of subchondral bone in
OA is of great relevance and interest, as are changes that occur in the syn-
ovial membrane, tidemarks, and periarticular structures in the course of the dis-
ease.1,2 Thus, acquired or genetically conditioned biomechanical and biochemical
alterations affecting any joint tissue may cause anomalous intra-articular stresses
and subsequent tissue damage associated with a failure of repair.3 OA is charac-
terized by pain, stiffness, and functional impairment ultimately resulting in chronic
disability and significant economic burden, especially in the elderly.
Subchondral bone
The bone underlying joint cartilage is composed of several specific anatomical re-
gions, including the subchondral cortical plate, subchondral trabecular bone, and
subarticular bone.4 Each region is likely to contribute to cartilage pathology in a dis-
tinct manner. Current imaging techniques show unclear anatomical boundaries be-
tween these tissues, generating some confusion with regard to their study.5 Bone at
the joint margins is markedly active and is frequently the site of osteophyte develop-
ment in primary OA or bone erosion in inflammatory arthritis. The close relationship
between subchondral bone and joint cartilage, two tissues that are adjacent to one
another as well as mechanically and biologically intertwined, makes them a function-
OA pathophysiology vs other rheumatological diseases Roman-Blas and Herrero-Beaumont
 OSTEOARTHRITIS:
al unit that contributes significantly to normal joint function.
Changes to either the mechanical or biological properties of
subchondral bone may alter the corresponding state of artic-
ular cartilage, and vice versa.6 When both tissues are damaged,
the relationship between them changes, thereby posing an as-
yet-unanswered question that has valuable therapeutic impli-
cations in the setting of chronic joint diseases.
Effect of systemic osteoporosis on subchondral
bone structure and remodeling
Systemic osteoporosis (OP) alters the microstructural and bi-
ological properties of subchondral bone. Compared with nor-
mal and osteoarthritic femoral heads, the femoral heads of
patients with OP show the least stiff and dense subchondral
bone plates (OA femoral heads show values in between nor-
mal and OP femoral heads). Although osteoporotic bone has
been found to contain less mineral, its organic and water con-
tents have been found to be proportionally higher, suggesting
no change in the relative amount of organic matrix.7 Studies in
different animal models have reported that OP has a negative
effect on subchondral bone integrity.8-10 In an experimental
model of OP in rabbits, which was induced by glucocorticoid
administration and ovariectomy, subchondral bone mineral
density was significantly lower compared with controls.8 This
experimental model also showed a decrease in subchondral
plate thickness and only a negative tendency in bone area
fraction and trabecular thickness values, while the microar-
chitecture index fractal dimension was increased. The de-
crease in subchondral plate thickness would indicate that
this experimental model of OP exhibits a much more profound
effect on subchondral cortical bone than subchondral tra-
becular bone. Increased remodeling in favor of subchondral
bone resorption has also been reported in osteoporotic rab-
bits, as determined by reduced alkaline phosphatase expres-
sion and increased matrix metalloproteinase (MMP)9 expres-
sion, also supported by a decrease in the osteoprotegerin
(OPG)/receptor activator of nuclear factor-B ligand (RANKL)
ratio compared with healthy controls.9 In ovariectomized sheep,
bone volume fraction was found to be reduced in subchon-
dral bone compared with controls. Trabeculae were also sig-
nificantly thinner in these animals, with reduced connectivity
density, and significant alterations observed in the trabecu-
lar architecture under the tibial plateau following 12 months
SELECTED ABBREVIATIONS AND ACRONYMS
ACLT anterior cruciate ligament transection
AIA antigen-induced arthritis
BML bone marrow lesion
MMP matrix metalloproteinase
OA osteoarthritis
OP osteoporosis
OPG osteoprotegerin
RANKL receptor activator of nuclear factor-kB ligand
OA pathophysiology vs other rheumatological diseases Roman-Blas and Herrero-Beaumont
A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE
of estrogen deficiency.10 Lastly, in an ovariectomized mouse
model, use of either estrogen supplementation or bisphos-
phonate treatment resulted in inhibition of tibial and patellar
subchondral cortical thinning.11 Taken together, these studies
demonstrate a relevant and negative effect of systemic OP on
the structure and metabolism of subchondral bone.
Influence of osteoporosis in the remodeling of
subchondral bone in osteoarthritis
It is increasingly acknowledged that articular cartilage home-
ostasis is dependent on the integrity of the underlying bone.12-15
Several studies have identified specific changes that occur to
the architecture and turnover of subchondral bone in OA.16,17
The study of the influence of OP on subchondral bone remod-
eling could reveal relevant mechanisms involved in the devel-
opment of OA. Thus, our group developed a rabbit model of
surgically-induced OA preceded by OP, and demonstrated
that microstructure impairment in subchondral bone asso-
ciated with increased remodeling increases cartilage dam-
age.9 Indeed, compared with control and OA knees, OPOA
knees demonstrated diminished subchondral bone area/tissue
area, trabecular thickness, and polar moment of inertia, as
well as a pronounced decline in subchondral plate thickness.
Compared with controls, the subchondral bone of OA, OP,
and OPOA knees showed a decrease in alkaline phosphatase
expression and OPG/RANKL ratio as well as an increase in
the fractal dimension and MMP-9 expression. In addition, the
severity of cartilage damage was increased in OPOA knees
versus controls. Remarkably, good correlations were observed
between structural and remodeling parameters in subchon-
dral bone, and furthermore, between subchondral structural
parameters and cartilage Mankin score.
In line with our results, a decrease in subchondral plate thick-
ness was also reported in an ovariectomized murine model
of intra-articular iodoacetate-induced knee OA,11 as well as
in experimental models of OA evaluating the early disease
stage.13,14,18-20 Thinning and porosity of the subchondral plate
were only present in the medial compartment and were relat-
ed to superjacent cartilage damage, while in the canine ante-
rior cruciate ligament transection (ACLT)medial meniscectomy
model of OA,20 trabecular bone changes were mostly found in
the lateral compartment and were related to mechanical un-
loading. Thickening of the subchondral plate has, however,
been described in animal models of surgically-induced OA cor-
responding to late-stage disease.13,19,21 Remarkably, in some
of these studies, the early decrease in subchondral plate thick-
ness was followed by late plate thickening.13,19 Furthermore,
in the rat ACLT and meniscectomy models of OA, increased
mRNA levels of cathepsin K and tartrate-resistant acid phos-
phatase were found in subchondral bone at week 2 postsur-
gery, as well as invasion of cathepsin K+ osteoclasts into the
articular cartilage from the subchondral region. These events
thus confirm that bone resorption is an early event in the dis-
ease course of OA. Upregulation of the osteoanabolic mark-
MEDICOGRAPHIA, Vol 35, No. 2, 2013 159
OSTEOARTHRITIS: A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE
ers runx2 and osterix was observed from week 4 to 6 post-
surgery, which is thought to constitute the pathophysiolog-
ical basis for late events in the disease course of OA such as
subchondral sclerosis and osteophyte formation. Local and
temporal regulation of matrix degradation, differentiation, and
vascular invasion markers was seen in articular cartilage in a
manner consistent with the aforementioned changes in sub-
chondral bone.22
In human knee OA, cartilage damage is frequently associat-
ed with thickening of the subchondral plate and osteophyte
development.16,23 Aside from this hypertrophic OA, some au-
thors consider that there is another variant, the atrophic form,
which is characterized by a lack of osteophytes and loss of
subchondral bone volume in OA patients with compromised
hip and knee.24 This atrophic form probably shares several
etiopathogenic mechanisms and phenotypic features with OA
associated with OP (Table). Furthermore, the correlation ob-
served in hypertrophic OA between serum levels of C-propep-
tide and type II collagenase has been found to be lost in atroph-
ic OA, the latter showing reduced type II collagen synthesis.25
This could contribute to the absence of osteophyte formation
as well as the increased subchondral bone turnover seen in
rapidly progressive hip and knee OA. Of note, the presence
Disease mechanism/phenotypic feature
Subchondral Systemic
Disease type bone remodeling osteoporosis
Atrophic OA* ++ (toward resorption) ++ ?
Hypertrophic OA ++ (toward formation) +/
Rheumatoid arthritis +++ ? +++
* Atrophic OA probably shares common development events with OA associated with osteoporosis.
+/ presence or absence; + mild; ++ moderate; +++ severe.
of subchondral bone attrition in knee OA, defined as flatten-
ing or depression of the osseous articular surface, is strong-
ly associated with subchondral bone marrow lesions (BMLs)
on magnetic resonance imaging. In turn, BMLs reflect the pres-
ence of active remodeling processes due to chronic overload.26
Cartilage loss occurs in the same knee subregions as sub-
chondral bone attrition.27 In addition, it is possible that in post-
traumatic OA, trabecular microarchitecture changes differ from
those in primary OA. Indeed it has been proposed that during
the early postoperative period in the canine ACL-deficient knee,
disuse osteopenia can potentially occur due to decreased
loadbearing.28 Likewise, subchondral bone in animal models of
OA with early stages of the disease has shown both decreased
volume and stiffness and increased remodeling.29 The impact
of these subchondral bone changes in OA is still a matter for
debate, in part due to the heterogeneity of the disease.
160 MEDICOGRAPHIA, Vol 35, No. 2, 2013 OA pathophysiology vs other rheumatological diseases Roman-Blas and Herrero-Beaumont
Effects of systemic osteoporosis in osteoarthritis
A complex and paradoxical relationship seems to exist be-
tween OA and OP, although there is increasing evidence to
support a close biomolecular and mechanical association be-
tween subchondral bone and cartilage.15 Indeed, microarray
profiles have identified a number of genes differentially ex-
pressed in osteoarthritic bone that are key players in the struc-
ture and function of both bone and cartilage. These include
genes involved in the Wingless-type mouse mammary tumor
virus/-catenin (Wnt/-catenin) and transforming growth fac-
tor/mothers against decapentaplegic (TGF-/SMAD) sig-
naling pathways and their targets.30 Furthermore, aggrecan
production, as well as SOX9, type II collagen, and parathyroid
hormonerelated protein mRNA expression, were inhibited in
sclerotic but not nonsclerotic osteoblasts, while expression
of MMP-3, MMP-13, and osteoblast-specific factor 1 by hu-
man OA chondrocytes was augmented in a coculture system.
Thus, sclerotic osteoarthritic subchondral osteoblasts may
contribute to cartilage degradation and chondrocyte hyper-
trophy.31 In addition, in our animal model of OA preceded by
OP, improvement in subchondral bone integrity was shown
to reduce the progression of cartilage damage, suggesting a
direct relationship between these two conditions.32 On the oth-
er hand, several cross-sectional studies have demonstrated
Role of osteoporosis
Cartilage in disease progression Table.
inflammation (cartilage degradation) Etiopathogenic
mechanisms
++ ++ (predominantly joint and phenotypic
space narrowing) features of
atrophic osteo-
arthritis (OA),
+++ ++ hypertrophic OA,
and rheumatoid
arthritis, and the
involvement of
osteoporosis.
an inverse relationship between OP and OA,33,34 although oth-
ers have produced opposite results.35 Confounding variables
such as race, obesity, and physical activity could explain the
mutually exclusive relationship between OA and OP, whereby
overweight individuals and/or those who undertake exces-
sive physical activity could have a higher risk of developing
OA and having a higher bone mass.
Recently, we proposed that high as well as low bone mass
conditions can result in OA induction and/or progression.5
Thus, both bone mass phenotypes may be considered risk
factors for OA initiation. The presence of other risk factors such
as skeletal shape abnormalities, joint overload, or obesity may
have a synergistic effect regarding OA initiation. In addition,
inflammatory mediators released by the articular cartilage in
OA may lead to subchondral bone loss through increased
 OSTEOARTHRITIS:
bone remodeling. Accordingly, treatment goals for OA must
consider improvement of subchondral bone integrity. This
therapeutic approach should be individualized according to
the patients bone mineral density status and OA pheno-
type, and the use of drugs should also subsequently be in-
dividualized for each patient. Recent findings suggest that
the same drugs could be useful for treating both processes
simultaneously, at least in a subgroup of patients with OA and
concomitant OP.32
Effect of chronic synovitis on subchondral
bone remodeling
Juxta-articular bone loss is related to the intensity of the in-
flammatory response in the affected joint.36,37 This fact is ob-
served not only in rheumatoid arthritis, but also in other arthri-
tides associated with a high degree of inflammation.38,39 Juvenile
idiopathic arthritis, seronegative spondyloarthropathies, sys-
temic lupus erythematosus, as well as septic arthritis, are all
rheumatic diseases in which intense inflammation is associ-
ated with skeletal pathology. Although some of the mecha-
nisms of skeletal remodeling are shared among these dis-
eases, each disease has a unique impact on articular bone or
the axial or appendicular skeleton.39
Various hormones, cytokines, and chemokines produced by
the inflamed synovial membrane have been reported to be
involved in juxta-articular osteoporosis in these diseases.36
The inflammatory mediators modulate the expression of the
crucial factor RANKL, in whose presence macrophages dif-
ferentiate into bone-resorbing osteoclasts in zones of contact
between the inflamed synovium and subchondral bone, as
described in rheumatoid arthritis.40 In addition to membrane-
bound RANKL in osteoblasts, RANKL secreted by synovial
cells actively promotes bone destruction in chronic inflamma-
tory arthritis.37 Hence, high local RANKL concentrations lead
to increased osteoclastogenesis at the bone-pannus interface.
We have recently described that RANKL expressed by chon-
drocytes also contributes significantly to the pathogenesis of
the juxta-articular bone loss associated with chronic arthritis
in a rabbit model that develops a more intense and destruc-
tive version of the well-established antigen-induced arthritis
(AIA).41 This experimental arthritis was found to be accom-
panied by severe juxta-articular bone loss, as estimated by
x-ray and bone mineral density measurement. The increase in
RANKL expression in the cartilage of AIA rabbits was linked
to the particular presence of extracellular RANKL in the cal-
cified cartilage. Previous results from our group have also
shown that RANKL is localized in the extracellular matrix of
human OA cartilage and could reach the subchondral bone
through the calcified cartilage.42 These results indicate that
chondrocyte-synthesized RANKL acts on subchondral bone
cells, stimulating juxta-articular bone loss. Other studies have
demonstrated that soluble RANKL produced by hypertrophic
chondrocytes is a biologically active molecule during bone
OA pathophysiology vs other rheumatological diseases Roman-Blas and Herrero-Beaumont
A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE
growth,43 acting in a paracrine manner on the subchondral
bone plate. We have also shown that RANKL synthesized by
prostaglandin E2stimulated mature articular chondrocytes
is also biologically active and is responsible for the mononu-
clear cell differentiation into osteoclast in the absence of ex-
ogenous RANKL.41
By contrast, in OA, mild synovial hyperplasia is predominant-
ly present, with proliferation and activation of lining cells as-
sociated with fibrosis-related changes.44-46 Synovial inflamma-
tory infiltrates are composed of mononuclear cells that appear
in far less abundance than in the synovium in rheumatoid arthri-
tis, and they are distributed in a patchy pattern, mostly con-
fined to areas adjacent to sites of damaged cartilage, there-
by increasing OA severity throughout the disease course.47,48
The inflammatory synovial changes are associated with in-
creased production of proinflammatory cytokines and medi-
ators of OA joint damage.49 The Krenn synovitis score was
found to be well correlated with subchondral bone structural
parameters in an experimental model of OA preceded by OP.46
Furthermore, rabbits with surgery-induced knee OA showed
a lower synovial inflammatory response and less subchondral
bone loss than rabbits with AIA.41 Remarkably, RANKL ex-
pression in OA cartilageparticularly in calcified cartilage
was less than in AIA cartilage, suggesting that the relevant
involvement of this osteoclastogenic molecule in subchondral
bone loss in OA is smaller in degree than in chronic inflamma-
tory arthritis.41
In addition, inflammation drives synovial angiogenesis through
macrophage activation, which in turn perpetuates inflamma-
tion and synovial hyperplasia, inducing pannus formation to
variable extents. This is a well-recognized pathogenic mech-
anism in the rheumatoid arthritis joint. Novel studies, howev-
er, have identified the presence of increased angiogenesis in
the synovium, osteophytes, menisci, and osteochondral junc-
tion in OA patients.50 Channels extending from subchondral
bone into noncalcified articular cartilage provide the anatom-
ical basis for angiogenesis and sensory nerve growth through
the osteochondral junction. Thus, to different extents, angio-
genesis also contributes to structural damage in chronic joint
diseases.50
In summary, the intensity of the inflammatory response of the
joint determines the juxta-articular bone loss in OA and
chronic inflammatory arthritides. In articular conditions such
as rheumatoid arthritis, the intense synovial and cartilage in-
flammation, pannus formation, and systemic bone loss will
lead to high production of key biological mediators such as
RANKL, which are involved in increased subchondral bone
turnover with subsequent juxta-articular bone loss. By con-
trast, during the OA disease process, mild and patchy synovi-
tis will occur with less RANKL expression in cartilage, resulting
in lower subchondral bone turnover and subsequent bone
loss than in rheumatoid arthritislike conditions. In addition,
MEDICOGRAPHIA, Vol 35, No. 2, 2013 161
OSTEOARTHRITIS: A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE
angiogenesis and sensory nerve growth also contribute to
joint damage to varying extents in these arthropathies. How-
ever, the main underlying pathogenic mechanisms may be
common among these joint diseases. Further elucidation of
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47. Ayral X, Pickering EH, Woodworth TG, Mackillop N, Dougados M. Synovitis:
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Keywords: inflammatory arthritis; osteoarthritis; subchondral bone

PHYSIOPATHOLOGIE DE LARTHROSE : RESSEMBLANCES ET DIFFRENCES AVEC

D AUTRES PATHOLOGIES RHUMATOLOGIQUES ; LE RLE DE L OS SOUS - CHONDRAL
Larthrose est non seulement une pathologie du cartilage mais aussi de toute larticulation. Dans larthrose et les ar-
thrites inflammatoires chroniques, lintensit de la rponse inflammatoire de larticulation dtermine la perte osseuse
juxta-articulaire. Ainsi, dans la polyarthrite rhumatode, linflammation intense du cartilage et de la synovie, la forma-
tion de pannus et la perte osseuse gnralise provoquent une augmentation du renouvellement osseux sous-chon-
dral entranant une perte osseuse juxta-articulaire. linverse, la synovite modre et clairseme de type arthrosique
conduit un renouvellement osseux sous-chondral plus faible et une perte osseuse ultrieure moins importante
que dans la polyarthrite rhumatode. Langiogense et la croissance des nerfs sensoriels contribuent galement cau-
ser des lsions articulaires de svrit diffrente dans ces arthropathies. Toutefois, les principaux mcanismes pa-
thognes sous-jacents sont probablement communs ces maladies articulaires. De nouvelles stratgies thrapeu-
tiques pour prvenir la perte osseuse et, ventuellement, lvolution des lsions articulaires pourraient tre labores
si les phnomnes impliqus dans la perte osseuse provoque par linflammation au cours de ces maladies taient
mieux compris.

OA pathophysiology vs other rheumatological diseases Roman-Blas and Herrero-Beaumont MEDICOGRAPHIA, Vol 35, No. 2, 2013 163

Radiography is the only EMA-
and FDA-recommended imaging
modality for defining the inclusion
criteria and efficacy end points of
a clinical trial. However, it has its
limitations and well-defined MRI-
based diagnostic criteria of OA are
needed. MRI plays a crucial role in
understanding the natural history
of the disease and in guiding fu-
ture therapies due to its ability to
image the knee as a whole organ
and to directly and three-dimen-
sionally assess cartilage morphol-
ogy and composition.
L
Ali GUERMAZI,a MD, PhD
Frank W. ROEMER,b MD
a,b
Quantitative Imaging Center
Department of Radiology
Boston University School of
Medicine, Boston, USA
b
Department of Radiology
Klinikum Augsburg
Augsburg, GERMANY
Harry K. GENANT, MD
Department of Radiology
University of California
San Francisco, USA
Address for correspondence:
Professor Ali Guermazi, Department
of Radiology, Boston University
School of Medicine, 820 Harrison
Avenue, FGH Building, 3rd Floor,
Boston, MA 02118, USA
(e-mail: guermazi@bu.edu)
www.medicographia.com
164 MEDICOGRAPHIA, Vol 35, No. 2, 2013
OSTEOARTHRITIS: A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE
Role of imaging in
osteoarthritis: diagnosis,
prognosis, and follow-up
b y A . G u e r m a z i , F. W. R o e m e r,
and H. K. Genant, USA and Germany
O
steoarthritis is a highly prevalent joint disorder primarily affecting eld-
erly people worldwide. The importance of imaging for assessment
of all the structures of the joint such as cartilage, meniscus, subartic-
ular bone marrow, and synovium for diagnosis, prognostication, and follow-
up has been well recognized over the past decade. Conventional radiography
is still the most commonly used imaging technique for evaluation of a patient
with a known or suspected diagnosis of osteoarthritis. However, recent MRI-
based knee osteoarthritis studies have begun to reveal the limitations of ra-
diography. The ability of MRI to image the knee as a whole organ and to di-
rectly and three-dimensionally assess cartilage morphology and composition
plays a crucial role in understanding the natural history of the disease and in
the search for new therapies. Use of the appropriate MRI pulse sequences is
crucial to assess the various features of osteoarthritis, and support from ex-
perienced musculoskeletal radiologists is necessary for study design, image
acquisition, and interpretation. This article describes the roles and limitations
of conventional radiography and MRI in osteoarthritis imaging, and also pro-
vides some insight into the use of other modalities such as ultrasound, nuclear
medicine, computed tomography, and computed tomography arthrography
in clinical practice and research in osteoarthritis, with a particular emphasis
on the assessment of knee osteoarthritis in the tibiofemoral joint.
Medicographia. 2013;35:164-171 (see French abstract on page 171)
steoarthritis (OA) is a highly prevalent joint disorder and is becoming in-
O creasingly common, posing major health and economic challenges for ag-
ing industrialized societies. Despite various surgical and symptom-oriented
approaches, there is still no definitive disease-modifying therapy, other than total
joint replacement, for this complex and heterogeneous disease.
Most research studies of knee OA involve acquisition of conventional radiographs
and magnetic resonance images, including the Osteoarthritis Initiative (OAI,
http://www.oai.ucsf.edu/datarelease/), one of the largest epidemiological OA stud-
ies.1 The OAI is an ongoing 4-year observational study of approximately 4800 par-
ticipants, sponsored by the National Institutes of Health, and targeted at identify-
ing the most reliable and sensitive biomarkers for evaluating the development and
progression of symptomatic knee OA. Data from baseline through the 48-month
follow-up visit for the entire cohort were made publically available in 2011. This ar-
ticle aims to describe the current role of radiography and magnetic resonance im-
Imaging of osteoarthritis Guermazi and others
 OSTEOARTHRITIS: A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE

aging (MRI) in OA imaging, and also

to give some insight into the use of A B
other modalities: ultrasound, nuclear
medicine, and computed tomogra-
phy (CT). Current research tends to
focus on the knee due to the high
prevalence of knee OA and the rel-
ative ease of use of MRI compared
with other central appendicular joints.
This nonsystematic review article will
focus primarily on the assessment
C D
of OA in the tibiofemoral joint of the
knee.

Conventional radiography
Radiography is the simplest and least
expensive imaging technique. It can
detect OA-associated bony features
including marginal osteophytes, sub-
chondral sclerosis, and subchondral
cysts.2 Radiography can also deter- Figure 1. Multitissue contribution to joint space narrowing.
(A) Baseline anterior-posterior radiograph showing doubtful joint space narrowing in the medial tibiofemoral com-
mine joint space width (JSW), an in- partment (arrowheads). (B) Follow-up image at 24 months showing a definite increase in joint space loss medially
direct surrogate of cartilage thickness (arrows).(C) Corresponding baseline intermediate-weighted magnetic resonance imaging (MRI) showing normal
and meniscal integrity, but precise cartilaginous tibiofemoral surface and no relevant meniscal extrusion. (D) MRI at 24 months showing definite menis-
cal extrusion (arrows) likely to be responsible for the joint space narrowing on the radiograph.
measurement of each of these artic-
ular structures is not possible by x-ray.3 Despite this, slowing The severity of OA can be estimated using semiquantitative
of radiographically detected joint space narrowing (JSN) is the scoring systems. Published atlases provide images that repre-
only structural end point currently recommended by the reg- sent specific grades.2 The most widely used system, the Kell-
ulatory bodies in the United States (US Food and Drug Ad- gren and Lawrence (K&L) classification,5 has limitations, espe-
ministration [FDA]) and in Europe (European Medicines Agency cially as K&L grade 3 includes all degrees of JSN, regardless
[EMA]) to prove the efficacy of disease-modifying OA drugs of the actual extent. In contrast, the Osteoarthritis Research
in phase-3 clinical trials. OA is defined radiographically by the Society International (OARSI) atlas2 classification grades tibio-
presence of osteophytes.4 Progression of JSN is the most femoral JSW and osteophytes separately for each compart-
commonly used criterion for the assessment of OA progres- ment of the knee. Compartmental scoring appears to be more
sion and the complete loss of JSW characterized by bone- sensitive to longitudinal radiographic changes than K&L grading.
on-bone contact is one of the indicators for joint replacement.
Methods of JSW measurement can be manual or semiauto-
mated using computer software. However, previously held be-
SELECTED ABBREVIATIONS AND ACRONYMS
liefs that JSN and its changes are the only visible evidence of
BML bone marrow lesion cartilage damage have been shown to be incorrect. Recent
CE-MRI contrast-enhanced MRI studies have demonstrated that alterations in the meniscus,
CT computed tomography such as meniscal extrusion or subluxation, also contribute to
DESS double-echo steady state JSN (Figure 1).3 The lack of sensitivity and specificity of radi-
dGEMRIC delayed gadolinium-enhanced MRI of cartilage ography for the detection of the pathologic features associ-
FLASH fast low-angle shot ated with OA, and the poor sensitivity to change at follow-up
GRE gradient-recalled echo imaging, are inherent limitations of radiography.
JSN joint space narrowing
JSW joint space width Interestingly, an older methoddigital tomosynthesishas
K&L Kellgren and Lawrence lately experienced a revival. Tomosynthesis generates an ar-
MRI magnetic resonance imaging bitrary number of section images from a single pass of the x-
OA osteoarthritis ray tube. Using 3T MRI as a reference, Hayashi et al found
OAI Osteoarthritis Initiative that tomosynthesis depicted more osteophytes and subchon-
PET positron emission tomography dral cysts than radiography.6 The clinical availability of these
SPGR spoiled gradient echo systems is currently limited, but the potential of this tech-
nique for OA research may be worth exploring.

Imaging of osteoarthritis Guermazi and others MEDICOGRAPHIA, Vol 35, No. 2, 2013 165
OSTEOARTHRITIS: A STORY OF CLOSE
BETWEEN BONE AND CARTILAGE
Magnetic resonance imaging
MRI offers a number of advantages for OA imaging.
First, MRI has a tomographic viewing perspective
and thus provides cross-sectional images of the
anatomy free of the projectional limitations of radi-
ography. Second, MRI is uniquely able to directly de-
pict all the components of the joint and their patholo-
gies, including the articular cartilage, menisci, intra-
articular ligaments, synovium, effusion, bone attrition,
bone marrow lesions (BMLs), subchondral cysts,
and intra- and periarticular cystic lesions (Figure 2).
The joint can be evaluated as a whole organ, pro-
viding a much more detailed picture of the changes
associated with OA than is possible with other tech-
niques.7 Third, MRI can detect the pathology of preradiograph-
ic OA and possible complications of the disease at a much
earlier stage than radiography.8
N Technical considerations
Several MRI systems are commercially available but 1.5T sys-
tems are the most widely used in clinical and research set-
tings. Examination times vary depending on the purpose of
the exam, but usually last between 20 and 40 minutes, in-
cluding patient positioning. High-field 3T MRI was introduced
for clinical application several years ago. A higher signal-to-
noise ratio is a definitive advantage, but disadvantages include
increased susceptibility artifacts, high costs, and the limited
commercial availability of coils. Most OA studies that include
MRI use 1.5T MRI systems because of their wide availability
and reliable image quality. The OAI is one of the few large stud-
ies to have used a 3T system (Figure 3).
So far, 7T MRI in humans has only been applied in research.9
In the future, 7T systems may be able to produce higher-res-
olution images with a shorter scan time than 3T systems. So
far, however, the available 7T protocols have not been any
better than 3T for knee cartilage evaluation.10
A B
Figure 3. Development of a focal cartilage defect over two years as visualized with 3T magnetic resonance imaging (MRI).
(A) Coronal intermediate-weighted image showing a small superficial cartilage defect in the weight-bearing part of the medial femoral condyle (arrow). (B) Follow-up
MRI at 12 months reveals extension of defect to the subchondral bone, now representing a full-thickness focal lesion (arrow). (C) MRI image at 24 months showing
a slight increase in the size of the focal full thickness defect.
166 MEDICOGRAPHIA, Vol 35, No. 2, 2013
R E L AT I O N S H I P
Figure 2. Osteoarthritis is a
whole-joint disease process that
can only be completely visualized
by magnetic resonance imaging.
This sagittal intermediate-weighted fat-
saturated image shows diffuse cartilage
loss in the medial tibio-femoral joint.
A horizontal-oblique tear extending to
the superior surface is seen in the pos-
terior horn of the medial meniscus
(arrowhead) and a small subchondral
cyst appears in the medial weight bear-
ing part of the femoral condyle (arrow).
There is also joint effusion and a popliteal
cyst (asterisk) and a small osteophyte
at the posterior medial femoral condyle
(no arrow).
The role of contrast-enhanced MRI (CE-MRI) in the clinical and
research environment remains to be fully established. Visu-
alization of synovitis in OA is superior on contrast-enhanced
scans using the intravenous paramagnetic agent gadolinium
with histological correlation,11 and recent studies have shown
that CE-MRI-detected synovitis is associated with knee pain
(Figure 4).12
Since different tissues are involved in OA and both morpho-
logic and quantitative analyses are needed, a variety of dif-
ferent sequences have been developed for whole-organ
assessment of OA. Selecting the appropriate MR pulse se-
quences to study specific features of OA is essential for suc-
cess. In general, fluid-sensitive fat-suppressed sequences
(eg, T2-weighted, proton-density-weighted, or intermediate-
weighted fast spin-echo sequences) are useful for evaluation
of cartilage, bone marrow, ligaments, menisci, and tendons.13
It is particularly important to use these sequences to assess fo-
cal cartilage defects and BMLs. Gradient-recalled echo (GRE)-
type sequences (eg, 3D-spoiled gradient echo at steady state
[SPGR], double-echo steady state [DESS], and fast low-an-
gle shot [FLASH]) are not suitable for marrow or focal defect
assessment. They are prone to susceptibility artifacts, which
C
Imaging of osteoarthritis Guermazi and others
 OSTEOARTHRITIS: A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE

Figure 4. Visualiza- Knee Score (MOAKS).22 MOAKS is a recent effort to combine

tion of synovitis on the strengths of existing systems, but little information on its
contrast-enhanced
use has been published to date. In addition to these scoring
magnetic resonance
imaging (MRI). systems based on non-enhanced MRI, semiquantitative scor-
Sagittal T1-weighted fat- ing systems for synovitis using contrast-enhanced MRI have
saturated image showing been proposed.12,23 In particular, the system proposed by Guer-
severe synovitis in the
suprapatellar recess (ar- mazi et al enables comprehensive assessment of synovitis
rowheads), at the Hoffa fat in the whole knee joint,12 rather than being restricted to the
pad (small arrow) and es-
pecially posterior to the peripatellar regions.23 These contrast-enhanced MRIbased
posterior cruciate ligament, scoring systems will enable longitudinal assessment of syn-
the most common location
of synovitis in osteoarthrit-
ovitis in future clinical trials.12
ic knees (large arrow). Syn-
ovitis cannot be visualized Recently, MRI-based semiquantitative scoring systems for
with nonenhanced MRI.
hand OA (Oslo Hand OA MRI score [OHOA-MRI]) and hip
hinder accurate interpretation of images.14 GRE-type se- OA (Hip OA MRI Scoring system [HOAMS]) have been pro-
quences also usually require long imaging times, and motion posed.24,25 However, further validation, evaluation of respon-
artifacts can degrade image quality.15 A recent study demon- siveness, and iterative refinement of these new systems are
strated that focal cartilage lesions were more conspicuous needed to assess their utility in clinical trials and epidemiolog-
and larger on the intermediate-weighted fast spin-echo se- ical studies. To the authors knowledge, no semiquantitative
quence with fat suppression compared with the DESS se- scoring systems enabling evaluation of other joints, such as
quence.16 It was also shown that GRE-
type sequences have limited sensitivity A B
to BMLs compared with fast spin-echo
sequences (Figure 5).17 For synovitis,
CE-MRI is preferable to nonCE-MRI,
but if only nonCE-MRI is available, gra-
dient-echo type sequences should again
be avoided because they are prone to
chemical shift artifacts, making accu-
rate assessment difficult.18

On the other hand, GRE-type sequences

do provide high spatial resolution and
excellent contrast of cartilage to sub-
chondral bone, and are well suited for
quantitative measurement of volume Figure 5. Sequence selection for visualizing specific osteoarthritis features.
and thickness.15 MRI is a powerful tool (A) Coronal proton-density-weighted fat-saturated image showing a large bone marrow lesion (BML) in the
central part of the medial femur (ill-defined area of hyperintensity indicated by arrows). A large BML is also
for OA research, but it is also complex depicted in the medial tibial plateau (asterisk). (B) Fast low-angle shot (FLASH) image. Although commonly
and how it is used is largely determined used for cartilage segmentation due to the excellent contrast between cartilage and subchondral bone and
by the goal of the research. Clinicians high resolution acquisition, the FLASH image depicts the femoral BML poorly compared with the proton-
density-weighted image (arrow). The large tibial BML can barely be distinguished on the FLASH image.
planning clinical OA research using MRI-
derived data should seek expert advice from trained and ex- the shoulder, elbow, and ankle, as a whole joint have been
perienced musculoskeletal radiologists on which pulse se- published. A limited number of small studies have been pub-
quences are best suited to their purpose. lished recently involving cartilage repair techniques or novel
imaging methodologies for these joints.26
N Semiquantitative MRI whole-organ scoring
Semiquantitative whole-organ scoring has been applied to N Compositional imaging of cartilage
a multitude of OA studies.7,19 Analyses based on semiquan- Compositional MRI can assess the biochemical properties of
titative scoring have added greatly to our understanding of different joint tissues and is thus very sensitive to early pre-
the pathophysiology and natural history of OA as well as to morphologic changes. The vast majority of studies applying
the clinical implications of structural changes. A short list of compositional MRI have focused on cartilage, although the
semiquantitative scoring systems includes the Whole-ORgan technique can also be used to assess other tissues such as
Magnetic resonance imaging Score (WORMS),7 the Knee Os- the meniscus or ligaments.27 T2 mapping has been used to
teoarthritis Scoring System (KOSS),20 the Boston Leeds Os- describe the molecular composition of hyaline cartilage in the
teoarthritis Knee Score (BLOKS),21 and the MRI OsteoArthritis knee on the basis of collagen structure and hydration.

Imaging of osteoarthritis Guermazi and others MEDICOGRAPHIA, Vol 35, No. 2, 2013 167
OSTEOARTHRITIS: A STORY OF CLOSE
BETWEEN BONE AND CARTILAGE
In healthy cartilage, T2 values increase from deep to super-
ficial cartilage layers.28 It has been shown that T2 values are
related to age and activity levels and that they are associated
with OA severity.29,30 T2* relaxation measures have also been
tested for their ability to depict the collagen matrix. T2* map-
ping was shown to be a reproducible process that can differ-
entiate between OA and non-OA subjects.31
T1rho is also sensitive to the interactions of water with macro-
molecules. It has been shown to correlate with the proteogly-
can concentration in cartilage,32 and is also sensitive to col-
lagen.33 Although T1rho has been shown to have a larger
A B
Figure 6. Biochemical magnetic resonance imaging.
(A) Sagittal intermediate-weighted fat-saturated image depicts a horizontal-oblique tear of the posterior horn of the medial meniscus (arrow). (B) Corresponding baseline
color-coded T1-weighted image showing normal delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) map of femoro-tibial cartilage. (C) At 24 months there is
a marked decrease in the dGEMRIC index in the medial femoral cartilage (coded in red - arrowheads). An incidental partial meniscal maceration is also seen (arrow).
dynamic range than T2,34 it is more complex to implement,
and is limited by radiofrequency power deposition. It has been
reported that T1rho and T2 values show different spatial dis-
tributions and may provide complementary information on car-
tilage degeneration.35
Sodium MRI and the delayed gadolinium-enhanced MRI of
cartilage technique (dGEMRIC) are designed to measure fixed
charge densities in cartilage and, by implication, its proteo-
glycan content (Figure 6).36 These techniques are based on
the premise that mobile ions will distribute themselves in car-
tilage in relation to the concentration of the charged proteo-
glycan molecules; in MRI, the mobile ions are the naturally
abundant sodium, or the negatively charged MRI contrast
agent Gd(DTPA)2 (Magnevist, Berlex, NJ, USA).
In the dGEMRIC technique, Gd(DTPA)2 is injected intravenous-
ly, and images are acquired typically around 90 minutes af-
ter injection. The negative charge on the Gd(DTPA)2 molecule
causes it to disperse into the cartilage in inverse relation to
the negatively charged glycosaminoglycan molecular concen-
tration.37 A recent interventional study evaluating the effect
of weight loss on articular cartilage showed an improvement
in cartilage quality reflected by an increase in the dGEMRIC
168 MEDICOGRAPHIA, Vol 35, No. 2, 2013
R E L AT I O N S H I P
index over 12 months in the medial but not in the lateral tibio-
femoral compartment. This finding supports the notion that
body weight affects disease progression and emphasizes the
role of weight loss in clinical and structural improvement.38
Novel compositional techniques have been reported. Raya et
al studied the feasibility of in vivo diffusion tensor imaging at
7T MRI and demonstrated better discrimination of OA ver-
sus non-OA knees than with T2 mapping.39 Although this tech-
nique shows promise, it will have to be more practical and
widely available for use with standard MRI systems before it
can be applied in broader clinical research settings.
C
N Quantitative cartilage morphometry
Quantitative analysis of knee OA features has been applied
mainly to cartilage morphology, where the three-dimensional
nature of MRI data can be exploited to assess tissue param-
eters such as volume, thickness, or other continuous vari-
ables. The real strength of quantitative measurements is that
they are more objective and less observer-dependent than
semiquantitative scoring methods and that relatively small
changes in cartilage thickness or volume can be detected over
time.40 Correctly segmenting the cartilage requires well-trained
users, working either manually or with segmentation software.
Most investigations have focused on measuring cartilage vol-
ume, but volume has its limitations. Discrimination of patients
with OA from healthy subjects is limited because men in
general, and anybody with large bones, will have larger joint
surfaces and more cartilage volume, so there is a wide over-
lap between groups.41 While this problem can be mostly over-
come by adjusting the analysis for the bone surface area in
each subject, a new analytic strategy called extended ordered
values has been proposed.42 The extended ordered values
approach sorts changes in subregional thickness in the me-
dial and lateral tibial and femoral cartilage plates in ascending
order. This analytic method enables more efficient measure-
ment of changes in cartilage thickness, independently of their
Imaging of osteoarthritis Guermazi and others
 OSTEOARTHRITIS:
anatomical locations, and shows better sensitivity for de-
tecting differences in longitudinal rates of cartilage loss than
anatomical subregions and radiography.42
Ultrasound
Ultrasound is a technique that enables multiplanar and real-
time imaging at a relatively low cost, without radiation expo-
sure. It has the ability to image soft tissue and to detect syn-
ovial pathology without the need for contrast administration.
Limitations of ultrasound are primarily that it is an operator-de-
pendent technique and that the physical properties of sound
hinder its application to deeper articular structures and the
subchondral bone. The ability to detect synovial pathology is
perhaps the major advantage of ultrasound over radiography.
Ultrasound-detected grey-scale synovitis has been validated
against arthroscopy, MRI, and histology in large-joint OA, and
ultrasound has been demonstrated to be more sensitive than
clinical examination in detecting synovial hypertrophy and joint
effusion.43 Additionally, color-coded Doppler signal has been
validated as an indirect measure of histological synovial vas-
cularity in large-joint OA.44 Tissues other than synovium have
also been studied using ultrasound. Saarakkala et al com-
pared knee ultrasonography to arthroscopic grading for de-
tecting degenerative changes in articular cartilage.45,46 The au-
thors concluded that positive findings on ultrasound are strong
indicators of degenerative changes in cartilage, but also stat-
ed that negative findings do not rule out degenerative cartilage
alterations. A study by Kawaguchi et al used ultrasound to
look at medial radial displacement of the meniscus in the
supine and weight-bearing positions and showed that the
medial meniscus was significantly displaced radially by weight
bearing in control knees and in knees with K&L grades 1-3.46
Its use with dynamic and weight-bearing conditions is one
of the inherent strengths of ultrasound and warrants further
exploration.
Computed tomography
CT is a valuable tool for the characterization of OA, particular-
ly when imaging of osseous changes or detailed presurgical
planning is required. Helical multidetector (MD) CT systems
enable acquisition of isotropic voxels and multiplanar recon-
structions in any given plane with quality equal to the original
plane. Cortical bone and soft tissue calcifications are better
depicted than on MRI. CT has an established clinical role in
assessing facet joint OA of the spine.47 Drawbacks are its low
soft-tissue contrast and the relatively high dose of radiation it
delivers. CT arthrography is an alternative method for indirect
visualization of cartilage and other intrinsic joint structures,
especially in the knee joint. CT arthrography may be relevant
especially where access to MRI facilities is limited or when
MRI is contraindicated. Spiral CT arthrography of the knee
and shoulder enables excellent imaging of the articular sur-
face.48 Penetration of contrast medium into the deeper layers
of the cartilage surface indicates an articular-side defect of the
chondral surface. The high spatial resolution and the high at-
Imaging of osteoarthritis Guermazi and others
A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE
tenuation difference between the cartilage and the contrast
medium within the joint make focal morphologic changes con-
spicuous. Limitations of the technique are its insensitivity to
changes of the deep layers of cartilage without surface alter-
ations and its invasive nature.
Nuclear medicine
Scintigraphy uses radiopharmaceuticals to visualize skeletal
metabolism, to contribute to the localization of disease, and
to assess the severity of pathologic changes in OA. 99mTC-hy-
droxymethane diphosphate scintigraphy shows increased
activity during the bone phase in the subchondral region in
nodal hand OA.49 This finding can be observed before the typ-
ical radiographic changes and reflects the osteoblastic activ-
ity of early cartilage loss. A study comparing MRI with scintig-
raphy in patients with chronic knee pain demonstrated good
agreement between MRI-detected subchondral BMLs and
radionuclide uptake, but generally poor agreement between
increased bone uptake and cartilage defects or osteophytes.50
A prospective study showed that a normal bone scan at base-
line was highly predictive of a lack of progression of knee OA
over a 5-year period.51 Two other recent studies showed that
scintigraphy may predict JSN, but no better than baseline ra-
diographic or pain status.52,53
Positron emission tomography (PET) demonstrates metabol-
ic changes in target tissues and can detect foci of inflamma-
tion, infection, and tumors. PET utilizes 2-18F-fluoro-2-deoxy
D-glucose (FDG) and reflects glucose metabolism. A recent
pilot study in knees with medial OA showed increased uptake
in periarticular regions, the intercondylar notch, and also in
areas of subchondral bone marrow corresponding to MRI-de-
tected BMLs.54 A recent animal study showed increased up-
take of FDG after experimentally induced knee OA in rats,
suggesting that PET could be useful for early detection of OA
changes.55 However, whether FDG-PET will have a role in the
assessment of OA in a clinical and research setting remains
to be seen. Limitations of PET include its limited availability,
high radiation exposure, and costs.
Conclusion
Conventional radiography is still the first and most widely used
imaging technique for evaluation of a patient with a known or
suspected diagnosis of OA. In research and clinical trials it is
the only EMA- and FDA-recommended imaging modality for
defining the inclusion criteria and efficacy end points of a clin-
ical trial. However, radiography has its limitations and well-de-
fined MRI-based diagnostic criteria of OA are needed. MRI
plays a crucial role in understanding the natural history of the
disease and in guiding future therapies due to its ability to
image the knee as a whole organ and to directly and three-
dimensionally assess cartilage morphology and composition.
Ultrasound and contrast-enhanced MRI play important sub-
sidiary roles in the diagnosis and follow-up of treatment of OA-
related synovitis. I
MEDICOGRAPHIA, Vol 35, No. 2, 2013 169
OSTEOARTHRITIS: A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE
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Keywords: magnetic resonance imaging, osteoarthritis, radiography, ultrasound

RLE DE L IMAGERIE DANS LARTHROSE : DIAGNOSTIC , PRONOSTIC , ET SUIVI

Larthrose est une maladie articulaire la prvalence leve touchant essentiellement les sujets gs du monde en-
tier. Les dix dernires annes ont reconnu limportance de limagerie dans lvaluation des structures articulaires (car-
tilage, mnisque, moelle osseuse sous-chondrale, synovie) pour le diagnostic, le pronostic et le suivi. La radiographie
conventionnelle est toujours la technique la plus couramment utilise dans lvaluation dun patient pour lequel lar-
throse est connue ou suspecte. Ses limites ont nanmoins t mises en vidence par des tudes rcentes sur lar-
throse du genou utilisant lIRM. La capacit de lIRM reprsenter le genou comme un organe part entire et
valuer la morphologie et la composition du cartilage directement et en trois dimensions joue donc un rle essen-
tiel dans la comprhension de lhistoire naturelle de la maladie et dans la recherche de nouveaux traitements. Lva-
luation des diffrentes caractristiques de larthrose ncessite des squences IRM adquates et la comptence de
radiologues expriments dans la pathologie musculosquelettique est indispensable pour la conception des tudes,
ainsi que pour lacquisition et linterprtation des images. Cet article prsente les rles et limites de la radiographie
conventionnelle et de lIRM dans limagerie de larthrose et aborde galement lutilisation dautres techniques comme
lchographie, la mdecine nuclaire, la tomodensitomtrie et larthro-scanner en pratique clinique et dans la re-
cherche sur larthrose, en insistant plus particulirement sur lvaluation de larthrose du genou au niveau de larti-
culation tibio-fmorale.

