Research

tude valide ?
Original Investigation

Efficacy and Safety of Single-Dose Zoledronic Acid

for Osteoporosis in Frail Elderly Women
A Randomized Clinical Trial AVQ=intime la personne
AVD=externe la personne
Susan L. Greenspan, MD; Subashan Perera, PhD; Mary Anne Ferchak, BSN; David A. Nace, MD;
Neil M. Resnick, MD
1 dose=compliance
Invited Commentary page 921
IMPORTANCE Eighty-five percent of institutionalized elderly people have osteoporosis and Supplemental content at
bone fracture rates 8 to 9 times higher than rates observed among community-dwelling jamainternalmedicine.com
elderly people. Nevertheless, most of these persons are left untreated and are excluded from
pivotal osteoporosis trials.

OBJECTIVE To determine the efficacy and safety of zoledronic acid to treat osteoporosis in
frail elderly women in long-term care facilities.

DESIGN, SETTING, AND PARTICIPANTS We conducted a 2-year, randomized, placebo-

controlled, double-blinded study from December 2007 through March 2012. Included were
181 women 65 or older with osteoporosis, including those with cognitive impairment,
immobility, and multimorbidity, who were living in nursing homes and assisted-living facilities.

INTERVENTIONS One 5-mg dose of zoledronic acid or placebo intravenously and daily calcium
and vitamin D supplementation.

MAIN OUTCOMES AND MEASURES Hip and spine bone mineral density (BMD) at 12 and 24
months and adverse events.

RESULTS There were no baseline differences in mean (SE) age (85.4 [0.6] years), BMD, or
functional or cognitive status, but the treatment group included more participants with
frailty, falls history, diabetes, and anticonvulsant medication use. Values for BMD were
available for 87% of participants at 12 months and 73% at 24 months. Mean (SE) BMD
changes were greater in the treatment group: 3.2 (0.7) and 3.9 (0.7) percentage-point
differences in the total hip at 12 and 24 months, respectively (P < .01 for both comparisons),
and 1.8 (0.7) and 3.6 (0.7) percentage-point differences at the spine (P < .01); adjusted
analyses were similar. The treatment and placebo groups fracture rates were 20% and 16%,
respectively (OR, 1.30; 95% CI, 0.61-2.78); mortality rates were 16% and 13% (OR, 1.24; 95%
CI, 0.54-2.86). Groups did not differ in the proportion of single fallers (28% vs 24%; OR, 1.24;
95% CI, 0.64-2.42; P = .52), but more participants in the treatment group had multiple falls
(49% vs 35%; OR, 1.83; 95% CI, 1.01-3.33; P = .047); however, this difference was no longer
significant when adjusted for baseline frailty.
Author Affiliations: Division of
Geriatric Medicine, Department of
CONCLUSIONS AND RELEVANCE In this group of frail elderly women with osteoporosis, 1 dose Medicine, University of Pittsburgh,
of zoledronic acid improved BMD over 2 years. The clinical importance of nonsignificant Pittsburgh, Pennsylvania (Greenspan,
increases in fracture and mortality rates in the treatment group needs further study. Since it is Perera, Ferchak, Nace, Resnick);
Division of Endocrinology and
not known whether such therapy reduces the risk of fracture in this cohort, any change in
Metabolism, Department of
nursing home practice must await results of larger trials powered to assess fracture rates. Medicine, University of Pittsburgh,
Pittsburgh, Pennsylvania
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00558012 (Greenspan); Department of
Biostatistics, University of Pittsburgh,
Pittsburgh, Pennsylvania (Perera).
Corresponding Author: Susan L.
Greenspan, MD, Department of
Medicine, University of Pittsburgh,
3471 Fifth Ave, 1110 Kaufmann Bldg,
JAMA Intern Med. 2015;175(6):913-921. doi:10.1001/jamainternmed.2015.0747 Pittsburgh, PA 15213
Published online April 13, 2015. (greenspn@pitt.edu).