Imaging of osteoarthritis Guermazi and others MEDICOGRAPHIA, Vol 35, No. 2, 2013 171

Guidelines for the medical
management of osteoarthritis fo-
cus on controlling pain and im-
proving function and quality of
life while minimizing therapeutic
toxicity Clinicians managing os-
teoarthritis are able to draw upon a
wide spectrum of therapeutic op-
tions, combining nonpharmaco-
logical approaches and pharma-
cological treatments both to relieve
pain and to attempt to delay dis-
ease progression The current
therapeutic options, however, are
neither exclusive nor sufficient.
Camille ROUBILLE, MD
L
Johanne MARTEL-PELLETIER, PhD
Jean-Pierre PELLETIER, MD
Osteoarthritis Research Unit
University of Montreal Hospital
Research Centre
University of Montreal
Montreal, Quebec, CANADA
Address for correspondence:
Professor Jean-Pierre Pelletier,
Osteoarthritis Research Unit,
University of Montreal Hospital
Research Centre (CRCHUM),
Notre-Dame Hospital,
1560 Sherbrooke Street East,
Montreal, Quebec H2L 4M1,
Canada (e-mail: dr@jppelletier.ca)
www.medicographia.com
172 MEDICOGRAPHIA, Vol 35, No. 2, 2013
OSTEOARTHRITIS: A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE
Osteoarthritis treatments:
where do we stand
at the moment?
b y C . R o u b i l l e , J . M a r t e l - Pe l l e t i e r,
a n d J . P. Pe l l e t i e r, C a n a d a
O
steoarthritis is the most common form of arthritis and results in pain
and reduced quality of life. Although a structure-modifying treatment
remains the greatest unmet need in osteoarthritis, several sympto-
matic treatments are available. This article will review the nonpharmacolog-
ical approaches and pharmacological treatments currently available for os-
teoarthritis management, as well as the surgical treatments available for the
condition. At present, a multimodal approach combining nonpharmacologi-
cal and pharmacological treatments is still the best option for the manage-
ment of osteoarthritis, as recommended in the guidelines of Osteoarthritis
Research Society International and the American College of Rheumatology.
Nonpharmacological management mainly relies on patient education, exer-
cise, prevention of injuries, weight loss in overweight patients, and use of or-
thotic devices. Pharmacological symptomatic treatments include a number
of analgesic options such as acetaminophen, nonsteroidal anti-inflammatory
drugs (NSAIDs), opioids, duloxetine, topical NSAIDs, capsaicin, lidocaine patch-
es, intra-articular corticosteroids and hyaluronic acid injections, and slow-
acting drugs including glucosamine and chondroitin sulfate, diacerein, and
avocado soybean unsaponifiables. When the combination of nonpharmaco-
logical and pharmacological approaches becomes unsuccessful at managing
symptoms, surgical treatment may be considered.
Medicographia. 2013;35:172-180 (see French abstract on page 180)
Nonpharmacological management
he combination of patient education, improved muscle strength, and reduced
T body mass index has been reported to be joint protective. Recent guidelines
from the American College of Rheumatology (ACR) strongly recommend weight
loss for overweight patients with knee or hip osteoarthritis, as well as cardiovascu-
lar and/or resistance land-based exercises and aquatic exercise.1 No preference
is made regarding aquatic versus land-based exercise, as the choice will depend
on individual ability. As to date there have been very few high-quality randomized
controlled trials reported in the literature, the ACR conditionally recommends self-
management programs, manual therapy in combination with supervised exercise,
psychosocial interventions, use of thermal agents, walking aids if needed, tai chi,
Chinese acupuncture, and transcutaneous electrical stimulation. For hand os-
teoarthritis, assistive devices, joint protection techniques, thermal modalities, and
trapeziometacarpal joint splints are also conditionally recommended by the ACR
guidelines.1
Osteoarthritis treatments: where do we stand at the moment? Roubille and others
 OSTEOARTHRITIS:
N Patient education
Patient education should form the cornerstone of nonphar-
macological management for osteoarthritis,2,3 and patients
should be involved in the management of their condition as
much as possible.3 Indeed, as with other chronic diseases, pa-
tients should know about their conditions evolution over time
as well as its management and any associated investigations,
and this can be achieved through use of books, regular tele-
phone calls, and education groups. It has been suggested
that education contributes to pain reduction and optimization
of health care resource usage.4
N Exercise programs
Physical activity involving aerobic and/or resistance land-based
exercises and/or aquatic exercises, including local muscle
strengthening and general fitness, is recommended for osteo-
arthritis patients.1 Strengthening exercises, especially for the
quadriceps femoris muscle, may improve muscular balance,
decrease impact loads, and support function, and they have
also been reported to reduce pain and disability in hip5 and
knee osteoarthritis.6 Water-based exercises have been shown
to have short-term effects on pain relief for patients with hip
and/or knee osteoarthritis.7 In addition, contrary to popular be-
lief, runningeven long distancesas part of normal nonpro-
fessional conditioning does not accelerate the development
of osteoarthritis of the knee.8 However, the risk of osteoarthri-
tis development may be different for middle-intensity levels of
running compared with high or competitive levels: moderate
regular running may be safe, whereas professional runners
may have an increased risk for osteoarthritis.9,10
N Prevention of injuries
Prevention of injuries is necessary in contact sports such as
soccer.11 Increased joint traumatisms such as anterior cruci-
ate ligament lesions or meniscal lesions increase the risk of
developing osteoarthritis. Effective treatment such as postop-
erative rehabilitation should decrease this risk.
N Weight loss
Does weight loss reduce osteoarthritis symptoms and pre-
vent overall progression of structural damage? This is a most
important and relevant question in the management of os-
teoarthritis. In obese patients, weight loss and maintenance
SELECTED ABBREVIATIONS AND ACRONYMS
ACR American College of Rheumatology
ASU avocado soybean unsaponifiables
COX cyclooxygenase
NSAID nonsteroidal anti-inflammatory drug
OARSI Osteoarthritis Research Society International
TKA total knee arthroplasty
UKA unicondylar knee arthroplasty
WOMAC Western Ontario and McMaster Universities Arthritis
index
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A STORY OF CLOSE R E L AT I O N S H I P
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of weight at a lower level seems to reduce osteoarthritis-re-
lated pain.12 Weight loss in obese people was reported to im-
prove the content of the macromolecule proteoglycan in the
cartilage, as well as the cartilage thickness in the medial, but
not lateral, compartment of the knee.13 Interestingly, obesity in-
creases the risk of progressive osteoarthritis in neutrally aligned
knees or those in valgus alignment, but not in patients with
varus alignment.14 Thus, overload alone across the joints does
not seem to be sufficient to induce the development of os-
teoarthritis. As obese individuals also have a higher incidence
of osteoarthritis in nonweight-bearing areas, including finger
joints, it has been suggested that factors such as adipokines,
one representative of this family being leptin, could promote
cartilage damage, thus inducing osteoarthritis.15,16 Therefore,
although mechanical factors may be one element favoring the
development of osteoarthritis in obese patients, inflammatory
mediators also appear to be important contributing factors.
Thus, in addition to weight loss, additional treatments may
eventually be required for optimal therapeutic intervention.
N Orthotic devices
Orthotic devices such as special footwear, insoles, knee brac-
ing, and canes are recommended for patients with hip and/or
knee osteoarthritis.2,17 The latest ACR guidelines recommend
medially-directed patellar taping, as well as medially-wedged
insoles for patients with lateral compartment knee osteo-
arthritis, and laterally-wedged subtalar strapped insoles for
those with medial compartment knee osteoarthritis.1 Canes
held in the contralateral hand as a walking aid can reduce pain
in patients with hip and knee osteoarthritis. In knee osteo-
arthritis, use of braces1 and sleeves was shown to have ben-
eficial effects compared with medical treatment alone (aceta-
minophen, nonsteroidal anti-inflammatory drugs [NSAIDs]),
as assessed by the Western Ontario and McMaster Universi-
ties Arthritis index (WOMAC) and function tests.18 Moreover,
braces seem to be more effective than sleeves, and laterally-
wedged insoles may decrease NSAID intake compared with
neutral insoles.18
N Alternative therapies
Acupuncture3 and transcutaneous electrical stimulation17 have
been reported to show some short-term pain relief efficacy,
and they are considered alternative strategies for the man-
agement of osteoarthritis. These strategies are conditionally
recommended by the ACR guidelines for those patients with
knee osteoarthritis who are candidates for total knee arthro-
plasty but are unwilling or unable to undergo surgery because
of comorbidities or concomitant medications contraindicating
such surgery.1
Pharmacological treatment
The prescribing habits of physicians have changed over time.
Because osteoarthritis is a chronic disease and is more com-
mon in people aged over 60 years, safety remains critical.
Guidelines for the medical management of osteoarthritis fo-
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BETWEEN BONE AND CARTILAGE

Treatment type Adverse effect/safety profile

Acetaminophen GI discomfort, bleeding; renal failure; hypertension; hepatotoxicity
NSAIDs; coxibs GI ulcer/bleeding; cardiovascular events; renal events
Oral Opioids Constipation; vomiting; somnolence; increased risk of fracture,
morbidity, and mortality in elderly
Duloxetine Constipation; nausea; hyperhidrosis
Symptomatic
drugs Topical NSAIDs Skin reactions; Gl events
Topical Capsaicin Skin burning sensation; long-term skin desensitization?
Lidocaine patches
Intra-articular corticosteroids Local infection, systemic effects
Injectable
Intra-articular hyaluronic acid Local reactions at the site of injection, swelling, flares of pain
or viscosupplementation
Glucosamine and chondroitin
sulfate
Slow-acting
symptomatic Oral Diacerein Lower GI effects
drugs
Avocado soybean
unsaponifiables

Table I. Adverse effects of different pharmacological options for the treatment of osteoarthritis.
Abbreviations: GI, gastrointestinal; NSAID, nonsteroidal anti-inflammatory drug.

cus on controlling pain and improving function and quality
of life while minimizing therapeutic toxicity (see Table I for an
overview of the adverse effects of the different pharmacolog-
ical treatments available).2,3,17 For hand osteoarthritis, the re-
cent ACR guidelines recommend topical capsaicin, topical
NSAIDs, oral NSAIDs including cyclooxygenase (COX)-2 in-
hibitors, and tramadol.1 They also advise against the use of
opioids or intra-articular treatments for this condition. For knee
and hip osteoarthritis, acetaminophen, oral NSAIDs, topical
NSAIDs (except for hip osteoarthritis), tramadol, and intra-ar-
ticular steroid injections are recommended.1
N Symptomatic treatments
N Oral analgesics
Acetaminophen remains the first-line therapeutic agent for
mild-to-moderate pain2,3,17 because of its low cost and its ef-
ficacy and safety profile for doses not exceeding 4 g per day
(although a maximum of 3 g is more advisable, in line with US
Food and Drug Administration recommendations). If found to
be successful at alleviating pain, it is recommended that acet-
aminophen be the preferred long-term oral analgesic.2 It has
been reported that acetaminophen is less effective at reliev-
ing osteoarthritis pain than NSAIDs19 but more effective than
placebo.20 However, this result was not confirmed by a study
using WOMAC and the Lequesne index to assess efficacy.20
The use of analgesics in osteoarthritis should take into account
the clinical context, however. Significant adverse effects have
been reported with acetaminophen, including gastric ulcera-
tions and bleeding, increased risk of mild loss of renal function
with long-term consumption, and hypertension with doses of
up to 3 g per day.21-23 Furthermore, even at therapeutic dos-
es, acetaminophen can cause asymptomatic elevation of liver
enzymes in healthy people.24 The implications of this remain
unclear, but it is recommended that acetaminophen should
not be used in patients with existing liver dysfunction or re-
lated risk factors. On the basis of the aforementioned infor-
mation, it is recommended that the lowest effective dose of
acetaminophen be used for pain relief.
NSAIDs are generally recommended for patients who are un-
responsive to appropriate dosages of acetaminophen. These
should be prescribed at the lowest dose and for the shortest
possible duration,17 and preferentially for inflammatory flares.
According to the new ACR guidelines,1 NSAIDs should be
used for the initial management of hand, hip, and knee os-
teoarthritis, as with acetaminophen and tramadol. Moreover,
for patients aged over 75 years, rather than prescribing oral
NSAIDs, guidelines recommend the use of topical NSAIDs,
duloxetine, tramadol, or intra-articular hyaluronan injections.
In patients suffering from upper gastrointestinal ulcers with-
out any gastrointestinal bleeding in the prior year, for cases
where the physician chooses to prescribe an NSAID, the ACR
and Osteoarthritis Research Society International (OARSI)
guidelines recommend the use of either a COX-2 inhibitor
rather than a nonselective NSAID, or a nonselective NSAID
combined with a proton-pump inhibitor.1,17 For patients with
reports of gastrointestinal bleeding within the past year, the
use of a COX-2 inhibitor in association with a proton-pump
inhibitor is recommended.1 Although NSAIDs are known to
be superior to acetaminophen for pain relief,19 their use is lim-
ited by a number of adverse effects, including gastrointestinal,
renal, and cardiovascular adverse effects, which increase with

174 MEDICOGRAPHIA, Vol 35, No. 2, 2013 Osteoarthritis treatments: where do we stand at the moment? Roubille and others
 OSTEOARTHRITIS:
age.25-27 The risk level varies according to the drug and dosage.
COX-2 inhibitors were shown to be as effective as convention-
al NSAIDs for pain relief, with fewer gastrointestinal compli-
cations,28 but with a potential cardiovascular risk27which is
also shared by conventional NSAIDs. Physicians should there-
fore take into account their patients comorbidities and as-
sess their individual global risk before prescribing NSAIDs.
In recent years, opioids have become a widely prescribed
class of drugs, especially for osteoarthritic patients who either
have contraindications or an intolerance to NSAIDs or who
have failed to respond to both acetaminophen and NSAID
treatment.2,17 Opioids are recommended by the new ACR
guidelines for patients with symptomatic knee osteoarthritis
who have not had an adequate response to nonpharmaco-
logical or pharmacological modalities and are either unwilling
to undergo or are not candidates for total joint arthroplasty.1
However, opioids are not recommended for the management
of hand osteoarthritisrelated pain.1 It is common to start with
a weak opioid such as codeine or tramadol, often in combi-
nation with acetaminophen, and if ineffective or not tolerated,
to use a stronger opioid like hydrocodone, oxycodone, mor-
phine, or transdermal fentanyl. However, adverse events are
frequent and significant, and include sedation, constipation,
urinary retention, nausea and vomiting, respiratory depression,
and confusion. Impaired coordination and judgment can lead
to falls, particularly in older adults who are more susceptible
to opioid-related effects as a result of renal insufficiency and/or
lower lean body mass. In elderly people, opioids may cause
severe injuries from falls, such as hip fractures, or even death.
Fracture risk appears to be greater with opioids than with
NSAIDs in older people, and the risk increases with higher opi-
oid dosage, especially during the first 2 weeks after initiating
short-term opioid therapy.29 Moreover, it seems that opioids
do not improve patient functioning30 or quality of life.
Patients with osteoarthritis have been shown to have higher
mortality than the general population, particularly because of
cardiovascular events. This appears to be strongly related to
walking disability and reduced physical activity.31 Thus, im-
mobility resulting from osteoarthritis may shorten lifespan. One
may wonder if opioids, by reducing patient mobility, may re-
duce life expectancy by increasing cardiovascular risk. How-
ever, this relationship has not yet been established.31 The use
of opioids in a chronic and painful disease such as osteoarthri-
tis is still controversial for many reasons. It is recommended
that opioid treatment be started at a low dose and gradually
adjusted upwards, taking into account renal function, age, and
other relevant risk factors. Long-term opioid use should be
avoided or at least regularly reevaluated.32 The benefits of us-
ing opioids should be weighed as judiciously as possible.
For the past few years, antidepressants have been used in
chronic pain management because of their reported analgesic
action, which is independent of their antidepressive effect. In
recent years, the chronic pain often observed in osteoarthritis
Osteoarthritis treatments: where do we stand at the moment? Roubille and others
A STORY OF CLOSE R E L AT I O N S H I P
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has been shown to involve centrally-mediated pain pathway
dysfunction, which has led to the study of drugs that have a
centrally-mediated action. Duloxetine is a selective serotonin
and norepinephrine reuptake inhibitor with central nervous sys-
tem activity that is already used in three chronic pain condi-
tions: diabetic peripheral neuropathic pain, fibromyalgia, and
chronic low back pain. Recently, duloxetine was found to im-
prove pain as well as function in knee osteoarthritis, as eval-
uated by clinically relevant outcomes in two 13-week trials.33
The drugs effect is related to a direct analgesic effect, inde-
pendent of improvement of depression and anxiety. The main
adverse events reported included nausea, constipation, and
hyperhidrosis. Duloxetine is recommended by the ACR guide-
lines as an alternative treatment for patients with symptomatic
knee osteoarthritis who have failed to respond to both phar-
macological and nonpharmacological options.1 Controlled
trials to compare duloxetine with other interventions in os-
teoarthritis and to evaluate its efficacy in combination with
other therapies may be useful to potentially enhance treat-
ment options.
N Topical treatments
Adjuvant topical therapies are interesting treatments that can
be used to decrease the consumption of analgesics. Topical
NSAIDs, such as diclofenac and ketoprofen, seem to be as
effective as oral NSAIDs34,35 but with a lower risk of systemic
exposure and gastrointestinal complications. Their principal
reported adverse effect is local skin reactions. They are rec-
ommended as alternative or adjuvant therapy,17 although ACR
guidelines recommend them for the initial management of knee
osteoarthritis and prefer them to oral NSAIDs for patients old-
er than 75 years of age.1
Capsaicin, the active principle ingredient of hot chili peppers,
can cause depletion of substance P from sensory nerve end-
ings and reduce or abolish the transmission of painful stimuli.
However, its effectiveness and safety in pain relief remains con-
troversial.36 A burning sensation is the most common adverse
effect, particularly during the first week of application.36 It is
still unclear if long-term capsaicin treatment can cause per-
sistent desensitization of the skin that may not be totally re-
versible. Capsaicin is recommended by guidelines for the
initial management of hand osteoarthritis, but not knee os-
teoarthritis.1,2
Lidocaine patches, which are approved for postherpetic neu-
ralgia, have also been reported to reduce neuropathic pain as-
sociated with moderate to severe osteoarthritis of the knee,
without any reported treatment-related adverse effects.37
N Injectable therapies
Intra-articular injection of a long-acting corticosteroid is rec-
ommended for relief of pain from osteoarthritic flares, especial-
ly if accompanied by effusion and when NSAIDs are ineffec-
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tive.2,17 The ACR guidelines recommend intra-articular cortico-
steroid injections for the initial management of knee and hip
osteoarthritis.1 Short-term pain reduction in knee osteoarthri-
tis occurs after 2 to 3 weeks, but has no significant effect on
function. The Cochrane Database of Systematic Reviews re-
ported that after 4 weeks, there was no effect on pain, phys-
ical function, or stiffness.38 However, repeated injections of in-
tra-articular corticosteroids every 3 months for 2 years showed
pain relief efficacy after 1 year but not after 2 years.38 The long-
term safety of repeated intra-articular steroid injections in
symptomatic knee osteoarthritis has been demonstrated, with
improvement of osteoarthritis symptoms for up to 2 years.39
Comparisons between corticosteroids have revealed that tri-
amcinolone hexacetonide is superior to beta-methasone.38
Viscosupplementation could have a significant benefit for knee
osteoarthritis, despite some reported local acute reactions
such as transient pain and swelling at the injection site.40 Vis-
cosupplementation is recommended by guidelines for knee
osteoarthritis,2 and compared with intra-articular corticos-
teroids, it shows delayed but prolonged efficacy.40 The OARSI
guidelines consider that intra-articular hyaluronate injections
may be useful for the treatment of knee osteoarthritis and have
a beneficial symptomatic effect.17 Moreover, the ACR guide-
lines conditionally recommend viscosupplementation for pa-
tients who have had an inadequate response to initial ther-
apy.1 By contrast, a single injection of hyaluronic acid in hip
osteoarthritis seems to be no more effective than placebo.41
More data are needed on the structural effect of viscosup-
plementation.
N Symptomatic slow-acting drugs for osteoarthritis
Disease-modifying agents that not only reduce joint pain but
also slow progression of the disease are of interest for allevia-
tion of the manifestations of osteoarthritis over the long term.
For the past 10 years, chondroitin sulfate and glucosamine
sulfate have been widely prescribed and used by osteoarthri-
tis patients for symptom relief. They are safe, and have pos-
sible structure-modifying effects.17 Glucosamine is a naturally
occurring amino monosaccharide, and chondroitin sulfate be-
longs to the group of glycosaminoglycans and is a major com-
ponent of the articular cartilage.
In osteoarthritis clinical trials, the symptomatic effect size of
glucosamine varies and is considered controversial. Howev-
er, the results of studies have greatly depended on the differ-
ent products used, the study population, and study design and
quality.42-45 Formulations of glucosamine that result in lower
plasma concentrations and potential low bioavailability, as well
as study populations with a low baseline level of pain, may
have contributed to the controversy.45 Glucosamine sulfate
and chondroitin sulfate have been approved as drugs for the
treatment of osteoarthritis in Europe, but not in North America,
where they are regulated not as drugs but as nutraceuticals.
As a consequence, substantial variation in their content is pos-
176 MEDICOGRAPHIA, Vol 35, No. 2, 2013 Osteoarthritis treatments: where do we stand at the moment? Roubille and others
sible.43 This explains why in the latest ACR guidelines, these
agents were not recommended for treatment of osteoarthritis.1
Glucosamine sulfate was found to be effective as an osteo-
arthritic pain relief treatment and for improvement of func-
tion.42 Recommendations using the Grading of Recommen-
dations Assessment, Development and Evaluation (GRADE)
system concluded that glucosamine sulfate demonstrated
pain reduction and improvement in physical function with very
low toxicity and with moderate-to-highquality evidence.44 The
latest OARSI guidelines recommend the use of glucosamine
sulfate and chondroitin sulfate for osteoarthritis treatment, as
they demonstrated pain relief with a moderate to large effect
size (0.58 and 0.75, respectively).3 When a purified preparation
of glucosamine sulfate is used, it appears to be safein partic-
ular, with no induction of glucose intolerance in healthy adults.46
The protective effect of glucosamine sulfate on structural pro-
gression of knee osteoarthritis was reported in two studies ex-
ploring the radiological progression of knee osteoarthritis af-
ter daily administration of glucosamine sulfate for 3 years.47-51
Chondroitin sulfate has been shown to improve knee joint
swelling and delay radiographic progression in patients with
knee osteoarthritis evaluated by x-rays,51,52 and more recent-
ly a magnetic resonance imaging study reported that chon-
droitin decreases cartilage loss and the progression of bone
marrow lesions.53 A recent post-hoc analysis of an osteoarthri-
tis clinical trial reported a trend favoring chondroitin sulfate
versus placebo for delayed occurrence of total knee replace-
ment at 4 years.54 However, the structural effects of glucos-
amine and chondroitin sulfate remain under debate, and these
treatments are not registered as structure-modifying agents.
Diacerein, an inhibitor of interleukin-1, is a slow-acting agent
with pain-relieving symptomatic effects in patients with knee
osteoarthritis,55 and which also reduces the progression of
hip osteoarthritis.56,57 Diacerein provides sustained pain relief
for several weeks after discontinuation, suggesting a long car-
ry-over effect,55 and an analgesic-sparing effect. Moreover,
the effect of diacerein has been found to be additive to that
of NSAIDs. Interestingly, it does not inhibit cyclooxygenase
or prostaglandin E2. Loose stools and diarrhea are the most
frequent adverse events. It is safer for the upper gastrointesti-
nal system than NSAIDs55 and has a good overall safety pro-
file, and it is therefore an alternative option to NSAIDs for the
treatment of osteoarthritis.
Avocado soybean unsaponifiables (ASU) are fractions of un-
saponifiable avocado and soybean oils. The symptomatic
efficacy of ASU has been assessed in patients with hip and
knee osteoarthritis.58 ASU seems to be effective at pain reduc-
tion and has shown some beneficial effects on clinical symp-
toms of knee and hip osteoarthritis, with a carry-over effect
that persists after treatment discontinuation.59 A recent study
reported that in hip osteoarthritis, a 3-year treatment with ASU
reduced the percentage of joint space width progressors, in-
dicating a potential structure-modifying effect.60
 OSTEOARTHRITIS: A STORY OF CLOSE R E L AT I O N S H I P
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arthroplasty [UKA] and total joint replacement).61 Arthroscopy

is a minimally invasive surgical technique used for chondral
surface debridement, lavage of joints, removal of torn menis-
Non- Pharmacological
pharmacological treatment cal fragments, and repair of menisci and cruciate ligament in-
treatment juries. It remains controversial because it usually provides a
Oral
Education Acetaminophen
Exercises
short-term benefit and does not seem to delay progression
NSAIDs and COX-2
Prevention of injuries inhibitors to joint replacement.62 Arthroscopy should be of interest for
Weight loss SYSADOA selected patients such as those with symptomatic meniscal
Orthotic devices Duloxetine
Opioids
Topical
Surgery NSAIDs
Arthroscopic Capsaicin
lavage
Lidocain patches
Cartilage repair Surgery
Intra-articular
Osteotomy
Corticosteroids Intra-articular
Arthroplasty
Hyaluronic acid Corticosteroids,
hyaluronic acid

Oral
Acetaminophen, NSAIDs,
Figure 1. Multimodal management of osteoarthritis. SYSADOA, opioids, duloxetine
Abbreviations: COX, cyclooxygenase; NSAID, nonsteroidal anti-inflammatory
drug; SYSADOA, symptomatic slow-acting drugs for osteoarthritis.
Topical
NSAIDs, capsaicin, lidocaine patches
Surgical treatment
Initial treatment of osteoarthritis should be conservative. How-
Nonpharmacological
ever, when pain and loss of function persist after the use of Education, exercise, prevention of injuries,
appropriate nonpharmacological and pharmacological treat- weight loss, orthotic devices
ments, surgery should be considered to reduce disease mor-
bidity. Surgical options for knee osteoarthritis are arthroscopy,
including lavage and debridement (the efficacy of which is Figure 2. Multimodal management of osteoarthritis: initiate with non-
controversial), cartilage repair surgery (bone marrow stimulat- pharmacological approaches (blue), follow with pharmacological
treatments (pink), and if ineffective, culminate in surgery (green).
ing techniques, transplantation of osteochondral grafts), osteo- Abbreviations: NSAID, nonsteroidal anti-inflammatory drug;
tomy with axis correction, and arthroplasty (unicondylar knee SYSADOA, symptomatic slow-acting drugs for osteoarthritis.

Treatment type Component

Nonpharmacological Education; exercise; injury prevention; weight loss; orthotic devices

Acetaminophen Table II.

Multimodal
NSAIDs and COX-2 inhibitors approach to
Oral
Opioids osteoarthritis
management
Duloxetine involving
Pharmacological Symptomatic Topical NSAIDs nonpharma-
drugs cological,
Topical Capsaicin pharmaco-
logical, and
Lidocaine patches surgical
Intra-articular corticosteroids treatment
Injectable options.
Intra-articular hyaluronic acid or Abbreviations:
viscosupplementation COX, cyclooxy-
genase; NSAID,
Glucosamine and chondroitin sulfate nonsteroidal
Slow-acting
anti-inflammato-
symptomatic Oral Diacerein ry drug; THR,
drugs total hip replace-
Avocado soybean unsaponifiables
ment; TKR, total
knee replace-
Surgical Arthroscopic lavage and debridement; cartilage repair; osteotomy with axis
ment; UKA, uni-
correction; arthroplasty (UKA, TKR, THR) condylar knee
arthroplasty.

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OARSI effect size*

Treatment type Intervention (95% CI)

Education 0.06 (0.03, 0.10)

Exercise
Strengthening for knee 0.32 (0.23, 0.42)
Aerobic for knee 0.52 (0.34, 0.70)
Nonpharmacological Exercises for hip 0.38 (0.08, 0.68)
In water for hip and knee 0.19 (0.04, 0.35)
Prevention of injuries
Weight loss 0.20 (0.00, 0.39)
Orthotic devices

Acetaminophen 0.14 (0.05, 0.22)

NSAIDs and COX-2 inhibitors 0.29 (0.22, 0.35)
Oral
Opioids 0.78 (0.59, 0.98)
Duloxetine
Topical NSAIDs 0.44 (0.27, 0.62)
Pharmacological Symptomatic
Topical Capsaicin
drugs
Lidocaine patches
Intra-articular corticosteroids 0.58 (0.34, 0.75)
Injectable Intra-articular hyaluronic acid or 0.60 (0.37, 0.83)
viscosupplementation
Glucosamine sulfate 0.58 (0.30, 0.87)
Symptomatic Glucosamine hydrochloride 0.02 (0.15, 0.11)
slow-acting
osteoarthritis Oral Chondroitin sulfate 0.75 (0.50, 1.01)
drugs Diacerein 0.24 (0.08, 0.39)
Avocado soybean unsaponifiables 0.38 (0.01, 0.76)

Arthroscopic lavage and debridement 0.21 (0.12, 0.54)

Surgical Osteotomy with axis correction
Arthroplasty (UKA, TKR, THR)

*An effect size of 0.2 is considered small, while 0.5 is considered moderate, and >0.8 is considered large.

Table III. Multimodal management of osteoarthritis and effect size of the different components of the 2010 guidelines from Osteoarthritis
Research Society International (OARSI).
Abbreviations: CI, confidence interval; COX, cyclooxygenase; NSAID, nonsteroidal anti-inflammatory drug; THR, total hip replacement; TKR, total knee replacement;
UKA, unicondylar knee arthroplasty.
Based on data from reference 3: Zhang et al. Osteoarthritis Cartilage. 2010;18:476-499. 2010, Osteoarthritis Research Society International.

tears, in whom it can be used to remove the degenerative
fragments and alleviate mechanical symptoms. Bone mar-
row stimulation through the use of a microfracture technique
induces subchondral injury and bleeding that may promote
chondrogenesis by mesenchymal stem cells in the defective
area. Its efficacy is uncertain, however, because of variability
in the volume of cartilage repair that has been achieved, as
well as possible functional deterioration.62
Patients with unicompartmental osteoarthritis of the knee can
be treated with a correction osteotomy17 or unicondylar or to-
tal knee arthroplasty (TKA). Osteotomy can be considered
when knee osteoarthritis is associated with valgus or varus
deformation. It transfers load-bearing from the pathological
compartment of the knee to the normal compartment in or-
der to reduce pain and delay joint replacement. Nevertheless,
its longevity is limited, and conversion to total knee replace-
ment often occurs within the following few years. UKA seems
to be as safe and effective for pain relief and functional im-
provement as TKA, as well as high tibial osteotomy in patients
with unicompartmental knee osteoarthritis.63 Long-term sur-
vival rates with UKA are variable but are reported to be around
90% at 10 years, which is less than for TKA (up to 98% at 15
years), except in younger patients.61 TKA remains a success-

178 MEDICOGRAPHIA, Vol 35, No. 2, 2013 Osteoarthritis treatments: where do we stand at the moment? Roubille and others
 OSTEOARTHRITIS:
ful treatment for end-stage symptomatic knee osteoarthritis,
especially in elderly patients. The main complications are per-
sistent postoperative pain (especially in the femoropatellar
compartment), infections, and stiffness of the knee. In order
to improve outcomes with TKA, computer-assisted naviga-
tion and minimally invasive techniques are being developed.
The choice of surgical treatment may be based on level of pain
and physical function, disease stage, patient age, and comor-
bidities. No specific cut-off point defining the requirement for
joint replacement currently exists.64 However, the aim of a
surgical intervention for osteoarthritis such as joint replace-
ment should be to restore patient mobility and give the pa-
tient enough capacity to perform the level of activity required
to help prevent cardiovascular diseases.
References
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Osteoarthritis treatments: where do we stand at the moment? Roubille and others
A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE
Conclusion
Clinicians managing osteoarthritis are able to draw upon a
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Keywords: analgesic; chondroitin sulfate; exercise; glucosamine sulfate; guideline; intra-articular; osteoarthritis; weight loss;
surgery

TRAITEMENTS DE LARTHROSE : O EN SOMMES - NOUS ACTUELLEMENT ?

Larthrose, la forme la plus courante des pathologies articulaires, entrane douleur et diminution de la qualit de vie.
Actuellement, pour cette maladie, plusieurs mdicaments symptomatiques sont commercialiss. Cependant, il nexiste
ce jour aucun traitement prvenant la dtrioration articulaire. Dans cet article seront dcrits les traitements non phar-
macologiques et pharmacologiques disponibles dans la prise en charge de larthrose, ainsi que les traitements chi-
rurgicaux possibles. Les recommandations actuelles de lOsteoarthritis Research Society International et de lAmerican
College of Rheumatology suggrent une approche multidimensionnelle, associant des traitements non pharmaco-
logiques et pharmacologiques. La prise en charge non pharmacologique de larthrose repose essentiellement sur
lducation du patient, lexercice physique, la prvention des blessures, la perte de poids lorsquelle est ncessaire
et lutilisation dorthses. Les traitements pharmacologiques axs sur la rduction des symptmes comprennent les
analgsiques tels que lactaminophne, les anti-inflammatoires non strodiens (AINS), les opiodes, la duloxtine,
les AINS locaux, la capsacine, les patchs de lidocane, les injections intra-articulaires de corticodes et dacide hya-
luronique, et les mdicaments daction lente comme la glucosamine et la chondrotine sulfate, la diacerhine et les
insaponifiables davocat et de soja. Le traitement chirurgical est envisag lorsque les approches non pharmacolo-
giques et pharmacologiques visant rduire les symptmes ont chou.

180 MEDICOGRAPHIA, Vol 35, No. 2, 2013 Osteoarthritis treatments: where do we stand at the moment? Roubille and others

Rates of total knee replace-
ment (TKR) are increasing world-
wide, and in 2010, more than
600 000 procedures were carried
out in the US alone, with rates
tripling over the last decade in
those aged between 45 and 64.
At over $20 000 per procedure, the
annual cost of TKR in the US now
exceeds $13 billion The reasons
for this increase are most certainly
multifactorial. Population growth,
the increasing number of elderly
people, and the increase in aver-
age body mass index (BMI) are, no
doubt, important factors.
O
L. Stefan LOHMANDER, MD, PhD
Department of Orthopedics
Clinical Sciences Lund
Lund University, SWEDEN
Research Unit for Musculoskeletal
Function and Physiotherapy
Department of Orthopedics
and Traumatology
University of Southern Denmark
DENMARK
O counts for a huge burden of pain, functional limitations, loss of productiv-
Address for correspondence:
Professor L. Stefan Lohmander,
Department of Orthopedics, Lund
University Hospital, 221 85 Lund,
Sweden
(e-mail: stefan.lohmander@med.lu.se)
www.medicographia.com
Knee replacement for osteoarthritis: facts, hopes, and fears Lohmander
OSTEOARTHRITIS: A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE
Knee replacement
for osteoarthritis: facts,
hopes, and fears
b y L . S . Lo h m a n d e r,
Sweden and Denmark
steoarthritis (OA) affects hundreds of millions of people worldwide and
is responsible for a huge burden of pain, functional limitations, and
loss of quality-adjusted life expectancy. OA of the knee accounts for
more than 90% of total knee replacements (TKR). By 2030, the incidence of
TKR in the US is expected to increase by more than 6-fold. Pain and difficulty
walking limiting participation in daily activities are the primary reasons for un-
dergoing TKR. However, among patients with disabling OA, only a minority are
willing to consider TKR. Reduced willingness to undergo TKR is associated
with increasing age, being black (in the US), overestimation of the pain and
disability needed to warrant TKR, and rejection of the medicalization of OA.
The perception of the benefits of TKR is less positive among women and those
of lower socioeconomic status. TKR is one of the most cost-effective medical
interventions. Data from joint registries show that the 10-year reoperation rate
for TKR is less than 5%. However, between 10% and 30% of patients under-
going TKR report little or no improvement following surgery, or are not satis-
fied. Patients expectations of joint replacement are relief of pain and improved
mobility. Following TKR, the expectations regarding pain relief, walking abil-
ity, and the ability to perform daily activities are fulfilled to a greater extent
than the expectations of being able to perform more physically demanding ac-
tivities. To ensure optimal patient satisfaction, health professionals should
provide sufficient information so that patients have realistic expectations of
the results of TKR.
Medicographia. 2013;35:181-188 (see French abstract on page 188)
steoarthritis (OA) affects hundreds of millions of people worldwide and ac-
ity, disability, and loss of quality-adjusted life expectancy.1,2 Any estimate of
the burden of OA is strongly dependent on the criteria used, and the population
and age group studied. The most recent estimates of the World Health Organization
(WHO) Global Burden of Disease Study 2010 reported that OA of the knee and hip
is now ranked as the 11th leading cause of years lived with disability (YLD [preva-
lence of a condition multiplied by the disability weight associated with that condition]),
up from the 15th position in 1990. There was an estimated 64% increase in the glob-
al burden of OA-related YLD between the years 1990 and 2010. OA of the knee is
responsible for four-fifths of the OA-related YLDs of the lower extremities. In the US,
it is estimated that the direct and indirect costs of OA exceed US $100 billion per
year.3-5 Excess mortality is observed in patients with OA and this is related to increas-
MEDICOGRAPHIA, Vol 35, No. 2, 2013 181
OSTEOARTHRITIS: A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE
ing functional impairment in those patients.6 OA most com-
monly affects the knees, hips, and hands, but may affect oth-
er joints as well, such as the shoulders, elbows, ankles, feet,
and spine. The prevalence rises steeply between the ages of
50 and 60 for both women and men, so that the majority of
patients with symptomatic OA are aged between 60 and 80
years. However, OA also occurs in younger and middle-aged
patients. In fact, effective treatment of OA represents a partic-
ularly difficult challenge in patients aged between 30 and 60
years.
OA of the knee represents a major share of the OA disease
burden, and OA is by far the most common reason for total
knee replacement (TKR), usually accounting for more than
90% of knee replacement procedures. The incidence of TKR
for OA is rising steeply, and should continue to rise dramat-
ically, with a more than 6-fold increase expected by 2030 in
the US.7 The following discussion will focus on knee replace-
ments for OA, but will also, where appropriate, use evidence
gathered from the study of hip replacement for OA.
Risk factors for knee OA
OA of the knee shares the same general risk factors as OA
of the other joints in that each patient and each joint carries
its own mix of genetic and environmental factors responsible
for the development of OA. For the knee, individual genetic
variability is thought to account for about 40% of the risk, with
environmental factors accounting for the remaining 60%. Ge-
netic variability may, for example, be expressed as individual
differences in the quality of the cartilage matrix, reactivity of
inflammation pathways, growth and repair pathways, and joint
shape. Environmental risks are mostly biomechanical, affect-
ing the dynamic loading of the joints and increasing stress on
joint tissues. This in turn will result in the activation of inflam-
mation and tissue degradation. Leading examples of such en-
vironmental joint stressors are overweight and obesity, joint
injury, and occupational overload. Genetically determined vari-
ations in joint shape may also influence the risk of OA by in-
creasing joint stress.
Epidemiology of knee OA
As already stated, the disease burden of OA is enormous. It
is the most common form of progressive joint disease, and
affects 50 million adults in the US and Europe,1,8 with OA of
the knee representing a major share of this burden. In the
US, knee OA accounts for more than 10 million quality-ad-
SELECTED ABBREVIATIONS AND ACRONYMS
BMI body mass index
NSAID nonsteroidal anti-inflammatory drug
OA osteoarthritis
TKR total knee replacement
YLD year lived with disability
182 MEDICOGRAPHIA, Vol 35, No. 2, 2013
Few
Surgery
Some
Drugs,
walking aids
All
Information, exercise,
weight loss, self-management
Figure 1. A stepwise approach to the management of osteoarthritic
patients.
justed years of life lost, and almost 1 million hospital admis-
sions per year.2,9,10 Although knee OA is usually perceived as
a disease of the elderly, the mean age at diagnosis is actually
56 years.11 The prevalence of knee OA is rising due to the ag-
ing of the population and increasing rates of joint injury and,
most importantly, obesity.
Management options for knee OA
A wide range of treatments are used for knee OA, including
nonpharmacological, pharmacological, and surgical approach-
es.12-14 OA management strategies are determined by disease
severity, patient preferences, local resources, and established
treatment modalities.
A stepwise approach to the management of osteoarthritis is
widely recommended, starting with patient empowerment and
self-management, and, if these simple approaches are un-
successful, the addition of specific medical or surgical inter-
ventions (Figure 1). With the exception of knee replacement,
the effect size for most therapeutic interventions in knee OA
is only small to moderate.
Basic management of osteoarthritis includes education, ex-
ercise, and weight loss (for overweight people), which can be
complemented as needed by simple analgesics, and, for hand
and knee joints, topical nonsteroidal anti-inflammatory drugs
(NSAIDs). Additional studies are needed to tailor the different
programs to different patients. Common sense suggests that
a combination of treatments benefits most patients.
Oral NSAIDs and paracetamol (acetaminophen) are often used
by patients with OA. However, gastrointestinal, renal, and car-
diovascular side effects are of particular concern with NSAIDs,
since many patients with OA are elderly and have comorbidi-
ties, and thus are at increased risk of some or all of these side
effects. These concerns add complexity to the task of pre-
Knee replacement for osteoarthritis: facts, hopes, and fears Lohmander
 OSTEOARTHRITIS: A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE

scribing pain relievers for patients with OA. The utility of opi-
oids for OA is limited by their side effects. Corticosteroid in-
jections are frequently used, but their benefit is short-lived (1
to 4 weeks). In addition to these treatments, patients with knee
OA use a wide range of alternative therapies.
The surgical management of knee OA commonly includes
arthroscopic surgery of the knee upon suspicion of a menis-
cus tear or cartilage derangement amenable to surgical treat-
Practice variations in the use of knee replacement
and future projections for TKR use
Joint replacement for OA of the knee may be the only inter-
vention with a large effect size, but it is only appropriate for
patients with advanced disease or substantial symptoms that
do not respond to other treatments. This group is but a minor-
ity of all those with knee OA, but still represents a very sub-
stantial number of patients. Rates of TKR are increasing world-
wide, and in 2010, more than 600 000 procedures were carried