(Reprinted) 913

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 Research Original Investigation
N
early 2 million frail elderly Americans reside in long-
term care (LTC) facilities, and another 4 to 6 million
similarly frail elderly people live in the community.1
Eighty-five percent of such individuals have osteoporosis, 2-4
and their bone fracture rates are 8 to 9 times higher than those
observed among less impaired elderly persons.5 Moreover, the
impact of an associated hip fracture is dire6,7: decreased mo-
bility and independence, frequent hospitalizations, and a
6-month mortality rate of up to 36%.8 Yet osteoporosis therapy
remains vastly underprescribed to such individuals.9,10
Few osteoporosis trials have focused on frail elderly indi-
viduals, and to our knowledge, none has evaluated the effi-
cacy or safety of a bisphosphonate in this group. Although post
hoc analyses of the pivotal osteoporosis trials suggest that
therapy is efficacious for healthy, community-dwelling par-
ticipants older than 75 years,11-13 these trials excluded func-
tionally impaired individuals, and so the findings might not
apply to them. In frail elderly persons, the link between bone
mineral density (BMD) and bone strength may be attenuated.
Once sufficient bone mass is lost, structural integrity of the re-
maining bone may be compromised due to impaired trabec-
ular connectivity, poor skeletal microstructure, and un-
healed stress fractures.14-16 Treatment that adds mass to the
remaining nonconnected bone stubs may add little if any
bone strength. The odds of this phenomenon occurring in frail
LTC residents are likely substantial because they are 10 to 15
years older than those included in the pivotal trials, with that
many more years of bone loss as well as greater comorbidity,
more frequent illnesses, a more sedentary lifestyle, and greater
renal impairment, all of which tend to accelerate bone loss. Sup-
port for this concern is heightened by results of the risedro-
nate hip fracture trial,17 which, despite having adequate power,
demonstrated a reduction in hip fractures for community-
based women younger than 80 years but not for those older
than 80 years (although evaluation of the older group did not
include BMD).17 Thus, it is unclear whether antiosteoporosis
therapy is effective in frail elderly persons. Because of the rapid
global growth of this older, more physically impaired group,
multiple organizationsincluding the National Institutes of
Healthhave for decades reiterated the critical need for os-
teoporosis research and treatment for these individuals.18-21
Obstacles to such studies are substantial,22 especially if the
goal is to demonstrate fracture reduction. However, virtually ev-
ery trial that has demonstrated fracture reduction by a potent
bisphosphonate has also demonstrated an increase in BMD.23,24
Although this does not prove that such an increase is required,
it suggests that fracture reduction would be unlikely in the ab-
sence of an impact on BMD. Thus, we used a stepwise ap-
proach in the present study. Our objective was to determine the
impact of a bisphosphonate on BMD and safety for 2 years in
frail women residents of LTC facilities. Although frail elderly
women are more likely to live outside of institutions, we en-
rolled an institutionalized group to ensure that we could de-
liver therapy and closely monitor its impact and adverse ef-
fects. We chose zoledronic acid because it can be given as a single
intravenous dose, the effect of which may last for 2 years25,26;
this eliminates difficulties inherent in administering an oral bis-
phosphonate on a regular basis in this setting.
914 JAMA Internal Medicine June 2015 Volume 175, Number 6 (Reprinted)
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Zoledronic Acid for Osteoporosis in Frail Elderly Women
Methods
Study Design
The present report describes findings of the ZEST study (Zole-
dronic acid in frail Elders to STrengthen bone), 22 a 2-year,
double-blind, placebo-controlled, randomized clinical trial
based in the Pittsburgh, Pennsylvania area. Participants were
enrolled and treated from December 2007 through March 2012
(ClinicalTrials.gov identifier: NCT00558012). The ZEST study
protocol is available in the Supplement.
Participants
We included frail women 65 years or older who resided in a
nursing home or assisted-living facility,22 who were not re-
ceiving a bisphosphonate, and who had either a history of ver-
tebral or hip fracture or a measured BMD below the treat-
ment cutoff for osteoporosis (based on 2003 National
Osteoporosis Foundation guidelines27: lower than 2.0 SD at
the spine, hip, or radius [ie, more than 2 standard deviations
below the bone density of a healthy 30-year-old]).28 All women
whose 25-hydroxyvitamin D levels were lower than 20 ng/dL29
received vitamin D supplements (50 000 IU/wk for 2 months)
and were rescreened. All participants received a daily di-
vided dose of vitamin D (800 IU/d) and 1200 mg/d of elemen-
tal calcium (supplement plus diet30).
We included women who had cognitive and functional im-
pairment, immobility, multiple medical conditions, and who
were prescribed multiple medications (including glucocorti-
coids and antiseizure medications). We excluded those with
a projected life expectancy of less than 2 years or an esti-
mated glomerular filtration rate below 30 mL/min.
Approval and Consent
The study was approved by the University of Pittsburgh insti-
tutional review board and the Pennsylvania Department of
Health. Informed consent was obtained for all participants.
Those with cognitive impairment provided assent, and the resi-
dents responsible party provided written consent.
Randomization and Blinding
The study biostatistician randomized participants in a 1:1 ra-
tio using random block sizes of 2 and 4. The research pharma-
cist provided identical-appearing active drug or placebo. In-
vestigators, study personnel, providers, and participants were
blind to treatment assignment.
Clinical Protocol and Intervention
Study visits were conducted at each participants facility. All
BMD assessments took place in a mobile unit that included a
motorized platform to facilitate access for participants with re-
stricted mobility. Baseline blood tests and BMD values were
obtained, and 10-year fracture risk (FRAX31) was calculated.
After completing the baseline assessment, participants