14 000 A 180 B
OA 160 Females
12 000
RA Males
Posttraumatic 140
10 000
Yearly incidence of knee
arthroplasty/100 000
120

8000
Number

100

6000 80

60
4000
40
2000
20

0 0
1975 1980 1985 1990 1995 2000 2005 2010 1975 1980 1985 1990 1995 2000 2005 2010
Year of operation Year of operation

Figure 2. (A) Annual number of knee replacements in Sweden for osteoarthritis (OA), rheumatoid arthritis (RA), and posttraumatic os-
teoarthritis between the years 1975 and 2010. (B) Annual incidence of knee replacements (all replacements) for men and women.
Reproduced with permission from reference 24: Annual report 2011. www.knee.nko.se. 2011, Swedish Knee Arthroplasty Register.

ment. However, high-quality trials comparing arthroscopic sur-
gical debridement (including meniscus resection) with sham
surgery, medical care as usual, or exercise programs found no
difference between the groups compared,15-18 thereby show-
ing that arthroscopic surgery is of no added benefit for these
patients. Over the age of 35, meniscus lesions are often part
of the early stages of the osteoarthritic process, and the di-
agnosis of a meniscus tear by magnetic resonance imaging
(MRI) of the osteoarthritic knee does not correlate with the
presence of symptoms.19
Valgus osteotomy of the tibia can provide long-lasting pain
relief and functional improvement in physically active pa-
tients of less than 60 years of age in whom OA is mainly lim-
ited to the medial knee compartment. If and when needed,
the osteotomy can later be converted to a knee replacement.
In a large national Swedish series of about 3000 patients who
had undergone tibial osteotomy for knee OA at a mean age of
52 years, the 10-year conversion rate to TKR was 30%.20
This suggests that osteotomy should remain a viable option for
patients in this group, thereby delaying or obviating the need
for knee replacement by more than 10 years in most cases.
out in the US alone, with rates tripling over the last decade in
those aged between 45 and 64.9,21 At over $20 000 per pro-
cedure, the annual cost of TKR in the US now exceeds $13
billion.5,22,23
National knee replacement registry data from the Scandina-
vian countries, UK, and Australia also confirm the continuous
and rapid increase in the incidence of knee replacement for
OA. For example, results from the Swedish Knee Arthroplas-
ty Register show that the annual rate of primary TKR for OA in
Sweden doubled between 2000 and 2010 (Figure 2), while
the annual rate of TKR in those younger than 55 increased
5-fold.24,25 The dramatic increase seen in younger patients may
in part reflect a change in surgical practice from the use of os-
teotomy and unicompartmental knee replacement to TKR
in younger patients.25
The mean age for TKR has changed over time, and in Swe-
den it now shows a decreasing trend, being about 69 years
for both women and men (Figure 3, page 184).24 Reflecting
the current routine widespread use of TKR as a procedure to
treat severe knee OA, 1 in 14 elderly women in Sweden has

Knee replacement for osteoarthritis: facts, hopes, and fears Lohmander MEDICOGRAPHIA, Vol 35, No. 2, 2013 183
OSTEOARTHRITIS: A STORY OF CLOSE
BETWEEN BONE AND CARTILAGE
74 A 110
Females
72
Males
70
Mean age
68
66
64
62
60
1975 1980 1985 1990 1995 2000
Year of operation
Figure 3. (A) Temporal shifts in the mean age at primary total knee replacement surgery for women and men in Sweden between 1975
and 2010. (B) Comparison of the 2000 and 2010 prevalence rates of knee replacement according to age for women and men in Sweden.
Reproduced with permission from reference 24: Annual report 2011. www.knee.nko.se. 2011, Swedish Knee Arthroplasty Register.
now had a TKR.24 Similarly, nearly 1 in 20 Americans over 50
years of age have had knee replacement surgery, which rep-
resents more than 4 million people.9,21
Direct comparisons of the rates of TKR for OA between dif-
ferent countries are hindered by the limited availability of high-
quality specific data for OA procedures, as well as by differ-
ences in population structure. The 2007-2009 estimated rates
of primary TKR for all diagnoses per 100 000 people varied
between 9 for Romania and 213 for the USA.26 Even between
countries with seemingly similar socioeconomic conditions,
national health care systems, and population structures, the
TKR rates per 100 000 varied greatly, ranging from 188 for
Germany, 178 for Finland, 112 for Sweden, to 98 for France.26
The reasons for these wide variations in usage are not clear,
but are likely to be due to differences on both the supply side
(health care services) and the demand side (patients).
Time-related trends in TKR use
The projections for future TKR rates have regularly been out-
done by reality. In the US, the demand for primary TKR was,
in 2005, expected to grow by more than 600%, to reach 3.48
million procedures by 2030.27 The growth of total knee revi-
sion surgeries was projected to be proportional, with the de-
mand for revision procedures expected to double between
2005 and 2015. If these predictions hold true, both health
care infrastructures and the training of orthopedic surgeons
will need to expand accordingly. The dramatic increase in TKR
rates inevitably leads to questions about financial feasibility in
the future: who will pay? So what are the possible reasons
for the steeply increasing demand for TKR seen over the last
decade? The reasons for this increase are most certainly mul-
184 MEDICOGRAPHIA, Vol 35, No. 2, 2013
R E L AT I O N S H I P
B
100 Females 2010
90 Males 2010
Females 2000
80 Males 2000
Prevalence /1000
70
60
50
40
30
20
10
0
2005 2010 50 60 70 80 90 100+
Age
tifactorial. Population growth, the increasing number of elder-
ly people, and the increase in average body mass index (BMI)
are, no doubt, important factors.
The increase in the age-standardized prevalence of knee OA
(for which there is limited evidence) may be driven by the
now global epidemic of overweight and obesity (for which
there is strong evidence), and by an increase in joint injury
rates. These two environmental risk factors may together
be responsible for up to 50% of knee OA cases in some so-
cieties.21 The importance of overweight and obesity in the risk
of severe knee OA leading to TKR was investigated in a pros-
pective population-based cohort study (Figure 4); a mean BMI
of 30 was associated with an 8-fold increase in TKR risk when
compared with a normal BMI of about 22.28 Even an increase
in BMI from 21-22 to 24-25 (ie, within a BMI range that is con-
sidered normal) was associated with a 3-fold risk increase in
the rate of TKR for OA. In fact, in this large population-based
study, very few TKR procedures were carried out on patients
in the lowest BMI quartile (Figure 4). In the US, the major im-
pact of obesity on the risk of knee OA and TKR can also be
illustrated by estimating the number of TKRs averted by re-
versing the prevalence of obesity to the levels of 10 years ago.
This would correspond to a mean BMI reduction of 0.6 or a
reduction in body weight of less than 2 kg for a person of av-
erage height. This means that more than 100 000 TKRs would
be averted over the remaining life span of this population.2
Population growth, aging, and an increase in BMI all seem
to result in an increase in the demand for TKR, even if these
factors do not fully explain the recent steep increase in de-
mand.21 However, increased availability on the supply side
Knee replacement for osteoarthritis: facts, hopes, and fears Lohmander

1.00
0.99
Fraction of the study population
0.98
0.97
0.96
0.95
0.94
0 2 4 6 8 10
Years of follow-up
Figure 4. Kaplan-Meier survival analysis of population fraction
without total knee replacement (TKR) or osteotomy for knee os-
teoarthritis.
The graph shows the fraction of the population studied who did not undergo
TKR or osteotomy for knee osteoarthritis. Individual survival plots show body
mass index (BMI) quartiles (population, n=11026 [men] + 16934 [women]), with
a statistically significant difference between each of the four survival curves.
Each BMI quartile consisted of 2756 men and 4233 women on average. The
median BMI values of the population quartiles were 22.5/21.1 (men/women)
(green), 25.0/23.6 (gray), 27.0/26.0 (blue), and 30.1/30.1 (red), respectively, for
BMI quartiles 1 to 4.
Modified from reference 28 with permission: Lohmander et al. Ann Rheum
Dis. 2009;68:490-496. 2008, BMJ Publishing Group Ltd & European League
Against Rheumatism.
is a further important and possible reason for the increase
in the incidence of TKR surgery, as total joint replacements
have changed from the early days of being boutique proce-
dures to now being a generally available commodity in many
settings.29,30
What determines patient demand for TKR?
Pain and difficulty walking limiting mobility and participation
in normal daily activities are the primary reasons for undergo-
ing TKR for OA. However, several studies have indicated that
among patients with a marked need for joint replacement, ie,
those with disabling OA, only a minority (around one-third)
were willing to consider joint replacement as a treatment op-
tion.31-33 Patients willingness to undergo total joint replace-
ment is, therefore, a critical predictor in determining the de-
mand for this procedure.34,35
Reduced willingness to consider joint replacement was shown
to be associated with increasing age, being black rather than
white (in the US), overestimation of the levels of pain and dis-
ability needed to warrant joint replacement, and rejection of
the medicalization of OAie, considering OA as a natural
and inevitable part of aging.34,35 The perception of the bene-
fits of joint replacement for OA was shown to be less positive
Knee replacement for osteoarthritis: facts, hopes, and fears Lohmander
OSTEOARTHRITIS: A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE
among women than men, and among those of lower socio-
economic status.36 Although blacks suffer from more severe
OA than whites in the US, they are less likely to consider sur-
gery as a solution to their problem, and this is associated
with less positive beliefs about the benefits of surgical pro-
cedures.37 A persons knowledge and beliefs regarding TKR
appears to be largely shaped by his or her interactions with
family and friends. The differences summarized here may at
least in part explain the inequities observed in joint disease
care.38,39
Given the low proportion of patients with OA in whom TKR is
indicated who are actually willing to undergo the procedure,
changes in willingness to undergo TKR seem to be an impor-
tant contributing factor in driving the recent increase in the
incidence of TKR, and also in driving a future increase in the
demand for TKR. Increased expectations regarding the main-
12 14
tenance of an active lifestyle into older age may influence will-
ingness, as may direct-to-consumer advertising, which is now
common in many countries. Studies investigating temporal
changes and changes in willingness to undergo TKR in differ-
ent settings would be of considerable interest.
Indications for TKR as perceived by health
professionals and patients
Several attempts have been made to develop consensus cri-
teria for TKR indications. As in all such efforts, the composi-
tion of the group and the method used to form the consensus
determine the result. Well-known examples of such criteria are
those developed in New Zealand and Canada.40,41 Compo-
nents of these scores include pain, functional impairment,
problems in care giving, and radiographic severity. However,
attempts to determine cut-off points leading to an appropri-
ate indication for TKR by correlating preoperative patient-
reported symptoms with recommendations for placement on
a TKR waiting list have not been successful.42 This suggests
that these more easily measured components explain only a
minor proportion of the decisions to place patients on waiting
lists for surgery.
Most TKR criteria have been dominated by the views of health
professionals, often orthopedic surgeons. The views of pa-
tients on the appropriateness of TKR have been explored to
some extent, and suggest that they do not always agree with
the views of health professionals. The concept of the capac-
ity to benefit from TKR suggests that the benefits should out-
weigh any likely risks or unintended consequences by a con-
siderable margin for TKR to be indicated.43,44
Effectiveness of knee replacement: what
determines outcome and patient satisfaction
after TKR for OA?
It has been said that total joint replacement doesnt bring
years to life, but brings life to years. This is true in the sense
that patient-reported outcomes of joint replacement are on
MEDICOGRAPHIA, Vol 35, No. 2, 2013 185
OSTEOARTHRITIS: A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE
average good to excellent, and it is particularly pertinent in
comparison with most nonsurgical treatments for severe OA.
The Scandinavian national joint registries have for many years
reported on the continuous improvement of outcomes over
time as a result of improved surgical, anesthesiological, and
care procedures and materials.45 In Sweden, the 10-year re-
vision (reoperation) rate is now estimated to be less than 5%
for patients operated with TKR for OA at the beginning of this
century.24 This means that for more than 95 out of 100 patients
undergoing TKR for OA, the patient will be survived by the im-
plant. Reoperation rates from other countries have general-
ly been somewhat higher, perhaps because of the choice of
implants, surgical techniques, and other factors.26 However, it
is well-known that the risk of reoperation is considerably high-
er for younger patients operated with TKR, than for older pa-
tients.24 Higher revision rates for younger patients operated
with TKR are expected in light of the changing demograph-
ics of TKR surgery, with rapidly increasing numbers of younger
patients undergoing joint replacement.46 The Swedish nation-
al registry reports no difference in revision rates between men
and women operated with TKR for OA in the 2000s.24
When considering these excellent results, it should be noted
that they represent reoperation rates, not patient-reported out-
comes. In fact, between 10% and 30% of patients undergo-
ing joint replacement report little or no improvement follow-
ing surgery, or are not satisfied with the outcome.47-50
Factors associated with a less than optimal patient-reported
outcome of TKR at 6 months include worse preoperative
pain and function, increased anxiety/depression, and living
in poorer areas.51 Multiple joint involvement negatively influ-
ences the outcome after TKR,52 while severe obesity results
in slower recovery after surgery, but with no difference at 3
years.53 It should be noted that the determinants of pain or
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The most important expectations of patients undergoing joint
replacement surgery are pain relief and improved mobility. It
appears that at 5 years following TKR, patients expectations
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Conclusion
The expectations, results, and patient satisfaction with TKR
surgery for OA summarized above reflect the current case
mix of patients with regard to disease severity, expectations
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as one of the most effective and cost-effective medical inter-
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BETWEEN BONE AND CARTILAGE
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PROTHSES DE GENOU POUR LARTHROSE : RALIT , ESPOIRS ET CRAINTES

Larthrose touche des centaines de millions de personnes dans le monde. Elle est responsable de douleurs, de res-
trictions fonctionnelles et de perte desprance de vie ajuste sur la qualit. Larthrose du genou est la cause de plus
de 90% des prothses totales de genou (PTG). Dici 2030, lincidence des PTG aux tats-Unis devrait tre multi-
plie par 6. Les principales raisons pour la pose dune PTG sont la prsence de douleur et une difficult la marche
limitant les activits de la vie quotidienne. Toutefois, seule une minorit de patients ayant une arthrose invalidante
sont prts envisager la PTG. Ce faible engouement pour la pose dune PTG est li au vieillissement, au fait dtre
Noir (aux tats-Unis), la surestimation de la douleur et du handicap ncessaires pour justifier une PTG et un rejet
de la mdicalisation de larthrose. Les femmes et les personnes dont le statut socio-conomique est bas ont une per-
ception des bnfices dune PTG moins positive que les autres. Le rapport cot-efficacit de la chirurgie pour PTG
est lun des meilleurs. Les donnes issues des registres sur les articulations montrent que le taux de rintervention
10 ans pour PTG est infrieur 5%. Cependant, de 10% 30% des patients ayant eu une PTG ne sont pas satis-
faits de lintervention, ou nont peru, au mieux, quune amlioration modre. Ce quattendent les patients dune pro-
thse, cest le soulagement de leur douleur et une mobilit amliore. Aprs la pose dune PTG, les attentes concer-
nant le soulagement de la douleur, laptitude la marche et la capacit effectuer les activits de la vie quotidienne
sont satisfaites dans une plus grande mesure que celles concernant la possibilit de pratiquer des activits plus phy-
siques. Les professionnels de sant devraient informer les patients de faon ce que leurs attentes soient ralistes,
ce qui leur assurerait une meilleure satisfaction.

188 MEDICOGRAPHIA, Vol 35, No. 2, 2013 Knee replacement for osteoarthritis: facts, hopes, and fears Lohmander

There may be some lessons
to be learned from the manage-
ment of rheumatoid arthritis, al-
though the disease-modifying os-
teoarthritis drugs (DMOADs) that
are used in the treatment of estab-
lished osteoarthritis (OA) are likely
to differ from disease-modifying
antirheumatic drugs (DMARDs) in
some respects. DMARDs are typ-
ically used in a younger population
where toxicity may be better toler-
ated and the absence of comor-
bidities and their concurrent ther-
apies permits the use of agents
with greater potential toxicity.
O
Andrew J. BARR, MBBS, MRCP
Philip G. CONAGHAN
MBBS, PhD, FRACP, FRCP
Division of Rheumatic and
Musculoskeletal Disease
University of Leeds and NIHR
Leeds Musculoskeletal
Biomedical Research Unit, UK
Address for correspondence:
Professor Philip G. Conaghan,
Division of Rheumatic and
Musculoskeletal Disease, Chapel
Allerton Hospital, Chapeltown Road,
Leeds LS7 4SA, UK
(e-mail: p.conaghan@leeds.ac.uk)
www.medicographia.com
DMOADs: what are they and what can we expect from them? Barr and Conaghan
OSTEOARTHRITIS: A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE
Disease-modifying osteo-
arthritis drugs (DMOADs):
what are they and what can
we expect from them?
b y A . J . B a r r a n d P. G . C o n a g h a n ,
United Kingdom
steoarthritis (OA) is the most common form of arthritis and represents
a huge burden on individuals and health economies. The mainstay
of current therapy involves a combination of nonpharmacological and
pharmacological interventions aimed at reducing pain and improving func-
tion. Current treatments do not inhibit structural deterioration of the OA joint;
yet, the unmet need for this type of treatment is immense. The current defi-
nition of a disease-modifying OA drug (DMOAD) is that of a drug that inhibits
structural disease progression and ideally also improves symptoms and/or
function. There are currently no licensed DMOADs but there are many prospec-
tive agents under investigation. The challenges of DMOAD development in-
clude the establishment of appropriate preclinical animal models that reflect
human OA, the limitations of the current radiographic standard for structural
assessment, and the lack of stratification of patients in trials by phenotype or
tissue involvement. Furthermore, DMOADs should probably be used in early
disease before irreversible molecular and biomechanical pathology is estab-
lished, as is commonly present at the time of diagnosis. DMOADs are likely
to be prescribed for long periods in this chronic illness of an aging popula-
tion, which demands excellent safety data in a target population with mul-
tiple comorbidities and the potential for drug interactions. Issues in DMOAD
development, potential DMOADs, magnetic resonance imaging biomarkers,
and lessons learned from the treatment of rheumatoid arthritis are briefly dis-
cussed in this review.
Medicographia. 2013;35:189-196 (see French abstract on page 196)
steoarthritis (OA) is the most common form of arthritis and represents a
O huge burden on both individuals and health economies. It is character-
ized by changes involving all the joint tissues. Affected individuals suffer
pain, functional limitation, and poor quality of life. We can predict a dramatic in-
crease in the burden of OA in aging and increasingly obese Western populations.
OA represents whole joint failure and occurs when the homeostatic equilibrium of
joint tissue repair and breakdown becomes unbalanced. Risk factors for disease
initiation and progression vary according to anatomical site and include age, obe-
sity,1,2 anthropometric and anatomical characteristics, joint malalignment, and trau-
ma.3 A genetic predisposition also contributes to OA risk; OA is a polygenic disease
whose susceptibility results from the interaction of many genes.4,5 The mainstay of
current therapy involves a combination of nonpharmacological and pharmacologi-
MEDICOGRAPHIA, Vol 35, No. 2, 2013 189
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BETWEEN BONE AND CARTILAGE
cal interventions aimed at reducing pain and improving func-
tion. The pharmacological interventions include paracetamol,
nonsteroidal anti-inflammatory drugs, and opiate analgesics.
Their utility is limited byat bestmoderate effect size,6 or by
significant toxicities, especially as OA is most prevalent in the
elderly where comorbidities are more common. Current treat-
ments do not appear to inhibit the structural deterioration of the
OA joint; the unmet need for such a treatment is immense.
What are disease-modifying osteoarthritis drugs?
A disease-modifying osteoarthritis drug (DMOAD) is a drug
that inhibits the structural disease progression of OA and
ideally also improves symptoms and/or function. There are
currently no licensed DMOADs. There are draft guidelines from
the US Food and Drug Administration (FDA) and the Euro-
pean Medicines Agency (EMA) both requiring that a DMOAD
should not only slow or halt radiographic structural disease
progression, but also achieve patient-reported long-term clin-
ical benefit.7,8 Historically, attempts at developing DMOADs
have focused primarily on preventing hyaline cartilage loss,
thereby providing putative chondroprotective agents. How-
ever, and perhaps appropriately, as typical clinical OA involves
multiple tissues, more recent attempts have been made at tar-
geting other tissues including the subchondral bone, which
plays an important role in OA pathogenesis.
There are a number of issues to consider in developing ther-
apies that modify structural disease progression.
Challenges in DMOAD development
N The current standard for structural assessment:
conventional radiography
Conventional radiography is widely available and radiograph-
ic joint space width (JSW) is the traditionally used surrogate
for assessing cartilage thickness. JSW can be used for both
defining and measuring structural disease progression. Man-
ual and semiautomated methods can be used to quantify JSW
from a conventional radiographic image, providing different
measures such as minimum, mean, or location-specific JSW.
Joint space narrowing (JSN) is used as the primary end point
in DMOAD trials in OA. Although JSN is a predictor of total
joint replacement,9 the limitations of radiographic JSN should
be appreciated. Indeed, while JSN is used to define cartilage
loss in knee OA, magnetic resonance imaging (MRI) studies
have shown that it measures a complex construct including
meniscal degeneration, meniscal extrusion, and hyaline car-
tilage loss.10
The annual rate and variability of JSN in the natural history of
OA is well described, which facilitates powering in clinical tri-
als.11,12 However, the average annual change in JSN is approx-
imately 0.1 to 0.2 mm per annum, with change occurring in a
small group of progressors. The relative insensitivity to change
of this surrogate measure of hyaline cartilage loss means
that long trials with large numbers of patients are needed in
190 MEDICOGRAPHIA, Vol 35, No. 2, 2013 DMOADs: what are they and what can we expect from them? Barr and Conaghan
order to adequately power a clinical study. Furthermore, the
sensitivity of this measure to change may be reduced by knee
repositioning variability in serial radiographic measurement of
JSW, so great care must be taken in repositioning methods.12
Conventional radiography does not detect early (preradiograph-
ic) OA changes in the subchondral bone, cartilage, or menis-
ci.13 Typically, inclusion criteria for research trials have includ-
ed patients with radiographically detectable JSN (Kellgren and
Lawrence grade 2). While this selects a group of patients
who no doubt have OA, multiple large MRI studies suggest
that these patients have complex multiple tissue pathologies,
with gait studies suggesting a high probability of abnormal
biomechanical features, meaning that these may be patients
in whom pharmacological intervention alone and aimed at a
single tissue would be unlikely to modify structural deterio-
ration. A preradiographic patient cohort with milder disease
may be more likely to respond. Treatment of rheumatoid arthri-
tis according to the concept of early disease has certainly rev-
olutionized the management of rheumatoid arthritis.
N Magnetic resonance imaging as a potential end point
Conventional radiography cannot capture the extent of the
multi-tissue involvement in OA joints. Typically, patients with
Kellgren-Lawrence grade 2 are recruited for DMOAD trials,
but these patients may lack uniformity in terms of joint tissue
involvement, and this is clinically indistinguishable. Stratifying
and monitoring these tissue changes among patients would
require MRI.
The advantages of MRI include the ability to examine the pres-
ence and extent of pathology in all of the individual joint tis-
sues in OA.14 There is good evidence of the reliability and re-
sponsiveness of MRI cartilage morphometry in knee OA and
there is some evidence of its predictive and construct valid-
ity.15,16 This includes quantitative loss of cartilage volume be-
ing a potential predictor of total knee replacement. The assess-
ment of subchondral bone marrow lesions and synovitis in
knee OA has also demonstrated good responsiveness for
SELECTED ABBREVIATIONS AND ACRONYMS
BMP-7 human bone morphogenetic protein 7
DMOAD disease-modifying osteoarthritis drug
DMARD disease-modifying anti-rheumatic drug
iNOS inducible nitric oxide synthase
IL-1 interleukin 1
JSW joint space width
JSN joint space narrowing
MRI magnetic resonance imaging
MMP matrix metalloproteinase
MSS musculoskeletal syndrome
OA osteoarthritis
TIMP tissue inhibitor of metalloproteinases
 OSTEOARTHRITIS:
semiquantitative MRI assessment.16 Further work is required
to investigate the predictive validity and quantification of these
noncartilage MRI pathologies. While MRI acquisition is, of
course, more expensive and time-consuming than plain radi-
ography, there are trade-offs in that increased responsiveness
should result in fewer patients being required to demonstrate
a structure-modifying effect.
MRI-based joint tissue measures of OA have not been rou-
tinely used as clinical outcome measures in structure-mod-
ification DMOAD trials. However, following the last decade
of MRI-OA cohort studies and trials, a recent Osteoarthritis Re-
search Society International (OARSI) working group recom-
mended that MRI cartilage morphology assessment be used
as a primary structural end point in clinical trials and noted
the rapid evolution of quantitative MRI assessments of sub-
chondral bone and synovium.17
N Novel end points: joint arthroplasty and virtual joint
arthroplasty
While pain and function outcomes are common outcomes
that may be adapted for DMOAD studies from symptom-mod-
ifying trials, less frequently used measures such as quality of
life and delay in time to joint replacement may also provide
important information about the value of a putative agent. Rate
of joint arthroplasty has been used as an end point reflecting
the severity of symptoms and structural damage, but many
variables influence both the decision to perform and the tim-
ing of this outcome measure. These include the surgeons or
physicians opinion and the patients comorbidities and will-
ingness to undergo surgery, in addition to local and national
health system variations in surgical waiting lists. In an attempt
to overcome these confounding factors influencing the time
to total joint replacement end point, an alternative has been
proposed. This is time to fulfilling criteria for total joint replace-
ment or virtual total joint replacement, which could be used
to evaluate treatment response to DMOADs in clinical trials.18
The criteria consist of a composite index of three domains:
physical function, pain, and structure19; its validity is currently
being assessed in an international study although provision-
al reports indicate that large patient numbers would be re-
quired to detect differences between groups in DMOAD ran-
domized control trials.20
N Symptomatic improvement
The current regulatory approval standard for DMOADs requires
that structural disease modification be linked with some clin-
ical benefit. However, in observational studies in OA there is
generally a weak relation between pain and/or function and
JSN and radiographic structural change.21 Furthermore, car-
tilage is not directly attributable as the cause of the typical OA
symptoms, including pain and stiffness.22 Importantly, most
trials of symptom-modifying drugs have been of short dura-
tion, often only 3 months long. DMOAD trials need to monitor
pain over long periods of time (1 to 2 years), where the effi-
DMOADs: what are they and what can we expect from them? Barr and Conaghan
A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE
cacy of existing analgesics has often not been clearly demon-
strated. Such long-duration trials are often associated with
patient drop-out, especially in an elderly population, and ro-
bust statistical modeling will be required to cope with miss-
ing data.
N DMOAD safety profile
Prospective DMOADs for use in established OA are likely to
require long-term administration in an aging population with
significant comorbidities, and will thus be prescribed along-
side a variety of medications. For that reason, prospective
DMOADs will be required to demonstrate a good safety pro-
file with respect to both patient tolerance and drug interac-
tions. Long-duration trials will therefore be needed to achieve
this.
N Preclinical models
Animal models can mimic certain aspects of human disease.
However, there is no single model that reflects all of the phe-
notypes and components of human OA. The marked differ-
ences between animal models and human disease may result
in dismissing drugs that may be viable DMOADs in humans
due to preclinical failure in animal models. Existing models
include primary idiopathic and secondary experimentally in-
duced disease. Small animal models may provide us with a
clearer understanding of the molecular pathways involved in
the pathogenesis of OA and the effects of prospective
DMOADs on these pathways.23 Although large weight-bear-
ing models may be more relevant, they are less frequently
used. Animal models generally achieve adequate severity of
OA but some may exceed that seen in humans. There is a
general consensus of opinion that animal models of less se-
vere OA will be better placed to establish the efficacy of pros-
pective human DMOADs. Furthermore, establishing animal
models with relevance to human OA will require standardiza-
tion of experimental techniques, disease severity, and treat-
ment responses.24
Are there candidate DMOADs?
A number of prospective DMOADs are under investigation
and some of those more advanced in development are sum-
marized in Table I (page 192). The degradation of cartilage
and that of subchondral bone are closely linked in OA. Ta-
ble I describes the mechanism of action of the prospective
DMOADs on cartilage, although they may also structurally
modify subchondral bone.
N Calcitonin
Calcitonin is responsible for regulating calcium homeostasis
and promotes osteoblastic bone formation. It inhibits bone
resorption by binding to calcitonin receptors on osteoclasts.
Calcitonin is indicated for the prevention of osteoporosis in
postmenopausal women. It can be administered orally, intra-
nasally, or subcutaneously. Its inhibition of subchondral bone
turnover may be chondroprotective and, therefore, it may in-
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sponse.33 Some potentially beneficial effects have nonethe-

Mechanism of action
Prospective DMOAD Anticatabolic Anabolic
Systemic therapy
Calcitonin
Bisphosphonates
Strontium ranelate
iNOS inhibitors
MMP-13 inhibitors
Aggrecanase inhibitors
Anti-IL-1
Doxycycline
Cathepsin K inhibitors
Local therapy
BMP-7
MMP-13 inhibitors
TIMP-3
FGF-18
Anti-IL-1
Table I. Prospective disease-modifying osteoarthritis drugs
(DMOADs) and their mechanisms of action on cartilage.
hibit the structural disease progression of OA.25 In a human
trial, bone resorption and cartilage degradation markers were
significantly lower in the oral salmon calcitonin group com-
pared with placebo.26 In a 2-year phase 3 trial of knee OA,
oral calcitonin modified symptoms and increased cartilage
volume but did not have an effect on JSW.27
N Bisphosphonates
Bisphosphonates are frequently used for treating conditions
with osteoclastic bone resorption, especially osteoporosis.
Increased subchondral bone turnover in OA is integral to the
pathogenic process of OA,28 and may be associated with pro-
gressive cartilage loss.29 This disease-specific pathogenic
process can be targeted using antiresorptive agents such as
bisphosphonates, which hinder the bone remodeling process
and could be chondroprotective. Animal models identified a
beneficial effect of bisphosphonates in OA through their im-
pact on subchondral bone, which includes inhibition of re-
modeling and osteophyte formation along with decreased
vascular invasion of calcified cartilage.30
Initially, a phase 2 study of risedronate31 reported promising
findings with a trend toward inhibition of JSN in knee OA. How-
ever, a subsequent phase 3 study of risedronate in knee OA
reported no significant change in JSN or symptom severity.32
As yet, no study has accounted for the heterogeneity of the
OA population regarding subchondral bone abnormalities
when selecting patients. The insensitivity to change of con-
ventional radiography used as an outcome measure (vide
supra) for structural change suggests that the above-men-
tioned studies were significantly underpowered to show a re-
less been observed. A reduction in biomarkers of cartilage
degradation at 6 months of therapy was noted, along with
slower knee OA progression.34
Zoledronic acid is a long-acting bisphosphonate that is li-
censed for postmenopausal osteoporosis. Along with other
bisphosphonates, zoledronic acid has demonstrated chon-
droprotective effects in animal models of OA35 in conjunction
with its impact on subchondral bone. In a 1-year random-
ized placebo controlled trial of zoledronic acid in patients with
knee OA, zoledronic acid demonstrated a reduction in bone
marrow edema (a marker associated with structural disease
progression) and knee pain.36 As it improves symptoms and a
marker of structural disease progression at the same time,
zoledronic acid represents an important prospective DMOAD.
N Strontium ranelate
Strontium ranelate is a drug used in the treatment of osteo-
porosis with antiresorptive and anabolic effects on the sub-
chondral bone. Strontium ranelate influences bone remod-
eling through calcium-sensing receptors on osteoclasts and
osteoblasts in subchondral bone and by an antiresorptive ac-
tion via inhibition of osteoclastogenesis.37 In vitro studies sug-
gest that strontium ranelate has anabolic effects on cartilage
by directly promoting the formation of human cartilage ma-
trix.38 In studies of human osteoporosis, strontium ranelate
reduces cartilage degradation markers and inhibits clinical
symptoms and radiographic features of spinal OA, indicating
its potential as a DMOAD.39 A double-blind, placebo-con-
trolled, randomized, international 3-year study of knee OA
demonstrated a chondroprotective effect and symptomatic
improvement in WOMAC (Western Ontario and McMaster
Universities) index scoring.40
N Bone morphogenetic protein
Human bone morphogenetic protein-7 (BMP-7)also known
as osteogenic protein-1 (OP-1)is a transforming growth fac-
tor with a broad range of effects on a variety of cells, including
cartilage. It signals through transmembrane serine-threonine
kinase receptors, and is involved in cartilage homeostasis and
repair via anticatabolic and anabolic properties.41 In animal
models, BMP-7 demonstrated reparative effects on cartilage
lesions.42 Human chondrocytes also promote cartilage forma-
tion in response to BMP-7 treatment.43 Clinical trials inves-
tigating the efficacy of BMP-7 in human knee OA have com-
menced.
N Inducible nitric oxide synthase
Nitric oxide is considered to play a pathogenic role in carti-
lage degradation and pain in OA.44 Nitric oxidealong with its
metabolitesinduces cartilage degradation and cytotoxic tis-
sue damage via inhibition of proteoglycan and collagen syn-
thesis, apoptosis of chondrocytes, and activation of matrix
metalloproteinases (MMPs).

192 MEDICOGRAPHIA, Vol 35, No. 2, 2013 DMOADs: what are they and what can we expect from them? Barr and Conaghan
 OSTEOARTHRITIS:
In animal models, selective inhibition of one isoform of nitric
oxide synthase (iNOS) significantly reduces articular cartilage
degradation and the number of osteophytes.45 There is also
a significant reduction in the severity and incidence of OA in
iNOS knock-out mice, indicating a potential role of iNOS in
human OA. However, in a recent 2-year randomized, dou-
ble-blind, placebo-controlled trial of an oral selective iNOS in-
hibitor, cindunistat, there was only a transient slowing of JSN
in Kellgren-Lawrence grade 2 OA, which was not sustained
at 2 years, and no significant evidence of inhibition of struc-
tural progression was seen in OA of greater radiographic
severity.46
N Matrix metalloproteinase inhibitors
MMPs are collagenases that cleave type II collagen and result
in loss of biomechanical integrity of normal human articular
cartilage. This important pathogenic process in OA can be in-
hibited using MMP inhibitors. However, these MMP inhibitors
have failed early clinical trials due to the frequent development
of a painful musculoskeletal syndrome (MSS). This has been
attributed to the broad spectrum of MMP inhibition. MMP-13
appears to be an important collagenase in human OA and
specific inhibitors targeting it are in development.47 This more
targeted approach will, hopefully, avoid MSS.
N Tissue inhibitors of metalloproteinases
Aggrecan is an important protein found in articular cartilage
that is degraded as part of the pathogenesis of OA. This
process occurs as a result of the action of a variety of differ-
ent aggrecanases, including a disintegrin and metallopro-
teinase with thrombospondin motifs (ADAMTS). Endogenous
inhibitors of MMPs include the tissue inhibitor of metallopro-
teinase TIMP-3, which can inhibit the action of these aggre-
canases.48 Greater cartilage degradation was noted in TIMP-3
knockout mice compared with wild-type mice.49 Therefore, tis-
sue inhibitors of metalloproteinases represent a prospective
DMOAD target.
N Vitamin D
Vitamin D is required for normal cartilage and bone metab-
olism. It regulates the expression of MMPs by chondrocytes.50
Vitamin D insufficiency is common and is associated with re-
duced osteoblast activity and reduced bone quality, which
may explain its association with structural progression of OA.51
Several clinical trials are investigating the effect of vitamin D
on structural disease progression
N Fibroblast growth factor 18
Fibroblast growth factor 18 (FGF-18) is involved in cartilage
and bone development during skeletal maturation.52 In ani-
mal models, it has been shown to promote chondrogenesis,
cartilage repair, and subchondral bone remodelling.53 It rep-
resents an important potential DMOAD and is currently un-
dergoing phase 2 clinical trials examining changes in cartilage
volume.
DMOADs: what are they and what can we expect from them? Barr and Conaghan
A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE
N Interleukin 1 inhibitors
Interleukin 1 (IL-1) has been proposed to be involved in the
degradation of articular hyaline cartilage based upon pre-
clinical studies. Inhibition of the enzyme that activates the
proinflammatory cytokine IL-1, interleukin-1 beta-convert-
ing enzyme (ICE), has been achieved with a highly selective
caspase-1 inhibitor called pralnacasan. In animal models, a
reduction in joint damage was demonstrated.54 However, in
human OA, monoclonal antibody IL-1 inhibitors have failed to
demonstrate an improvement in symptoms.55
N Neutraceuticals and supplements
Glucosamine, an amino sugar, is a substrate for the forma-
tion of glycosaminoglycans, and chondroitin sulfate is a sul-
fated glycosaminoglycan. Glycosaminoglycans are important
constituents of articular cartilage. The availability of these sub-
strates may limit the formation of cartilage and therefore glu-
cosamine and chondroitin were used in trials as prospective
DMOADs. A recent meta-analysis of glucosamine and chon-
droitin concluded that there is no structural modifying effect
of these agents based upon trials using JSN as a clinical end
point.56
Collagen hydrolysate is another dietary supplement. It is formed
as a result of collagen hydrolysis and has only demonstrated
small clinical improvement in OA. Phase 2/3 trials with colla-
gen hydrolysate are yet to be published.
N Doxycycline
Although there is no evidence to support an infectious eti-
ology in OA, doxycycline has demonstrated potential as a
DMOAD based on preclinical data. Possible mechanisms of
action include inhibition of type XI cartilage degradation, in-
hibition of collagenase activity and a decrease in iNOS mRNA
transcription. A randomized, placebo-controlled, double-blind
trial of doxycycline of over 30 months that included 431 obese
women with unilateral radiographic knee OA reported a small
reduction in the rate of JSN in knees with established OA.11
Doxycycline is not currently recommended for the treatment
of OA.
N Cathepsin K
Cathepsin K, a cysteine proteinase, appears to play a role in
the pathogenesis of OA.57 In preclinical models, cathepsin K
inhibition reduced evidence of cartilage degradation.58 It is,
therefore, a prospective DMOAD.
Can we learn lessons from disease modification
in rheumatoid arthritis?
There may be some lessons to be learned from the manage-
ment of rheumatoid arthritis, although the DMOADs that are
used in the treatment of established OA are likely to differ from
disease-modifying anti-rheumatic drugs (DMARDs) in some
respects. DMARDs are typically used in a younger population
where toxicity may be better tolerated and the absence of co-
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morbidities and concurrent therapies to treat them permits the
use of agents with greater potential toxicity. DMOADs for es-
tablished OA will require excellent toxicity profiles in light of the
greater prevalence of comorbidities and potential for drug
interactions. However, DMOADs, like DMARDs, are likely to re-
quire chronic administration. OA affects a significantly greater
proportion of the population than rheumatoid arthritis and,
therefore, its treatment may represent a significant burden to
health services. Ideally, DMOADs should be inexpensive, pa-
tient-administered, and require little or no monitoring in com-
parison with DMARDs such as tocilizumab and infliximab.
DMARDs are often prescribed in combination to improve the
efficacy of treatment in terms of symptoms and structural dis-
ease progression. Similarly, DMOADs may also need to be
prescribed in combination, particularly if a single joint tissue
is targeted by the DMOAD. It is important to recognize that
OA is a whole joint disease involving pathophysiological in-
teractions between subchondral bone, cartilage, synovium,
and ligaments and it is likely that an individual DMOAD will
only target a single tissue, thereby increasing the need for
combination therapy.
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and non-cartilaginous structures in knee osteoarthritis. Osteoarthritis Cartilage.
194 MEDICOGRAPHIA, Vol 35, No. 2, 2013 DMOADs: what are they and what can we expect from them? Barr and Conaghan
The cornerstone of DMARD therapy has been effective tar-
geting of synovitis. While the synovium is only one of the tis-
sues involved in OA pathogenesis, synovitis may contribute to
disease progression.59 Therapies that modify synovitis could
therefore potentially modify OA structural progression. Stud-
ies in this area are ongoing.
Conclusion
OA is the most common form of arthritis and is a chronic and
progressive disease of the whole joint with only moderately
effective treatment options currently available. There are a
number of prospective targets for structural and symptomatic
disease modification in patients with established OA, early
OA, or at the time of acute joint injury, with a view to prevent-
ing structural progression, improving symptoms and function,
and avoiding the need for total joint replacement. DMOADs
are the highest unmet need in the field of OA and prospective
DMOADs will need to demonstrate excellent safety profiles in
view of their target population. However, DMOAD trials will
require improved biomarkers and clinical end points to ap-
propriately demonstrate the construct of OA structure mod-
ification. I
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24. Poole R, Blake S, Buschmann M, et al. Recommendations for the use of pre-
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25. Manicourt DH, Altman RD, Williams JM, et al. Treatment with calcitonin suppress-
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28. Hayami T, Pickarski M, Zhuo Y, Wesolowski GA, Rodan GA, Duong le T.
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29. Kothari A, Guermazi A, Chmiel JS, et al. Within-subregion relationship be-
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30. Hayami T, Pickarski M, Wesolowski GA, et al. The role of subchondral bone
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31. Bingham CO 3rd, Buckland-Wright JC, Garnero P, et al. Risedronate decreas-
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32. Spector TD, Conaghan PG, Buckland-Wright JC, et al. Effect of risedronate
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R625-R633.
33. Hellio Le Graverand-Gastineau MP. OA clinical trials: current targets and trials
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34. Garnero P, Aronstein WS, Cohen SB, et al. Relationships between biochem-
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in patients with knee osteoarthritis receiving risedronate: the Knee Osteoarthri-
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35. Muehleman C, Green J, Williams JM, Kuettner KE, Thonar EJ, Sumner DR. The
effect of bone remodeling inhibition by zoledronic acid in an animal model of
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36. Laslett LL, Dore DA, Quinn SJ, et al. Zoledronic acid reduces knee pain and
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37. Brennan TC, Rybchyn MS, Green W, Atwa S, Conigrave AD, Mason RS. Os-
teoblasts play key roles in the mechanisms of action of strontium ranelate. Br
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38. Henrotin Y, Labasse A, Zheng SX, et al. Strontium ranelate increases cartilage
matrix formation. J Bone Miner Res. 2001;16(2):299-308.
39. Bruyere O, Delferriere D, Roux C, et al. Effects of strontium ranelate on spinal
osteoarthritis progression. Ann Rheum Dis. 2008;67(3):335-339.
40. Reginster J CR, Christiansen C, Genant H, Bellamy N, Bensen W. Structure
modifying effects of strontium ranelate in knee osteoarthritis. Osteoporosis Int.
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41. Chubinskaya S, Hurtig M, Rueger DC. OP-1/BMP-7 in cartilage repair. Int Or-
thop. 2007;31(6):773-781.
42. Jelic M, Pecina M, Haspl M, et al. Regeneration of articular cartilage chondral de-
fects by osteogenic protein-1 (bone morphogenetic protein-7) in sheep. Growth
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43. Gavenis K, Heussen N, Schmidt-Rohlfing B. Effects of low concentration BMP-7
on human osteoarthritic chondrocytes: comparison of different applications.
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A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE
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44. Abramson SB. Nitric oxide in inflammation and pain associated with osteo-
arthritis. Arthritis Res Ther. 2008;10(suppl 2):S2.
45. Pelletier JP, Jovanovic D, Fernandes JC, et al. Reduced progression of exper-
imental osteoarthritis in vivo by selective inhibition of inducible nitric oxide syn-
thase. Arthritis Rheum. 1998;41(7):1275-1286.
46. Hellio le Graverand MP, Clemmer R, Brunell RM, Hayes CW, Miller CG, Vi-
gnon E. Considerations when designing a disease-modifying osteoarthritis drug
(DMOAD) trial using radiography. OARSI OA Biomarker Meeting 2012. http:
//www.oarsi.org/pdfs/biomarkers/MP_Hellio_le_Graverand_2.pdf.
47. Baragi VM, Becher G, Bendele AM, et al. A new class of potent matrix metal-
loproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of
histologic and clinical efficacy without musculoskeletal toxicity in rat models.
Arthritis Rheum. 2009;60(7):2008-2018.
48. Kashiwagi M, Tortorella M, Nagase H, Brew K. TIMP-3 is a potent inhibitor of
aggrecanase 1 (ADAM-TS4) and aggrecanase 2 (ADAM-TS5). J Biol Chem.
2001;276(16):12501-12504.
49. Sahebjam S, Khokha R, Mort JS. Increased collagen and aggrecan degrada-
tion with age in the joints of Timp3(-/-) mice. Arthritis Rheum. 2007;56(3):905-
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50. Tetlow LC, Woolley DE. Expression of vitamin D receptors and matrix metallo-
proteinases in osteoarthritic cartilage and human articular chondrocytes in vitro.
Osteoarthritis Cartilage. 2001;9(5):423-431.
51. McAlindon TE, Felson DT, Zhang Y, et al. Relation of dietary intake and serum
levels of vitamin D to progression of osteoarthritis of the knee among partici-
pants in the Framingham Study. Ann Intern Med. 1996;125(5):353-359.
52. Haque T, Nakada S, Hamdy RC. A review of FGF18: Its expression, signaling
pathways and possible functions during embryogenesis and post-natal de-
velopment. Histol Histopathol. 2007;22(1):97-105.
53. Moore EE, Bendele AM, Thompson DL, et al. Fibroblast growth factor-18 stim-
ulates chondrogenesis and cartilage repair in a rat model of injury-induced os-
teoarthritis. Osteoarthritis Cartilage. 2005;13(7):623-631.
54. Rudolphi K, Gerwin N, Verzijl N, van der Kraan P, van den Berg W. Pralnacasan,
an inhibitor of interleukin-1beta converting enzyme, reduces joint damage in
two murine models of osteoarthritis. Osteoarthritis Cartilage. 2003;11(10):738-
746.
55. Cohen SB, Proudman S, Kivitz AJ, et al. A randomized, double-blind study of
AMG 108 (a fully human monoclonal antibody to IL-1R1) in patients with osteo-
arthritis of the knee. Arthritis Res Ther. 2011;13(4):R125.
56. Wandel S, Juni P, Tendal B, et al. Effects of glucosamine, chondroitin, or place-
bo in patients with osteoarthritis of hip or knee: network meta-analysis. BMJ.
2010;341:c4675.
57. Kozawa E, Nishida Y, Cheng XW, et al. Osteoarthritic change is delayed in a
Ctsk-knockout mouse model of osteoarthritis. Arthritis Rheum. 2012;64(2):
454-464.
58. Hayami T, Zhuo Y, Wesolowski GA, Pickarski M, Duong le T. Inhibition of cathep-
sin K reduces cartilage degeneration in the anterior cruciate ligament transec-
tion rabbit and murine models of osteoarthritis. Bone. 2012;50(6):1250-1259.
59. Conaghan PG, D'Agostino MA, Le Bars M, et al. Clinical and ultrasonograph-
ic predictors of joint replacement for knee osteoarthritis: results from a large,
3-year, prospective EULAR study. Ann Rheum Dis. 2010;69(4):644-647.
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LES MDICAMENTS CONTRE LARTHROSE MODIFIANT LA MALADIE (DMOAD) :

QUE SONT- ILS ET QUE PEUT- ON EN ATTENDRE ?
Larthrose, forme la plus courante des arthropathies, reprsente un lourd fardeau pour les individus et les conomies
de la sant. Les traitements actuels reposent sur lassociation dinterventions pharmacologiques et non pharmaco-
logiques dans le but de rduire la douleur et damliorer la fonctionnalit. Ces traitements ne permettent pas dvi-
ter la dtrioration structurale de larticulation arthrosique ; les besoins pour ce type de traitement sont donc im-
menses. La dfinition actuelle dun mdicament contre larthrose modifiant la maladie (DMOAD) est celle dun pro-
duit qui inhibe la progression structurale de la maladie et qui, idalement, amliore aussi les symptmes et/ou la
fonctionnalit. ce jour, aucun DMOAD na obtenu lAMM, mais il existe de nombreux produits en cours de d-
veloppement. Le dveloppement des DMOAD est confront la mise en place de modles animaux prcliniques
adquats reproduisant larthrose humaine, aux limites du standard radiographique utilis actuellement pour lvalua-
tion structurale de la maladie et au manque de stratification des patients par atteinte tissulaire ou phnotypique dans
les tudes. De plus, il va probablement falloir utiliser les DMOAD dans les stades prcoces de la maladie, avant lta-
blissement dune pathologie irrversible, comme cest frquemment le cas au moment du diagnostic. Dans cette pa-
thologie chronique dune population vieillissante, les DMOAD vont vraisemblablement devoir tre prescrits sur de
longues priodes, ce qui exige dexcellentes donnes de scurit pour leur utilisation chez une population sujette
de multiples comorbidits et donc, potentiellement, de nombreuses interactions mdicamenteuses. Dans cet ar-
ticle, nous passons brivement en revue les questions relatives au dveloppement des DMOAD, les DMOAD poten-
tiels, les biomarqueurs utiliss en imagerie par rsonance magntique et les leons tires du traitement de la poly-
arthrite rhumatode.

196 MEDICOGRAPHIA, Vol 35, No. 2, 2013 DMOADs: what are they and what can we expect from them? Barr and Conaghan
 OSTEOARTHRITIS: A STORY OF CLOSE R E L AT I O N S H I P

BETWEEN BONE AND CARTILAGE

OA has a substantial effect

not only on health care budgets
but also on patients, their employ-
ers, and their caregivers. For ex-
ample, in Belgium, the costs of OA
in active patients are distributed
The economic weight of
among the employers (45%), the
health care system (41%), and the
patients themselves (14%). There-
osteoarthritis in Europe
fore, in addition to pain and a
poorer quality of life, patients liv-
ing with OA may face significant
personal expenses due to OA.

b y M . H i l i g s m a n n a n d J . Y. R e g i n s t e r,
The Netherlands and Belgium

T
his article aims to describe the economic weight of osteoarthritis (OA)
in Europe based on published data and to underline the principal cost
headings and their respective weights for patients and governments.
This review suggests that OA has a significant economic effect not only on
health care budgets, but also on patients, their employers, and their caregiv-
ers. The average total annual cost of OA per patient in Europe ranges from
1330 to 10 452. When considering only direct medical costs, the annual
cost of OA ranged from 534 to 1788. In active patients, the indirect costs
were found to be much higher than the direct costs. European studies are,
however, not directly comparable with each other because of differences in
L
the approach taken, in patient characteristics, in health care systems, and in
Mickal HILIGSMANN,a,b PhD
the calculation of productivity losses. Our review confirms the immense bur-
Jean-Yves REGINSTER,b MD, PhD
a den of OA in Europe, which is expected to rise substantially further in the fu-
Department of Health Services
Research, School for Public Health ture with demographic changes and increasing obesity. Developing effective
and Primary Care (CAPHRI) and efficient treatment programs for OA is becoming increasingly important
Maastricht University
to reduce the clinical and economic consequences of this major public health
THE NETHERLANDS
b problem worldwide.
Department of Public Health
Epidemiology and Health Economics Medicographia. 2013;35:197-202 (see French abstract on page 202)
University of Lige, BELGIUM

steoarthritis (OA), the most common form of arthritis, is a serious disease

O affecting the joints.1,2 OA affects nearly 10% of the population worldwide.3

Address for correspondence:
Dr Mickael Hiligsmann
Department of Health Services
Research, Maastricht University
PO Box 616. 6200 MD, Maastricht,
The Netherlands (e-mail:
m.hiligsmann@maastrichtuniversity.nl)
www.medicographia.com
In the United Kingdom, the lifetime risk of developing symptomatic knee
and hip OA is estimated to be 44.7% and 25.3%, respectively.4,5 OA causes pain,
stiffness, and severe disability. In the United States, knee OA is one of the five lead-
ing causes of disability among noninstitutionalized people.6 Symptomatic hip and
knee OA are also associated with excess mortality7 and account for many hospi-
talizations, primarily related to knee and hip replacement surgery.8 Since OA is a
disease whose prevalence increases with age, its prevalence and burden are ex-
pected to increase substantially in the near future due to demographic changes.
In addition, obesity, which is rising worldwide, is a strong risk factor for knee and hip
replacement.9 An increased trend in the prevalence of symptomatic knee OA and
in the number of OA-related hospitalizations has already been observed recently.10
The economic cost of OA is also particularly high, resulting from decreased quality
of life, hospitalizations, and loss of productivity. Cost-of-illness studies have be-
come increasingly important to identify how much society is spending on a partic-
ular disease and thus help decision makers establish research and treatment prior-

The economic weight of osteoarthritis in Europe Hiligsmann and Reginster MEDICOGRAPHIA, Vol 35, No. 2, 2013 197
OSTEOARTHRITIS: A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE
ities. In the United States, the annual medical care expendi-
tures for OA were estimated at $185.5 billion (in 2007 dol-
lars), of which $149.4 billion were insurer expenditures and
$36.1 billion were paid directly by the patients. In Europe,
some data has been published over the last few years on the
economic impact of OA on individuals, including those in the
workplace. The goal of this article is to review these publica-
tions so as to clarify the economic weight of OA in Europe
based on available published data. Specific attention will be
devoted to describing the principal cost headings (visits to
health professionals, drugs, loss of productivity, etc.) and
their respective weights for patients and governments.
Cost-of-illness evaluation
Burden-of-disease evaluation of OA aims to describe the im-
pact of OA on society, including its impact on health care sys-
tems, patients, their caregivers, and their employers. Meas-
uring the burden of disease can be very helpful in guiding the
setting of health research priorities.11
The burden of OA can be measured with epidemiological pa-
rameters (incidence, prevalence) or with the impact of the dis-
ease on mortality, morbidity, quality of life, or health care costs.
Cost-of-illness studies evaluate the direct and indirect health
care costs of a particular disease over a period of time. This
can be done using two different approaches: a prevalence-
based approach and an incidence-based approach. While
the incidence-based approach estimates the costs of new
cases of the disease during the period of time considered,
the prevalence-based approach includes the costs of all the
patients affected by the disease. Prevalence-based studies
are far more common and are more suitable for the estimation
of the annual burden of a disease.12
The cost of a disease can be estimated using either a top-
down or a bottom-up approach. The top-down approach
examines the costs in an aggregated form (such as nation-
al indicators) while in the bottom-up approach, the overall
cost is based on the costs for the individuals.11 Most cost-
of-illness studies of OA in Europe have used the bottom-up
method to estimate the economic burden of OA (see below).
The cost of a disease can be categorized into direct and in-
direct costs. Direct costs are those directly related to the dis-
ease, including, for example, visits to health care profession-
als, medical examinations, drug therapy, hospital admissions,
and nonmedical costs. Indirect costs include productivity loss-
SELECTED ABBREVIATIONS AND ACRONYMS
GNP gross national product
OA osteoarthritis
WOMAC Western Ontario and McMaster Universities Osteo-
arthritis index
198 MEDICOGRAPHIA, Vol 35, No. 2, 2013
es attributable to the disease resulting from absence from
work and reduced effectiveness at work. These costs may
be related to the patients themselves or to their caregivers.
Cost of osteoarthritis in Europe
A literature review was conducted using PubMed to find ar-
ticles assessing the burden of OA in European countries be-
tween January 2000 and July 2012. The bibliographies of the
papers included were also analyzed to search for additional
references. Published studies on the economic cost of OA
were found in Belgium, France, Germany, Italy, the Nether-
lands, and Spain. All of these studies, with the exception of the
French study, used a bottom-up approach.
Informal care
Contact with
(2%)
health care
professionals
(22%)
Medical
examinations
(8%)
Hospital
stays
Work (6%)
disability
Drugs
(58%)
(4%)
Figure 1. Direct and indirect costs of osteoarthritis in Belgium.
Based on a sample of 1811 active subjects with a mean age of 51 years. Total
cost per year = 1330. Direct costs are represented in red and indirect costs
in blue.
Data from reference 13: Rabenda et al. J Rheumatol. 2006;33:1152-1158.
2006, The Journal of Rheumatology.
N Belgium
In Belgium, the cost of OA was assessed in 2004 in a sam-
ple of 1811 active subjects employed by the Lige City Coun-
cil (mean age, 51 years) who were followed prospectively for
6 months.13 The self-reported prevalence of OA was 34%. The
burden of OA was measured comprehensively, taking into
account the direct medical costs (consultations with health
professionals and with alternative medicine professionals, the
number and type of medical examinations, the number of hos-
pital stays and emergency department consultations, and all
drugs taken) and the indirect costs (the number of sick leave
days, and the number of days off work taken by active sub-
jects helping relatives or friends with OA).
The mean total direct and indirect costs were estimated at
44.50 and 66.30 per OA patient-month, respectively,
which, when extrapolated to 1 year, came to 1330 per OA
patient annually. The average distribution of costs is shown in
The economic weight of osteoarthritis in Europe Hiligsmann and Reginster
 OSTEOARTHRITIS: A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE

Figure 1. Consultations with health professionals, medical ex-
aminations, drugs, and hospital stays accounted for 23.70,
8.70, 6.70, and 4.90 per OA patient-month, respective-
ly. Of all these direct costs, 29.10 (65%) was covered by the
Belgian health care system and 15.40 (35%) was paid out
of pocket by the patients. The average number of sick-leave
days was 0.8 per OA patient-month, yieldingfrom the pay-
ers perspectivea cost of 64.50 per OA patient-month. The
Belgian health care system covered 25.9% of all sick-leave
payments, with employers covering the remaining 74.1%. In-
formal care was estimated to cost employers 1.80 per ac-
tive subject-month, based on a mean of 0.02 days off work
per active subject-month. Multiple regression analyses showed
that age was a significant predictor of direct medical costs
and that poorer quality of life was a major determinant of di-
rect and indirect costs.
N Italy
In Italy, the direct and indirect costs of knee OA were assessed
retrospectively in a sample of 254 patients (mean age, 65
years) over a period of 12 months in 2000-2001.14 The cost
per patient per year was estimated at 2170, of which 43%
were direct costsincluding medical (hospitalization, diag-
nosis, and therapies) and nonmedical costs (transport, tem-
porary caregivers, and auxiliary devices)and 57% were in-
direct costs (productivity losses and informal care).
The distribution of costs is shown in Figure 2. Hospitalization
represented the largest medical cost, absorbing 25% of the
direct resources (mean annual cost, 233). The annual cost
of therapy was 136, of which 42% was spent on drugs and
58% on physiotherapy. Nonmedical costs (which represent
37% of the total costs) were mainly driven by temporary care-
givers. In contrast with the study of Rabenda et al in Belgium,13
which only included active patients, the indirect costs were
found to be mainly due to informal care provided by primary
caregivers, which accounted for around 60% of the total in-
direct costs. The remaining indirect costs were due to loss of
productivity (31%) and to other caregivers (9%). Sensitivity
analyses revealed higher costs for patients with comorbidities
and for women. Age was also shown to be a predictor of costs.
N Netherlands
In the Netherlands, the productivity and medical costs of work-
ing patients with knee OA were recently assessed by Her-
mans et al.15 Loss of productivity and health care consump-
tion were assessed by questionnaires in a sample of 117 knee
OA patients participating in a randomized clinical trial inves-
tigating cost-effectiveness (mean age, 52 years). Interest-
ingly, this study included the measurement of reduced work
productivity while present at work in addition to loss of pro-
ductivity resulting from absence from work.
The average total monthly knee OArelated costs were es-
timated at 871 per patient. The productivity costs account-
ed for 83% (722) and the medical costs accounted for 17%
(149) of these costs. As observed in Figure 3, the medical
costs were primarily driven by visits to primary (62) and sec-
ondary care (33), and by imaging (40). Reduced produc-
tivity while present at work accounted for the majority (62%)
of the productivity costs. The inclusion of loss of productivity
while being present at work, which represented around 50%

Loss of productivity Aids

Hospitalization Imaging (1%)
other caregivers Loss of
(11%) Medication (4%)
Loss of (5%) productivity
productivity use (1%) present at work
primary Diagnosis (51%)
caregiver Visits
(10%) (11%)
(34%)

Compensation
for work
Therapy in the
(7%) household
(9%)
Transport
(2%)

Auxillary
devices
(2%)
Loss of
Temporary
productivity
caregivers
Loss of absent from work
(12%)
productivity (23%)
patient (17%)
Figure 3. Direct and indirect costs of osteoarthritis in the Nether-
Figure 2. Direct and indirect costs of osteoarthritis in Italy. lands.
Based on a sample of 254 patients with a mean age of 65 years. Total cost per Based on a sample of 117 active patients with a mean age of 51 years. Total cost
year = 2170. Direct costs are represented in red and indirect costs in blue. per year = 10 452. Direct costs are represented in red and indirect costs in blue.
Data from reference 14: Leonardi et al. Clin Exp Rheumatol. 2004;22:699-706. Data from reference 15: Hermans et al. Arthritis Care Res. 2012;64:853-861.
2004, Clinical and Experimental Rheumatology. 2012, American College of Rheumatology.

The economic weight of osteoarthritis in Europe Hiligsmann and Reginster MEDICOGRAPHIA, Vol 35, No. 2, 2013 199
OSTEOARTHRITIS: A STORY OF CLOSE R E L AT I O N S H I P
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of the total costs (448 per patient-month), could explain the
relatively high cost of OA found in this study. Logistic regres-
sion analyses reported that increased pain during activity and
performing physically intensive work were significantly asso-
ciated with loss of productivity.
4.7 billion, which represents 0.5% of the gross national prod-
uct (GNP) of Spain. Using regression models, the authors also
found that higher costs were associated with comorbidity,
poorer health status, and lower WOMAC score (Western On-
tario and McMaster Universities Osteoarthritis index).

N Spain N France
The direct and indirect costs of osteoarthritis in Spain were In France, the direct and indirect costs of osteoarthritis were
estimated by Loza et al in 2007.16 Based on a sample of 1071 estimated by Le Pen et al using the top-down approach with
patients aged over 50 years (mean age, 71 years) with symp- nationwide data from 2001 to 2003.17 The direct costs of os-
tomatic and radiologic knee and/or hip OA who were seen teoarthritis were estimated at 1.6 billion Euros (2002), rep-
at primary care centers in all provinces of Spain, data related resenting approximately 1.7% of the expenses of the French
to OA health resources utilization, patient and caregiver ex- health insurance system. Hospitalization represented 50% of
penses, and time lost in the previous 6 months were collect- the direct expenses. The costs of medication and physicians
ed in two separate interviews. The costs were divided into were estimated at 574 million (34%) and 270 million (16%),
direct costs, including medical costs (professional time [all respectively. A 156% increase in direct medical costs was re-
consultations], image, laboratory, and other tests, medications, ported compared with 1993, which was related to an increase
and hospital admissions); and nonmedical costs (help at work in the number of OA patients (+54%). The authors mentioned
and home, and self-care adaptive aids, devices, and assis- that the cost per patient increased by only 2.5% per year.
tive household equipment purchased), and indirect costs
including compensation payments for lost productivity and N Germany
housekeeping help costs if the patient was a homemaker.16 In a recent article, Sabariego et al aimed to determine the di-
rect medical costs in patients with osteoporosis, osteoarthri-
tis, back pain, or fibromyalgia in Germany.18 The mean direct
Help for housewives cost of OA was estimated at 1511 in a sample of 97 OA pa-
Lost labor/ at home (8%) tients. Medication, outpatient physician visits, nonphysician
productivity
(6%) Professional services, and inpatient services accounted for 699, 357,
time 171, and 175, respectively.
Transport (21%)
(0%)
N Other European countries
Aid
devices For other European countries, no detailed estimations of the
(9%)
Image and cost of OA have been published in any of the journals includ-
laboratory ed in the database we searched. In the United Kingdom, how-
tests ever, the National Institute for Clinical Excellence (NICE) has
(10%)
reported that the burden of OA represents 1% of the GNP.19

Drugs
(5%)
House/work/
Hospital
self-care help
admissions
(28%)
(13%)
Figure 4. Direct and indirect costs of osteoarthritis in Spain.
Based on a sample of 1071 patients with a mean age of 71 years. Total cost
per year = 1502. Direct costs are represented in red and indirect costs in blue.
Data from reference 16: Loza et al. Arthritis Rheum. 2009;61:158-165. 2009,
American College of Rheumatology.
The average total annual cost of osteoarthritis was estimat-
ed at 1502 per patient (2007). Direct costs accounted for
86% of the total cost, mostly due to home, work, and self-
care help (29%), professional medical time (21%), and hos-
pital admissions (13%) (Figure 4). Indirect costs represented
only 14% of the total cost, with the largest component relat-
ed to providing help for housewives at home. Assuming a
prevalence of knee and hip OA of, respectively, 10% and 4%
in Spain, the authors estimated the national cost of OA at
Discussion
This review suggests that OA represents a significant eco-
nomic burden to patients and society in Europe. The annual
cost of OA per patient ranges from 1330 to 10 452, de-
pending on the country and the approach taken (Table). When
considering only the direct medical costs, the annual cost
of OA ranges from 534 to 1788. Drug therapies repre-
sent between 5.3% and 24.8% of the total direct medical
costs,13-16 while hospitalizations and visits to health care pro-
fessionals range from 15.2% to 39.6%,13,14,16 and from 35.5%
to 53.9%,13-16 respectively. Indirect costs range from 205 to
8664 per year, depending on patient characteristics and
the mode of calculation of productivity losses.13-16 The direct
and indirect costs of OA were shown to increase with patient
age and with poorer quality of life in several studies.13,14,16
Our review highlights the importance of indirect costs on the
burden of OA. In particular, in studies assessing the burden of
OA in active patients, indirect costs were found to be greater

200 MEDICOGRAPHIA, Vol 35, No. 2, 2013 The economic weight of osteoarthritis in Europe Hiligsmann and Reginster
 OSTEOARTHRITIS: A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE

costs of OA in active patients are distributed among the em-

Total Direct medical
Country costs costs
Belgium13 1330 534
Italy14 2170 588
Netherlands15 10 452 1788
Spain16 1502 724
Germany18 NR 1511
Table. Annual total costs, direct medical costs, and indirect costs
of osteoarthritis per patient in Europe. NR, not reported.
than direct costs.13,15 Indirect costs are especially high in OA
as patients have to take days off work or early retirement, and/
or are less efficient at work.11 The analysis performed in the
Netherlands showed that the indirect costs related to reduced
work efficiency were considerable, representing more than
50% of the total cost of OA. 15 To adequately estimate the
burden of OA, it is therefore important to estimate not only the
indirect costs due to time off from work but also to reduced
work efficiency at work.
Cost variations were observed across the European studies.
These studies are, however, not directly comparable because
of differences in the approach taken, in patient characteristics,
and in health care systems. Moreover, there are methodolog-
ical differences in the calculation of productivity losses and
no time adjustment was made for the costs. Despite such po-
tential differences, the direct medical costs were very similar
in Belgium, Italy, and Spain.13,15,16
The burden of OA is considerable, both from a societal and
individual patient perspective. OA has a substantial effect not
only on health care budgets but also on patients, their em-
ployers, and their caregivers. For example, in Belgium, the
Indirect ployers (45%), the health care system (41%), and the patients
costs
themselves (14%). Therefore, in addition to pain and a poor-
796 er quality of life, patients living with OA may face significant
1237 personal expenses due to OA.
8664
Our review confirms the great magnitude and economic
205
impact of OA worldwide. Non-European countries have also
NR
reported a substantial burden of OA. For example, in the
United States, the average direct cost of OA is approxi-
mately $2600 per year per person living with OA20, while in
Canada, the excess burden of OA was recently estimated
at Can$-1200.21
Cost-of-illness studies could be very useful in guiding health
care priorities but there are limitations to their use for health
care decision-making and they do not necessarily lead to more
efficient health care systems. Cost-effectiveness analyses are
potentially more interesting in order to assign health care re-
sources more efficiently. By comparing the costs and effects
of health interventions, health economic evaluation is a pow-
erful tool for decision makers.22 However, current economic
analyses in OA are limited and mainly pragmatic studies.23
Providing high-quality economic evaluations in OA would be
of major importance to help decision makers make rational
decisions and efficiently allocate health care resources ded-
icated to OA.
In summary, this review illustrates the immense burden of OA
to patients and society in Europe. Developing adequate treat-
ment programs for OA is becoming increasingly important
to reduce the clinical and economic consequences of this
major public health problem worldwide. Establishing the most
effective treatments and determining the best use of resources
should also become a priority in this area. I

References
1. Felson DT, Lawrence RC, Dieppe PA, et al. Osteoarthritis: new insights. Part 1:
the disease and its risk factors. Ann Intern Med. 2000;133:635-646.
2. Reginster JY. The prevalence and burden of arthritis. Rheumatology (Oxford).
2002;41(suppl 1):3-6.
3. Helmick CG, Felson DT, Lawrence RC, et al. Estimates of the prevalence of
arthritis and other rheumatic conditions in the United States. Part I. Arthritis
Rheum. 2008;58:15-25.
4. Murphy L, Schwartz TA, Helmick CG, et al. Lifetime risk of symptomatic knee
osteoarthritis. Arthritis Rheum. 2008;59:1207-1213.
5. Murphy LB, Helmick CG, Schwartz TA, et al. One in four people may develop
symptomatic hip osteoarthritis in his or her lifetime. Osteoarthritis Cartilage.
2010;18:1372-1379.
6. Guccione AA, Felson DT, Anderson JJ, et al. The effects of specific medical con-
ditions on the functional limitations of elders in the Framingham Study. Am J
Public Health. 1994;84:351-358.
7. Nuesch E, Dieppe P, Reichenbach S, Williams S, Iff S, Juni P. All cause and
disease specific mortality in patients with knee or hip osteoarthritis: population
based cohort study. BMJ. 2011;342:d1165.
8. Arden N, Nevitt MC. Osteoarthritis: epidemiology. Best Pract Res Clin Rheu-
matol. 2006;20:3-25.
9. Felson DT, Zhang Y, Anthony JM, Naimark A, Anderson JJ. Weight loss reduces
the risk for symptomatic knee osteoarthritis in women. The Framingham Study.
Ann Intern Med. 1992;116:535-539.
10. Nguyen US, Zhang Y, Zhu Y, Niu J, Zhang B, Felson DT. Increasing preva-
lence of knee pain and symptomatic knee osteoarthritis: survey and cohort data.
Ann Intern Med. 2011;155:725-732.
11. Hunsche E, Chancellor JV, Bruce N. The burden of arthritis and nonsteroidal
anti-inflammatory treatment. A European literature review. Pharmacoeconomics.
2001;19(suppl 1):1-15.
12. Segel J. Cost-of-Illness Studies - A primer. RTI-UNC Center of Excellence in
Health Promotion Economics. 2006.
13. Rabenda V, Manette C, Lemmens R, Mariani AM, Struvay N, Reginster JY. Di-
rect and indirect costs attributable to osteoarthritis in active subjects. J Rheu-
matol. 2006;33:1152-1158.
14. Leardini G, Salaffi F, Caporali R, et al. Direct and indirect costs of osteoarthritis
of the knee. Clin Exp Rheumatol. 2004;22:699-706.
15. Hermans J, Koopmanschap MA, Bierma-Zeinstra SMA, et al. Productivity costs
and medical costs among working patients with knee osteoarthritis. Arthritis
Care Res. 2012;64:853-861.
16. Loza E, Lopez-Gomez JM, Abasolo L, et al. Economic burden of knee and hip
osteoarthritis in Spain. Arthritis Rheum. 2009;61:158-165.
17. Le Pen C, Reygrobellet C, Grentes I. Financial cost of osteoarthritis in France.
The COART France study. Joint Bone Spine. 2005;72:567-570.
18. Sabariego C, Brach M, Stucki G. Determinants of major direct medical cost cat-
egories among patients with osteoporosis, osteoarthritis, back pain or fibromyal-
gia undergoing outpatient rehabilitation. J Rehabil Med. 2011;43:703-708.

The economic weight of osteoarthritis in Europe Hiligsmann and Reginster MEDICOGRAPHIA, Vol 35, No. 2, 2013 201
OSTEOARTHRITIS: A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE

19. National Institute for Health and Clinical Excellence. Osteoarthritis: the care and
management of osteoarthritis in adults. Clinical Guideline 59. London, UK: NICE;
2008.
20. Gabriel SE, Crowson CS, Campion ME, OFallon WM. Direct medical costs
unique to people with arthritis. J Rheumatol. 1997;24:719-725.
21. Tarride JE, Haq M, OReilly DJ, et al. The excess burden of osteoarthritis in the
province of Ontario, Canada. Arthritis Rheum. 2012;64:1153-1161.
22. Drummond M, Sculpher M, OBrien B, Stoddart G, Torrance G. Methods for
the economic evaluation of health care programmes. 3rd edition. New York, NY:
Oxford University Press; 2007.
23. Bruyre O, Reginster J. The need for economic evaluation in osteoarthritis. Aging
Health. 2009;5:591-594.

Keywords: burden, cost-of-illness, direct cost, economic, indirect cost, osteoarthritis

LE POIDS CONOMIQUE DE LARTHROSE EN EUROPE

Cet article dcrit, laide de donnes publies, le poids conomique de larthrose en Europe et souligne les prin-
cipaux cots et leur poids respectif pour les patients et les gouvernements. Il montre que larthrose entrane des
consquences conomiques significatives non seulement sur les budgets de soins de sant mais aussi sur les pa-
tients, leurs employeurs et leurs soignants. Le cot annuel total moyen de larthrose par patient en Europe varie de
1 330 10 452 . Si lon ne prend en compte que les cots mdicaux directs, le cot annuel de larthrose varie de
534 1 788 . Chez les patients actifs, les cots indirects sont beaucoup plus levs que les cots directs. Les
tudes europennes ne sont cependant pas directement comparables les unes avec les autres car les approches,
les caractristiques du patient, les systmes de soins et le calcul des pertes de productivit diffrent. Notre article
confirme limmense fardeau de larthrose en Europe, qui augmentera de faon importante dans le futur, avec les
changements dmographiques et laugmentation de lobsit. Il devient donc crucial de dvelopper des programmes
de traitement efficaces pour larthrose, afin de rduire les consquences cliniques et conomiques de ce problme
majeur de sant publique dans le monde entier.

202 MEDICOGRAPHIA, Vol 35, No. 2, 2013 The economic weight of osteoarthritis in Europe Hiligsmann and Reginster
 THE QUESTION CONTROVERSIAL QUESTION

lthough the development

A of secondary osteoarthritis
can readily be pinpointed,
the boundary between age-asso-
ciated changes in articular carti-
lage and the pathogenetic changes
Can normal age-related
related to primary osteoarthritis is
not so easy to define. Changes in
cartilage with age are likely univer-
changes in cartilage
sal, but development of osteoarthri-
tis is not. This article will discuss
the way to differentiate these two
be distinguished from early
fates of the joint.
osteoarthritic changes?

1. L. A. Alekseeva, Russia

2. J. P. A. Arokoski, Finland

3. F. N. Birrell, United Kingdom

4. S. Blkbai,
s Turkey

5. O. P. Bortkevych, Ukraine

6. P. Hork, Czech Republic

7. A. El Maghraoui, Morocco

8. A. Mahmoud Ali Elsayed, Egypt

9. A. Migliore, Italy

10 . T. Pap, Germany

11. J. del Pino-Montes, Spain

12 . C. A. F. Zerbini, Brazil

Can age-related cartilage changes be distinguished from early OA changes? MEDICOGRAPHIA, Vol 35, No. 2, 2013 203
CONTROVERSIAL QUESTION
1. L. A. Alekseeva, Russia
Lyudmila A. ALEKSEEVA, MD, PhD
Department of Metabolic Disorders of
Musculoskeletal System
Osteoarthritis and Osteoporosis Laboratories
Research Institute of Rheumatology
(Russian Academy of Medical Sciences)
34 A, Kashirskoye shosse
115522 Moscow, RUSSIA
(e-mail: alekseeva@irramn.ru)
C
urrently, osteoarthritis (OA) is the most common of
all the musculoskeletal diseases, and this relates to
the general increase in life expectancy and the ac-
cumulation of risk factors. The main symptom of OA and im-
mediate reason for seeking medical care is pain, and this re-
mains a permanent symptom over time. Despite traditional use
of analgesic and anti-inflammatory drugs, most patients with
OA continue to experience pain.
There are many reasons for the occurrence of pain in OA and
many factors determining its severity. The proportion of pa-
tients with so-called painful or overtly symptomatic knee OA
increases with age and reaches almost 80% in the oldest age
group.1 Moreover, the individual perception of pain by each pa-
tient cannot be ignored, and may depend not only on changes
in the joint, but also on the emotional and social status of the
patient.
The source of pain in OA can be almost any structure of the
joint: the synovial membrane, bone, or soft tissues.2 Mecha-
nisms of pain perception may include activation and local re-
lease of pro-inflammatory mediators, such as prostaglandins
and cytokines. Clinically, however, there is often a disparity be-
tween the degree of pain perception and the extent of de-
structive changes in the joint. A study with functional magnet-
ic resonance imaging revealed that numerous areas in the
brain are involved in the occurrence of pain in OA. This study
demonstrated that perception of pain in OA is a complex
mechanism involving local factors and the activation of cen-
tral pain pathways.3
204 MEDICOGRAPHIA, Vol 35, No. 2, 2013
On the other hand, articular cartilage has no innervation and
cannot be a direct cause of pain, but the reduction in its thick-
ness and volume with OA results in a higher load on the sub-
chondral bone within the weight-bearing areas of the joint. Re-
modeling processes, which take place in these areas, lead to
the development of osteosclerosis, osteophytes, and micro-
fractures, and eventually to an increase in the stiffness of sub-
chondral bone that can cause significant syndromic pain. An-
other cause of pain is the formation of foci of bone marrow
edema and an increase in the intramedullary pressure.4
In recent years, evidence has accumulated about the role of
subchondral bone in the development of OA. Subchondral
bone has been found to be able to produce a large number
of proinflammatory cytokines and growth factors. Changes in
its microarchitecture can influence the intensity of pain, and
the bone mineral density value in subchondral areas of the
tibia can be considered as a predictor of OA progression.
All of this demonstrates the importance of investigating pain
in OA, especially given the available information that pain can
affect disease prognosis. As was described in the National
Health and Nutrition Examination Survey (NHANES)1 and by
Mazzuca and colleagues,5,6 the initial level of pain in the knee
joint in OA is a risk factor for the development of functional
impairment and radiological progression in the future. I
References
1. McAlindon TE, Cooper C, Kirwan JR, Dieppe PA. Knee pain and disability in the
community. Br J Rheumatol. 1992;31:189-192.
2. Creamer P, Hunt M, Dieppe P. Pain mechanisms in osteoarthritis of the knee: ef-
fect of intraarticular anesthetic. J Rheumatol. 1996;23:1031-1036.
3. Sofat N, Ejindu V, Kiely P. What makes osteoarthritis painful? The evidence for
local and central pain processing. Rheumatology. 2011;50:2157-2165.
4. Sowers MF, Hayes C, Jamadar D, et al. Magnetic resonance-detected subchon-
dral bone marrow and cartilage defect characteristics associated with pain and
X-ray-defined knee osteoarthritis. Osteoarthr Cartil. 2003;11:387-393.
5. Hassan BS, Doherty SA, Doherty M. Effect of pain reduction on postural sway,
proprioception, and quadriceps strength in subjects with knee osteoarthritis. Ann
Rheum Dis. 2002;61:422-428.
6. Mazzuca SA, Brandt KD, Schauwecker DS, et al. Severity of joint pain and Kell-
gren-Lawrence grade at baseline are better predictors of joint space narrowing
than bone scintigraphy in obese woman with knee osteoarthritis. J Rheumatol.
2005;32:1540-1546.
Can age-related cartilage changes be distinguished from early OA changes?

2. J. P. A. Arokoski, Finland
Jari P. A. AROKOSKI, MD, PhD
Clinical Lecturer and Adjunct Professor
(docent) of Physical and Rehabilitation
Medicine, Department of Physical
and Rehabilitation Medicine
Kuopio University Hospital
P. O. B. 1777, FI-70211 Kuopio
FINLAND
(e-mail: jari.arokoski@kuh.fi)
T
he etiology of osteoarthritis (OA) is not fully understood,
but there are known to be several predisposing risk fac-
tors for the condition.1 These include obesity, injuries to
the joints, andmost importantlyold age. The prevalence
and incidence of OA increases with age.2 However, although
epidemiological studies seem to indicate that primary OA and
aging are interrelated, aging does not directly cause OA.3 Age-
related changes in the musculoskeletal system may contribute
to the development of OA by making the joints more suscep-
tible to the effects of other OA risk factors.3 Several novel ag-
ing theories such as progressive apoptotic cell loss, mitochon-
drial degeneration, and cell senescence have been proposed
to account for the cartilage degeneration in OA.4
The pathogenetic changes in primary, and especially early, OA
are difficult to distinguish clinically from normal aging, but there
are some differences discernible between these two fates of
the joint. The current research in this area focuses on artic-
ular cartilage.
Age-related changes in cartilage
Articular cartilage undergoes significant structural and me-
chanical changes with age.2 Articular cartilage collagen and
proteoglycan metabolism are relatively active during growth
and adolescence, but in adult individuals, the metabolism with-
in cartilage is more sluggish.5 There is evidence of an increas-
ing prevalence of articular surface fibrillation with age,2 and car-
tilage also thins with age, suggesting a loss of the cartilage
matrix.3
This might be due to the fact that chondrocytes become less
responsive to the proliferative and anabolic effects of growth
factors with increasing age.3 Aggrecan, the major cartilage pro-
teoglycan, decreases in molecular size and content,5 and this
would be expected to reduce cartilage stiffness and hydra-
tion.3 There is no major change in the content of total collagen
and pyridinoline during aging, but there is a marked increase
in the formation of advanced glycation end products, includ-
ing pentosidine crosslinks, making the cartilage more brittle.3
Can age-related cartilage changes be distinguished from early OA changes?
CONTROVERSIAL QUESTION
Cartilage in osteoarthritis
OA is characterized by a deterioration and progressive loss
of articular cartilage, and it manifests clinically with pain that
does not occur in normal aged cartilage.1 In experimental mod-
els of OA, some of the first detectable abnormalities that can
be observed even before there is any deterioration visible on
the cartilage surface include a decrease in the superficial pro-
teoglycan concentration, increased water content, and the
separation and disorganization of the superficial collagen fib-
rils.1 In early OA, the synthesis of both type II collagen and
proteoglycans is increased. Advanced OA with fibrillation is
accompanied by a net loss and damage to type II collagen
fibrils, as well as a loss of proteoglycans. The loss of proteo-
glycans and collagen results in diminished cartilage stiffness.
At the molecular level, OA is viewed as being a metabolically
active process, including both cartilage destruction and re-
pair.5 This equilibrium is regulated by the complex interplay
between anabolic growth factors (especially TGF and IGF-1)
and catabolic proinflammatory cytokines (especially IL-1 and
TNF ). In a normal joint, these mediators are present at low
levels to maintain the homeostasis of cartilage, but in OA,
these processes become imbalanced, with the increased pro-
teolytic degradation being mediated by matrix metalloprotein-
ases, ie, collagenases and stromelysins.
Early diagnosis of osteoarthritis
The traditional diagnostic techniques, plain X-ray imaging or
arthroscopic examination, can only detect late and major tis-
sue changes in OA and are incapable of differentiating early
cartilage OA changes from age-associated changes. How-
ever, early diagnosis would be highly advantageous as initial
OA changes may still be reversible.6 Recent developments in
quantitative imaging techniques, including magnetic resonance
imaging and ultrasound methods, as well as more sensitive
biomarkers, mean that diagnostic evaluation of cartilage in ear-
ly OA may in the future become reality.6 I
References
1. Arokoski JPA, Jurvelin J, Vtinen U, Helminen HJ. Normal and pathological
adaptation of articular cartilage to joint loading. Scand J Med Sci Sports. 2000;
10:186-198.
2. Martin JA, Buckwalter JA. Roles of articular cartilage aging and chondrocyte
senescence in the pathogenesis of osteoarthritis. Iowa Orthop J. 2001;21:1-7.
3. Loeser RF. Age-related changes in the musculoskeletal system and the devel-
opment of osteoarthritis. Clin Geriatr Med. 2010;26:371-386.
4. Aigner T, Richter W. OA in 2011: age-related OAa concept emerging from in-
fancy? Nat Rev Rheumatol. 2012;10:70-72.
5. Goldring MB, Goldring SR. Osteoarthritis. J Cell Physiol. 2007;213:626-634.
6. Chu CR, Williams AA, Coyle CH, Bowers ME. Early diagnosis to enable early treat-
ment of pre-osteoarthritis. Arthritis Res Ther. 2012;14:212.
MEDICOGRAPHIA, Vol 35, No. 2, 2013 205
CONTROVERSIAL QUESTION
3. F. N. Birrell, United Kingdom
Fraser N. BIRRELL, MD, PhD, FRCP
Musculoskeletal Research Group
Institute of Cellular Medicine
4th Floor, Cookson
Framlington Place, Newcastle University
Newcastle NE2 4HH, UK
(e-mail: fraser.birrell@ncl.ac.uk)
T
he short answer is yes. However, interest and a degree
of controversy derive from the techniques that are avail-
able to discriminate between the two and considera-
tion of whether osteoarthritis (OA) is a disease restricted to
cartilage alone or should more correctly be considered a dis-
ease of the whole joint.
The main techniques used to investigate cartilage include im-
aging, histology, and gene expression profiling. Clinically, the
most useful test would be one that is noninvasive and read-
ily available. Unfortunately, plain radiographs usually provide
no direct visualization of cartilage, unless chondrocalcinosis
is present, and the indirect evidence is limited by difficulties
in interpreting joint space, which is affected by positioning,
and the variable interposition of other low-density tissues such
as menisci. High-resolution musculoskeletal ultrasound and
magnetic resonance imaging can directly visualize cartilage, but
there is a lack of true population data on age-related changes,
even with magnetic resonance imaging. Large studies, for ex-
ample Osteoarthritis Initiative, sponsored by the National In-
stitutes of Health in the United States,1 have focused on a sin-
gle joint (the knee) and used convenience sampling.
Histological techniques include macroscopic examination of
cartilage sections for thinning and fibrillation and microscopic
examination with stains for proteoglycans (such as Safranin O).
While grading systems for cartilage are discriminating for ad-
vanced disease, early OA changes may be difficult to discrim-
inate from age-related change using grading systems for car-
tilage alone.2 Three other approaches to discriminate early
OA changes are: microscopic examination of the whole joint,
measurement of specific enzymes upregulated in OA, and
gene expression profiling. Pathological changes around the
206 MEDICOGRAPHIA, Vol 35, No. 2, 2013
joint in early OA include synovitis and ligament/enthesis and
subchondral bone abnormalities: the importance of these
changes relates to their association with pain, which in clinical
studies has been of stronger importance than early joint space
narrowing (although advanced disease has a very strong re-
lationship with radiographic change,3 in contrast to earlier as-
sertions). Specific enzymes, such as matriptase, are upregu-
lated in OA cartilage,4 which suggests potential relevance as
a target for treatment.
However, probably the most definitive current technique for
distinguishing OA from age-related change alone in cartilage
is gene expression profiling. A recent study by Loeser et al 5
has shown that there are quite different profiles in young ver-
sus aged mice, with 493 genes showing differential expres-
sion and an age-related decrease in matrix gene expression
and increase in immune and defense response gene expres-
sion. Thus, there is a characteristic aging gene profile signa-
ture in mice. Replication in humans will provide us with an in-
vasive tool for discriminating age-related change: arguably
a controversial answer to the controversial question.
A growing appreciation of OA as a disease of the whole joint
suggests that a narrow focus on cartilage alone is, however,
probably counterproductive. Ongoing longitudinal studies will
allow us to define which changes in and around the joint are
associated with progression and response to treatment. We
should increasingly use these predictors and regard cartilage
changes as just one of several key outcomes of OA. I
References
1. Osteoarthritis Initiative. Available at: http://oai.epi-ucsf.org/datarelease/. Accessed
November 21, 2012.
2. McNulty MA, Loeser RF, Davey C, Callahan MF, Ferguson CM, Carlson CS.
Histopathology of naturally occurring and surgically induced osteoarthritis in
mice. Osteoarthritis Cartilage. 2012;20:949-956.
3. Neogi T, Felson D, Niu J, et al. Association between radiographic features of
knee osteoarthritis and pain: results from two cohort studies. BMJ. 2009;339:
b2844.
4. Milner JM, Patel A, Davidson RK, et al. Matriptase is a novel initiator of cartilage
matrix degradation in osteoarthritis. Arthritis Rheum. 2010;62:1955-1966.
5. Loeser RF, Olex AL, McNulty MA, et al. Microarray analysis reveals age-related
differences in gene expression during the development of osteoarthritis in mice.
Arthritis Rheum. 2012;64:705-717.
Can age-related cartilage changes be distinguished from early OA changes?