were randomized to infusion with either 5 mg of intravenous
zoledronic acid or placebo. Patients were assessed for imme-
diate adverse reactions for 3 days after infusion.32 Subse-
quent follow-up visits occurred at 6, 12, and 24 months.
jamainternalmedicine.com
 Zoledronic Acid for Osteoporosis in Frail Elderly Women
Outcome Variables
The primary outcome was percentage change in BMD of the
total hip and spine at 12 months. Secondary outcomes in-
cluded adverse events and bone turnover markers. Addi-
tional outcomes included change in BMD through 24 months
at other skeletal sites, bone turnover markers, physical and cog-
nitive function, comorbidity, survival, and an exploratory as-
sessment of fragility fractures at 12 and 24 months.
Bone Mineral Density
Measured sites included the hip (total hip, femoral neck),
spine (posterior-anterior and lateral projection), and distal
one-third of the radius. Dual energy x-ray absorptiometry was
performed using a Discovery densitometer (Hologic Inc); the
precision ranged from 1.2% to 1.9% at these skeletal sites.33
Vertebral Fractures
Fractures of T6-L4 were detected by vertebral fracture assess-
ment performed by dual energy x-ray absorptiometry (DXA)
at baseline and at 12 and 24 months and were classified by the
Genant criteria as mild, moderate, or severe.34 We included new
fractures and fracture grade progression. Compared with con-
ventional radiography, the sensitivity and specificity of DXA
vertebral fracture assessment are 100% and 95%, respectively,35
with a statistic of 0.92.35
kappa=reproductibilit
Fragility Fractures (concordance)
In addition to medical record review, we asked participants
every 6 months about clinical fragility fractures (defined as a
fracture following a fall from standing or sitting height). Frac-
tures were confirmed by radiology reports.
Markers of Bone Turnover and Vitamin D
Bone resorption was assessed by serum Ctelopeptide cross-
links type I collagen (CTX; Crosslaps, Osteometer Biotech).
Bone formation was assessed by serum intact N-terminal pro-
peptide type I procollagen (P1NP; Orion Diagnostica). Serum
25-hydroxyvitamin D level was assessed by liquid chromatog-
raphymass spectrometry.
Functional Assessments
Function was assessed using the Katz Activities of Daily Liv-
ing scale,36 Instrumental Activities of Daily Living scale,37 gait
speed,38,39 Short Portable Mental Status Questionnaire,40 Co-
morbidity Index,41 Patient Health Questionnaire (PHQ-9) de-
pression scale,42 modified Fried Frailty Index (categorized as
frail, prefrail, or robust),43 and the Physical Performance Test.44
Safety and Adverse Events
We collected information on adverse events from patients and
medical records at scheduled visits. To improve reporting of
serious adverse events, we created an electronic database alert
system.22
Sample Size
A priori assumptions, statistical power, and sample size jus-
tification have been published elsewhere.22 Briefly, assump-
tions were based on available data from younger, postmeno-
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Original Investigation Research
pausal women in whom zoledronic acid increased mean (SE)
BMD at 12 months by 4.5% (3.6%) at the spine and 3.0% (2.9%)
at the femoral neck.45,46 We assumed 25% less improvement
in our cohort, no change in our placebo group, and 30% attri-
tion over a year. This suggested that randomizing 180 women
would yield 126 completers at 1 year and provide 95% power 80%
to detect an absolute difference in BMD between groups of 2.4
percentage points at the spine and 86% power to detect a 1.6
percentage-point difference at the femoral neck (2-tailed test;
= .05). b=1-p
galit 2
Statistical Analysis mdicaments= 95%
To compare baseline characteristics in the treatment and pla-
cebo groups, we used independent sample t, Wilcoxon rank
sum, 2, and Fisher exact tests. For the main analysis, we fit-
ted a series of linear mixed models, using percentage change
between baseline and follow-up assessment in each of the BMD
and biomarker measures as the dependent variable; treat-
ment arm (active or placebo), follow-up assessment (6, 12, and
24 months), and their interaction as fixed effects of interest;
baseline value of the measure as a fixed effect covariate; and
a participant random effect to account for multiple measure-
ments from the same participant over time and the resulting
nonindependence of observations. We used appropriately con-
structed contrasts to compare treatment arms at each of the
6-, 12-, and 24-month assessments. To assess robustness of the
main results, we conducted sensitivity analyses using raw
change in measurements instead of percentage change from
baseline; last value carried forward and a multiple imputa-
tion approach for missing database data on multivariate nor-
mality and the Markov Chain Monte Carlo method; addi-
tional covariate adjustments for participant characteristics that
differed significantly at baseline (frailty, falls risk, diabetes, and
anticonvulsant use); and log transformations of markers of
bone turnover.47,48 Finally, we used 2 and Fisher exact tests
to compare the proportions of participants in each group who
experienced each and any type of adverse event. We fitted lo-
gistic regression models for events of specific interest (deaths,
falls, fractures) with covariate adjustments for frailty, falls risk,
and diabetes. We used SAS software, version 9.3 (SAS Insti-
tute Inc), with MIXED and LOGISTIC procedures for the main
analyses.
Results
We contacted 733 women; 252 consented to screening, and 181
received the infusion (Figure 1). At baseline (Table 1), both
groups had substantial impairment: 95% of participants were
categorized as frail or prefrail; 74% were dependent in at least
1 basic activity of daily living (and 31% in at least 3); 93% had
at least 1 deficit measured in the Instrumental Activities of Daily
Living37 (and 70% in at least 3); 85% had a gait speed charac-
teristic of frailty (<0.8 m/s), and most participants were cog-
nitively impaired. There were no group differences in age, body
mass index, or calcium or vitamin D intake. However, com-
pared with the placebo group, more women in the treatment
group were categorized as frail by the modified Fried Frailty
(Reprinted) JAMA Internal Medicine June 2015 Volume 175, Number 6 915
 Research Original Investigation Zoledronic Acid for Osteoporosis in Frail Elderly Women