4. S. Blkbai, Turkey
Seluk BLKBAI, MD
Department of Orthopedics
and Traumatology
Gazi University School of Medicine
06500 Besevler
Ankara, TURKEY
(e-mail: selcukb@gazi.edu.tr)
C
urrently, it is not possible to give an exact answer to
this question. In order to begin to answer the ques-
tion, one must first elucidate whether or not aging of
the cartilage is the same process as cartilage degradation.
As the role of mitochondria is known in degenerative diseases,
a study was conducted to investigate mitochondrial function
in healthy chondrocytes and osteoarthritic chondrocytes, as
well as age-related changes in mitochondria. The study showed
that mitochondrial mass was increased in osteoarthritic chon-
drocytes, but no correlation was found between mitochon-
drial function and age in normal and osteoarthritic chondro-
cytes.1 This result suggests that cartilage aging and cartilage
degradation are two separate processes.1
In another study, the matrix homeostasis of a healthy human
ankle was evaluated.2 Type I collagen synthesis and denatu-
ration were found to be associated with the pericellular ma-
trix, and the type II collagen (CII) and proteoglycan content in
the matrix were determined as remaining constant through-
out life. Age had an important effect on the denaturation of CII,
which decreased as age increased, relative to collagenase-
mediated cleavage.2 These observations suggest that carti-
lage aging and the osteoarthritic process are two separate
processes, since the aging of the ankle cartilage bore no re-
semblance to the molecular degenerative changes of osteo-
arthritis.2 Thus, a clear difference emerges between aging and
osteoarthritis.
On the basis of the two aforementioned studies, new inves-
tigative molecular studies could in the future be used routine-
ly to help differentiate the early stage of osteoarthritis from car-
tilage aging. Currently, however, the results of studies such
as these are not completely clear and remain to be clarified.
Additionally, contrary to the aforementioned results, aging is
one of the most important risk factors in the development of
osteoarthritis, and more than 50% of the population over the
age of 60 years have osteoarthritic joints.3 Because osteo-
Can age-related cartilage changes be distinguished from early OA changes?
CONTROVERSIAL QUESTION
arthritis is a multifactorial disease and age is the major (but not
only) risk factor, it is difficult to determine whether cartilage
degradation and cartilage aging are different processes.
In an experimental study, the accumulation of advanced gly-
cation end products (AGEs) was investigated in relation to os-
teoarthritis.3 AGEs adversely affect the formation of cartilage,
lead to the formation of osteoarthritis, and increase with aging.
In this study, the accumulation of AGEs was found to cause a
tendency to develop osteoarthritis. The results showed that
higher AGE levels in the cartilage increased the severity of os-
teoarthritis, and they provided the first in vivo molecular ev-
idence to demonstrate the role of aging in the development of
osteoarthritis.3
With the development of microarray technology, studies have
emerged suggesting that gene expression analysis of sub-
chondral bone can be conducted in early experimental os-
teoarthritis and can be used in its diagnosis and treatment.4
However, it is currently impossible to obtain suitable subchon-
dral bone and cartilage samples from humans and animals
in order to study the beginning and early stages of osteo-
arthritis.4 Another study indicated that by measuring certain
biomarkers of bone, cartilage, and synovial metabolism (sC2C,
uCTX-II, sCPII, uNTx, and sHA), changes in cartilage matrix
and early structural changes in cartilage could be identified.5
This and many similar studies show that biomarkers may be
important indicators of early-stage osteoarthritis. With such
biomarkers, it could be possible to differentiate early osteo-
arthritis from cartilage aging.
To date, studies have not been able to clearly reveal the dis-
tinction between osteoarthritis and cartilage aging. It is there-
fore difficult to distinguish primary osteoarthritis in its early
stages from cartilage aging, hence the need for further stud-
ies in this area. I
References
1. Manerio E, Martin MA, Andres MC, et al. Mitochondrial respiratory activity is al-
tered in osteoarthritic human articular chondrocytes. Arthritis Rheum. 2003;48:
700-708.
2. Aurich M, Poole R, Reiner A, et al. Matrix homeostasis in aging normal human
ankle cartilage. Arthritis Rheum. 2002;46:2903-2910.
3. De Groot J, Verzijl N, Wenting-van Wijk MJG, et al. Accumulation of advanced
glycation end products as a molecular mechanism for aging as a risk factor in
osteoarthritis. Arthritis Rheum. 2004;50:1207-1215.
4. Zhang Y, Fang H, Chen Y, et al. Gene expression analyses of subchondral bone
in early experimental osteoarthritis by microarray. PloS One. 2012;7:1-19.
5. Ishijima M, Watari T, Naito K, et al. Relationships between biomarkers of carti-
lage, bone, synovial metabolism and knee pain provide insights into the origins
of pain in early knee osteoarthritis. Arthritis Res Ther. 2011;13:R22.
MEDICOGRAPHIA, Vol 35, No. 2, 2013 207
CONTROVERSIAL QUESTION
5. O. P. Bortkevych, Ukraine
Oleg P. BORTKEVYCH, MD, PhD, DMedSc
Department of Clinical Rheumatology
National Scientific Centre M. D. Strazhesko
Institute of Cardiology
5, Narodnogo Opolcheniya St, 03151
UKRAINE
(e-mail: bortkevych@yahoo.com)
O
steoarthritis (OA) is a disease of the joint affecting all
joint tissues. Similarly, joint aging is systemic. Age is
the most prominent risk factor for OA, and although
the relationship between aging and OA is well known, its mech-
anisms are not fully understood.
Joint changes that are both intrinsic and extrinsic (sarcope-
nia, altered bone remodeling, reduced proprioception) con-
tribute to OA development. The concept that aging contributes
to, but does not directly cause OA, is consistent with the mul-
tifactorial nature of the condition and the joints most com-
monly affected. OA normally develops after long periods of
exposure to risk factors such as obesity, joint trauma, joint
malalignment, or abnormal shape and leg length inequality.
Age-related changes occur in the joint tissues of all individu-
als, most notably in articular cartilage. However, symptomatic,
radiographic, macroscopic, or microscopic signs of OA do not
manifest in all individuals, even at an advanced age. This sug-
gests that aging does not necessarily cause OA, rather age-
related changes provide a basis upon which OA can develop.
Individuals with OA risk factors may undergo an accelerated
rate of change similar to that associated with aging, consis-
tent with the concept that aging results from an imbalance be-
tween stressors causing damage and mechanisms that re-
pair or protect against damage.
In both aging and OA, changes occur in the total amount and
composition of articular cartilage extracellular matrix, which
also undergoes proteolysis and other modifications. The su-
perficial zone is where the earliest age-related changes occur
in human articular cartilage. In OA, increased proteolytic ac-
tivity in cartilage and synovial fluid causes cartilage matrix
changes and increased degradation of collagen molecules.
There is also a decrease in fixed charge density due to degra-
dation and loss of aggrecan.
208 MEDICOGRAPHIA, Vol 35, No. 2, 2013
Normal aging involves a marked increase in the formation of
advanced glycation end products, including pentosidine cross-
links. The resultant increased crosslinking of collagen mole-
cules can alter the biomechanical properties of cartilage, re-
sulting in increased stiffness and susceptibility to fatigue.
A highly prevalent change in aging cartilage is deposition of
calcium-containing crystals due to increased pyrophosphate
production by chondrocytes. Calcium crystals may stimulate
chondrocyte production of inflammatory mediators and extra-
cellular matrixdegrading enzymes, contributing to the onset
and progression of OA, and may play a role in erosive OA, a
more destructive form of OA most commonly seen in the dis-
tal interphalangeal joints in elderly women.
Age-associated cellular changes in articular cartilage include
cell depletion and impaired responses to extracellular stimuli
resulting in abnormal gene expression and cell differentiation.
In full-thickness cartilage, cell density decreases with aging. In
OA-affected cartilage, chondrocyte proliferation in the form
of cell clusters or cloning has been observed in areas of
fibrillation. Cells in these clusters express progenitor cell mark-
ers and a wide spectrum of proteins associated with abnor-
mal chondrocyte activation and differentiation. This represents
a tissue repair response of progenitor cells. The activation pat-
tern of the cluster cells also underscores the notion that aging
does not uniformly affect all cells in cartilage and that certain
cell subsets in aging and OA-affected cartilage are capable
of proliferation and activation.
With increasing age, chondrocytes become less responsive
to the proliferative and anabolic effects of growth factors,
which may contribute to an imbalance between anabolic and
catabolic activity. Altered cell signaling in response to growth
factors may also account for the reduced anabolic response
with age.
Conceptually, age-related pathologies originate from limitations
in the maintenance and repair mechanisms of DNA, anom-
alies in the antioxidant mechanisms that contribute to the de-
toxification of reactive oxygen species, or abnormalities in
mechanisms for removal of abnormal proteins and organelles.
A clear distinction between aging and OA has not always been
provided, so that it can be difficult to differentiate primary age-
related changes from those that are part of the OA process. I
Can age-related cartilage changes be distinguished from early OA changes?

6. P. Hork, Czech Republic
Pavel HORK, MD, PhD
Department of Internal Medicine
Nephrology, Rheumatology, Endocrinology
Faculty of Medicine and Dentistry
Palack University of Olomouc
I. P. Pavlova 6
772 00 Olomouc
CZECH REPUBLIC
(e-mail: pavel.horak@fnol.cz)
O
steoarthritis (OA) is a slow-developing disease of the
diarthrodial joints associated with progressive car-
tilage damage, soft tissue and subchondral bone
changes, bony osteophytes, and joint inflammation. OA is most
common in the hands, causing significant pain and function-
al loss, but involvement of the knees or hips is usually more
disabling. Aging is the most important risk factor, followed
by obesity, previous joint injury, female sex, and genetic dis-
position. Two fundamental mechanisms lead to OA: normal
load on abnormal cartilage (primary OA) or abnormal load on
normal cartilage (secondary OA). Although cartilage aging is
universal, OA is not found in all elderly people; a proportion of
them are free of symptomatic and radiographic OA, indicat-
ing the presence of additional risk and/or protective factors.
There are several theories explaining the pathogenesis of pri-
mary OA. The oldest theory, wear and tear of the cartilage ma-
trix, emphasizes the effect of mechanical load over a lifetime.
The extracellular matrix theory links OA to intrinsic changes
in proteoglycans, the collagen network, and chondrocyte bi-
ology that are caused by advanced glycation end products
and oxidative stress. The apoptotic theory views OA as the
result of chondrocyte apoptosis or other types of cell death.
The mitochondrial theory emphasizes the role of mitochon-
drial DNA damage, which may be advanced by inflammato-
ry cytokines, contributing to chondrocyte energy failure and
death. A recent theory on cell senescence describes OA as
the increasing inability of the chondrocytes to keep up with
mechanical or inflammatory attacks leading to failure in main-
taining cartilage integrity.
The causes of cell aging remain unclear, but it is increasingly
accepted that there are a limited number of cell replication
cycles, culminating in replicative senescence. Replication is
limited by telomere exhaustion. Telomeres are eroded by each
division cycle, eventually down to the minimum length for DNA
replication, resulting in cycle arrest.
In adults, subchondral bone isolates cartilage from the vas-
cular system, resulting in no influx of progenitor cells into car-
tilage. Chondrocytes are postmitotic, with little or no cell turn-
Can age-related cartilage changes be distinguished from early OA changes?
CONTROVERSIAL QUESTION
over, and are among the oldest cells in the body. They ac-
cumulate age-related changes and are also unable to move
from damaged regions due to the constraint of the extracel-
lular matrix. Aside from aging, repeated injuries (joint insta-
bility) increase the requirements for replication and damage
repair and thus contribute to the exhaustion of mitotic po-
tential. As a result of the specific local environment, oxida-
tively damaged molecules can accumulate in chondrocytes,
leading to a decreased ability to maintain matrix synthesis and
homeostasis. Chondrocyte senescence reduces the ability
to respond to growth factor stimulation, contributing to an
imbalance in cartilage formation and degradation, as well as
decreased chondrocyte anabolic activity. Furthermore, senes-
cence-associated secretory phenotype (SASP) may negative-
ly affect the local environment. Cells exhibiting SASP pro-
duce proinflammatory cytokines and matrix metalloproteinases
very similar to those in OA. Another cell senescence factor,
high-mobility group box protein 2, regulates gene transcrip-
tion and decline in the superficial zone of aging chondro-
cytes and is associated with increased chondrocyte death in
OA models.
Current findings support the view that cartilage aging usually
occurs before overt primary OA. In many cases, it is impossi-
ble to distinguish the senescent chondrocyte from the osteo-
arthritic chondrocyte because cell senescence is the number
one precondition for OA. There is some evidence of increased
chondrocyte proliferation during the development of OA, and
chondrocyte death has also been observed, with reduced
numbers particularly in the superficial regions of cartilage.
However, it is not clear if the cell damage and reactivity rep-
resent changes associated with the aging process, early OA,
or a continuum from aging to OA.
A better understanding of the role of senescence biology in OA
development may translate practically into the development
of new strategies to delay the onset of chondrocyte senes-
cence and prevent the development or progression of OA. I
Further reading
1. Aigner T, Richter W. Age related OAa concept emerging from infancy? Nat
Rev Rheumatol. 2012;8:70-72.
2. Horton Jr WE, Bennion P, Yang L. Cellular, molecular, and matrix changes in
cartilage during aging and osteoarthritis. J Musculoskelet Neuronal Interact.
2006;6:379-381.
3. Loeser RF. Aging and osteoarthritis. Curr Opin Rheumatol. 2011;23:492-496.
4. Anderson AS, Loeser RF. Why is osteoarthritis an age-related disease? Best
Pract Res Clin Rheumatol. 2010;24:15-26.
5. Martin JA, Buckwalter JA. Aging, articular cartilage chondrocyte senescence
and osteoarthritis. Biogerontology. 2002;3:257-264.
6. Loeser RF. Age-related changes in the musculoskeletal system and the devel-
opment of osteoarthritis. Clin Geriatr Med. 2010;26:371-386.
MEDICOGRAPHIA, Vol 35, No. 2, 2013 209
CONTROVERSIAL QUESTION
7. A. El Maghraoui, Morocco
Abdellah El MAGHRAOUI, MD
Professor of Rheumatology
Rheumatology Department
Military Hospital Mohammed V
Rabat
MOROCCO
(e-mail: aelmaghraoui@gmail.com)
O
steoarthritis (OA) is a common age-related disorder,
often described as a chronic degenerative disease
and thought by many to be an inevitable conse-
quence of growing old. Epidemiological studies show that age
remains the most prominent risk factor for the initiation and
progression of primary OA in susceptible joints.1 The preva-
lence of OA increases with age: radiographic surveys of mul-
tiple joints (hands, spine, hips, and knees) reveal the pres-
ence of OA in at least one joint in over 80% of older adults.2
However, not all older adults with symptoms of joint pain have
radiographic evidence of OA in the painful joint, and only about
half of people with radiographic OA experience significant
symptoms. Moreover, it is well-known that not all older adults
develop OA and not all joints in the body are affected to the
same degree. It is also well-known that radiographic OA
changes, particularly osteophytes, are common in the aged
population, but symptoms of joint pain are frequently inde-
pendent of radiographic severity. Consequently, due to the dis-
crepancies between osteoarthritic pain and radiographic ev-
idence of OA, most current epidemiological studies define OA
through a combination of clinical and radiographic criteria.
The current concept is that OA is a disease of the whole joint,
which involves a complex series of molecular changes at the
cell, matrix, and tissue levels and complex interactions be-
tween the tissues that make up the joint. Aging is the major
risk factor, and it contributes to, but does not directly cause
OA. This is consistent with the multifactorial nature of the con-
dition and the differing joints most commonly affected. Be-
sides age, the common risk factors for OA include obesity,
previous joint injury, genetics, and anatomical factors includ-
ing joint alignment. These risk factors appear to interact with
age to determine which joints are affected by OA and how
severe the condition will be. Thus, there are important differ-
ences between an aged joint and one with OA. Age-related
210 MEDICOGRAPHIA, Vol 35, No. 2, 2013 Can age-related cartilage changes be distinguished from early OA changes?
mechanical stress on joint cartilage (arising from a number of
factors, including altered gait, muscle weakness, degenera-
tion of ligaments, changes in proprioception, and changes in
body weight), and changes within the joint (including cell and
matrix changes in joint tissues, thickening of the subchondral
bone, variable degrees of synovial inflammation, loss of menis-
cal tissue, and hypertrophy of the joint capsule contributing
to joint enlargement) contribute to the development of OA
when other OA risk factors are also present.3 The patholog-
ical changes noted in the other joint tissues also contribute
to the loss of normal joint function, and because, unlike carti-
lage, they contain pain fibers, these tissues are responsible
for the pain experienced by people with OA.
Thus, it is very important to question how to distinguish nor-
mal age-related changes in cartilage that do not progress to
OA from early changes that reliably do progress to OA. In this
regard, magnetic resonance imaging (MRI) studies have shown
promising results. New methodological approaches for quan-
titative assessment have been introduced, and an MRI-based
definition of OA has been suggested.4 A recent study using
MRI methods sensitive to cartilage matrix composition demon-
strated that subjects at risk for OA have both higher and more
heterogeneous cartilage T2 values than controls, and that T2
parameters are associated with morphologic degeneration.5
One could speculate that the development of these kinds of
techniques could help to distinguish age-related changes in
cartilage that predispose patients to OA from those that do
not. More information is needed to better understand how
aging changes in the bone, meniscus, and ligaments con-
tribute to the development of OA. I
References
1. Aigner T, Richter W. OA in 2011: age-related OAa concept emerging from in-
fancy? Nat Rev Rheumatol. 2012;8:70-72.
2. Loeser RF. Age-related changes in the musculoskeletal system and the develop-
ment of osteoarthritis. Clin Geriatr Med. 2010;26:371-386.
3. Heijink A, Gomoll AH, Madry H, et al. Biomechanical considerations in the patho-
genesis of osteoarthritis of the knee. Knee Surg Sports Traumatol Arthrosc. 2012;
20:423-435.
4. Hunter DJ, Arden N, Conaghan PG, et al. Definition of osteoarthritis on MRI: re-
sults of a Delphi exercise. Osteoarthritis Cartilage. 2011;19:963-969.
5. Joseph GB, Baum T, Carballido-Gamio J, et al. Texture analysis of cartilage T2
maps: individuals with risk factors for OA have higher and more heterogeneous
knee cartilage MR T2 compared to normal controlsdata from the osteoarthri-
tis initiative. Arthritis Res Ther. 2011;13:R153.

8. A. Mahmoud Ali Elsayed, Egypt
Adel Mahmoud ALI ELSAYED, MD
Professor of Internal Medicine
Head of Rheumatology Division
Ain Shams University
53 El Makrizy Street
Roxy, Cairo
EGYPT
(e-mail: dr_adel_mahmoud25@yahoo.com)
A
rticular cartilage is a unique tissue from the perspec-
tive of aging, in that chondrocytes and the majority
of the extracellular matrix proteins experience little
turnover, thus resulting in a tissue that must withstand years
of use and can also accumulate years of aging-associated
changes. It has been known for a very long time that aging
is the most prominent risk factor for the initiation and progres-
sion of osteoarthritis. This might be related to continuous me-
chanical wear and tear and/or time/age-related modifications
of cartilage matrix components. In addition, a mere loss of vi-
able cells over time due to apoptosis or any other mechanism
might contribute. More recent evidence, however, supports
the notion that stressful conditions for the cells might pro-
mote chondrocyte senescence and be particularly important
in the progression of the osteoarthritic disease process.1
In animal models, aging predisposes articular cartilage to
changes in viable cell density and to expression of specific pro-
apoptotic genes. Also, fetal and young (but still skeletally ma-
ture) bovine chondrocytes behave similarly, while aged chon-
drocytes display diminished proliferation, slightly reduced
proteoglycan accumulation, and significantly less collagen ac-
cumulation per cell compared with the younger cells. Histo-
logical observations and mechanical properties support these
findings, and a particularly significant reduction in the tensile
stiffness produced by aged chondrocytes compared with
younger cells has been observed.2
In humans, chondrocytes from normal but aged subjects dis-
play biochemical properties closer to osteoarthritic-derived
cartilage than to normal young cartilage, as indicated by cell
Can age-related cartilage changes be distinguished from early OA changes?
CONTROVERSIAL QUESTION
morphology, cell proliferation rate, and patterns of protein se-
cretion (in particular stromelysin-1 and interstitial collagenase).3
During aging, nonenzymatic glycation results in the accumu-
lation of advanced glycation end products (AGEs) in cartilage
collagen. The highest AGE levels are found in tissues with
slow turnover, such as cartilage. AGEs exert their effects by ad-
versely affecting the biomechanical, biochemical, and cellu-
lar characteristics of the tissue, as well as by modulating tis-
sue turnover.
This ultimately increases cartilage stiffness and brittleness, in-
creases chondrocyte-mediated proteoglycan degradation,
reduces resistance to matrix metalloproteinasemediated de-
gradation, and decreases proteoglycan synthesis by chon-
drocytes. Articular cartilage becomes more prone to damage
and development of osteoarthritis.4
In addition, an age-associated reduction in growth factor sig-
naling and an increase in oxidative stress may also play an im-
portant role in the age-osteoarthritis connection.5
Although different studies have shown that age is inversely as-
sociated with cartilage volume, cartilage turnover, and aggre-
can expression in healthy individuals, the exact differentiation
between aged cartilage and early osteoarthritic cartilage seems
difficult, and age-related changes leading to failure of human
articular cartilage to resist damage are considered to be OA. I
References
1. Aigner T, Haag J, Martin J, Buckwalter J. Osteoarthritis: aging of matrix and
cellsgoing for a remedy. Curr Drug Targets. 2007;8:325-331.
2. Tran-Khanh N, Hoemann CD, McKee MD, Henderson JE, Buschmann MD.
Aged bovine chondrocytes display a diminished capacity to produce a colla-
gen-rich, mechanically functional cartilage extracellular matrix. J Orthop Res.
2005;23:1354-1362.
3. Dozin B, Malpeli M, Camardella L, Cancedda R, Pietrangelo A. Response of
young, aged and osteoarthritic human articular chondrocytes to inflammatory
cytokines: molecular and cellular aspects. Matrix Biol. 2002;21:449-459.
4. DeGroot J. The age of the matrix: chemistry, consequence and cure. Curr Opin
Pharmacol. 2004;4:301-305.
5. Loeser RF Jr. Aging cartilage and osteoarthritiswhat's the link? Sci Aging
Knowledge Environ. 2004;pe31.
MEDICOGRAPHIA, Vol 35, No. 2, 2013 211
CONTROVERSIAL QUESTION
9. A. Migliore, Italy
Alberto MIGLIORE, MD
Director UOS of Rheumatology
Hospital Villa S. Pietro
Rome, ITALY
(e-mail: albertomigliore@terra.es)
A
ging is the main risk factor for primary osteoarthritis
(OA) and OA is the disease most strongly correlated
with aging. Both in humans and other animals, OA
development seems to be not rigorously time-dependent, but
to hold pace with the aging process. Despite older age being
the greatest risk factor for OA, OA is not an unavoidable con-
sequence of growing old. Moreover, radiographic changes in-
dicative of OAmainly osteophytesare frequent in the aged
population, but symptoms of joint pain may not correlate with
the severity of radiographic findings in many older subjects.
OA is a degenerative disease characterized by structural
changes to joint tissues that include synovial inflammation,
catabolic destruction of articular cartilage, alterations in sub-
chondral bone, and decreasing muscle strength.
This article will only address differences between cartilage
changes caused by OA and those caused by aging. The ef-
fects of aging involve the whole articular cartilage. Major ex-
tracellular matrix changes comprise reduced cartilage thick-
ness, proteolysis, advanced glycation, and calcification. Cellular
changes consist of decreased cell density, cellular senes-
cence with reduced chondrocyte survival, decreased mitotic
and anabolic activity, anomalous cytokine excretion, and im-
paired cellular resistance.
One of the most pronounced age-related changes in chon-
drocytes is a senescent phenotype, which is caused mainly
by the accumulation of reactive oxygen species (ROS) and
advanced glycation end products. Senescent chondrocytes
display an impaired ability to respond to many mechanical
and inflammatory insults. Protein secretion is also altered in
aging chondrocytes, as demonstrated by a decrease in an-
abolic activity and increased production of proinflammatory
cytokines and matrix-degrading enzymes. The senescent se-
212 MEDICOGRAPHIA, Vol 35, No. 2, 2013 Can age-related cartilage changes be distinguished from early OA changes?
cretory phenotype has some features in common with the OA
chondrocyte phenotype, including increased production of
cytokines and matrix metalloproteinases.
The age-related increase in ROS levels could play an impor-
tant role in OA. The various inflammatory mediators that are
increased in OA, including IL-1, IL-6, IL-8, TNF-, and other
cytokines, can all stimulate additional production of ROS. Ex-
cess ROS production can directly damage intracellular pro-
teins and DNA, as well as the extracellular matrix, by stimu-
lating matrix metalloproteinase production and activity, thus
playing a significant role in stimulation of cartilage degrada-
tion in OA.
The extracellular and cellular changes in aging compound each
other, leading to biomechanical dysfunction and tissue de-
struction. Some of these changes differ from those seen in OA,
which is also characterized by cell activation with increased
proliferation and gene expression. Disruption of the articu-
lar surface or superficial zone (SZ) seems to be a key trigger-
ing event for the chronic and progressive extracellular ma-
trix degradation process leading to OA. The SZ contains the
majority of mesenchymal stem cells in adult cartilage. The
presence of stem cells endows the SZ with the capacity for
self-renewal, which may be required to respond to mechan-
ical stress. However, the SZ can be compromised by acute
or chronic mechanical stress and by age-related cellular dys-
function. Once the SZ is disrupted, cartilage cells are acti-
vated, and through the production of matrix-degrading en-
zymes, lesions enlarge causing joint inflammation, pain, and
dysfunction. Loss of cells (eg, via apoptosis) is among the ma-
jor changes that occur in the SZ due to aging and exposure
to mechanical stress.
Cartilage degradation results in the production of fragments of
extracellular matrix molecules. Some of these molecules may
be detected in blood, serum, synovial fluid, and urine, and
can act as useful biomarkers. The ability to detect biomarkers
of cartilage degradation may enable clinicians to differentiate
the appearance of subclinical OA from natural joint aging. Bio-
markers indicating early phases of degeneration would be
useful in detecting preradiographic OA changes. Proteomic
techniques have the potential to improve our understanding
of OA pathophysiology. I

10. T. Pap, Germany
Thomas PAP, MD
Institute of Experimental
Musculoskeletal Medicine
University Hospital Mnster
Domagkstrasse 3
D-48149 Mnster
GERMANY
(e-mail: thomas.pap@uni-muenster.de)
O
steoarthritis (OA) is the most frequent joint disease
and an important cause of disability in the Western
world. It involves all parts of articular joints and is
characterized primarily by the progressive, irreversible loss of
articular cartilage. Given that the incidence of osteoarthritic
changes increases with age, the question of whether OA is a
mere aging phenomenon or as with cardiovascular disorders,
cancer, or neurodegenerative diseases, becomes more fre-
quent during aging because of the cumulative effects of path-
ogenic factors (which in principle can affect individuals at any
age), is a controversial, yet important, one.
One main reason for the difficulty in answering this question
is that the processes that lead to and characterize normal
cartilage aging remain largely unknown. While it is well accept-
ed that the composition of the extracellular matrix changes
with aging, aside from the loss of proteoglycans, disease-spe-
cific alterations in osteoarthritic cartilage are poorly charac-
terized and understood. Also, OA most likely does not con-
stitute a uniform disease, but rather an initially complex yet
ultimately narrow path of how cartilage responds to different
types of stress. In this context, it has been suggested that in-
flammation is a distinguishing factor between normal aging
and OA.1 However, the role of inflammation as a trigger and
accelerating force of osteoarthritic changes remains contro-
versial, and while some recent data suggest a key role for
inflammatory signals, the most recent studies have failed to
demonstrate a key role for IL-1mediated inflammation in
murine models of OA.2 Of interest, several lines of evidence
indicate that osteoarthritic changes are linked to the reex-
pression in chondrocytes of molecules and pathways that
are characteristic of different stages of endochondral ossi-
fication during embryonic development.3
Members of the syndecan family of transmembrane heparin
sulfate proteoglycans, particularly syndecan-4, are prominent
examples in this respect.4 We were able to show that syn-
decan-4, which is expressed prominently in hypertrophic chon-
drocytes of developing joints in the embryo, is reexpressed
both in human OA and in animal models of the disease, and
Can age-related cartilage changes be distinguished from early OA changes?
CONTROVERSIAL QUESTION
its concentration correlates with disease severity.4 Interest-
ingly, the loss of syndecan-4 in genetically modified mice, as
well as its inhibition by specific antibodies, was capable of
preventing the development of OA-like changes.4 These data
are also of interest because according to recent data, in-
creased expression of syndecan-2 can compensate for the
loss of syndecan-4 during embryogenesis but not during OA,
due to differential regulation of these two syndecans. While
the exact mechanisms are not fully understood, these data
suggest that while the program appears to be similar, the
triggers and mechanisms of cartilage remodeling during en-
dochondral ossification and OA may be distinct.
Given that during endochondral ossification, deposition of ba-
sic calcium phosphate crystals is an important part of bone
formation, calcification of articular cartilage during OA is an-
other indication of similarities between both conditions. Our
group found that the calcification of hyaline cartilage is a reg-
ular event in human OA and is strongly associated with the
hypertrophic differentiation of chondrocytes.5 The mechanisms
involved in pathological cartilage calcification during OA, and
particularly the pathways that link chondrocyte differentiation
to the calcification of the surrounding matrix, are not com-
pletely understood. However, changes in the synthesis and
transport of inorganic pyrophosphate, as well as in extracel-
lular pyrophosphate metabolism, have been found to be as-
sociated with this process.6
Collectively, these data indicate that while mechanistically sim-
ilar and part of a rather uniform program, the developmental
processes that occur either during embryogenesis or during
aging can be distinguished from the pathological changes
seen in OA. Distinguishing factors appear to include the na-
ture, strength, and duration of underlying stimuli. I
References
1. Furuzawa-Carballeda J, Macip-Rodriguez PM, Cabral AR. Osteoarthritis and
rheumatoid arthritis pannus have similar qualitative metabolic characteristics and
pro-inflammatory cytokine response. Clin Exp Rheumatol. 2008;26:554-560.
2. Bougault C, Gosset M, Houard X, et al. Stress-induced cartilage degradation does
not depend on NLRP3 inflammasome in osteoarthritis. Arthritis Rheum. 2012;64:
3972-3981
3. Saito T, Fukai A, Mabuchi A, et al. Transcriptional regulation of endochondral os-
sification by HIF-2alpha during skeletal growth and osteoarthritis development.
Nat Med. 2010;16:678-686.
4. Echtermeyer F, Bertrand J, Dreier R, et al. Syndecan-4 regulates ADAMTS-5 ac-
tivation and cartilage breakdown in osteoarthritis. Nat Med. 2009;15:1072-1076.
5. Fuerst M, Bertrand J, Lammers L, et al. Calcification of articular cartilage in hu-
man osteoarthritis. Arthritis Rheum. 2009;60:2694-2703.
6. Bertrand J, Nitschke Y, Fuerst M, et al. Decreased levels of nucleotide pyrophos-
phatase phosphodiesterase 1 are associated with cartilage calcification in osteo-
arthritis and trigger osteoarthritic changes in mice. Ann Rheum Dis. 2012;71:
1249-1253.
MEDICOGRAPHIA, Vol 35, No. 2, 2013 213
CONTROVERSIAL QUESTION
11. J. del Pino-Montes, Spain
Javier DEL PINO-MONTES, MD, PhD
Professor of Medicine
University of Salamanca
Service of Rheumatology
University Hospital of Salamanca
Paseo San Vicente, 54
37007 Salamanca
SPAIN
(e-mail: jpino@usal.es)
O
steoarthritis (OA) is probably the most common
chronic joint disorder. It is defined by focal lesions
of the articular cartilage, a hypertrophic reaction in
the subchondral bone, and new bone formation. OA is often
considered a chronic degenerative disease, with degradation
of articular cartilage attributed to wear and tear. Although ag-
ing is a known risk factor for OA, the condition is not a con-
sequence of growing old, but involves a destructive chronic
active inflammatory mechanism mediated by cells within the
articular cartilage.1
In OA, there is a change in the normal adult chondrocyte state
characterized by cell proliferation, cluster formation, and in-
creased production of matrix proteins and matrix-degrading
enzymes. Chondrocytes in OA cartilage express cytokine and
chemokine receptors, matrix metalloproteinases (MMPs), and
other proteins that enhance or modulate inflammatory and
catabolic responses. MMPs such as aggrecanases and col-
lagenases are found in the osteoarthritic joint. In early OA,
MMP-3 and ADMTS-5 degrade aggrecan.2 Next, collagenas-
es degrade type II collagen and the collagen network. As the
articular cartilage matrix proteins are degraded, fragments
of matrix proteins such as fibronectin and small leucine-rich
proteoglycans are produced, which can feed back and stim-
ulate further matrix destruction. This early stage may reflect an
effort by the hypertrophic chondrocytes to repair cartilage dam-
age. As OA progresses, the proteoglycan level eventually
drops very low, causing cartilage to soften and lose elastic-
ity, thereby further compromising joint surface integrity.
Aging produces a gradual loss of cartilage matrix as well as
a decrease in cartilage hydration and cellularity. Aging carti-
lage is characterized by an age-related loss in the ability of cells
and tissues to maintain homeostasis. Normal aging chondro-
cytes are reduced in number, rarely divide, and exhibit no
cellular proliferation or hypertrophic cells. They show short-
ened telomeres characteristic of cellular senescence. Howev-
er, aging chondrocytes can exhibit a senescence secretory
phenotype, characterized by increased production of cyto-
kines, MMPs, and several growth factors.3 As a result, in the
elderly, there is increased age-related cartilage catabolism.
214 MEDICOGRAPHIA, Vol 35, No. 2, 2013
Besides these mechanisms, the chondrocyte anabolic re-
sponse to growth factors decreases with age. Under such cir-
cumstances, the chondrocyte is unable to maintain cartilage
homeostasis. Cell death has also been related to aging, and
formation of advanced glycation end products (AGEs) in-
creases with age.4 Modification of collagen by AGE formation
results in increased crosslinking of collagen molecules affect-
ing the biochemical properties of cartilage and making it more
brittle. Moreover, there is an age-related increase in reactive
oxygen species, and this may contribute to cell death and
matrix degeneration.5
There is no clear frontier between the features of articular car-
tilage in aging and OA, and both share some common char-
acteristics. Senescent and osteoarthritic chondrocytes share
a secretory phenotype. Cell death has been observed during
the development of OA as well as in aging cartilage. Age-re-
lated loss of autophagy, a protective mechanism for normal
chondrocytes that protects cells during the stress response,
is associated with cell death and OA development.6 Age-re-
lated changes in cartilage matrix could also be important in
contributing to the development of OA. The increased ac-
cumulation and expression of AGEs that occurs in aging
chondrocytes is associated with enhanced sensitivity to cy-
tokines and chemokines, which trigger expression of MMPs.
The increased production of reactive oxygen species could
also play an important role in OA.
The relationship between aging and OA is well known, but
the mechanisms by which aging predisposes the joint to OA
development are not fully understood. Age-related changes
observed in cell and cartilage matrix may increase the sus-
ceptibility to OA, but they do not directly cause it in older
adults. More information is needed to better understand how
aging changes in the bone, meniscus, and ligaments con-
tribute to the development of OA. I
References
1. Goldring MB, Marcu KB. Cartilage homeostasis in health and rheumatic diseases.
Arthritis Res Ther. 2009;11:224.
2. Wang M, Shen J, Jin H, Im HJ, Sandy J, Chen D. Recent progress in under-
standing molecular mechanisms of cartilage degeneration during osteoarthritis.
Ann N Y Acad Sci. 2011;1240:61-69.
3. Leong DJ, Sun HB. Events in articular chondrocytes with aging. Curr Osteo-
poros Rep. 2011;9:196-201.
4. DeGroot J, Verzijl N, Wenting-van Wijk MJ, et al. Accumulation of advanced gly-
cation end products as a molecular mechanism for aging as a risk factor in os-
teoarthritis. Arthritis Rheum. 2004;50:1207-1215.
5. Del Carlo M Jr, Loeser RF. Cell death in osteoarthritis. Curr Rheumatol Rep.
2008;10:37-42.
6. Goldring MB. Chondrogenesis, chondrocyte differentiation, and articular carti-
lage metabolism in health and osteoarthritis. Ther Adv Musculoskelet Dis. 2012;
4:269-285.
Can age-related cartilage changes be distinguished from early OA changes?