appliquer sur population

Figure 1. Enrollment and Study Design Flowchart
733= diminuer l'effet
733 Assessed for eligibility

226 Refused to participate

NNT*2 143 Did not meet inclusion criteria
112 Undecided
LNH*2
252 Consented to screening

23 Did not meet inclusion criteria curateur, mandat non-homologu

32 Withdrew consent
biais de volontoriat = meilleur de rsultat
197 Consented to randomization
effet placebo.
16 Withdrew consent

181 Underwent randomization

89 Assigned to receive zoledronic acid 92 Assigned to receive placebo

12 Months 12 Months
75 Completed any DXA 83 Completed any DXA
69 Completed spine DXA only 77 Completed spine DXA only
24 Months 24 Months
60 Completed any DXA 72 Completed any DXA
55 Completed spine DXA only 67 Completed spine DXA only
4 Completed labs/questionnaires only 2 Completed labs/questionnaires only
14 Died 12 Died
9 Lost to follow-up 4 Lost to follow-up
2 Discontinued study 2 Discontinued study

input
89 Included in the analysis 92 Included in the analysis
DXA indicates dual energy x-ray
absorptiometry.

Index,43 more tended to be fallers in the year prior to the
study, more had a diagnosis of diabetes mellitus, and more
were taking anticonvulsant medications. Baseline safety labo-
ratory values were similar between the 2 groups, as were
markers of bone turnover, BMD, the number of women with
vertebral fractures, and the 10-year calculated risk of osteopo-
rotic fractures. Seventy-six percent of patients (n = 138) com-
pleted 24 months of follow-up.
frle = plis
Bone Mineral Density fragile =casse
Mean (SE) total hip BMD increased more in the treatment group
than in the placebo group, both at 12 months (2.8% [0.5%] vs
0.5% [0.4%]; P < .001) and 24 months (2.6% [0.6%] vs 1.5%
[0.7%]; P < .001); the adjusted mean (SE) difference was 3.9 (0.7)
percentage points at 24 months (P < .001) (Figure 2). Similar dif-
ferences were observed in the femoral neck, with an adjusted
difference of 2.7 (1.0) percentage points at 24 months (P = .01).
Mean (SE) spine BMD also increased more in the treat-
ment group than in the placebo group at 12 months (3.0% [0.5%]
vs 1.1% [0.5%]; P = .01) and 24 months (4.5% [0.8%] vs 0.7%
[0.5%]; P < .001), with an adjusted difference of 3.6 (0.7) per-
centage points at 24 months (P < .001) (Figure 2). At 24 months,
the improvement from zoledronic acid was 4.8 (1.1) percent-
age points greater (P < .001) at the lateral spine and 1.2 (0.6)
percentage points greater (P = .04) at the distal one-third of the
radius. When BMD was stratified by diabetes, trends were simi-
lar, as were trends when group differences were assessed for
missing data by the last value carried forward and multiple im-
putation methods.
Results were nearly identical when adjusted for the base-
line imbalance in frailty, diabetes, and anticonvulsant use: the
adjusted mean (SE) difference for spine BMD was 2.0 (0.7) per-
centage points at 12 months and 3.8 (0.7) at 24 months
(P < .001); for total hip BMD, it was 3.2 (0.7) percentage points
at 12 months and 3.8 (0.7) at 24 months (P < .001 for each); and
for femoral neck BMD, it was 3.7 (0.9) percentage points at 12
months (P < .001) and 2.9 (1.0) at 24 months (P = .004).
Biochemical Markers of Bone Turnover
As assessed by serum Ctelopeptide cross-links type I colla-
gen, bone resorption decreased in the treatment group at 12 and
24 months (by 0.095 and 0.087 nmol/L, respectively) (P = .01)
and increased in the placebo group at 12 and 24 months (by
0.068 and 0.070 nmol/L, respectively) (P < .05); the adjusted
mean (SE) between-group difference was 0.135 (0.035) nmol/L
bone collagen equivalent at 24 months (P < .001) (Figure 3). As