12. C. A. F. Zerbini, Brazil
Cristiano A. F. ZERBINI, MD
Rheumatology Department
Hospital Helipolis
Rua Conego Xavier #276
04231-030, So Paulo, SP
BRAZIL
(e-mail: criszerb@uol.com.br)
O
steoarthritis (OA) is considered a characteristic age-
related disease. Its prevalence increases with age, af-
fecting 30% to 50% of adults aged over 65 years.1
Although it is the greatest risk factor for OA, older age alone
is not responsible for its development. Age, obesity, female
sex, previous trauma (knee injury), and hand OA were report-
ed as consistent risk factors for knee OA in people aged 50
years and older.2 Risk factors for OA such as obesity, genet-
ics, anatomical abnormalities, and joint injury are well known,
but how they interact with age to initiate and develop OA is
still unclear. Recent advances in molecular biology are start-
ing to clarify the connection between cellular aging changes
and the propensity to develop OA.
Chondrocytes are the only cell type in articular cartilage, and
they particularly suffer during aging. They are responsible
for the synthesis and breakdown of the cartilaginous matrix
and are driven by signals from growth factors, cytokines, and
the matrix itself. The chondrocytes of older cartilage are the
same cells present in the cartilage during youth. Chondrocytes
rarely divide or die in normal adult articular cartilage, with the
same cells remaining active for many years. Chondrocytes
have a very long lifespan, but in older individuals they may ex-
press changes characteristic of cell senescence. Cell senes-
cence found in chondrocytes is called stress-induced or
extrinsic senescence, as opposed to replicative or intrin-
sic senescence. Stress-induced senescence can develop
from stimuli including activated oncogenes, ultraviolet radia-
tion, and chronic inflammation. Stress-induced senescence
is associated with oxidative DNA damage, which results in
telomere shortening (as in replicative senescence). Many age-
related changes in chondrocytes, particularly oxidative DNA
damage, may induce development of the senescence-asso-
ciated secretory phenotype (SASP).3 This phenotype when
expressed in chondrocytes may link the articular aging process
with the development of OA. SASP is characterized by in-
creased production of inflammatory mediators such as cy-
tokines and matrix metalloproteinases, which may induce car-
tilaginous matrix degradation and joint impairment and may
also be found in osteoarthritic cartilage. SASP expression in
chondrocytes may be linked to the production of reactive oxy-
gen species (ROS) by dysfunctional mitochondria, resulting in
Can age-related cartilage changes be distinguished from early OA changes?
CONTROVERSIAL QUESTION
mitochondrial and nuclear DNA damage. Mitochondrial DNA
damage can be observed in OA and is associated with in-
creased matrix degradation and decreased matrix synthesis.
ROS production may be induced by inflammatory cytokines
such as IL-1 and TNF-, and is also associated with me-
chanical injury to joints. An increase in ROS may contribute
to chondrocyte death.4
Thus, ROS, mitochondrial dysfunction, and DNA damage may
be features of chondrocyte senescence associated with de-
velopment of SASP and may lead to cartilage matrix impair-
ment and development of OA.
Aged and osteoarthritic chondrocytes have a reduced ability
to respond to transforming growth factor- and insulin-like
growth factor-1 (IGF-1) stimulation. This leads to a reduced
capacity for matrix repair, and consequently, a degeneration
of the articular cartilage. The decrease in chondrocyte respon-
siveness to IGF-1 is associated with increased ROS levels.5
Autophagy is a mechanism used by the cell to degrade and
recycle dysfunctional proteins. It is an important mechanism
by which cells are protected against stress. Autophagy de-
clines with age, and its loss has been associated with in-
creased chondrocyte death. Recent studies in autophagy have
attempted to clarify the possible role of this process in senes-
cence and OA.6
Thus, to answer the question, we must determine if and when
the aging process results in the development of SASP. Senes-
cent chondrocytes developing this phenotype are very sim-
ilar to chondrocytes found in osteoarthritic joint tissues. In
my opinion, development of this phenotype with its associ-
ated inflammatory cytokines, or lack of it, will determine how
much we can distinguish between normal age-related changes
in cartilage and early osteoarthritic changes. I
References
1. Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of arthri-
tis and other rheumatic conditions in the United States: Part II. Arthritis Rheum.
2008;58:26-35.
2. Blagojevic M, Jinks C, Jeffery A, et al. Risk factors for onset of osteoarthritis of
the knee in older adults: a systematic review and meta-analysis. Osteoarthritis
Cartilage. 2010;18:24-33.
3. Freund A, Orjalo AV, Desprez PY, et al. Inflammatory networks during cellular
senescence: causes and consequences. Trends Mol Med. 2010;16:238-246.
4. Loeser RF. Aging and osteoarthritis. Curr Opin Rheumatol. 2011;23:492-496.
5. Yin W, Park JI, Loeser RF. Oxidative stress inhibits insulin-like growth factor-I
induction of chondrocyte proteoglycan synthesis through differential regulation
of phosphatidylinositol 3-Kinase-Akt and MEK-ERK MAPK signaling pathways.
J Biol Chem. 2009;284:3197231981.
6. Carames B, Taniguchi N, Otsuki S, et al. Autophagy is a protective mechanism in
normal cartilage, and its aging-related loss is linked with cell death and osteoarthri-
tis. Arthritis Rheum. 2010;62:791-801.
MEDICOGRAPHIA, Vol 35, No. 2, 2013 215

While noninvasive treatments
such as exercise and physical ther-
apy should be started in the earlier
phases, injective treatments should
be considered for the management
of patients after noninvasive pro-
cedures have failed. Prosthetic re-
placement, which is an irreversible
procedure, should of course be re-
served as a last option during the
advanced and debilitating phas-
es of osteoarthritis refractory to
other treatments.
Elizaveta KON, MD
III Clinic, Biomechanics Laboratory
Rizzoli Orthopaedic Institute
Bologna, ITALY
Address for correspondence:
Dr Elizaveta Kon, Biomechanics
Laboratory, Rizzoli Orthopaedic
Institute, Via Di Barbiano, 1/10,
40136 Bologna, Italy
(e-mail: e.kon@biomec.ior.it)
www.medicographia.com
216 MEDICOGRAPHIA, Vol 35, No. 2, 2013
INTERVIEW
Nonpharmacological
treatments in osteoarthritis
I n t e r v i e w w i t h E . Ko n , I t a l y
T
he goal of this interview is to better understand the role of nonpharma-
cological treatments in osteoarthritis. A wide spectrum of treatment op-
tions is available, ranging from adaptation of activity levels, exercise,
and physiotherapy, to intra-articular injections, surgical unloading of the de-
generated joint compartment, and knee replacement. While the aim of all treat-
ments is to improve symptoms, function, and therefore quality of life, each has
its own advantages and disadvantages and is more suitable for certain specif-
ic phases of joint osteoarthritis. There is currently no agreement on the most
effective management of osteoarthritis, and none of the available treatment
options have been proven to produce better results over all others or have been
clearly shown to have disease-modifying properties. In general, the optimal
conservative management of knee osteoarthritis requires a combination of
pharmacological and nonpharmacological treatment modalities. Among non-
pharmacological treatments, a combination of different approaches is also
recommended. Aside from considering the treatment to be applied, one must
also consider that osteoarthritis is a chronic condition and that long-term dis-
ease management can be cumbersome. Thus, therapeutic education of pa-
tients with osteoarthritis is of major importance. Finally, prostheses produce
a high percentage of good results but require adaptation to the activity level
of the patient and also carry some important risks related to the surgical im-
plant. Thus, when treating a patient affected by osteoarthritis, it is important
to consider all the available options for improving the clinical condition of the
patient and keep prosthetic replacement as a last option for when functional
limitations and symptoms prove to be refractory to less invasive procedures.
Medicographia. 2013;35:216-220 (see French abstract on page 220)
When should nonpharmacological management of osteoarthritis
be started?
he etiology of osteoarthritis (OA) is multifactorial. Age is the major independ-
T ent risk factor for OA; however, aging and OA are interrelated, not interde-
pendent. It is becoming apparent that age-related changes in the musculo-
skeletal system contribute to the development of OA by working in conjunction with
other factors that are both intrinsic (eg, malalignment, overloading) and extrinsic (eg,
genetics) to the joint. Regardless of the initial cause, once started, osteoarthritic
alterations lead to progressive loss of hyaline cartilage, leading eventually to end-
stage OA.1
Nonpharmacological treatments in osteoarthritis Kon

Thus, nonpharmacological OA management should be start-
ed even before the clinical onset of symptoms, with the aim
of treating the predisposing factors. Early OA should be de-
tected. Clinical recurrence of pain and discomfort of the knee
and/or short periods of stiffness, in between long periods with
very few clinical manifestations, should set the stage for per-
forming additional investigations such as radiographs, ultra-
sound, magnetic resonance imaging (MRI), or arthroscopy.2
Malalignment, loss of meniscal tissue, cartilage defects, and
joint instability or laxity should be evaluated, and treatment (in-
cluding surgery if appropriate) should be discussed with the
patient, taking into consideration their activity level and expec-
tations as well as the risks of failure and complications asso-
ciated with every procedure.
In addition to its preventative use in the early phase, nonphar-
macological management should also always be considered
when OA is clearly established. Of course, when considering
treatment options, one should also always take into consid-
eration the disease phase and the invasiveness of the pro-
cedure.
Nonpharmacological management is a broad definition, rang-
ing from physiotherapy to knee replacement. While noninva-
sive treatments such as exercise and physical therapy should
be started in the earlier phases, injective treatments should
be considered for the management of patients after noninva-
sive procedures have failed. Prosthetic replacement, which
is an irreversible procedure, should of course be reserved as
a last option during the advanced and debilitating phases of
OA refractory to other treatments.
What is the cornerstone of nonpharmacological
treatment?
here is no cornerstone of nonpharmacological treat-
T ment. As previously underlined, this is a broad defini-
tion, ranging from adaptation of activity levels to ex-
ercise, from physiotherapy to intra-articular injections, from
surgical unloading of the degenerated joint compartment to
knee replacement, and so on.3,4 While all treatments are aimed
at improving symptoms, function, and therefore quality of life,
every treatment presents its own advantages and disadvan-
tages and is more appropriate for specific phases of joint OA.
One nonpharmacological approach that is probably indicat-
ed across different phases of articular degeneration with min-
imal contraindications is exercise.
SELECTED ABBREVIATIONS AND ACRONYMS
MRI magnetic resonance imaging
OA osteoarthritis
OARSI Osteoarthritis Research Society International
Nonpharmacological treatments in osteoarthritis Kon
INTERVIEW
International clinical guidelines recommend exercise as an ef-
fective approach in the management of knee OA. The aims of
exercise in these patients are to reduce pain, improve physi-
cal function and health status, and prevent progression of the
disease. While the optimal dosage (frequency, intensity, and
duration) has not yet been determined, good results have been
reported for different types of exercise.5 In general, physical
activity is beneficial, rather than detrimental, to joint health, and
an MRI study showed that moderate exercise may also im-
prove the knee cartilage glycosaminoglycan content in pa-
tients at high risk of developing OA, but long-term effective-
ness still needs to be clarified.6
As mentioned, injective treatments also play an important role
in the management of OA, ranging from corticosteroids to vis-
cosupplementation and also to more innovative biological
procedures such as the use of blood derivatives to aid the
restoration of joint homeostasis and tissue regeneration.7
Moreover, although the degenerative OA environment is an ob-
stacle to tissue regeneration, progress made in bioengineer-
ing and the development of new scaffolds seems to represent
a promising solution that may help to avoid, or at least delay,
the need for more sacrificing metal resurfacing procedures.8
How should cost, availability, or practicality
of delivery be taken into account?
ost, availability, and practicality of delivery should al-
C ways be taken into account in the management of OA
patients, especially when one considers that there is
currently no agreement on the most effective management of
these patients and none of the available treatment options
have been proven to produce better results over all others or
have been clearly shown to have disease-modifying properties.
Luckily, one of the nonpharmacological treatments proven to
be comparatively more effective for OA patients is exercise.
Hydrotherapy was found to produce a small-to-moderate im-
provement in function and quality of life and a small reduc-
tion in pain in osteoarthritic patients. Hydrotherapy is not al-
ways available, however, but other exercise modalities have
also proven to be useful: strength and aerobic training, range-
of-motion exercises, and stretching have beneficial effects in
modulating pain, increasing range of motion, reducing or elim-
inating soft tissue inflammation, inducing relaxation, improv-
ing repair, extensibility, or stability of contractile and noncon-
tractile tissues, facilitating movement, and improving function.
Tai-chi, a traditional Chinese exercise that enhances balance,
strength, and flexibility, has also been shown to be effective
in treating knee OA.
A special comment should be made about the cost, availabil-
ity, and practicality of delivery of the new injective procedures.
Among these, platelet-rich plasma therapy, a procedure based
MEDICOGRAPHIA, Vol 35, No. 2, 2013 217
INTERVIEW
on the injection of platelet concentrate to encourage tissue
regeneration through the release of growth factors contained
in the platelet alpha-granules, has been recently gaining pop-
ularity as a promising therapeutic option for early OA. How-
ever, despite some promising clinical results, the beneficial
effect of this procedure is limited over time.9 Thus, it is im-
portant to consider that the high costs, the contraindications
for several comorbidities, and the need for specialist centers
are major limitations that favor more classic injective proce-
dures. Among these, viscosupplementation seems to offer a
clinical benefit, albeit limited over time, without side effects on
the joint tissues. However, in patients where the joint has al-
ready degenerated, corticosteroid injections can be consid-
ered as a cheap option that is easily and widely accessible.
Other more invasive surgical procedures also present specific
limitations with regard to cost, availability, or practicality of de-
livery. Patient comorbidities should also be taken into consid-
eration when contemplating more invasive surgical procedures,
as comorbidities can complicate treatment, and logistical prob-
lems and the need for assistance during the sometimes long
postoperative rehabilitation phase also need to be considered.
How important is therapeutic education
in osteoarthritis and why?
herapeutic education in OA is of major importance. OA
T is a chronic condition, and long-term management of
a disease can be cumbersome. Aside from occasional
injections or other medical procedures, patients affected by
OA are required to undergo much more difficult changes in
their life. In fact, correct management of OA often involves life-
style adaptation with continuous exercise, frequent physical
therapy, and diet modification. None of this is achievable with-
out proper therapeutic education. Patients need to be aware
of their condition, of the factors affecting the disease, and of
their responsibility in following the correct lifestyle and pre-
scribed therapies. In terms of pharmacological therapy, pa-
tients must follow the treatment indications to obtain optimal
results, and personal initiatives or treatment adaptations that
do not follow the physicians indications can only lead to less-
er benefits. A recent review of the role of exercise in OA man-
agement focused on the different methods of treatment de-
livery, which can entail individual treatment, treatment within
a supervised group, or exercise performed at home. No dif-
ference was found in terms of the beneficial effects of exer-
cise when patients had received proper therapeutic education
and performed the prescribed exercise. However, regular su-
pervision may improve adherence to exercise, which is required
to maintain the benefits over time, and a recent study report-
ed that the effects of exercise were better when conducted
over more than 12 supervised sessions.5 Supervised sessions
allowed for more therapeutic education and more control over
patients, who as a consequence followed their therapies bet-
ter and thus achieved better results.
218 MEDICOGRAPHIA, Vol 35, No. 2, 2013
Therapeutic education is also of fundamental importance af-
ter surgery in order to limit the risk of complications such as
infection, or even fatal events, and to optimize treatment. For
example, biological implants for tissue regeneration require a
maturation phase during which the healing structure has to
be protected, and even after metal resurfacing, therapeutic
education is mandatory to ensure adaptation of life activities
and preservation of the prosthetic joint over time.
How long can nonpharmacological management
put off surgical intervention?
onpharmacological management can put off the need
N for surgical intervention, but in this regard every sin-
gle case must be considered individually. First, it has
to be stressed that sometimes it can be counterproductive to
put off surgical intervention. This is particularly true when there
are clearly recognized predisposing factors that could be ad-
dressed surgically. A previous total meniscectomy, joint in-
stability due to ligament rupture, incongruity of the articular
surface due to previous intra-articular fractures, misalignment
causing overload, and degeneration of an articular compart-
ment are just some examples of clinical conditions for which
delaying surgical treatment would only result in a worsening
of the joint condition with a worse final outcome.
On the other hand, when there are no clear predisposing fac-
tors or when patients present with comorbidities that contra-
indicate surgical treatments, nonpharmacological manage-
ment can be used to put off surgical intervention. Of course
every case is different, but it is possible to state that in the ma-
jority of cases, proper management of OA can delay the need
for prosthetic replacement for several years. Lifestyle adapta-
tion with diet modification and exercise, together with other
medical treatments such as physical therapy or injections to
treat the acute inflammatory OA phases, can improve the clin-
ical condition and delay the need for more invasive surgery.
It is important for the patient to have clear expectations about
all the treatment options. Surgery can sometimes be consid-
ered by the patient as an easy way to improve their clinical
condition, but knowledge of the limitations and risks of sur-
gery can give them the correct perspective in understanding
the importance of properly applying nonsurgical manage-
ment for major beneficial effects and the longest delay be-
fore surgical intervention.
Is there any randomized controlled study available
on the nonpharmacological approach?
ome randomized controlled studies are available on the
S nonpharmacological approach, but results are still far
from conclusive. Controversial findings, as well as the
incredibly high number of variables differing between each
study, make comparison of the available studies difficult.
Nonpharmacological treatments in osteoarthritis Kon

Surprisingly, the definition of OA has not changed since 1986.
The diagnosis of knee OA can usually be made from the pa-
tient history and physical examination, and includes signs/
symptoms of knee pain with stiffness, joint crepitus and func-
tional limitations, and typically an age above 50 years. Diagno-
sis is confirmed by radiograph demonstrating changes such
as osteophytes and joint space narrowing, subchondral bone
sclerosis, and cysts, and is graded according to the classifi-
cation of Kellgren and Lawrence (Kellgren & Laurence grades
II-IV). It appears clear that this definition of OA cannot distin-
guish between the pathological changes in different tissues.
Thus, study populations can be heterogeneous and can re-
spond differently to different treatments, even though they ap-
parently present in the same disease phase.
There is no agreement in the literature on the best treatment
option for OA, and this is reflected in clinical practice where
treatment is mainly empirical and based on the personal ex-
perience of the individual physician. Moreover, leaving aside
the contradictory findings of the different studies, it is also dif-
ficult to translate the study results into clinical practice be-
cause the selected study populations are often a specific cat-
egory of patients that is rare in the normal population. Patients
in clinical practice typically present with more complex clinical
situations and with comorbidities and combined treatments.
New imaging techniques are required to better assess the
disease phase and to properly classify study populations,
and more randomized controlled trials are needed to prove
which treatment approach is more suitable for each of the
different phases of OA degeneration.
Can nonpharmacological treatment be combined
with pharmacological treatment?
hile it is true that properly applied nonpharmaco-
W logical treatment can sometimes limit the need for
pharmacological treatment, it is also well accepted
that combined treatment can often offer a better clinical out-
come. In general, the optimal conservative management of
knee OA requires a combination of pharmacological and non-
pharmacological treatment modalities, and among the non-
pharmacological treatments, a combination of different ap-
proaches is recommended.
Osteoarthritis Research Society International (OARSI) pro-
duced a list of 25 recommendations regarding the treatment
of OA. These cover the use of 12 nonpharmacological modal-
ities: education and self-management, regular telephone con-
tact, referral to a physical therapist, aerobic, muscle strength-
ening and water-based exercises, weight reduction, walking
aids, knee braces, footwear and insoles, thermal modalities,
transcutaneous electrical nerve stimulation, and acupuncture.
Nonpharmacological treatments in osteoarthritis Kon
INTERVIEW
A further 8 recommendations cover pharmacological treat-
ment modalities, and finally, 5 recommendations cover sur-
gical modalities: total joint replacements, unicompartmental
knee replacement, osteotomy and joint-preserving surgical
procedures, joint lavage and arthroscopic debridement in
knee OA, and joint fusion as a salvage procedure when joint
replacement has failed.
These strategies can be combined according to the specific
requirements of the patient with the aim of producing tailored
treatment and thus more satisfactory clinical results.
What can you tell us about life after knee
replacement surgery?
any options are currently available for knee replace-
M ment, from focal metal resurfacing to total prosthet-
ic replacement of the affected joint.10 Of course,
functional improvement and limitations will depend strictly
on the implant type as well as the specific characteristics of
the patient, and also eventually on the presence of any sur-
gical complications.
In general, this procedure offers a dramatic improvement in
the clinical condition. Most patients have minimal pain by 3
months (or sooner) after surgery and return to their normal
daily activities. It is not unusual to have occasional muscle
aches and persistent (but usually slight) swelling of the knee
and extremity for several months, and some patients require
a longer time to achieve good and stable results. Depending
on numerous factors, a persistent limp is usually expected,
but results tend to improve over time.
Unfortunately, 5% of patients will be unsatisfied because of
the persistence of pain or the onset of complications. More-
over, it has to be remembered that despite the technological
improvements of the last decades, implants still have limited
longevity and may require revision surgery. Age is one of the
major factors in determining reduced longevity. Younger pa-
tients wear out their replacements more quickly than older
patients, and this has to be taken into consideration in the
management of a patient affected by OA.
In general, prostheses give good results, but they also require
adaptation to the activity level of the patient and there are some
important risks related to the surgical implant. Thus, when treat-
ing a patient affected by OA, it is important to consider all
the available options to improve their clinical condition and to
keep prosthetic replacement as a last option when function-
al limitations and symptoms prove to be refractory to less in-
vasive procedures. I
The author declares that she has no conflict of interest.
MEDICOGRAPHIA, Vol 35, No. 2, 2013 219
INTERVIEW

References
1. Heijink A, Gomoll AH, Madry H, et al. Biomechanical considerations in the patho-
genesis of osteoarthritis of the knee. Knee Surg Sports Traumatol Arthrosc.
2012;20:423-435.
2. Luyten FP, Denti M, Filardo G, Kon E, Engebretsen L. Definition and classifica-
tion of early osteoarthritis of the knee. Knee Surg Sports Traumatol Arthrosc.
2012;20:401-406.
3. Gomoll AH, Filardo G, de Girolamo L, et al. Surgical treatment for early osteo-
arthritis. Part I: cartilage repair procedures. Knee Surg Sports Traumatol Ar-
throsc. 2012;20:450-466.
4. Gomoll AH, Filardo G, Almqvist FK, et al. Surgical treatment for early osteo-
arthritis. Part II: allografts and concurrent procedures. Knee Surg Sports Trau-
matol Arthrosc. 2012;20:468-486.
5. Kon E, Filardo G, Drobnic M, et al. Non-surgical management of early knee os-
teoarthritis. Knee Surg Sports Traumatol Arthrosc. 2012;20:436-449.
6. Roos EM, Dahlberg L. Positive effects of moderate exercise on glycosamino-
glycan content in knee cartilage: a four-month, randomized, controlled trial in
patients at risk of osteoarthritis. Arthritis Rheum. 2005;52:3507-3514.
7. Kon E, Filardo G, Di Martino A, Marcacci M. Platelet-rich plasma (PRP) to treat
sports injuries: evidence to support its use. Knee Surg Sports Traumatol Ar-
throsc. 2011;19:516-527.
8. Kon E, Delcogliano M, Filardo G, Altadonna G, Marcacci M. Novel nano-com-
posite multi-layered biomaterial for the treatment of multifocal degenerative car-
tilage lesions. Knee Surg Sports Traumatol Arthrosc. 2009;17:1312-1315.
9. Kon E, Mandelbaum B, Buda R, et al. Platelet-rich plasma intra-articular injec-
tion versus hyaluronic acid viscosupplementation as treatments for cartilage
pathology: from early degeneration to osteoarthritis. Arthroscopy. 2011;27:1490-
1501.
10. Marcacci M, Bruni D, Zaffagnini S, et al. Arthroscopic-assisted focal resurfac-
ing of the knee: surgical technique and preliminary results of 13 patients at 2
years follow-up. Knee Surg Sports Traumatol Arthrosc. 2011;19:740-746.

Keywords: injective treatment; nonpharmacological management; osteoarthritis; replacement surgery

TRAITEMENTS NON PHARMACOLOGIQUES DE LARTHROSE

Le but de cette interview est de mieux comprendre le rle des traitements non pharmacologiques de larthrose. Lven-
tail de traitements est large : adaptation des niveaux dactivit, exercice physique, physiothrapie, injections intra-
articulaires, dchargement chirurgical du compartiment articulaire abm et prothse de genou. Tous les traitements
visent amliorer les symptmes, le fonctionnement et donc la qualit de vie ; toutefois, chacun dentre eux prsente
ses propres avantages et inconvnients et convient mieux certaines phases spcifiques de larthrose articulaire. Il
ny a actuellement aucun consensus sur la prise en charge la plus efficace de larthrose, et aucun des traitements
disponibles na montr de meilleurs rsultats que les autres ou na clairement manifest des proprits modifiant la
maladie. En gnral, la prise en charge conservatrice optimale de larthrose du genou ncessite une association de
traitements pharmacologiques et non pharmacologiques. Parmi les traitements non pharmacologiques, lassociation
des diffrentes approches est galement recommande. Hormis les considrations sur le choix traitement, il faut
aussi tenir compte du fait que larthrose est une pathologie chronique et que sa prise en charge long terme peut
tre pesante. Lducation thrapeutique des patients arthrosiques est donc dune extrme importance. Enfin, les pro-
thses ont un fort pourcentage de bons rsultats mais ncessitent dtre adaptes au niveau dactivit du patient et
prsentent aussi des risques importants lis la prothse implante. Lorsque lon traite un patient atteint darthrose,
il est important de prendre en compte toutes les options disponibles pour amliorer son tat clinique et garder la
pose dune prothse comme dernire solution, lorsque les symptmes et les limitations fonctionnelles ne rpondent
pas des procdures moins invasives.

220 MEDICOGRAPHIA, Vol 35, No. 2, 2013 Nonpharmacological treatments in osteoarthritis Kon

It is clear that changes in sub-
chondral bone parallel the progres-
sion of osteoarthritis and may even
be causally involved. The subchon-
dral compartment may therefore
be a treatment target to delay or
prevent progression of the disease.
Since this compartment is richly
innervated, and cartilage is devoid
of nerves, bone is also a legitimate
treatment target for joint pain. How-
ever, treatments designed to nor-
malize the bone changes in osteo-
arthritis are controversial
O
David M. FINDLAY, PhD
Discipline of Orthopaedics
and Trauma
University of Adelaide
Adelaide, South Australia
AUSTRALIA
Address for correspondence:
Professor David M. Findlay, Discipline
of Orthopaedics and Trauma,
University of Adelaide, Level 4 Bice
Building, Royal Adelaide Hospital,
Adelaide, South Australia, 5000,
Australia (e-mail:
david.findlay@adelaide.edu.au)
www.medicographia.com
The role of subchondral bone in osteoarthritis pathophysiology and pain Findlay
FOCUS
Long overlooked:
the role of subchondral
bone in osteoarthritis
pathophysiology and pain
b y D . M . F i n d l a y, A u s t ra l i a
steoarthritis was previously considered to be solely a disease of car-
tilage degeneration. However, it is now recognized that all structures
in the joint are affected by the disease, notably subchondral bone, in
which characteristic changes occur throughout disease progression. These
changes in the bone seem to parallel disease progression and are associat-
ed with joint pain. This article focuses on the role played by subchondral bone
remodeling in the pathogenesis of osteoarthritis and in the expression of pain
in this condition. It examines the evidence for altered osteoblast and osteoclast
function and the possible involvement of osteocytes in establishing changes
in the subchondral bone environment in osteoarthritis. It also explores the bio-
mechanical and genetic influences that may lead to an altered interaction be-
tween bone and cartilage. A large number of genes have been found to be
differentially expressed in subchondral bone in osteoarthritis compared with
osteoporotic or normal bone, and many of these changes persist in osteoblasts
derived from osteoarthritic bone. Relevant questions include how the cellular
and molecular changes give rise to structural changes in subchondral bone,
including bone marrow lesions; what the evidence is that bone marrow le-
sions are predictive or even causal of disease progression; and whether treat-
ments targeting the subchondral bone could have efficacy in delaying or re-
versing degeneration of the overlying articular cartilage.
Medicographia. 2013;35:221-227 (see French abstract on page 227)
steoarthritis (OA) is characterized by progressive degenerative damage to
O articular cartilage, although it is also associated with weakened muscles,
synovial inflammation, joint stiffness, altered bone alignment, loss of joint
congruency, and structural changes in the subchondral bone.1,2 There are well-de-
scribed changes observed in the subchondral bone in OA,1-4 which include scle-
rotic but less mineralized bone, the formation of osteophytes, and subchondral cysts.
In addition, the development of bone marrow lesions (BMLs) that can be visualized
by magnetic resonance imaging (MRI) is frequently seen in OA, and these lesions
seem to be predictive of degeneration in the overlying cartilage compartment.5 The
changes in bone structure and remodeling are due ultimately to changes in the ac-
tivity of bone cells, osteoclasts, osteoblasts, and osteocytes, driven in turn by altered
expression of key regulatory genes. These changes are likely in response to altered
loading of the joint and/or systemic changes, and the way that these influences are
transduced to gene expression and cell activity needs to be understood in order to
find effective treatments for OA. Since there is evidence of important communica-
MEDICOGRAPHIA, Vol 35, No. 2, 2013 221
FOCUS
tion between articular cartilage and its underlying bone, al-
tered events in the subchondral bone may have significant
implications for cartilage health, which validates attempts to
treat OA by directing treatment to the subchondral bone.
Bone shape and osteoarthritis
It is clear that shape deformities in bone are associated with
OA and may either predispose to the disease, or result from
it.6,7 Malalignment of the knee, with varus or valgus alignment,
has been thought to predispose individuals to knee OA. How-
ever, as reviewed by Hunter et al,8 it is unclear whether mal-
alignment is a risk factor for OA or comes about as a result
of the disease, and more longitudinal data are required to de-
termine the link. Congenital dysplasia or dislocation of the hip,
whether occurring as a result of perinatal dislocation or con-
genitally incorrect morphology of the acetabulum or femoral
head, can give rise to hip OA because of the lack of congru-
ency of the joint and the concentration of load in a small re-
gion of the joint. Genetics may play an important role in OA
that has bone deformity as its underlying cause. Waarsing et
al9 have described a range of shape modes for the proximal
femur, several of which predispose to OA, but apparently only
in carriers of susceptibility alleles of genes that associate with
OA. Haverkamp et al10 have obtained similar data for the knee,
suggesting that a larger tibial plateau area associates with OA.
Pincer deformities of the acetabulum and cam deformities of
the femoral neck,11 which result in various degrees of impinge-
ment of the hip joint, are thought to lead to OA. Nicholls et
al12 examined the relationship between cam deformity and the
19-year risk of total hip arthroplasty (THA) for end-stage hip
OA. Their intriguing results showed that individuals with THA
had a higher prevalence of cam deformity than their respec-
tive controls, although the study was limited by small num-
bers of subjects after exclusions. Further studies in this area
are warranted given the prospect that it might be possible to
predict the risk of hip OA from hip shape. Two recent stud-
ies addressed the important question of whether such defor-
mities are inevitable or whether they may be preventable. It
was found that cam deformity seemed to arise from vigorous
SELECTED ABBREVIATIONS AND ACRONYMS
ACLT anterior cruciate ligament transection
BML bone marrow lesion
ES/BS eroded surface/bone surface ratio
MRI magnetic resonance imaging
OA osteoarthritis
OARSI Osteoarthritis Research Society International
OPG osteoprotegerin
OS/BS osteoid surface/bone surface ratio
TGF transforming growth factor
THA total hip arthroplasty
WOMAC Western Ontario and McMaster Universities Osteo-
arthritis index
222 MEDICOGRAPHIA, Vol 35, No. 2, 2013 The role of subchondral bone in osteoarthritis pathophysiology and pain Findlay
sporting activity, being more prevalent in elite young basket-
ball players than in age-matched controls.13 Similarly, the preva-
lence of flattening of the femoral head-neck junction was sig-
nificantly increased in young male soccer players compared
with controls, and the presence of a convex prominence (cam
deformity) was found only in the soccer players.14 These stud-
ies highlight the responsiveness of bone to influences such as
loading, which has already been well described as a mech-
anism by which bone strengthens in response to increased
demand.15,16 They are also a reminder that bone is a dynamic
tissue that is constantly undergoing remodeling,17 thereby per-
haps contributing to OA, but also offering potential points of
intervention.
Microstructural changes in bone in osteoarthritis
The microstructure of subchondral bone differs in osteoarthrit-
ic bone compared with nonosteoarthritic bone, particularly
with respect to the subchondral plate and adjacent trabec-
ular bone, but also in regions more distal from the affected
joint.18,19 For example, Kumarasinghe et al20 reported increased
bone volume fraction in cancellous bone from the intertro-
chanteric region in individuals with OA compared with those
with normal or osteoporotic bone, with increased trabecular
number and decreased trabecular spacing. Reduced hard-
ness of trabecular bone from the femoral head was also not-
ed in hip OA compared with normal subjects,21 probably due
to decreased mineralization of the bone in OA.22 These changes
combine to produce bone that is stiffer and stronger than
normal or osteoporotic bone.22 It is not known at which stage
of human disease these changes appear, and whether they
are, in some way, causative of the disease process or sim-
ply describe it. For the most part, animal models show that
changes in the subchondral bone occur in parallel with carti-
lage degradation.23 Longitudinal mouse studies that used high-
resolution imaging to investigate joints in a mouse strain that
spontaneously develops knee OA compared with one that
does not showed that susceptible mice developed more tra-
becular bone in a region-specific manner, and particularly in
the tibial compartment, in parallel with arthritic changes in the
articular cartilage.24
In addition to the generalized changes in subchondral bone in
OA, areas of subchondral bone that appear bright with MRI,
which are termed BMLs, are commonly observed in both es-
tablished OA and early OA, but rarely in symptom-free individ-
uals.25,26 BMLs have not been extensively characterized, but
they arise in regions of predicted high loading and contain ab-
normal bone with areas of osteocyte death and areas of bone
sclerosis with reduced mineral density.27 Subchondral bone
attrition28 and repair of fractured trabeculae have also been
observed.29 BMLs are interesting clinically due to the fact that
longitudinal studies have shown that their presence is a po-
tent risk factor for structural deterioration in knee OA30-32 and
for future joint replacement.5 BMLs have been shown to be
dynamic, increasing and decreasing in size, and they have

also been found to disappear over a 2-year period.33 In a com-
munity-based population of older males and females, similar
proportions of BMLs were found to worsen and improve (as-
sessed by measuring maximal area).34 Importantly, a change
in BML size was associated with changes in pain, perhaps
linking fluctuating knee pain to BML changes, at least in in-
dividuals with early-stage disease. Enlargement of BMLs has
been strongly associated with increased cartilage loss.5,31 Sub-
chondral cysts, which are characteristic of established and
severe OA, arise at the same sites as BMLs.35 A number of
studies have indicated possible causal factors for BMLs, in-
cluding mechanical loading,36 dietary fatty acid intake,37 and
total serum cholesterol and triglycerides.38
Bone remodeling in osteoarthritis
As stated, bone is constantly being remodeled, and this may
have special significance in OA in ways that require more at-
tention.17 Understanding bone remodeling in the particular
context of OA is complex. The topic was recently the subject
of an excellent review by Burr and Gallant,39 who cited evi-
dence for increased remodeling, accompanied by increased
vascularity, in the subchondral bone in early OA. By contrast,
late-stage disease is characterized by reduced bone resorp-
tion, with a bias toward bone formation. In addition to these
temporal variations, it is likely that bone remodeling varies
spatially within the joint; for example, medially versus lateral-
ly in the knee. There is histological and biochemical evidence
of increased bone remodeling in subchondral bone contain-
ing BMLs.40 Increased subchondral bone remodeling as de-
tected by bone scans has been described in established OA,
where it has been reported to predict joint space narrowing.41
In contrast, a report by Berry et al42 concluded that higher lev-
els of bone remodeling (assessed by serum bone turnover
markers) is associated with reduced cartilage loss (assessed
by MRI). It is difficult to determine whether changes in bone
turnover are a cause or effect in human OA; however, work in
Hartley guinea pigs showed that subchondral cancellous bone
was fragile before the onset of cartilage degeneration.43 In the
rat anterior cruciate ligament transection model of OA, in-
creased subchondral bone resorption was associated with
early development of cartilage lesions, which preceded sig-
nificant cartilage thinning and subchondral bone sclerosis.44
At the level of the bone cell, remodeling is a function of the
actions of osteoclasts, which resorb bone, and osteoblasts,
which are the bone-forming cells. The activities of both of
these cell types are regulated by osteocytes embedded with-
in the bone matrix.45 There is good evidence that osteocytes
detect damage within the mineralized bone matrix and di-
rect its repair by initiating targeted osteoclastic resorption of
the affected bone,46 and in OA, there is evidence of increased
microdamage and microfractures in subchondral bone in over-
loaded areas of the joint.47 Recent evidence suggests that
osteocytes are the major source of the osteoclast differenti-
ating cytokine, receptor activator of nuclear factor -B ligand
The role of subchondral bone in osteoarthritis pathophysiology and pain Findlay
FOCUS
(RANKL), in mature bone.48,49 Osteocytes also produce scle-
rostin, a Wnt inhibitor that negatively regulates bone forma-
tion.50 Individuals and animals deficient in sclerostin show bone
overgrowth.51 Sclerostin appears to mediate the actions of a
number of factors that influence bone formation, so that load-
ing of bone, a known anabolic influence, decreases sclerostin
expression in bone,52,53 and unloading of bone, which is cata-
bolic for bone, increases its expression.52 Both of these con-
ditions might apply at different times during the progression
of OA. Interestingly, increased sclerostin expression has been
observed in cartilage overlying sclerotic bone, while the latter
by contrast shows decreased sclerostin expression.54,55 Since
osteocytes have such a strong influence on bone metabolism
and turnover, it may be an important finding that in osteo-
arthritic subchondral bone, osteocyte morphology was altered,
showing rough and rounded cell bodies with fewer and disor-
ganized dendrites compared with the osteocytes in control
samples.56 In addition, and this has been particularly noted
in BMLs, there is evidence of osteocyte apoptosis, which, as
stated, can be a stimulus for osteoclastic resorption and bone
turnover.46
Differential gene expression in osteoarthritic bone
The structural changes in osteoarthritic bone follow changes
in bone cell activity, which are in turn driven by, and evidenced
as, altered gene expression in osteoarthritic bone compared
with bone from age- and sex-matched controls or osteoporot-
ic individuals. The opportunity to investigate bone in OA is
essentially limited to sampling during joint replacement sur-
gery in end-stage disease, and the gene expression observed
at this time likely represents the decrease in remodeling de-
scribed in late-stage OA. In fact, both the gene and protein
expression that have been described in human late-stage OA
are largely consistent with the reduced bone turnover, scle-
rosis, and lower bone mineralization that have been described
in OA bone tissue at this time.39 Kuliwaba et al57 measured RNA
extracted from the cancellous bone in the intertrochanteric
region of the proximal femur, a site distal from the articular sur-
face of the femur, and compared patients with end-stage OA
with age-matched autopsy controls. Differential gene expres-
sion was found in OA bone, which had the hallmarks of re-
duced inflammatory cytokines and bone resorption markers
and increased bone formation. Messenger RNA species en-
coding interleukin (IL)-6 and IL-11 and RANKL were signifi-
cantly less abundant in the OA group, while osteoprotegerin
(OPG) mRNA expression was no different from controls.58 In
a separate study, an additional increase in the anti-osteoclas-
togenic cytokine interferon gamma was also observed in OA.59
Both RANKL mRNA levels and the ratio of RANKL:OPG mRNA
were strongly associated with eroded surface/bone surface
ratio (ES/BS) and osteoid surface/bone surface ratio (OS/BS)
in trabecular bone from control individuals; the former would
be expected for this cytokine, which is a potent driver of bone
resorption, and the latter is likely due to the fact that bone re-
sorption and formation are coupled in healthy adult bone.58
MEDICOGRAPHIA, Vol 35, No. 2, 2013 223
FOCUS
Intriguingly, these relationships were not apparent in osteo-
arthritic bone, suggesting that bone turnover is regulated dif-
ferently in OA. In terms of bone formation, osteocalcin mRNA
expression was significantly greater in OA and, curiously, in-
creased significantly with age in the OA group but not in con-
trols.57 In addition, there was a significant positive correlation
between the osteocalcin mRNA levels and OS/BS in OA bone,
which was not seen in the control cohort. Work by the same
group showed elevated alkaline phosphatase, osteocalcin, os-
teopontin, and COL1A1 (collagen, type I, alpha 1) and COL1A2
(collagen, type I, alpha 2) mRNA in osteoarthritic bone com-
pared with control,60 which the authors suggested reflects an
increase in osteoblastic biosynthetic activity in OA.
Hopwood et al61,62 performed gene microarray analysis on
bone from the same region of the femur, and identified a large
number of differentially expressed genes in OA compared with
control or osteoporotic bone. A substantial number of the top-
ranking differentially expressed genes are known to play roles
in bone formation, and many of these genes are targets of
either the Wnt or transforming growth factor (TGF)/bone
morphogenetic protein signaling pathways. These findings are
consistent with the increased amounts of insulin-like growth
factor types I and II and TGF protein measured in osteoarthrit-
ic bone from the iliac crest.63 This latter result, and the findings
from bone derived from the intertrochanteric region, are con-
sistent with both increased anabolic stimulus in osteoarthritic
bone and the notion that bone metabolism may be system-
ically disturbed in OA.
Osteoblasts from osteoarthritic bone
Gene expression has also been explored in osteoblasts taken
from osteoarthritic subchondral bone. Interestingly, these cells
appear to retain their phenotypic differences from control cells
in culture. Thus, one group showed that cultured OA osteo-
blasts produced a similar degree of mineralization to control
cells, but with dramatically variable calcium:phosphate ratios
compared with control osteoblasts and normal bone (ap-
proximately 1.6).20 A second group showed that mineraliza-
tion by OA osteoblasts was reduced compared with control
osteoblasts, which they found to be due to a threefold higher
COL1A1:COL1A2 mRNA ratio in the OA cells.64 This finding in
cells was similar to the differential expression of these genes
in osteoarthritic bone.60 Alkaline phosphatase and osteocal-
cin levels were also found to be elevated in OA osteoblasts
compared with normal osteoblasts, whereas osteopontin lev-
els were similar.64 In this study, the authors obtained evidence
that TGF1 levels are approximately fourfold higher in OA os-
teoblasts than in normal osteoblasts, and that inhibiting TGF1
in OA osteoblasts corrected the abnormal COL1A1:COL1A2
ratio and increased cell mineralization. It was subsequently
shown that the increased TGF in OA cells induces increased
Dickkopf-related protein 2 (DKK-2), and that silencing of either
TGF or DKK2 in these cells normalized the OA phenotype, in-
cluding the decreased mineralization of OA osteoblasts.65
224 MEDICOGRAPHIA, Vol 35, No. 2, 2013 The role of subchondral bone in osteoarthritis pathophysiology and pain Findlay
Massicotte et al66 performed measurements of conditioned
media from osteoblasts derived from osteoarthritic subchon-
dral bone, and reported two subgroups of cells based on
production of IL-6 and prostaglandin E2, while TGF levels
were increased in all osteoarthritic osteoblasts compared
with normal osteoblasts. Kumarasinghe et al20 performed an
extensive analysis of gene expression in primary osteoblasts
derived from OA and control femoral bone. They found that
the dysregulated expression of TWIST1 (twist-related pro-
tein 1), TGF1, and SMAD3 (mothers against decapentaplegic
homolog 3) mRNA observed by Hopwood et al62 in OA bone
is also present in OA osteoblasts when these cells are cul-
tured ex vivo, and they proposed that at least part of the eti-
ology of OA is due to altered intrinsic properties of the os-
teoblasts.
Directing treatments for osteoarthritis to the
subchondral bone
It is clear that changes in subchondral bone parallel the pro-
gression of OA and may even be causally involved. The sub-
chondral compartment may therefore be a treatment target to
delay or prevent progression of the disease. Since this com-
partment is richly innervated, and cartilage is devoid of nerves,
bone is also a legitimate treatment target for joint pain. How-
ever, treatments designed to normalize the bone changes in
OA are controversial, largely because the promise of efficacy
seen in animal models has not been matched by human stud-
ies. It would seem reasonable that treatment with antiresorp-
tive agents in early disease might be effective, since this phase
of the disease is characterized by increased bone remodel-
ing. Accordingly, in two rat models of knee OA, the bispho-
sphonate alendronate suppressed both subchondral bone
resorption and the later development of OA symptoms in the
knee joint.67 Similarly, calcitonin reduced the levels of circu-
lating bone turnover markers and the severity of OA lesions
in the dog model of anterior cruciate ligament transection
(ACLT).68 Kadri et al69 used OPG to block RANKL-mediated
bone resorption and remodeling in a mouse menisectomy
model of OA, and observed protection from meniscectomy-
related bone loss, lower OA scores, and reduced ADAMTS-4
and ADAMTS-5 expression following meniscectomy. In a high
bone turnover version of the same mouse model, pamidronate
dramatically preserved the bone mass and reduced the Os-
teoarthritis Research Society International (OARSI) score
while at the same time almost normalizing the expression of
ADAMTS-4 and ADAMTS-5 in the overlying joint cartilage.70
Such marked effects of antiresorptive agents have not been
consistently observed in human trials of antiresorptive agents
in OA subjects, where symptom relief, radiographic joint space
narrowing, or Western Ontario and McMaster Universities
Arthritis index (WOMAC) were used as end points,71 and it
has been argued that such agents are unlikely to show effi-
cacy in late-stage OA because bone resorption is already sup-
pressed at this stage.39 Interestingly, results of a trial in which

postmenopausal women were treated with strontium ranelate
indicated that subjects with early OA (C-terminal crosslinked
telopeptide type II collagen [CTX-II] was used as a surrogate
marker of disease) obtained the greatest benefit, again in
terms of CTX-II reduction.72 It is thus clear that earlier defin-
itive diagnosis of OA is required so that these treatments
might be applied during periods of high bone turnover.6 In ad-
dition, more informative outcome measures for human clin-
ical trials will assist in determining efficacy. A recent trial of
zolendronic acid showed a reduction over 6 months in BML
area as well as in pain,73 showing the potential utility of BMLs
as informative markers. Although there are likely several sources
of pain in OA, it seems logical that antiresorptives should re-
duce bone pain caused by elevated levels of bone remod-
eling, since this is the case in the high bone turnover states
of Pagets disease,74 osteogenesis imperfecta,75 and cancer-
induced bone pain.76 The results of the trial by Laslett et al73
suggest that this is a possibility in OA.
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The role of subchondral bone in osteoarthritis pathophysiology and pain Findlay
FOCUS
Conclusion
Changes in the bone of articulating joints are apparent from
the time of the earliest symptoms of OA, and are due to al-
tered bone structure, altered biochemistry, and altered bio-
mechanics, which in turn cause altered gene expression in
bone. This altered bone remodeling needs to be better under-
stood temporally, spatially, mechanistically, and molecularly,
so that informed treatments can be developed for application
at a time point when efficacy can be achieved, starting as
early in the disease course as possible. In the evaluation of ap-
proaches that target the bone in OA, end points will be re-
quired that are based on better imaging and that are much
more informative of all the compartments of the joint, carti-
lage, synovium, tendon and muscle, and bone. I
Acknowledgements. Funding from the National Health and Medical Re-
search Council of Australia and the support of the Department of Or-
thopaedics and Trauma, Royal Adelaide Hospital and the University of
Adelaide, Adelaide, Australia is gratefully acknowledged.
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stream of the SOST gene in patients with van Buchem disease. J Med Genet.
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Keywords: antiresorptive; gene expression; osteoarthritis; remodeling; subchondral bone
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68. Manicourt DH, Altman RD, Williams JM, et al. Treatment with calcitonin sup-
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71. Saag KG. Bisphosphonates for osteoarthritis prevention: "Holy Grail" or not?
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74. Reid IR. Pharmacotherapy of Paget's disease of bone. Expert Opin Pharmaco-
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75. Glorieux FH. Experience with bisphosphonates in osteogenesis imperfecta. Pe-
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380-387.
 FOCUS

UN GRAND OUBLI : LE RLE DE LOS SOUS-CHONDRAL

DANS LA PHYSIOPATHOLOGIE ET LA DOULEUR ARTHROSIQUES
Larthrose a longtemps t considre comme tant uniquement une pathologie de dgnrescence du cartilage.
Il est dsormais reconnu que toutes les structures articulaires sont touches par la maladie, et notamment los sous-
chondral, qui subit des modifications caractristiques tout au long de la maladie. Ces modifications osseuses
semblent suivre la progression de la maladie et sassocient une douleur articulaire. Cet article porte sur le rle jou
par le remodelage osseux sous-chondral dans la pathogense de larthrose et lexpression de la douleur dans cette
pathologie. Il examine les arguments en faveur de laltration des fonctions ostoblastique et ostoclastique et lim-
plication probable des ostocytes dans les modifications de lenvironnement osseux sous-chondral dans larthrose.
Il explore aussi les influences biomcaniques et gntiques qui peuvent modifier linteraction entre los et le cartilage.
De nombreux gnes sexpriment de faon diffrentielle dans los sous-chondral au cours de larthrose par rapport
los normal ou ostoporotique, et nombre de ces changements persistent dans les ostoblastes issus de los ar-
throsique. On peut donc se poser les questions suivantes : comment les modifications cellulaires et molculaires don-
nent-elles naissance aux changements structuraux dans los sous-chondral, y compris aux lsions mdullaires ? Les
lsions mdullaires sont-elles des signes avant-coureurs ou mme la cause de la progression de la maladie ? Enfin,
les traitements ciblant los sous-chondral peuvent-ils tre efficaces pour diffrer ou inverser la dgnrescence du
cartilage articulaire sous-jacent ?