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 Zoledronic Acid for Osteoporosis in Frail Elderly Women Original Investigation Research

Comparable?
Table 1. Baseline Clinical Characteristics, Functional Status, Markers of Bone Turnover,
and Bone Mineral Densitya
erreur type sur la moyenne
Zoledronic Acid Placebo
Characteristic (n = 89) (n = 92) P Value
Age, y 85.4 (0.6) 85.5 (0.5) .85
BMI 28.2 (0.6) 26.9 (0.5) .29
Total calcium intake, mg/d 807 (48) 763 (44) .50
Vitamin D intake, IU/d 163 (15) 168 (15) .83
Anticonvulsant medication use, % 10 1 .01
statistiquement significatif p <= 5%
Calcium antacids use, % 8 0 .01
ADL (0-14)b,c 11.5 (0.3) 11.7 (0.3) .45
AVQ
IADL (0-14)b,d AVD 7.7 (0.4) 8.2 (0.4) .42
Gait speed, m/s 0.5 (0.0) 0.6 (0.0) .16
vite = tombe moins
Physical performance test44 (0-24)b 19.2 (0.5) 20.1 (0.5) .20
Fried Frailty Index43 frail proportion, %) 72 58 .04
Comorbidity Index41 (0-8 domains)e 3.5 (0.2) 3.3 (0.1) .39
Abbreviations: ADL, Activities of
Diabetes, % 26 13 .03
Daily Living36; BCE, bone collagen
e
SPMSQ score (0-10 errors) 1.8 (0.3) 1.8 (0.3) .99 equivalent; BMD, bone mineral
PHQ-9 score (0-27)e 4.2 (0.5) 3.6 (0.4) .33 density; BMI, body mass index
(calculated as weight in kilograms
Fall once in the previous year, % 50 36 .06
divided by height in meters squared);
Recurrent falls in the previous year, % 26 18 .16 CTX, serum Ctelopeptide cross-links
Albumin, g/dL 3.8 (0.03) 3.8 (0.04) .64 type I collagen; eGFR, estimated
glomerular filtration rate;
Albumin-corrected calcium, mg/dL 9.5 (0.03) 9.6 (0.04) .28
FRAX, 10-year fracture risk31;
25 hydroxyvitamin D, ng/mL 29.6 (1.4) 29.8 (1.4) .89 IADL, Instrumental Activities of Daily
eGFR, mL/min/1.73 m2 64.3 (2.3) 68.4 (2.0) .18 Living37; PHQ, Patient Health
Questionnaire42; P1NP, serum intact
CTX, nmol/L BCE 0.425 (0.024) 0.405 (0.024) .56
N-terminal propeptide type I
P1NP, g/L 49.6 (2.9) 48.2 (2.5) .72 procollagen; SPMSQ, Short Portable
BMD, g/cm2 Mental Status Questionnaire.40
a
Spine 0.932 (0.020) 0.967 (0.021) .22 Unless otherwise noted, data are
mean (SE) values.
Total hip 0.681 (0.015) 0.698 (0.015) .42
b
Lower score is worse.
Femoral neck 0.607 (0.014) 0.620 (0.013) .50 c
ADL include eating, dressing,
BMD T scores (SD)f grooming hair, walking, transferring,
Spine 0.8 (0.2) 0.6 (0.2) .48 bathing, and getting to the
Total hip 2.1 (0.1) 2.0 (0.1) .69 bathroom.
d
Femoral neck 2.3 (0.1) 2.1 (0.1) .49 IADL include using the phone,
traveling, shopping, preparing
BMD osteoporosis classification, % 48 45 .92 meals, doing housework, taking
Vertebral fractures, % 52 41 .16 medication, handling money.
e
FRAX, % Higher score is worse.
f
Hip 9.7 (1.5) 7.7 (0.8) .25 The T score reports the difference
from the BMD of a healthy
Major osteoporosis 22.7 (1.5) 20.3 (1.1) .21
30-year-old in number of SDs.

expected, P1NP, the marker of bone formation, decreased in the
treatment group at 12 and 24 months by 21.9 and 20.4 g/L, re-
spectively (P < .01); the mean (SE) adjusted between-group dif-
ference was 16.95 (3.15) g/L at 24 months (P < .001).
Function and Mental Status
Both cognitive and physical function declined significantly in
both groups over time, but differences between the 2 groups
were not significant.
Adverse Events
Ninety-seven percent of participants had an adverse event,
and 64% had a serious adverse event, but there were no group
differences (Table 2). As expected, in the 3 days following the
infusion, the treatment group experienced more acute symp-
toms, but there were no group differences in the laboratory
safety parameters other than a small drop in serum calcium
level on day 2 in the zoledronic acid group (0.52 mg/dL less
than control; P < .001) that was not significantly different at 6
months. Overall, there were no significant differences in
number of deaths, fractures, or cardiac disorders, including
atrial fibrillation (Table 2). Specifically, 14 participants in the
treatment group (16%) and 12 in the placebo group (13%) died
during the study period (odds ratio [OR], 1.24; 95% CI, 0.54-
2.86; (P = .61). Eighteen women in the treatment group (20%)
and 15 in the placebo group (16%) experienced any fracture
(OR, 1.30; 95% CI, 0.61-2.78; P = .50), 6 of them vertebral in the
treatment group (7%) and 8 vertebral in the placebo group
(9%) (OR, 0.76; 95% CI, 0.25-2.28) (P = .62). Patients who expe-
rienced fractures were neither unmasked nor treated.

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 Research Original Investigation Zoledronic Acid for Osteoporosis in Frail Elderly Women

Graphique avec barres d'erreur

Figure 2. Mean Unadjusted Change in Bone Mineral Density (BMD) Figure 3. Mean Unadjusted Absolute Change in Biochemical Markers
of Bone Turnover
Active Placebo
A Total hip BMD
4 Hanche A CTX
Active Placebo
P <.01a,b P <.01a,b
3 0.55 rsorption osseuse P <.05a
P <.01a,b P <.01a,b P <.01b
densit 0.50
BMD Change, %

CTX, nmol/L BCE

1 0.45
masse 0
0.40
osseuse % 1
0.35
2

3 check-up mois P <.05a 0.30

P <.01a
0 6 12 18 24 P <.01a
0.25
Follow-up, mo 0 6 12 18 24
No. of patients
Active 89 78 69 54 Follow-up, mo
No. of patients
Placebo 92 77 71 63 Active 89 80 71
B Femoral neck diminution n Placebo 92 75 61

4
Col fmoral B P1NP
P <.01a P <.01a,b
3 55
P <.01b
2 ? P <.01b 50
BMD Change, %

1
0 45

P1NP, ug/L
P <.01a,b
1
40
2
3
P <.05a 35
4 P <.01a
P <.01a 30
5
0 6 12 18 24 P <.01a
25
Follow-up, mo 0 6 12 18 24
No. of patients
Active 89 78 69 54 Follow-up, mo
No. of patients
Placebo 92 77 71 63 Active 89 80 71
Placebo 92 75 61
C Spine BMD
6
colonne >12 mois =P <.01
oka,b
Error bars represent standard error; BCE, bone collagen equivalent; CTX, serum
5 Ctelopeptide cross-links type I collagen; P1NP, serum intact N-terminal
propeptide type I procollagen.
BMD Change, %

4 P <.01a,b *ok*
P <.05b a
Paired t test for change from baseline.
3 P <.01a b
Linear mixed models for comparison of zoledronic acid (active treatment arm)
2 with placebo.
1

0 73.5; P < .001) but numbers were small, and confidence inter-
0 6 12 18 24
vals wide. Results did not differ appreciably in any of the
No. of patients
Follow-up, mo sensitivity analyses.
Active 89 77 69 55
Placebo 92 84 77 67