The role of subchondral bone in osteoarthritis pathophysiology and pain Findlay MEDICOGRAPHIA, Vol 35, No. 2, 2013 227

The concept of osteoarthritis
as organ failure with multitissue
damage opens up novel therapeu-
tic perspectives Current treat-
ments for osteoarthritis are es-
sentially aimed at controlling the
painful symptoms, thereby reduc-
ing the disability that is essentially
related to the pain in osteoarthri-
tis. The real therapeutic goal for
osteoarthritis in the coming years
will be to find a treatment that can
permanently reduce cartilage de-
struction.
L
Xavier CHEVALIER, MD, PhD
Florent EYMARD
Service de Rhumatologie
Hpital Henri Mondor
Universit Paris XII UPEC
Crteil, FRANCE
Address for correspondence:
Professor Xavier Chevalier, Service
de Rhumatologie, Hpital Henri
Mondor, Universit Paris XII UPEC,
Crteil, France
(e-mail: xavier.chevalier@hmn.aphp.fr)
www.medicographia.com
228 MEDICOGRAPHIA, Vol 35, No. 2, 2013
U P DAT E
Clinical research in
osteoarthritis: whats new?
by X. Chevalier and F. Eymard, France
N
ew therapeutic perspectives in osteoarthritis are focused on blocking
the degradative process by inhibiting tissue remodeling in the bone
and cartilage and inflammation of the synovial membrane. None of the
so-called slow-acting drugs that are currently available for the management
of osteoarthritis can be considered to be targeted treatments. A great hope
surfaced after initial trials with antinerve growth factor therapy showed a dra-
matic effect on pain in patients with knee osteoarthritis. Unfortunately, trials
were later stopped because of unexplained rapidly destructive arthropathies.
Biotherapies involving interleukin-1 blockers have been used in knee osteo-
arthritis, but so far have shown no efficacy on pain. Biotherapy for hand osteo-
arthritis involving the use of tumor necrosis factor blockers to slow down dis-
ease progression has failed. Nitric oxide inhibitors also failed to demonstrate
a chondroprotective effect in a large trial involving patients with knee osteo-
arthritis. Inhibitors of enzymes involved in cartilage matrix degradation are in
a preclinical phase of development, but constitute an appealing approach.
Targeting of subchondral bone is also a promising approach. Although pre-
vious chondroprotective trials using bisphosphonates have produced nega-
tive results, a recent large trial with strontium ranelate showed diminished joint
space narrowing over 3 years of follow-up. Another therapeutic approach cur-
rently under consideration is stimulation of chondrocyte anabolism. Intra-artic-
ular injection of growth factors is in the initial development phase. Finally, a new
lubricant called lubricin has shown very attractive results in animal models.
Medicographia. 2013;35:228-233 (see French abstract on page 233)
steoarthritis is the most common form of joint disease, affecting millions of
O people throughout the world, and it represents a major and recognized cause
of pain and disability, particularly in the elderly.1 The aim of this review is to
provide an update on potentially chondroprotective molecules, as well as disease-
modifying antirheumatic drugs in clinical trials. Other therapeutic approaches such
as chondrocyte transplantation, stem cells, gene therapy, and intra-articular injec-
tions of conditioned media or platelet concentrates are very interesting possibilities
for the future in terms of chondroprotection, but as they are still in the early stages
of clinical development, they will not be discussed in this article.
Understanding the disease in order to treat it
Osteoarthritis is often wrongly considered to simply be the slow and inexorable
wear of cartilage, hence the term degenerative disease. Actually, it is a disease of a
Clinical research in osteoarthritis: whats new? Chevalier and Eymard

whole organ, the joint.2,3 The tissue changes observed in os-
teoarthritis include not only cartilage degradation, but also
sclerosis of subchondral bone, osteophyte formation, and
to varying degrees over time and space, inflammation of the
synovial membrane.3 The concept of osteoarthritis as organ
failure with multitissue damage opens up novel therapeutic
perspectives whereby not only the cartilage damage can be
targeted, but also synovitis and remodeling of subchondral
bone, the latter two participating in a major way in the de-
struction of cartilage.4,5
Current treatments for osteoarthritis, as defined by the latest
international consensus conferences, are essentially aimed at
controlling the painful symptoms, thereby reducing the disabil-
ity that is essentially related to the pain in osteoarthritis.6,7 The
real therapeutic goal for osteoarthritis in the coming years will
be to find a treatment that can permanently reduce cartilage
destruction.
Data on the currently available treatments
For the purposes of slowing down the progression of osteo-
arthritis, a therapeutic class of drugs known as slow-acting
anti-arthritic agents is used. These drugs include derivatives
of avocado and soya, diacerein, chondroitin sulfate and glu-
cosamine sulfate, and hydroxychloride salts. The status of
some of these molecules is that of a nutrient rather than a true
medicine. These molecules have shown a favorable risk-ben-
efit ratio in lower limb osteoarthritis, but their analgesic effec-
tiveness remains modest and controversial.7,8 A recent trial
using 800 mg of chondroitin sulfate for osteoarthritis of the
fingers showed that it could significantly reduce the painful
symptoms over a period of 6 months.9 In terms of chondro-
protection, these molecules have been shown in various trials
to slow the narrowing of the joint space by about 0.1 mm per
year, especially in osteoarthritis of the knee, and to reduce the
number of patients defined as rapid progressors.8 Such a min-
imal annual slowdown still needs to be translated in terms
of clinical relevance. The end point could be, for example,
whether this annual slowdown can delay the need for the im-
plementation of a total prosthesis of the treated joint.10
SELECTED ABBREVIATIONS AND ACRONYMS
DORA Digital Osteoarthritis in Refractory hand OA (study)
FGF18 fibroblast growth factor 18
IL-1 interleukin 1
MRI magnetic resonance imaging
NGF nerve growth factor
NO nitric oxide
TIMP tissue inhibitor of metalloproteinase
TNF- tumor necrosis factor
TNZ tanezumab
WOMAC Western Ontario and McMaster Universities Arthritis
index
Clinical research in osteoarthritis: whats new? Chevalier and Eymard
U P DAT E
Targeting proinflammatory mediators and other
players in osteoarthritis
N Biotherapy
Biotherapy involves specifically blocking a molecule (cytokine
or growth factor) involved in the inflammatory and/or painful
process in osteoarthritis.11
N Targeting pain by inhibiting nerve growth factor
Nerve growth factor (NGF) is a molecule directly involved in
the pathways responsible for pain transmission.12 This mol-
ecule was first described in the nervous system. It acts by
means of two tyrosine kinasetype receptors.12 By binding to
its receptor, it may modify the phosphorylation of vanilloid-
like pain receptors (nociceptors).12
NGF has been identified in the joint, particularly the osteo-
arthritic joint, and it is present at detectable levels in synovial
fluid.13 It was therefore logical to investigate the use of an in-
hibitor of NGF as a potential treatment. Tanezumab (TNZ) is
a fully human monoclonal antibody directed against NGF; it
was used in a randomized trial versus placebo that involved
perfusions every 8 weeks at different doses in patients suffer-
ing from painful knee osteoarthritis (n=450). The results at 16
weeks were impressive, with a very substantial reduction in
pain of between 45% to 62% in the TNZ groups compared
with 21% in the placebo group.14 Unfortunately, in addition to
some adverse neurological side effects, phase 3 clinical trials
revealed an increased number of rapidly destructive arthro-
pathies (similar to neurological arthropathies) that led to the
implementation of prostheses, resulting in the suspension of
trials with this type of antibody.14 Use of nonsteroidal anti-in-
flammatory drugs in conjunction with anti-NGF seems to in-
crease this risk. Since the publication of a recent report by the
US Food and Drug Administration, however, the use of NGF
inhibitors under specific conditions and without the concomi-
tant use of nonsteroidal anti-inflammatory drugs has again
been authorized.
N Biotherapies targeting proinflammatory cytokines
Osteoarthritis is in part an inflammatory disease, as indicated
by its name. The inflammation is localized mainly in the synovial
membrane, but also in the subchondral bone and cartilage,
and involves a cascade of proinflammatory mediators (frag-
ments of the matrix, cytokines, complement components).15,16
These mediators not only contribute to the degradation of the
cartilage matrix during attacks of synovitis, but are also in-
volved in pain transmission pathways.17,18
Two proinflammatory cytokines play a major role in osteoarthri-
tis: interleukin 1 (soluble form of interleukin 1[IL-1]) and tumor
necrosis factor (TNF-).2,3,15 Through in vitro studies, and
later with the use of animal models in vivo, it was demon-
strated that IL-1 is a key molecule favoring cartilage degra-
dation, inhibition of chondrocyte synthesis, and apoptosis.15
Use of an IL-1 inhibitor through local intra-articular adminis-
MEDICOGRAPHIA, Vol 35, No. 2, 2013 229
U P DAT E
tration in experimental animal models of osteoarthritis showed
a slowdown in chondrolysis.19-22 Two randomized trials have
been conducted on two different inhibitors of IL-1 versus pla-
cebo in patients with knee osteoarthritis. We conducted the
first biotherapy trial in osteoarthritis using an IL-1 antagonist
(anakinra) administered by a single intra-articular injection (dose
of 50 mg or 150 mg) versus a placebo injection of physiolog-
ical saline.23 In this trial, there was no significant difference in
the Western Ontario and McMaster Universities Arthritis Index
(WOMAC) global score or level of pain at 1 month, 3 months,
and 6 months. However, at 4 days, there was a small but sig-
nificant difference in the level of pain reported in the patient
group that received 150 mg of the IL-1 receptor antagonist.23
In fact, pharmacokinetic studies have shown a very short half-
life of about 6 hours for IL-1 receptor antagonists in serum,
which is incompatible with having a residual effect on pain.23
The second randomized trial compared repeated systemic
injections (by subcutaneous injection) of a monoclonal anti-
body blocking the type 1 receptor of IL-1 with placebo.24 The
injections were administered monthly. Again, up to 3 months,
IL-1 inhibition demonstrated no significant analgesic effect.
In addition, constant neutropenia was reported and a case
of death from severe pneumonia was also observed.24 On
the other hand, functional magnetic resonance imaging (MRI)
demonstrated changes in the subgroup of patients showing
a beneficial effect from IL-1 inhibition.24
From these two trials, we can conclude that at present, in-
hibition of IL-1 has not enabled observation of an analgesic
effect in knee osteoarthritis. However, IL-1 seems to be a good
therapeutic target. Thus, in the future, it will be necessary to
think about modes of administration, including the intra-ar-
ticular mode, which can prolong the action of this inhibitor,
and to see whether prolonged inhibition of this cytokine can
delay the progression of osteoarthritis.
The second potentially interesting molecule to target is TNF-,
which has an important proinflammatory effect and whose
effect on cartilage degradation potentiates that of IL-1.15 A
recent study conducted in a rabbit model of osteoarthritis
involving cross-section of the medial meniscus showed that
monthly intra-articular injections of infliximab (10 mg/kg or
20 mg/kg) over a 3-month period significantly decreased car-
tilage lesions compared with saline injections.25 In a case re-
port, repeated subcutaneous injections of a blocking mon-
oclonal antibody against TNF (adalimumab) in a patient with
congestive knee osteoarthritis was able to reduce pain and de-
crease subchondral edema observed with MRI at 6 months.26
TNF- is mainly used as a target in digital osteoarthritis, which
can involve a more painful and inflammatory condition called
erosive osteoarthritis.27 Systemic administration of a TNF-
inhibitor is logical in this polyarticular form of osteoarthritis.
Repeated subcutaneous injections of adalimumab produced
230 MEDICOGRAPHIA, Vol 35, No. 2, 2013
no evidence of a decrease in the structural evolution of digi-
tal osteoarthritis compared with placebo over a period of 1
year.28 Only the subgroup of patients with clinically detectable
effusion at baseline at the interphalangeal joints showed a
lower incidence of new erosions.28 In other words, it seems
that anti-TNF may be active on the structural progression of
the disease in a subgroup of patients suffering clinically from
a more inflammatory disease. The French study, Digital Os-
teoarthritis in Refractory hand OA (DORA), aimed to assess
the symptomatic effect of two injections of a monoclonal an-
tibody directed against TNF-.
N Nitric oxide inhibition
Nitric oxide (NO) is a gas that plays many physiological roles,
particularly in terms of regulation of arterial vasodilation, but it
may also play a deleterious role when produced in excess.
It has been demonstrated that NO produced in excess dur-
ing osteoarthritis could contribute to cartilage destruction
through protein nitrosylation, but could also favor apoptosis
of chondrocytes through combined action with free radicals.29
It was therefore logical to consider that inhibition of NO could
reduce the progression of osteoarthritis. A recent randomized
placebo-controlled trial used two doses of an inhibitor of NO
administered orally (50 mg and 200 mg). The trial investigated
chondroprotection in knee osteoarthritis, with the main out-
come criterion being evolution of radiographic joint space nar-
rowing observed at 2 years.30 This study showed no difference
in the overall study population at 2 years in terms of reducing
progression of radiographic joint space narrowing. There was
only a trend favoring the molecule in the subgroup of patients
with a Kellgren-Lawrence grade superior to 2 at 48 weeks.30
To sum up, this trial does not allow us to conclude on the ef-
ficacy of NO inhibition in reducing the progression of knee os-
teoarthritis.
N Inhibition of metalloproteases and enzymes involved
in cartilage degradation
Degradation of the extracellular matrix of cartilage is due to
the increased activity of enzymes such as metalloproteases,
as well as aggrecanase enzymes and a number of serine pro-
teases.3 These enzymes are activated in situ by the action of
proinflammatory mediators such as cytokines. It seems log-
ical, therefore, to block these enzymes in order to slow the
progression of osteoarthritis. The first trials to be conducted
in this area used nonselective inhibitors with many side effects,
including skeletal muscle disorders and tendinitis, which led
to discontinuation of their production.31 Highly selective inhib-
itors are currently available, however, including matrix metal-
loproteinase (MMP)-13 inhibitor. The major role of MMP-13 has
been well demonstrated in knockout mouse models of os-
teoarthritis.32 In an experimental model of osteoarthritis in dogs,
a selective inhibitor of this enzyme showed a convincing chon-
droprotective effect.33 The use of these kinds of inhibitors could
thus be tested clinically in future.34 Similarly, one can consider
the use of natural inhibitors of these metalloproteases, which
Clinical research in osteoarthritis: whats new? Chevalier and Eymard

are designed as tissue inhibitors of metalloproteinase (TIMPs).
Indeed, it has already been demonstrated that intra-articular
injections of TIMP3 could slow the evolution of degenerative
lesions in experimental animal models of osteoarthritis.35
Targeting subchondral bone
There are many arguments in favor of a major role for subchon-
dral bone in the genesis and progression of degenerative joint
disease (see article by Professor David Findlay in this issue).
In animal models, there are early lesions of the subchondral
plate (microcracks) in vivo, with accelerated bone remodel-
ing. In situ, there is a break in the bone-cartilage calcified di-
viding line, leading to neovascularization of the deep layers
of cartilage and a change in chondrocyte phenotype under
the influence of factors such as vascular endothelial growth
factor. In vivo, MRI has revealed subchondral bone lesions
(bone marrow lesions) in the form of a hypersignal next to the
affected cartilage, which can predict the progression of knee
osteoarthritis. Finally, radiographs reveal late subchondral scle-
rosis.36,37
The use of treatments designed to slow remodeling of the sub-
chondral bone appears appropriate in order to preserve the
adjacent cartilage. The use of parathyroid hormone (either in
a curative or preventive capacity) in an experimental model of
osteoarthritis in mice has shown very promising results in terms
of chondroprotection.38 A few clinical trials have been con-
ducted using various anti-osteoporotic drugs to examine their
possible chondroprotective effect.
N Use of bisphosphonates
The use of risedronate at different doses in a randomized tri-
al versus placebo conducted over 2 years was not able to
demonstrate any chondroprotective effect.39 The poor pro-
gression in patients included in this study may account for
the failure of bisphosphonates. However, decreased urinary
levels of collagen CTX2 (Human C-telopeptide of Type II Col-
lagen) were observed in this trial, perhaps indicating a reduc-
tion in joint remodeling.39
A recent randomized placebo-controlled trial used a single
perfusion of zoledronic acid in 30 patients with symptomatic
osteoarthritis of the knee and subchondral edema revealed
by MRI.40 At 6 months, there was a significant decrease in
pain and bone edema observed on MRI in the patients re-
ceiving zoledronic acid. However, at 12 months, there was no
longer any significant difference.40
N Use of oral calcitonin
A large-scale trial involving nearly 1200 patients with knee os-
teoarthritis compared the use of two doses of oral calcitonin
with placebo. Patients were followed up over a 2-year period.
The main purpose of the study was to assess the ability of
oral calcitonin to slow joint space narrowing as assessed by a
standard knee x-ray.41 On the basis of this criterion, the test
Clinical research in osteoarthritis: whats new? Chevalier and Eymard
U P DAT E
was negative; however, patients also underwent MRI. A sig-
nificant difference in cartilage volume favoring calcitonin was
observed at 12 months compared with placebo. It is difficult
to interpret the observed effect solely on the basis of MRI data.
Moreover, the rate of side effects observed with calcitonin was
very high and led to patient discontinuation on the grounds
of intolerance in nearly 20% of cases.41
N Use of strontium ranelate
The use of strontium ranelate for OA treatment has two ad-
vantages; on the one hand, there is an indirect effect on bone,
but there is also a potential direct effect on cartilage. Indeed,
the use of strontium ranelate specifically (the same effect was
not observed with calcium ranelate) produced increased syn-
thesis of proteoglycans in vitro, and a synergistic effect with
insulin-like growth factor-1 on the anabolism of chondrocytes
in vitro.42 On the basis of this observation, the largest-ever
chondroprotection study was conducted using two doses of
strontium ranelate (1 g and 2 g) compared with placebo over
a period of 3 years in patients with symptomatic knee osteo-
arthritis.43 Over 1600 patients were recruited. The proportion
of patients who completed the study was approximately 55%
and 60%, respectively, which is consistent with what has been
observed in previous trials.44 The results of this trial were pos-
itive, and showed an annual slowdown of 0.14 mm in the
group receiving 1 g of strontium ranelate and 0.10 mm in the
group receiving 2 g of strontium ranelate. In addition, the group
of patients defined as radiological progressors (ie, those with
a loss of more than 0.5 mm over the 3-year period) was sig-
nificantly reduced in the strontium ranelate groups compared
with placebo: 33% in the placebo group compared with 22%
and 26% in the strontium ranelate groups, respectively.44
Finally, for the highest dose of 2 g, a combined effect on pain
was also observed, especially in patients experiencing a painful
condition as well as rapid progression of their disease.44 This
large-scale study opens up interesting perspectives, and could
eventually lead to the use of anti-osteoporotic agents such as
strontium ranelate for the prevention of cartilage loss.
Stimulating anabolism by the use of growth factors
There is another interesting therapeutic option whose aim is
not to limit the destruction of cartilage, but rather to favor car-
tilage repair, even when it is naturally weak. The possibility of
direct intra-articular injection of growth factors (bone mor-
phogenetic protein-7 or fibroblast growth factor 18; FGF18)
is still in its early stages, and phase 1/2 trials are currently on-
going.45,46 One study, published only as an abstract, used in-
tra-articular injections of FGF18 (either a single injection or
two cycles of three intra-articular injections) in knee osteo-
arthritis.46 There was no evidence of a slowdown in the nar-
rowing of the joint space compared with placebo, but there
was a benefit in terms of cartilage volume gain as assessed by
MRI at 1 year.46 With regard to local injections of either platelet-
rich autologous plasma or autologous conditioned serum, the
MEDICOGRAPHIA, Vol 35, No. 2, 2013 231
U P DAT E
principle of which is to concentrate growth factors or contra-
inflammatory cytokines, clinical efficacy on pain still needs to
be validated in large-scale placebo-controlled trials, and no
chondroprotection study has been conducted thus far.47,48
Protecting the superficial layers of cartilage
Protection of the superficial layers of cartilage is the princi-
ple behind the use of hyaluronic acid, which serves as a pro-
tective gel. Lubricin is a glycoprotein present in the synovial
fluid, which acts by adhering to the most superficial layers of
cartilage. Animal tests have shown the ability of this molecule
to prevent cartilage degradation when it is administered by in-
tra-articular injection.49 The future may involve combined ther-
apy using lubricin and hyaluronic acid.
References
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Conclusion
A better understanding of the physiopathogenesis of degen-
erative disease in osteoarthritis, particularly the involvement
of different tissues of the joint such as the synovial membrane
and the subchondral bone, has allowed us to consider some
very interesting prospective therapeutic options. Combina-
tion of different treatments may also eventually be consid-
ered, which at different time points could target the synovial
membrane, stem cell cartilage repair, and limitation of long-
term remodeling of the subchondral bone. Nevertheless, it will
also be necessary to demonstrate that modulatory effects on
these structural components can also have an impact on and
a clinical relevance for a hard criterion, such as delaying the
need for total joint replacement surgery. I
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teoarthritis. Bull Acad Natl Med. 2006;190:1411-1420.
20. Chevalier X. Intraarticular treatments for osteoarthritis: new perspectives. Curr
Drug Targets. 2010;1:546-560.
21. Caron JP, Fernandes JC, Martel-Pelletier J, et al. Chondroprotective effect of in-
tra-articular injections of interleukin-1 receptor antagonist in experimental os-
teoarthritis. Suppression of collagenase-1 expression. Arthritis Rheum. 1996;39:
1535-1544.
22. Pelletier JP, Caron JP, Evans C, et al. In vivo suppression of early experimental
osteoarthritis by interleukin-1 receptor antagonist using gene therapy. Arthritis
Rheum. 1997;40:1012-1019.
23. Chevalier X, Goupille P, Beaulieu AD, et al. Intraarticular injection of anakinra in
osteoarthritis of the knee: a multicenter, randomized, double-blind, placebo-
controlled study. Arthritis Rheum. 2009;61:344-352.
24. Cohen SB, Proudman S, Kivitz AJ, et al. A randomized, double-blind study of
AMG 108 (a fully human monoclonal antibody to IL-1R1) in patients with os-
teoarthritis of the knee. Arthritis Res Therapy. 2011;13:R125.
25. Zhang Q, Lv H, Chen A, Liu F, Wu X. Efficacy of infliximab in a rabbit model of
osteoarthritis. Connect Tissue Res. 2012;53:355-358.
26. Grunke M, Schulze-Koops H. Successful treatment of inflammatory knee osteo-
arthritis with tumour necrosis factor blockade. Ann Rheum Dis. 2006;65:555-
556.
27. Punzi L, Ramonda R, Sfriso P. Erosive osteoarthritis. Best Pract Res Clin Rheu-
matol. 2004;18:739-758.
28. Verbruggen G, Wittoek R, Cruyssen BV, Elewaut D. Tumour necrosis factor
blockade for the treatment of erosive osteoarthritis of the interphalangeal finger
joints: a double blind, randomised trial on structure modification. Ann Rheum
Dis. 2012;71:891-898.
29. Abramson SB. Nitric oxide in inflammation and pain associated with osteo-
arthritis. Arthritis Res Ther. 2008;10(suppl 2):S2.
30. Hellio Le Graverand MP, Clemmer R, Redifer P, et al. A 2-year randomized, dou-
ble-blind, placebo-controlled, multicentre study of oral selective iNOS inhibitor,
cindunistat (5SD-6010), in patients with symptomatic osteoarthritis of the knee.
Ann Rheum Dis. 2013;72:187-195.
31. Krzeski P, Buckland-Wright C, Blint G, et al. Development of musculoskeletal
toxicity without clear benefit after administration of PG-116800, a matrix met-
alloproteinase inhibitor, to patients with knee osteoarthritis: a randomized, 12-
month, double-blind, placebo-controlled study. Arthritis Res Ther. 2007;9:R109.
32. Little CB, Barai A, Burkhardt D, et al. Matrix metalloproteinase 13-deficient mice
are resistant to osteoarthritic cartilage erosion but not chondrocyte hypertro-
phy or osteophyte development. Arthritis Rheum. 2009;60:3723-3733.
33. Settle S, Vickery L, Nemirovskiy O, et al. Cartilage degradation biomarkers pre-
dict efficacy of a novel, highly selective matrix metalloproteinase 13 inhibitor in
a dog model of osteoarthritis: confirmation by multivariate analysis that mod-
ulation of type II collagen and aggrecan degradation peptides parallels patho-
logic changes. Arthritis Rheum. 2010;62:3006-3015.
34. Li H, Feng F, Bingham CO 3rd, Elisseeff JH. Matrix metalloproteinases and inhib-
itors in cartilage tissue engineering. J Tissue Eng Regen Med. 2012;6:144-154.
35. Black RA, Castner B, Slack J, Tocker J, Eisenman J. Injected TIMP-3 protects
cartilage in a rat meniscal tear model. Osteoarthritis Cartilage. 2006;14(sup-
pl B S23):A14.
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 U P DAT E

36. Pesesse L, Sanchez C, Henrotin Y. Osteochondral plate angiogenesis: a new
treatment target in osteoarthritis. Joint Bone Spine. 2011;78:144-149.
37. Hunter DJ, Zhang W, Conaghan PG, et al. Systematic review of the concur-
rent and predictive validity of MRI biomarkers in OA. Osteoarthritis Cartilage.
2011;19:557-588.
38. Sampson ER, Hilton MJ, Tian Y, et al. Teriparatide as a chondroregenerative
therapy for injury-induced osteoarthritis. Sci Transl Med. 2011;3:101ra93.
39. Bingham CO 3rd, Buckland-Wright JC, Garnero P, et al. Risedronate de-
creases biochemical markers of cartilage degradation but does not decrease
symptoms or slow radiographic progression in patients with medial compart-
ment osteoarthritis of the knee: results of the two-year multinational knee os-
teoarthritis structural arthritis study. Arthritis Rheum. 2006;54:3494-3507.
40. Laslett LL, Dor DA, Quinn SJ, et al. Zoledronic acid reduces knee pain and
bone marrow lesions over 1 year: a randomised controlled trial. Ann Rheum
Dis. 2012;71:1322-1328.
41. Karsdal MA, Alexandersen P, Dam EB, et al. Oral calcitonin demonstrated symp-
tom-modifying efficacy and decreased cartilage volume loss: results from a 2
year phase 3 trial in patients with osteoarthritis of the knee. Presented at: Amer-
ican College of Rheumatology Scientific Meeting; November 8, 2011; Chicago,
IL. Late breaking abstract L9.
42. Henrotin Y, Labasse A, Zheng SX, et al. Strontium ranelate increases cartilage
matrix formation. J Bone Miner Res. 2001;16:299-308.
43. Cooper C, Reginster JY, Chapurlat R, et al. Efficacy and safety of oral strontium
ranelate for the treatment of knee osteoarthritis: rationale and design of randomised,
double-blind, placebo-controlled trial. Curr Med Res Opin. 2012;28:231-239.
44. Reginster JY, Badurski J, Bellamy N, et al. Efficacy and safety of strontium
ranelate in the treatment of knee osteoarthritis: results of a double-blind, ran-
domised placebo-controlled trial. Ann Rheum Dis. 20113;72:179-186.
45. Hunter DJ, Pike MC, Jonas BL, Kissin E, Krop J, McAlindon T. Phase 1 safety
and tolerability study of BMP-7 in symptomatic knee osteoarthritis. BMC Mus-
culoskelet Disord. 2010;11:232.
46. McPherson R, Flechenshar K, Hellot S, Eckstein F. A randomized, double blind,
placebo-controlled, multicenter study of RHFGF18 administered intraarticular-
ly using single or multiple ascending doses in patients with primary knee osteo-
arthritis (OZA), not expected to require knee surgery within a year. Osteoar-
thritis Cartilage. 2011;19(suppl S35):65.
47. Kon E, Mandelbaum B, Buda R, et al. Platelet-rich plasma intra-articular injec-
tion versus hyaluronic acid viscosupplementation as treatments for cartilage
pathology: from early degeneration to osteoarthritis. Arthroscopy. 2011;27:
1490-1501.
48. Baltzer AW, Moser C, Jansen SA, Krauspe R. Autologous conditioned serum
(Orthokine) is an effective treatment for knee osteoarthritis. Osteoarthritis Car-
tilage. 2009;17:152-160.
49. Jay GD, Elsaid KA, Kelly KA, et al. Prevention of cartilage degeneration and gait
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ate ligament transection. Arthritis Rheum. 2012;64:1162-1171.

Keywords: anti-osteoporotic drug; biotherapy; cartilage; metalloprotease; nitric oxide; osteoarthritis; strontium ranelate

LA RECHERCHE CLINIQUE DANS LARTHROSE : QUOI DE NEUF ?

Les nouvelles perspectives de traitement de larthrose se concentrent sur le blocage du processus de dgradation
en inhibant le remodelage tissulaire dans los et le cartilage, ainsi que linflammation de la membrane synoviale. Au-
cun des mdicaments anti-arthrosiques daction lente actuellement disponibles ne peut tre considr comme un
traitement cibl. Les premires tudes sur le traitement par antagonisme du facteur de croissance du nerf ayant
montr un effet spectaculaire sur la douleur des patients souffrant darthrose du genou, ont soulev un grand es-
poir. Malheureusement, ces tudes ont par la suite t arrtes en raison de la survenue inexplique darthropathies
rapidement destructives. Des biothrapies utilisant des bloqueurs de linterleukine 1 ont t utilises dans larthrose
du genou mais se sont jusqu maintenant montres inefficaces sur la douleur. La biothrapie de larthrose de la
main par blocage du facteur de ncrose tumorale pour ralentir la progression de la maladie, a galement chou. De
mme, les inhibiteurs du monoxyde dazote nont pas russi montrer deffet protecteur du cartilage dans une large
tude sur des patients souffrant darthrose du genou. Lutilisation dinhibiteurs des enzymes impliques dans la d-
gradation de la matrice cartilagineuse est en phase prclinique et reprsente une approche intressante. Cibler los
sous-chondral reprsente galement une approche prometteuse. Alors que les rsultats dtudes antrieures sur
la protection du cartilage par les bisphosphonates ont t ngatifs, une grande tude rcente a montr une diminu-
tion du rtrcissement de lespace interarticulaire aprs 3 ans de traitement par le ranlate de strontium. Le traite-
ment par stimulation de lanabolisme du chondrocyte est galement ltude. Linjection intra-articulaire de facteurs
de croissance est en phase initiale de dveloppement. Enfin, un nouveau lubrifiant appel lubricine a montr des
rsultats trs intressants dans des modles animaux.

Clinical research in osteoarthritis: whats new? Chevalier and Eymard MEDICOGRAPHIA, Vol 35, No. 2, 2013 233
 A TOUCH
OF FRANCE
y inventing the film camera,

B and perforations to advance

the film through a camera
and a projector, France, through
the Lumire brothers, gave birth
to the cinema. On 19 March 1895,
they produced the first footage
ever made, albeit on an admit-
tedly dull topic, that of workers
leaving a factory after their days
work. Touch of France looks at
the early history of the motion pic-
ture and its developments in the
fields of science and medicine
(Christian Rgnier), and at the gi-
gantic effort to preserve the lega-
cy of the cinema, with the French
Cinmathque founded by Henri
Langlois (Isabelle Spaak). And re-
member, the love affair between
France and the cinema is still alive
and kicking: do The Artist and Au-
drey Tautou mean anything to you?

Cinema, science, and

medicine in France
C . R g n i e r, Fra n c e Page 237

Children of the Cinmathque

I . S p a a k , Fra n c e Page 246
 A TOUCH OF FRANCE

ublic health propaganda us-

P ing moving pictures spread

in France during World War I
after the setting up of an extra-
parliamentary commission to study
how to extend the use of cinema-
Cinema, science, and
tography to other areas of teaching.
Most films shown by the Rocke-
feller mission, some 150 in all,
medicine in France
were produced by Path and by
Gaumont. Their titles left little to
the imagination: Dont Spit on the
Ground, Beware the Fly, Dont Lick
your Fingers to Turn the Page, The
Slums Must be Vanquished, Fin-
gernails in Mourning.

b y C . R g n i e r, Fra n c e

I
n the 1870s, a forerunner of the motion picture settled a bothersome ques-
tion. Does a galloping horse ever become airborne? More prosaically, are
all four of its hooves ever off the ground at the same time? It fell to the Eng-
lish photographer Eadweard Muybridge to find the answer. Hired by a former
governor of California and racehorse owner, Muybridge placed glass-plate
cameras along the edge of a race track. As the horse passed each camera it
All rights reserved

broke a thread and triggered the shutter, thus generating a series of photo-
graphs. Muybridge copied these as silhouettes onto a disc and, using his in-
vention the zoopraxiscope, showed that there was indeed unsupported tran-
sit, a fleeting moment when the horse was airborne. The zoopraxiscope later
Christian RGNIER, MD came to be regarded as an early movie projector, and with it Muybridge wrote
Praticien Attach Consultant a page in the history of early cinematography. So too did the French astron-
de lHtel-Dieu de Paris
Socit Internationale omer Jules Janssen, with his photographic revolver, which he used in Japan
dHistoire de la Mdecine in 1874 to record the transit of Venus across the face of the sun. And above
9 rue Bachaumont all there was tienne-Jules Marey, a French doctor and physiologist who de-
75002 Paris
(e-mail: veloped the chronophotograph and other instruments for pioneering analy-
dr.christian.regnier@wanadoo.fr) sis in humans and animals of locomotion and physiological processes like
blood flow, breathing, and the beating heart. These and other pioneers were
driven by their thirst for scientific understanding. Others, meanwhile, had their
eyes on the immense commercial and artistic potential of the new technique
of motion pictures. At the close of the 19th century, the American engineer
Thomas Edison, the French industrialists Louis and Auguste Lumire, and
the French illusionist Georges Mlis joined the adventure of the new cine-
matography. Industrial logic, the drive for profitability, and the lure of wealth
drove them, and led to clashes with scientists who saw cinematography pure-
ly as a research and educational tool. From its beginnings in the laboratories
of science, cinema had become a show, a leisure activity accessible to every-
one. Dubbed the seventh art (after architecture, sculpture, painting, music,
poetry, and dance) by the Italian film theoretician Ricciotto Canudo, the motion
picture was able to portray all aspects of life whether scientific or fictional.
Medicographia. 2013;35:237-245 (see French abstract on page 245)

Left page: Louis Lumire,

inventor of the cinematograph
together with his brother
Augusteinspecting a film
(photo dated 1935).
AKG-images/Walter Limot.

www.medicographia.com

Cinema, science, and medicine in France Rgnier MEDICOGRAPHIA, Vol 35, No. 2, 2013 237
A TOUCH OF FRANCE
odays cinemagoers, accustomed as they are to com-
T puter-generated three-dimensional images full of sound
and fury, would have scant regard for a 45-second silent
film with the humdrum title Workers Leaving the Lumire Fac-
tory. Yet motion pictures were born that March day in 1895,
when the Lumire brothers Louis and Auguste showed their
film to a gathering of scientists at the Grand Caf on the Bou-
levard des Capucines in Paris. Sons of a manufacturer of pho-
tographic equipment, the Lumires screened the film using
238 MEDICOGRAPHIA, Vol 35, No. 2, 2013
their cinematograph, which combined a camera and projec-
tor to recreate movement. Not everyone present was thrilled.
tienne-Jules Marey, the President of the Academy of Sci-
ences, was sickened by what he saw: intellectual theft. The
Lumire brothers projector, he said, was his invention, the
chronophotograph, hijacked and poorly disguised by the ad-
dition of a cam for perforated films. Marey was interested sole-
ly in science and biology, and was hostile to the commercial
exploitation of moving pictures.1,2 As a pioneer of the analy-
sis of movement, he developed a chronophotographic pro-
jector using unperforated film to record and study normal and
abnormal human gait, the beating of a perfused frog heart,
airborne birds and insects, swimming rays, even the move-
ment of smoke trails.
Cinema, a godsend for showmen and
industrialists
The principle of moving images was not new and various an-
imation devices were invented in the middle years of the 19th
century. The thaumatrope, beloved of every child, relies on the
persistence of vision to combine two separate images into
one: a bird on one side of a spinning card, its cage on the
Charles-mile Reynauds praxinoscope projector (invented in
1877) and projection image (1887). Bettmann/CORBIS.
Frames from Moving Horse, filmed by physiologist tienne-Jules
Marey (left) and Workers Leaving the Lumire Factory, filmed by
the Lumire Brothers in 1895. Album/Oronoz/akg-images.
Cinema, science, and medicine in France Rgnier
 A TOUCH OF FRANCE

Left: Thomas Edison (1847-1931), inventor of the phonograph, the light bulb, and the motion picture camera, and holder of 1093
patents, in his laboratory, ca 1915. Bettmann/CORBIS. Right: Thomas Edisons first motion picture camera (1891). CORBIS.

other. The phenakistiscope, zootrope, kinetiscope, and prax-
inoscope (the latter invented in France in 1877 by Charles-
mile Reynaud) all created the illusion of movement, and in
1891 Thomas Edison patented his kinetoscope and a cam-
era, the kinetograph, which used perforated 35-mm film. The
kinetoscopes continuous lighting offered closed loop images
for one viewer at a time. This wealth of ideas and inventions
knew no limit; nor, it should be added, did intellectual prop-
erty disputes or wrangling over patent applications (nearly 150
in France in 1896).1
Sprinkler Sprinkled that December day was the illusionist
Georges Mlis. He quickly acquired a camera and in 1897
opened a film studio at Montreuil-sous-Bois, near Paris, where
he founded his company Star-Film. A pioneer in special effects,
Mlis made one thousand 125-meter (4-minute) films, and
won worldwide acclaim with his masterpiece Le Voyage Dans
la Lune (A Trip to the Moon). Mlis trod not the cinematic road
of the quest for knowledge, but that of a storyteller making
films for the general public.1

In December 1895, the Lumire broth-

ers screened what was probably the
first ever comedy film. LArroseur Ar-
ros (The Sprinkler Sprinkled) was
shown to an audience of 33 in the In-
dian Salon of the Grand Caf, on the
boulevard des Capucines in Paris.
The entry charge was 1 francto put
this into context, the salon could be
rented for a whole year for 30 francs.
The success was immediate, and last-
ing as word of mouth ensured that
for weeks on end people came to the
film show at the Grand Cafbe-
tween 2000 and 2500 every day. Em-
boldened by their triumph, the Lumire
brothers trained operators and sent
them on filming trips around the world,
while use of their cameras spread
among fairground cinemas. Among Poster for LArroseur Arros (The Sprinkler Sprinkled) screened in 1895 by the Lumire
those at the first screening of The Brothers. Bettmann/CORBIS.

Cinema, science, and medicine in France Rgnier MEDICOGRAPHIA, Vol 35, No. 2, 2013 239
A TOUCH OF FRANCE

Film still from A Trip to the Moon, a movie by Georges Mlis (1902), based on the novel From the Earth to the Moon, by Jules Verne.
Mlis directed 555 films between 1896 and 1914. Bettmann/CORBIS.