Error bars represent standard error. Discussion

a
Paired t test for change from baseline.
b To our knowledge, this is the first randomized trial of a po-
Linear mixed models for comparison of zoledronic acid (active treatment arm)
with placebo.
Although there were no differences in serious falls, there
were more fallers in the treatment group than in the placebo
group over the 2-year study. There was no significant differ-
ence between groups in the number of single fallers (28% vs
24%; OR, 1.24; 95% CI, 0.64-2.42; P = .52) but more partici-
pants in the treatment group had multiple falls (49% vs 35%;
OR, 1.83; 95% CI, 1.01-3.33; P = .047). When adjusted for base-
line frailty, however, the difference in the proportion of mul-
tiple fallers was no longer significant (OR, 1.60; 95% CI, 0.85-
2.99; P = .14). When incident falls were stratified by diabetes,
there were more falls in the treatment group than in the pla-
cebo group (87% [n = 20] vs 33% [n = 4]; OR, 13.3; 95% CI, 2.42-
tent antiresorptive therapy administered to a group of frail el-
derly women. We found that, compared with calcium and vi-
tamin D alone, adding a single dose of intravenous zoledronic
acid significantly improved BMD of the hip and spine over 2
years. Improvements were similar to those found in healthy
younger women in the pivotal zoledronic acid trial.32 Changes
in bone turnover suggest that zoledronic acid had a contin-
ued effect for 2 years after a single dose. There were no sig-
nificant differences in serious adverse events through 24
months, although fracture and mortality rates were descrip-
tively higher in the zoledronic acid group.
Our cohort was more impaired than the one previously in-
vestigated from assisted-living communities.49 Those partici-
pants were 8 years younger than these, and all were cogni-
tively intact, mobile, able to self-administer a daily medication,

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 Zoledronic Acid for Osteoporosis in Frail Elderly Women Original Investigation Research

n=89 n=92
Table 2. Adverse Events During the Study Perioda (%) Signification statistique
Adverse Event Zoledronic Acid Placebo P Valueb
Any 87 (98) 88 (96) .68
Serious 60 (67) 55 (60) .29
Cardiac disorders 28 (32) 25 (27) .53
Atrial fibrillation 5 (6) 5 (5) .96
Fallers
Total 69 (78) > 54 (59) .01
Single 25 (28) 22 (24) .52
>
Multiple 44 (49) 32 (35) .046
>
Serious 4 (4) 5 (4) >.99
Event within 3 days after infusion
Headache 14 (16) > 6 (7) .048
Pyrexia 7 (8) 0 .01
>
Fatigue 21 (24) 14 (15) .15
double insu=valide
Arthralgias 10 (11) 6 (7) .26
Myalgias 7 (8) 3 (3) .21
Influenza-like illness 6 (7) 2 (2) .16 Abbreviation: eGFR, estimated
Falls 4 (5) 3 (3) .72 glomerular filtration rate.
a
Albumin-adjusted calcium on day 2 <8.4 g/dL 2 (2) 0 .24 Unless otherwise noted, data are
2 number (percentage) of
eGFR <30 mL/min/1.73 m at any follow-up 3 (3) 3 (3) >.99
participants.
Albumin-adjusted calcium at 6 months <8.4 mg/dL 0 0 >.99 b
P value from 2 or Fisher exact test.