Industrialists, too, sought to exploit the potential of moving
images. Georges Demen, Mareys assistant at the physiol-
ogy annex of the Collge de France, started out studying the
movements of the mouth during speech. In May 1892, at
the first International Exhibition of Photography in Paris, he
presented thirty or so moving images mouthing the phrase
je vous aime (I love you). Demen also invented the phono-
scope, which recorded both images and sound, to teach
deaf-mutes how to speak. He soon recognized, though, the
commercial potential of his invention, changed tack, and set
up a company (Socit Gnrale du Phonoscope) to focus
on the industrial exploitation of his process.3
Using an improved version of his phonoscope, Demen then
filmed short photograms, living portraits of people uttering
a few words, and everyday scenes unrelated to his original sci-
entific endeavors. The breach with Marey, who was opposed
to the commercial exploitation of moving pictures, was not
long in coming, and in 1894 Demen was forced to resign from
the Collge de France. Unfazed, Demen is believed to have
filmed the national funeral of Louis Pasteur on 5 October 1895
using 6-mm film, and two years later invented the 35-mm ver-
sion of his camera. Unversed in the ways of business, Demen
sought help from Lon Gaumont, the founder of the French
production company L. Gaumont et Cie, which manufactured
projection equipment and cameras. Demen fared badly in
the venture and his process was bought by Gaumont, thus
bringing to an untimely end this first marriage between sci-
ence and industry.1,3
Birth of the French scientific film
In 1898, Dr Eugne Doyen, a well-known surgeon, paid some-
one to film him performing a hysterectomy and a craniotomy
(his specialties) in his private clinic on the rue Piccini in Paris.
When his surgeon colleagues of the Academy of Medicine
balked at showing his films in public, Doyen himself paid for
their projection. They showed medium-close shots, with no
dcor, and were intended for teaching purposes, though
Doyen did not hesitate to show them to an impressionable
public. The surgeon Jean-Louis Faure, another pioneer of sur-
gical films, said of Doyens films that they were of great edu-
cational value, but tended to showiness, which, he felt, marred
the demonstration of the surgical technique.
A few years later Doyen hired a camera operator to film his
surgical separation of Doodica and Radica, conjoined twins
who starred in Barnum and Baileys touring cabinet of curiosi-
ties. The sober staging and style seemed to invite viewers to

240 MEDICOGRAPHIA, Vol 35, No. 2, 2013 Cinema, science, and medicine in France Rgnier

The conjoined twins Doodica and Radica, joined at the chest
(xiphopagus twins), surgically separated by Eugne Doyen in 1902.
Although the operation itself was a success, Doodica died shortly
after the separation, and Radica succumbed to tuberculosis in
1903. IAM/akg/World History Archive.
abandon their role as onlookers and become protagonists.
The resulting scientific filmLa Sparation des Surs Sia- microcinematography capable of 8- to 10-fold magnification.7,8
moises Doodica et Radicatrespassed into the realm of show
business. Worse was to come. Negatives of the film were kept
by the camera operator and distributed in France and be-
yond for projection at cafs chantants. What had started life
as a medical demonstration, ended in ghoulishness. Tarnished
by this unseemly episode, and by the resulting legal tussles
and controversy, Doyen fell from grace.
Then there was the question of copyright. Who exactly owned
such films? The filmmaker or the surgeon? And what of the
patient, without whom there would be no film? The fifty or
so films of Doyens surgical procedures were leased to the
clipse company, later transferred to
Gaumont, and then acquired by Doyens
heirs, only to go up in smoke during a
bombing raid in World War II.4-6
Up to the outbreak of war in 1914, in-
dustrial scientific films were highly pop-
ular in France. Most French production
companiesPath, Gaumont, clair,
clipseopened studios to make short
films which in general were shown in cin-
emas, before the newsreel and the main
feature. When the production units joined
One of the Rockefeller Foundations trav-
eling educational units (roulottes dhygiene),
which crisscrossed France from 1917
to 1925 as part of a mission to fight tuber-
culosis. Photo published in Cinmagazine
No. 49, on 23 December 1921.
Cinema, science, and medicine in France Rgnier
A TOUCH OF FRANCE
forces with genuine laboratories with animal facilities, an aquar-
ium, a vivarium, biology, chemistry, and physics departments,
their films acquired an educational purpose. Some 450 one-
reelers popularizing science were produced in the four years
before the war. To kindle the interest of younger viewers and
to overcome any mind-wandering, the films showed odd or
unfamiliar creatures and insects. The industrialist Charles Path
was convinced of their educational value, saying that the
cinematograph will be the theater, newspaper, and school
of tomorrow. douard Petit, the chief inspector of schools,
begged to differ, believing that in the cinema the somewhat
rushed sequence of images deforms the slow and progres-
sive work of nature.7-9
To adapt to the large variations in the duration of natural or bi-
ological phenomena, the scientific film from the outset used
techniques that would later be adopted by those making films
for cinematic storytelling: slow motion and time-lapse pho-
tography. One of Mareys collaborators, the photographer Lu-
cien Bull, originated high-speed cameras which, in the early
1900s, filmed at 1200 and then 4000 images per second, and
over the years he refined them until by 1951 they could record
one million images per second. Bull also invented a camera for
Interest in scientific films waned at the start of the First World
War and laboratories were dismantled and their staff laid off.
Scientific documentaries took their place, but were less pop-
ular and designed for a different purpose: the dissemination
of scientific knowledge to prepared minds and the creation
of audiences keen on this type of film.
Using itinerant film shows to teach public hygiene
In 1917, as the United States of America joined forces with
the Allies in World War I, the Rockefeller Foundation sent a
commission to France to aid that country in organizing a fight
MEDICOGRAPHIA, Vol 35, No. 2, 2013 241
A TOUCH OF FRANCE
upon tuberculosis, by which under ex-
isting conditions the population was se-
riously menaced.10 The Commission for
the Prevention of Tuberculosis in France
was solemnly welcomed by French Pres-
ident Raymond Poincar on 9 August
1917. It was funded by The Rockefeller
Foundation to the tune of $522 459 (the
equivalent today of roughly 45 million eu-
ros), and included training courses for
doctors and health visitors, the running
of dispensaries throughout France (70%
of the population lived in rural areas),
and a campaign of popular education
by means of traveling exhibits, lectures,
slides, moving pictures, posters, pam-
phlets, and press articles.10 Five circu-
lating educational units known as the
roulottes dhygine (hygiene caravans)
traveled the length and breadth of France.
Aboard each were an electrical generator, film projection equip-
ment, films, documents, 42 exhibition posters, and five peo-
ple: the (American) film director, a female lecturer, a male lec-
turer, a mailman, and a driver-cinematographer.
Public health propaganda using moving pictures spread in
France during World War I after the setting up of an extra-
parliamentary commission to study how to extend the use of
cinematography to other areas of teaching. Most films shown
by the Rockefeller mission, some 150 in all, were produced by
Path and by Gaumont. Their titles left little to the imagination:
Jean Painlev (1902-1989) filming an aquarium for his documentary LHippocampe,
with a high-speed Debrie GV camera, in Port-Blanc, Brittany, around 1925.
Les Documents cinmatographiques, Paris.
242 MEDICOGRAPHIA, Vol 35, No. 2, 2013
Doctor Jean Comandon (1877-1970), a
precursor of medical and hygiene documen-
taries, with more than 400 films to his credit.
Dont Spit on the Ground, Beware the
Fly, Dont Lick your Fingers to Turn the
Page, The Slums Must be Vanquished,
Fingernails in Mourning.11 These and like
films were aimed at teachers and univer-
sity lecturers, the middle classes, soldiers,
housewives, and workers. And above all
children, for whom the Rockefeller lectur-
ers ran health crusades with the added
incentive of prizes. Between 1917 and
1922, the Rockefeller mission organized
6800 talks, distributed 15 million leaflets,
and launched extensive American-style
press campaigns. Close to three million
French people attended the talks and
lectures.11 After World War I, public health
education using films continued, notably in the fight against
tuberculosis through the National Committee for Defense
Against Tuberculosis (which took over the films of the Rocke-
feller mission). The task of making new films was entrusted
to Jean Benot-Lvy, who between 1920 and 1944 made to
order for various governmental ministries almost 300 one-
reelers and 15 features. These scientific and educational films
were made in consultation with medical officers, notably Dr
Louis Devraigne, head of the maternity ward at the Lariboi-
sire Hospital in Paris, who gave advice (and provided scripts).
In 1927 alone ten million French people attended these film
shows, which were the educational medi-
um most popular with the working class-
es and rural populations.12,13
Designed to appeal to, and so to edu-
cate, the general public, Benot-Lvys
films extolled the values of humanism and
of republican science. Produced by the
Socit ddition cinmatographique
franaise, which Benot-Lvy created in
1922, there were films on cancer, the pre-
vention of syphilis, and alcoholism. The
first great film recounted the life and work
of Louis Pasteur. Others followed, like
The Mother-To-Be on infant care, The Sa-
cred Veil on visiting nurses, and Mater-
nity, which advocated a pro-birth policy.
In a December 1932 interview, Benot-
Lvy spoke of his belief that education-
al films have much in common, and of-
tentimes are confused, with drama films,
from which they borrow ideas on how
to be more compelling. Benot-Lvy felt
Cinema, science, and medicine in France Rgnier
 A TOUCH OF FRANCE

that educational films fall into two clearly distinct genres:
those used to illustrate a talk and to transmit understanding,
and those shown in ordinary film theaters and intended to
appeal to heart and soul. Education, Benot-Lvy believed,
speaks above all to the intellect in the first genre, and to the
sentiments in the second, provided, that is, mind and heart
can be partitioned so neatly.12,14
Making the transition to the talkies, Benot-Lvy produced
two realistic filmsItto and Hlnein which the image of the Chironomidae family (which contains some 5000 species).
rebellious woman, mistress of her own destiny, contrasted
sharply with the silent images of Maternity.12 He also made
films for the teaching of surgery, as part of a medical-surgical
cinematographic encyclopedia, a project curtailed by the out-
break of war in 1939.
erthe world of science scoffed at Painlevs eclecticism,
unconvinced that cinema was a tool of scientific research.
Painlev was one of the founders of the Institut de Cinma-
tographie Scientifique and of the Commission Suprieure de
lImage et du Son, which allied science and cinema. He even
acted in the film The Unknown Woman of Six Days direct-
ed by Ren Sti to fund the anatomy and histology laborato-
ry of the Sorbonne. He gave talks illustrated by films at the
French Academy of Sciences on the larvae of midges of the
Also a diver, Painlev made numerous scientific documen-
taries of aquatic animal life, like the landmark documentary on
sea horses LHippocampe ou Cheval Marin (filmed through
an aquarium!).

A new genre: the independent

science documentary
Dr Jean Comandon filmed the invisible.
A maker of scientific films before World
War I, Comandon later moved on to doc-
umentaries. His research on microcine-
matography at the Saint Louis Hospital
in Paris was given technical backup by
Path, which he joined in 1906 to work
its laboratory. There he made films like
Crystallization, The Curious Soldier Flies:
The Stratiomyidae, and The Movement
of Plants.

Beset by financial difficulties, Path

stopped producing scientific films in
1926 and closed the laboratory where
Comandon worked. Already the recip-
ient of various distinctions and awards
for his work, Comandon set up a scien-
tific cinematography lab at the Institut
Pasteur in Garches (near Paris) where
he made films like The Phagocytosis of
Trypanosomes by White Blood Cells and
The Circulation of Blood.15,16

In the 1920s, film clubs, educational cin-

ema offices, and specialized projection
rooms ensured the survival of scientific
cinema in a new form where mostly doc-
umentary films were shown to the pub-
lic. Jean Painlev bestrode French sci-
entific cinema of the 1920s. Biologist,
scriptwriter, friend of the surrealists, hu-
manist, jewelry designer, racing car driv-

Buste d'Hippocampe (sea horse bust),

photographed by Jean Painlev, around 1930.
Les Documents cinmatographiques, Paris.

Cinema, science, and medicine in France Rgnier MEDICOGRAPHIA, Vol 35, No. 2, 2013 243
A TOUCH OF FRANCE
Painlev was friends with renowned film
directors like Jacques Prvert, Henri Lan-
glois, Georges Franju, Sergei Eisenstein,
Luis Buuel, Jean Vigo, and Abel Gance.
He used musicians in the making of his
documentaries like LHippocampe, for
which Darius Milhaud wrote the music,
and in The Vampire, in which the life of a
vampire bat was illustrated by the music
of Duke Ellington, including Echoes of the
Jungle (Painlev was a jazz pianist too!).
In all, Painlev took part in the making of
almost 200 films, using the latest tech-
nologies: underwater filming, special ef-
fects, steadycam. In 1930, he made a
militant four-minute film in which he de-
clared his support for the use of citrate in
anticoagulation to stem massive bleed-
ing, as recommended by a physician with the rank of gen-
eral in the French military, but recently refused by the French
Defense Health Service Authorities.17,18 Dr Pierre Thvenard
started his career as a film scientific director in 1934 by mak-
ing 35-mm films on urologic surgery and followed this up with
CINEMOPHTHALMIA, THE BANE OF EARLY CINEMAGOERS
In the early 20th century, a visit to the newfangled cinema
was a risky affair. Eighteen-year-old Miss R. of Bordeaux
paid for her cinematic passion with conjunctivitis after every
show. And M. C., a barber of that same French city, was
unable to read his newspaper for days after every visit to
a film theater. What was happening? In 1909, local oph-
thalmologist Dr Ginestous provided the answer when he
gave a paper on a new medical phenomenon he had dis-
covered: cinemophthalmia.
In the early years of cinematography, the persistence of
luminous impressions on the retina was calculated to last
2/25 of a second, and so filmmakers adopted a projection
speed of 16 images/second for 35-mm film. To produce
the cinematographic illusion, the succeeding images must
remain superimposed on the retina for long enough to
give the impression of movement. Each projected image
requires an illumination phase and a phase during which
the film is advanced at a fixed speed by one frame. The
resulting scintillation of the image generated eye strain, par-
ticularly as knavish film theater directors tended to slow
the projection speed so as to lengthen the show: a 1000-
meter film lasted 54 minutes when projected at 16 images/
second and 62 minutes at 14 images/second. This new
ailment of cinemophthalmia discovered by Dr Ginestous
was believed to be triggered by the poor quality of films,
244 MEDICOGRAPHIA, Vol 35, No. 2, 2013
Doctor Albert Calmette (1863-1933), who,
together with his assistant Camille Gurin,
developed the BCG vaccine against tuber-
culosis. Wellcome Library, London.
an uninterrupted series of science doc-
umentaries and films, some of which won
awards: Beware of Vipers, Ultrasound,
The Killer Mushroom, The True Culprit, a
drama commissioned by the French wel-
fare system to warn of the dangers of in-
duced abortion, The Question of Cancer,
an encyclopedic review in thirteen reels,
and The Adventures of a Bluebottle. A
good number of Thvenards films were
set to music by Andr Jolivet, while pop-
ular actors and members of the Com-
die-Franaise did the voiceovers. After
Thvenard joined the scientific cinema-
tography laboratory of the Institut Pasteur, he was commis-
sioned to make a documentary on Albert Calmette, co-dis-
coverer of the bacillus Calmette-Gurin, used in vaccination
against tuberculosis. This and other films brought Thvenard
international renown.8,19
which were stained and scratched, by celluloid of uneven
thickness and grain, by poor shots dotted with fuzzy and
indistinct details that force the viewers eye constantly to
change focus (accommodation), and by deterioration of
the film perforations resulting in slippage of the film.
Cinemophthalmia had several clinical variants: simple eye
watering with photophobia, inflammatory erythema of the
eyelids and of the conjunctiva, problems focusing, exhaus-
tion of ocular reflexes, notably fatigue of the internal eye
muscles, and retinal asthenopia without loss of visual acu-
ity or abnormal refraction. Despite this alarming list of dis-
orders, Dr Ginestous sought to hearten, saying that in fact
ophthalmias of this type had a good prognosis and usu-
ally resolved quickly, even without treatment. As for pro-
phylaxis, Dr Ginestous had the answers: choose a better
class of film theater where they use new reels of film (no slip-
page) and the correct projection speed; wear blue-tinted
glasses; peer at the screen through fanned fingers or fi-
brous palm leaves; use eyedrops containing cocaine or
adrenaline.
Cinemophthalmia receded after World War I, like a fad-
ing retinal image, pushed into a footnote on the history of
medicine by improvements in cinema projection equip-
ment, filming techniques, and celluloid film.21-24
Cinema, science, and medicine in France Rgnier
 A TOUCH OF FRANCE

Epilogue
Movies have long depicted stories of medical practitioners
in a bewildering array of guises: the hospital bigwig, a coun-
try doctor, a physician and humanist, the doomed hero, the
medic guilty of malpractice, a doctor in the colonies, murder-
ers, cranks. Illness and the afflicted too have well served many
an intrigue on the silver screen: the Machiavellian gimp, the
fragile and vulnerable heart patient, the erratic mental patient,
the consumptive condemned to a slow death, loathsome mis-
shapenness and disfigurement, the chilling diagnosis of can-
cer, traumatic childbirth. The sick and the lame have served
as a mirror, a conceit, a vehicle for a social conception of dis-
ease and suffering.20 I

References
1. Sicard M. LAnne 1895: lImage cartele Entre Voir et Savoir. Paris, France:
Les Empcheurs de Penser en Rond: 1994.
2. Leuba M. Marey, Pionnier de la Synthse du Mouvement, Beaune: Muse Marey,
1995.
3. Drevon A. Les travaux de Georges Demen In: Martinet A et al. Le Cinma et
la Science; Paris, France: ditions du CNRS; 1994.
4. Lefebvre T. La Chair et le CellulodLe Cinma Chirurgical du Docteur Doyen.
Brionne, France: Jean Doyen; 2004.
5. Doyen E. LEnseignement de la Technique Opratoire par les Projections Ani-
mes. Paris, France: Socit Gnrale des Cinmatographes clipses; 1911. 18. Millet R. Jean Painlev cinaste. In: Martinet A et al. Le Cinma et la Science;
6. Faure JL. Les films chirurgicaux. Bull Soc Fr Hist Med. 1937;31:245-248.
7. Lefebvre T. De la science lavant garde. In: Berthoz A et al. Images, Science,
Mouvement. Paris, France: LHarmattan-SMIA; 2003.
8. Thvenard P, Tassel G. Le Cinma Scientifique Franais. Paris, France: La Jeune
Parque; 1948.
9. Petit E. Lcole et le cinma. Film-Revue. 1913;53:1-2.
10. The Rockefeller Foundation Annual Report 1920. www.rockefellerfoundation.org/
.../annual-reports.
11. Picard JF. La Fondation Rockefeller et la Recherche Mdicale. Paris, France:
PUF; 1999.
12. Vignaux V. Jean Benot-Lvy ou le Corps Comme Utopie, une Histoire du Cin-
ma Educateur Dans lEntre-Deux-Guerres en France, Paris,France: AFRHC;
2007.
13. Viborel L. ducation populaire et cinmatographe. La Vie Saine. 1957;44.
14. Laot F et al. LImage dans lHistoire de la Formation des Adulte. Paris, France:
LHarmattan; 2010.
15. Do OGomes I. Luvre de Jean Comandon In: Martinet A et al. Le Cinma et
la Science; Paris, France: ditions du CNRS; 1994.
16. Comandon J. Pierre de Fondbrune (1901-1963). Annales de lInstitut Pasteur.
1964;106(4):515-518.
17. Berg B. De charmants petits rien. In: Leuba M et al. Marey, Pionnier de la Syn-
thse du Mouvement. Beaune, France: Muse Marey; 1995.
Paris, France: ditions du CNRS; 1994.
19. Raynal A. Le docteur Thvenard, cinaste et scientifique. In: Martinet A et al.
Le Cinma et la Science. Paris, France: ditions du CNRS; 1994.
20. Broussouloux C. Cinma et Mdecine. Le Mdecin lcran. Paris, France:
Ellipses; 2001.
21. Cahan D. Hermann von Helmholtz and the Foundation of Nineteenth-Century
Science. Berkeley, CA: University of California; 1994.
22. Helmholtz H. Handbuch der Physiologischen Optik. Leipzig, Germany: Leopold
Voss; 1867.
23. Lefebvre T. Une maladie au tournant du sicle: la cinmaophtalmie. In: Mari
M et al. Cinma des premiers temps: Nouvelles contributions franaises. Tho-
rme. 1996;4:131-145.
24. Ginestous E. Hygine Oculaire de la Premire Enfance. Paris, France: Vigot; 1909.

CINMA, SCIENCE ET MDECINE EN FRANCE

Le cinma demeure avant tout un procd technique scientifique dexploration des mouvements des tres vivants.
Cest la capacit dinventer des appareils capables de saisir des images grande vitesse puis de les assembler
qui constitue limage anime. Les grands dcouvreurs furent lastronome franais Jules Janssen, inventeur du revol-
ver astronomique (1874), le photographe anglais Eadweard Muybridge qui mit au point le zoopraxiscope pour d-
composer les mouvements du cheval (1879) et surtout le mdecin franais tienne-Jules Marey qui dveloppa le
chronophotographe et la pellicule souple non perfore (1882). Ces hommes demeurrent des hommes de science
qui produisirent donc des films vise exclusivement scientifique. Dun autre ct, lingnieur amricain Thomas
Edison (1894), les industriels franais Louis et Auguste Lumire (1895), le magicien franais Georges Mlis (1895)
comprirent que cette nouvelle technique de limage anime offrait des perspectives commerciales et artistiques
immenses. Ils se lancrent alors dans le cinma-spectacle qui connut immdiatement un immense succs. La lo-
gique industrielle, la rentabilit animaient ces pionniers qui sopposrent souvent aux savants. Le cinma devint un
art, un spectacle, un loisir accessible tous. Cet art nouveau, le septime ainsi dsign par le critique franco-italien
Ricciotto Canudo, intgrait toutes les composantes de la vie. La mdecine, le mdecin, la maladie et le malade fi-
gurent en bonne place dans la thmatique des films franais tant comme acteurs de fiction ou comme agents din-
trigues. Pour autant, le cinma scientifique, le documentaire, le film de propagande hyginique connurent aussi,
en France, de belles heures de gloire. Attachs la propagation de la science, de la mdecine, de lhygine par
limage, ces faiseurs dimages bouleversrent souvent la technique cinmatographique au plus grand bnfice du
film de fiction.

Cinema, science, and medicine in France Rgnier MEDICOGRAPHIA, Vol 35, No. 2, 2013 245

ecause Langlois considered
B film images as reflecting how
people dressed, moved, ate,
entertained themselvesin short
livedat a particular time and
place, determining how those
coming after it would view it, he
viewed every frame as testimony.
His motto was Everything must
be saved. It was thanks to him
that the work of the Lumire broth-
ers and Georges Mlis was res-
cued from oblivion, that pre-War
cinema has been handed down to
posterity, and that the French New
Wave was made possible.
Isabelle SPAAK
Journalist
(e-mail:
isabelle.spaak@wanadoo.fr)
www.medicographia.com
246 MEDICOGRAPHIA, Vol 35, No. 2, 2013
A TOUCH OF FRANCE
Children of
the Cinmathque
b y I . S p a a k , Fra n c e
A
s with film institutes or cinematheques the world over, the vocation
of the Cinmathque, founded in Paris in 1936, was to preserve, re-
store, research, and show films, playing the same role for the moving
image as libraries for books or museums for paintings. That the Cinmathque
is perhaps the best endowed of its kind, holding around 40 000 films, is large-
ly down to one man, Henri Langlois. Born in Izmir in 1914 and a devotee of film
from childhood, Langlois founded a silent film preservation club in Paris in
1935. A year later, aged 22, he became the first director of the Cinmathque,
which he and two friends set up to save and preserve every film wherever
made, whether masterpiece or middling. His ambition also extended to rescu-
ing from oblivion anything related to film, including scenarios, sets, costumes,
and projectors. Larger than life, a law unto himselfthe archetypal sacred
monsterHenri Langlois let nothing stand between himself and film. During
the Second World War and the Occupation, he saved the Cinmathques
collection from destruction. His obsession was his strength. He forged close
friendships with Chaplin and Hitchcock, and encouraged New Wave directors
on both sides of the Atlantic. As the soul and archeologist of the moving im-
age, he was for the poet Jean Cocteau the dragon standing guard over our
treasure, all of which is now on exhibition in the rejuvenated 12th arrondisse-
ment of Paris to the delectation of modern movie-lovers.
Medicographia. 2012;35:246-254 (see French abstract on page 254)
re cinephiles an extant species in the 21st century? Are there still people
A who take moviegoing so seriously that they are prepared to spend whole
days in dark theaters watching endless reruns of grainy reels of celebrated
or often completely unknown films when they could be consuming avalanches of
technically superior images in the comfort of their own homes thanks to DVDs, the
Internet, social networking sites, and other forms of video on demand? And what
meaning does cinephiliaa word coined in the early 1950s by the philosophizing
champions of an art form touted as the equal of painting or literaturehave in the
21st century? It was the young cinephiles of the 1950s grouped around the ex-
travagant figure of Henri Langlois, cofounder (with Georges Franju, Jean Mitry, and
Paul-Auguste Harl) of the Paris Cinmathque in 1936, who went on to revitalize
French cinema. Franois Truffaut, Eric Rohmer, Claude Chabrol, Jacques Rivette,
Jean Rouch, and Jean-Luc Godard were all nurtured at the Cinmathque: they
were each so entranced with cinema that they had to make films themselves. All
of them discovered gems at the Cinmathque that they would never otherwise
Children of the Cinmathque Spaak
 A TOUCH OF FRANCE

have seen had not Langlois, driven (Truffaut) by his mono-

maniacal obsession, spent his days, nights, and entire life at-
tempting to preserve everything that had been filmed since
images were first made to move. Langlois was a larger than
life figure, a law unto himselfthe archetypal sacred monster.
Had he not been obsessed by the urgent necessity of saving
everything, what would have become of the Lumire broth-
ers archive or the cinemagic of Georges Mlis? Who, but for
him, would have seen Marlene Dietrich in The Blue Angel were
it not for its miraculous escape from destruction from Ger-
man wartime censorship? How else would France have been
introduced to Soviet cinema, Hollywood epics, and Japan-
ese masterpieces? Filmmakers the world over are indebted
to the dragon, as the poet Jean Cocteau called him, for
having been there to stand guard over the treasures of their
profession.

But Langlois was not content to track films down, identify

them, and show them. He also saw himself as an archeol-
ogist. His aim was to save everything and anything that was
related directly or indirectly to cinema, including scenarios, ob-
jects, costumes, sets, and projectors. His collection had more
than a hint of Ali Babas cave to it. But who else was able to
forge links of mutual respect and friendship so strong that
Charlie Chaplin himself donated part of the cogwheels from
Modern Times, Martine Carol the dresses she wore in Max
Ophuls Lola Monts, Louise Brooks the buckles from her
stage shoes, Fritz Lang the robot he dreamed up for Metro-
polis, or Alfred Hitchcock the death head of Anthony Perkins
mother in Psycho, posted in a large cardboard box?
Henri Langlois (1914-1977): cofounder and iconic figure of the
French Cinmathque. Cond Nast Archive/Corbis.
Our spiritual home
When the Cinmathque left the Palais de Chaillot and moved
to the new quarters in the 12th arrondissement, in a build-
ing designed by Frank Gehry, Martin Scorsese declared at
the opening: Filmmakers the world over are familiar with the
French Cinmathque, even if they have never been here.
Its our spiritual home.

The new
Cinma-
thque
Franaise
building,
designed by
Frank Gehry
(the same
architect who
designed the
Guggenheim
Musem in
Bilbao) and
opened to
the public on
28 Septem-
ber 2005.
Ginies/
epa/Corbis.

Children of the Cinmathque Spaak MEDICOGRAPHIA, Vol 35, No. 2, 2013 247
A TOUCH OF FRANCE
This moving testimony reflected the reputation of an institu-
tion brought into being in 1936 by three devotees of what
in France is commonly referred to as the seventh art: direc-
tor Georges Franju (1912-1987), film critic Jean Mitry (1907-
1988), and Henri Langlois (1914-1977).
248 MEDICOGRAPHIA, Vol 35, No. 2, 2013
Charlie
Chaplin in
the satire
of the dehu-
manizing in-
dustrialized
world, Mod-
ern Times
(1936).
Bettmann/
CORBIS.
Franju and Langlois had met in the early 30s at a printers
where the young Langlois had been apprenticed by his fa-
ther after failing his exams. Born in Izmir, ex-Smyrna, in 1914
to French parents forced to return to France after the Greek
city was taken by Turkey in 1922, Henri Langlois had only one
interest: cinema. It was the one and only pas-
sion in his life, to the extent that he chose to go
to the movies rather than sit for his baccalau-
reat, to the great despair of his father. Franju and
Langlois found themselves partners in the same
passion.
Together they borrowed 500 francs (equivalent
to 375 euros in 2013 [INSEE indicator]) from
Henris parents to set up a sort of film club, Le
Cercle du Cinma (The Cinema Circle), where
they showed silent films, encouraged by the film
historian Jean Mitry who was convinced that
the advent of the talkies would condemn the
masterpieces of silent cinema to oblivion if no-
body bothered to preserve the reels. There was
no institution of any kind devoted to the protec-
Brigitte Helm as the Robot Maria in Metropolis,
directed by Fritz Lang in 1926, in Germany.
Bettmann/CORBIS
Children of the Cinmathque Spaak
 A TOUCH OF FRANCE

tion or preservation of what was yet to be acknowledged as

the seventh art. The founding principle of the Cinmathque
was the desire to preserve a heritage under threat. Barely 22,
yet already steeped in film history and culture, there was no
one more fitting to preside over such an institution than Henri
Langlois.

His ambition was to preserve everything: the good along with

the not so good, final cuts along with outtakes. He excluded
nothing: scale models, scenarios, stills, sets, costumes, pro-
jectors, etc. Langlois was the first to look beyond, or beneath,
the masterpieces of cinema and take an interest in all films.
He saved everything, even the stinkers. Bad films too are a
record of their time. That is what drove Langlois. I wanted
the shades of the living to mingle with those of the dead,
said Langlois in justifying his approach under the triple guise
of archeologist, sociologist, and historian, because that is
The Palais de Chaillot, which housed the Cinmathque from
what cinema is about. 1963 to 2005. Bettmann/CORBIS.

Everything must be saved
Because Langlois considered film images as reflecting how
people dressed, moved, ate, entertained themselvesin short
livedat a particular time and place, determining how those
coming after it would view it, he viewed every frame as tes-
timony. His motto was Everything must be saved. It was
thanks to him that the work of the Lumire brothers and
Georges Mlis was rescued from oblivion, that pre-War cin-
ema has been handed down to posterity, and that the French
New Wave was made possible.
The Cinmathques first home, like its current home, was
in the 12th arrondissement, but in the rue Marsoulan. From
the start it was designed as both museum and cinema. Lan-
glois had the appetite of an ogre. He increased the Cinma-
thques archive from ten films in 1936 to over 60 000 in 1970.
But if anything he was even keener to show them. Langlois
saved films by recovering them, but also by restoring them
when they had begun to decompose. Most were made of cel-
luloid, a fragile material that disintegrates under adverse stor-
age conditions.

Director
Abel Gance
and crew
filming scene
in Napoleon,
in 1927.
Bettmann/
CORBIS

Children of the Cinmathque Spaak MEDICOGRAPHIA, Vol 35, No. 2, 2013 249
A TOUCH OF FRANCE
The Cinmathque was built on the donation of films by film-
makers and producers thanks to a relationship with Langlois
based on mutual gratitude and admiration. Langlois was able
to show the films without paying fees, but they remained the
property of those who entrusted them with him. Perhaps the
bulk of the collection belonged to Langlois himself, a com-
pulsive collector and inspired flea-market trawler, who was
snapping up items long before governments recognized the
need to establish cinematographic archives.
Americans in particular were grateful to the Cinmathques
director for having preserved works that would no longer have
existed without his intervention. It is thanks to Langlois, for in-
stance, that we still have Abel Gances magnificent Napoleon
(1927), one of the masterpieces of silent cinema.
The German Occupation deprived the Cinmathque of a
home of its own. To get round the censor, Langlois organized
clandestine viewings at his mothers, attended in particular by
Simone Signoret, who had no hesitation, despite her Polish-
Jewish father, in crossing Paris under the Occupiers nose
pushing a pram full of reels. The first time I saw Battleship Po-
temkin, remembered Signoret, was in 1941, rue Troyon, in
the dining room at Langlois mothers. All the Soviet films, and
all the films by Renoir or Prvert that were banned under the
Occupation, in fact the only great films that I saw during this
period, were shown to me by Langlois who used to carry his
250 MEDICOGRAPHIA, Vol 35, No. 2, 2013
reels around in the mtro. It sounds funny now, but at the
time it was dangerous. Without Langlois and his daring in-
genuity, Robert Wienes The Cabinet of Dr Cagliari (1919), or
Georges Mlis Joan of Arc (1900), or Josef von Sternbergs
The Blue Angel with Marlene Dietrich, to take but three ex-
amples, would have been lost to history. Many items in the
Cinmathque archive were under threat during the Occu-
pation, and Langlois managed to hide them by secreting his
films in any number of hiding places in Paris, burying some in
Marlene
Dietrich on
the set of The
Blue Angel,
directed by
Joseph von
Sternberg,
based on
Heinrich
Manns novel
Professor Un-
rat (Professor
Garbage).
John
Springer
Collection/
CORBIS.
Michel Simons garden, and hiding othersthose by Chaplin
and Soviet directorsin a Bordeaux wine estate. By 1944,
Langlois had saved 40 000 films. As soon as the War ended
he set out to find a home for them.
The small theater on the rue de Messine
In 1948, he found premises at 8 rue de Messine, near the
Champs-Elyses. Keeping to the same fundamentals: pre-
serve and show, he decided to show only once. The single-
showing idea was simple, and caught on. It was the key to his
success.
Hungry to catch the one-off showings of Langlois rare finds,
cinephiles were assiduous in their attendance, meeting up
for each weeks program of unmissable films that Langlois
used to stencil on a single sheet of paper. They included the
Children of the Cinmathque Spaak
 A TOUCH OF FRANCE

young Claude Chabrol, Franois Truffaut,

Eric Rohmer, Jean-Luc Godard, Alain
Resnais, Jacques Rivette, and others,
all irrevocably committed to film, with
Langlois as their spiritual godfather. Its
thanks to Langlois that they saw their
first undubbed Japanese film and their
first Buster Keaton (subtitled in Czech).
It was Langlois who trained and sharp-
ened their eye. Enjoying cinema, Lan-
glois used to say, means enjoying life.

Competition was fierce for the sixty seats

of the little theater on the rue de Mes-
sine. Jean-Paul Sartre and Simone de
Beauvoir were regulars, as were Andr
Gide, Georges Braque, Fernand Lger,
and the future French president Georges
Pompidou. After each showing discus-
sion would go on for hours in the street
outside as Langlois had no time for the
French director Franois Truffaut shooting La Sirne du Mississippi (Mississippi Mermaid)
staged dissection of films after they were in 1969. Alain Dejean/Sygma/Corbis.
shown. Langlois did not only rescue rich-
es from the past. He also celebrated, made known and en- That didnt stop him being warm, provided you agreed to
couraged the directors of the future, such as the French New board the train of his conversation, which was more exactly
Wave, the violently controversial Rainer Werner Fassbinder, a conspiracy-centered monologuethe conspiracy being
and Nicholas Ray, one of the leading post-War Hollywood di- the constant threat of a State stranglehold over his collection.
rectors (Johnny Guitar, 1954, and Rebel Without a Cause,
1955, with James Dean). The work by the French Cinma- Langlois was paranoid. But he was not mad. He knew that
thque was without doubt the most important individual ef- the Cinmathque had outgrown the era of heroic one-man
fort in cinema history, said Ray in support of Langlois in Feb- effort. Its riches had become an incitement to State lust. An-
ruary 68. dr Malraux, the then Minister of Culture, made a first attempt
at modifying the status and management of the Cinmathque
A man driven in 1963, more exactly to convert it from a private association
Langlois was characterful to have only attracted admirers. His to a fully State-funded institution. In exchange for State sup-
detractors accused him of being muddle-headed, a hope- port, a theater in the Palais de Chaillot, and increased fund-
less manager, and a thief to boot. Langlois behaved like a ing, Malraux wanted a leading role on the board of directors
scavenger, with the ethics and clothing to match. He was ac- and the power to appoint a regular and dependable financial
cused of keeping negatives any old how, of letting reels rust officer. In February 1968, Malraux stopped beating about the
in his bath (a rumor which only compounded his unwashed bush: he dismissed Langlois.
image), and of alarming nontransparency as to both the pre-
cise methods by which he acquired some of the items in his World cinema takes to the street
collection or their exact location. He was shielded by a close The events of May 68, when the country rose up against a
guard of volunteers who were prepared, like Langlois himself, deaf and authoritarian government, were only weeks away,
for any sacrifice that would enrich or protect his collection, and Malraux underestimated the stature and loyalty of the
especially as they were convinced that the whole world was troops at Langlois command. Indeed, so spontaneous was
out to wrest them from him. The renowned film critic Serge the loyalty that command was unnecessary. Within twenty-
Daney sketched a realistic portrait of the poet of film: Like four hours, world cinema had taken to the street: Abel Gance,
all driven men, Henri Langlois divided the world, people and Franois Truffaut, Jean-Luc Godard, Jean Renoir, and Robert
events into two blocks: 1. Those that were good for the Ci- Bresson banned the State from showing their films. They were
nmathque. 2. Those that were not good for the Cinma- joined by dozens of other filmmakers, including Charlie Chap-
thque. Even if hed known you for ten years, he didnt waste lin, Roberto Rossellini, Fritz Lang, Richard Lester, Carl Dreyer,
time asking after your health or your family because the very Orson Welles, and Jerry Lewis. Three thousand people demon-
notions of health or family only had meaning in terms of the strated outside the Palais de Chaillot. The police charged.
health of the Cinmathque or the family of the Cinmathque. Godard was wounded, and Franois Truffaut used scenes

Children of the Cinmathque Spaak MEDICOGRAPHIA, Vol 35, No. 2, 2013 251
A TOUCH OF FRANCE

Filmmakers demonstrating in the streets of Paris in February 1968to reinstate Henri Langlois who had just been fired by the French
Minister of Culture Andr Malraux. Georges Pierre/Sygma/Corbis.

from the demonstration in Stolen Kisses, which he dedicated
to the Cinmathque when it came out the following year.
There were riots outside the Cinmathque offices in the rue
de Courcelles. A petition gathered 700 signatures from the
international cinematographic elite: the directors Michelangelo
Antonioni, Ingmar Bergman, Luis Buuel, Peter Brook, Alfred
Hitchcock, Elia Kazan, Akira Kurosawa, Pier Paolo Pasolini,
Claude Berri, Satyajit Ray, and Andy Warhol; actors such as
Jean-Paul Belmondo, Brigitte Bardot, Catherine Deneuve,
Michel Simon, Simone Signoret, Marlene Dietrich, Jane Fonda,
Katharine Hepburn, Peter OToole, and Gloria Swan-
son; as well as writers, artists and philosophers, such
as Roland Barthes, Samuel Beckett, Alexander Calder,
Truman Capote, Max Ernst, Eugene Ionesco, Pablo
Picasso, Paul Ricoeur, Jean-Paul Sartre, Henri Cartier-
Bresson, and Norman Mailer. The power of this Whos
Who of world culture was such that the government
climbed down and Langlois could only be reinstated.
He spent his remaining years on his singular creation,
leaving behind him a Cinmathque envied by the rest
of the world.

The Cinmathque was duly rescued from the jaws of

French director and producer Caude Berri (left), actor Michel Simon
(middle), and screenwriter and producer Claude Chabrol (right) during a
demonstration at the Cinmathque on 12 February 1968. James
Andanson/Sygma/Corbis.
the State, but paid for it by having its subsidies reduced
to a minimum. Langlois fought to the end of his life to
maintain his artistic ideal: a film museum designed to
turn people into filmmakers rather than to satisfy con-
sumers. He always maintained that true cinema was
made by mauvais lves, bad pupils who refuse to sit
dutifully at their desks swallowing the teachers curricu-

252 MEDICOGRAPHIA, Vol 35, No. 2, 2013 Children of the Cinmathque Spaak
 A TOUCH OF FRANCE

Ingrid
Bergman
handing reel
to Roberto
Rossellini
(left) in 1949.
Bettmann/
CORBIS.

lum. Once an ardent defender of the sacred monster, Truffaut

eventually moved away, finding it increasingly difficult to tol-
erate Langlois ever more autocratic behavior and his ten-
dency to show commercial films to bring in much-needed
cash. In 1974, Henri Langlois received an honorary Oscar for
his contribution to cinema. He and his wife Mary Meerson man-
aged to keep the Cinmathque afloat by dint of round-the-
clock work. After his death on January 13 1977, his friends
clubbed together to build a fitting monument over his grave in
the Montparnasse cemeterya sloping slab that reproduces
scenes from iconic films.

From dormancy to rebirth

Bereft of its creator, the Cinmathque and Museum of Cin-
ema entered a dark period of semi-dormancy lasting two
decades compounded in 1997 by a fire and the subsequent
flood caused by the firemens hoses directed onto the roof
of the Palais de Chaillot. The collections were saved, but the
Cinmathque found itself confined to a little theater on the
Grands Boulevards until it was reborn and rehoused in 2005
in the building designed by Frank Gehry.
Our turn now to push open the door of this reincarnation. We
find a Cinmathque that has modern technologies to help
it fulfill its timeless mission: to preserve and put on films, run
Alfred Hitchcock receiving the French Legion of Honor from the
hands of Henri Langlois in 1971. Michel Ginfray/Apis/Sygma/
Corbis.
the great classics, but also organize retrospectives and fes-
tivals dedicated to specific filmmakers, actors, producers, and
technicians, archive the collections, display some of the fab-
ulous objects in the museum, mount temporary exhibitions to
give glimpses into the wealth of its holdings, and reinforce the
links between film and the other arts. The Cinmathque
also has a library and archive at the disposal of students and

Children of the Cinmathque Spaak MEDICOGRAPHIA, Vol 35, No. 2, 2013 253
A TOUCH OF FRANCE

researchers. After its record 300 000 visitors in the summer of DVD. It was made under pressure during the German Occu-
2012 for the temporary exhibition on the director Tim Burton, pation by those wholike the films writer Jacques Prvert and
with over 500 drawings, photographs, and scale models, the the actors Jean-Louis Barrault, Arletty, and Pierre Brasseur
Cinmathque staged an exhibition in honor of Marcel Carn, were out to prove that the French spirit was still free even if
another monument in the history of film. Generations of cine- France itself was not, much as Langlois always remained a
philes were raised on Carns cult film, Children of Paradise free spirit even when his Cinmathque appeared threatened
(1945), which has since been re-released in theaters and on by chains. I

LA CINMATHQUE FRANAISE
51 rue de Bercy
75012 Paris
Monday to Saturday 12 AM to 7 PM
Sunday 10 AM to 8 PM
www.cinematheque.fr

Paris burning? Raging flames engulf

the Palais de Chaillot on 22 July 1997,
threatening to destruct the collections of
the Cinmathque. AFP.

LES ENFANTS DE LA C INMATHQUE

Comme toutes les cinmathques au monde, la Cinmathque franaise fonde en 1936 a pour vocation dorga-
niser un lieu de conservation et de dcouverte des films comme les bibliothques le sont pour les livres ou les
muses pour les tableaux. Mais, si la Cinmathque Franaise est lune des plus riches qui existe avec quelque
40 000 films, elle le doit surtout la volont et lnergie dun seul homme : Henri Langlois (1914-1977). Fou de ci-
nma ds son plus jeune ge, ce natif de Smyrne se lance partir de 1935 dans laventure dun cinclub consa-
cr la prservation des films muets. A vingt-deux ans, il devient le premier directeur de la Cinmathque quil a
initie avec deux amis. Son but : tout sauver, tout conserver. Les chefs-duvre comme les films moins bons, les
franais mais aussi les russes, les japonais. Il entend aussi prserver de loubli tout ce qui touche aux films : d-
cors, scnarios, matriel de projection, costumes. Monstre sacr, Henri Langlois ddie sa vie son projet. Durant
la seconde guerre mondiale et lOccupation, il sauve les films de la destruction. La force de Langlois est son ob-
session. Il noue des amitis fortes avec Charlie Chaplin ou Alfred Hitchcock, encourage les jeunes ralisateurs de
la Nouvelle Vague et du renouveau Hollywoodien. Monstre sacr qui veille sur nos trsors dira de lui le pote
Jean Cocteau, il est lme et larchologue de limage anime. Ses trsors sont exposs Paris dans le douzime
arrondissement et continuent denchanter les cinphiles daujourdhui.

254 MEDICOGRAPHIA, Vol 35, No. 2, 2013 Children of the Cinmathque Spaak
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Mr C. ERTLE
Laboratorios Servier de
Mxico S.A. de C.V., Palmas 830
Lomas de Chapultepec
C.P. 11 000 - Mxico D.F.
Tel: (52-55) 52 02 33 59
Morocco
Mr D. PERILLEUX
Servier Maroc
Espace Jet Business Class
Lotissement 16-19
Ettawfik la Colline
20190 Casablanca
Tel: (212) 522 97 48 49
Netherlands
Mr P. ETORRE
Servier Nederland Farma BV
Einsteinweg 5B
2333 CC Leiden
Tel: (31-71) 5246700
Pakistan
Dr R. MAJEED
Servier Research &
Pharmaceuticals, (Pakistan)
PVT Ltd, 65 Main Boulevard
Gulberg - Lahore
Tel: (92-42) 5879500