and able to attend a centralized study site for assessments.
Nonetheless, bone mass response to a single dose of zole-
dronic acid in the current group was similar to that seen in the
less impaired group, who took an oral bisphosphonate (alen-
dronate) daily for 2 years.
Despite the robust increase in BMD at the hip and spine,
we did not observe a reduction in total or vertebral fractures.
Our study was neither designed nor powered to examine
absolute fracture reduction, but our point estimates contrast
with findings from the pivotal zoledronic acid study, which
reported a 60% reduction in vertebral fractures after 1 year
and a 30% reduction in clinical fractures after 2 years.32 It is
possible that the significantly greater frailty of our treatment
group masked beneficial differences in fracture rates. It is also
possible that, despite the improvement in bone density, such
frail individuals may not benefit from therapy because skel-
etal integrity may be so compromised that poor connectivity,
impaired microstructure, altered microgeometry, unhealed
stress fractures, restricted mobility (less weight bearing),
reduced life expectancy, or other factors may prevent fracture
reduction.15,16 However, neither the limited statistical power
of this study nor the point estimates observed can be used to
infer that fracture reduction would or would not be seen in a
larger study50; strong computational evidence suggests that
only a fracture-reduction study will suffice. Based on our data
demonstrating a positive impact on both BMD and bone turn-
over, we believe that such a study is now justified and essen-
tial. The need for such a trial is also timely, since many payers
use bisphosphonate treatment as a quality-assessment mea-
sure in this population despite the lack of safety and fracture-
reduction data.
Approximately 30% of community-dwelling elderly
people fall annually, as do at least half of LTC residents.51,52
Our treatment group experienced more noninjurious falls
than the control group. However, the treatment group also
included more participants at baseline who met criteria for
frailty, had a history of falls and diabetes, and took anticon-
vulsant medications. Moreover, there were no differences in
serious falls or fractures and, after adjusting for baseline
frailty, the difference in falls was no longer significant. We do
not know of other studies that reported an increase in falls as
a potential adverse effect of zoledronic acid or other bisphos-
phonates; this finding is likely owing to poorer baseline status
of participants in the treatment arm in our study or simply
owing to chance.
In addition to its randomized design, a strength of our
study was the use of a single infusion of zoledronic acid to
benefit skeletal health for at least 2 years. Extended benefit
has also been reported in younger patients. 25,26 Another
strength was inclusion of residents with immobility and cog-
nitive impairment as well as those taking glucocorticoids
and anti-seizure medications; such patients are generally
excluded from pivotal trials. Third, we were able to capture
serious adverse events in a timely matter through use of an
electronic record system rather than relying on patient
recall. Finally, as in all LTC facilities, falls were well captured
owing to regulation.
Our study also had limitations. First, despite randomiza-
tion, the treatment group contained more participants with
frailty, falls, diabetes, and anticonvulsant use. Despite the
baseline differences, however, the adjusted analyses were
similar, confirming the robustness of the findings. Second,
our study was neither designed nor powered to examine frac-
ture reduction, although we did gather fracture data from
adverse events and vertebral fracture assessment examina-
tions. Instead, this was a proof-of-concept study. It was

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 Research Original Investigation Zoledronic Acid for Osteoporosis in Frail Elderly Women

designed to assess the impact of therapy on the surrogate

markers of BMD and bone turnover and thereby to determine
whether a larger trial of fracture reduction would be justified
in a frail elderly population. If we had found that these
patients were too frail or too sick to achieve differences in
BMD or bone turnover, a fracture study would not be worth-
while. Finally, and not surprisingly in such a debilitated popu-
lation, there were a number of dropouts by 24 months. How-
ever, the use of 2 different approaches to account for their
missing data did not change the findings.
Conclusions
In summary, we found that a single infusion of zoledronic acid
in frail, cognitively challenged, less mobile elderly women im-
proved bone density and reduced bone turnover for 2 years. This
suggests that even a very frail cohort may benefit. However, prior
to changing practice, larger trials are needed to determine
whether improvement in these surrogate measures will trans-
late into fracture reduction for vulnerable elderly persons.

ARTICLE INFORMATION REFERENCES [abstract SAT0357]. http://www.eular.org. Accessed

Accepted for Publication: October 6, 2014. 1. Kelsey JL, Hoffman S. Risk factors for hip February 24, 2015.

Published Online: April 13, 2015.
doi:10.1001/jamainternmed.2015.0747.
Author Contributions: Dr Greenspan had full
access to all the data in the study and takes
responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Greenspan, Nace,
Resnick.
Acquisition, analysis, or interpretation of data:
Greenspan, Perera, Ferchak, Nace, Resnick.
Drafting of the manuscript: Greenspan, Perera,
Ferchak, Resnick.
Critical revision of the manuscript for important
intellectual content: Greenspan, Perera, Nace,
Resnick.
Statistical analysis: Perera, Resnick.
Obtained funding: Greenspan, Nace.
Administrative, technical, or material support:
Ferchak, Nace, Resnick.
Study supervision: Greenspan, Nace, Resnick.
Conflict of Interest Disclosures: Dr Greenspan
reports receipt of grants to her institution from
Amgen and Eli Lilly. Dr Perera reports receipt of
grants to his institution from Merck, Ortho Biotech,
and Eli Lilly. Dr Nace reports receipt of grants to his
institution from Sanofi. No other disclosures are
reported.
Funding/Support: Support for this project was
provided by National Institutes of Health (NIH)/
National Institute on Aging (NIA) grant R01
AG028068 (Dr Greenspan), NIH/The National
Institute of Diabetes and Digestive and Kidney
Diseases grant K24DK062895 (Dr Greenspan),
Pittsburgh Older Americans Independence Center
NIA grant P30 AG024827, Pharmaceutical
Outcomes Research Program in Aging award K07
AG033174, and Clinical Translational Science
Institute NIH/National Center for Research
Resources grant Ul1 RR024153. Study medication
and matching placebo were provided free of charge
by Novartis Pharmaceuticals, East Hanover, NJ.
Role of the Funder/Sponsor: The supporting
institutions, including Novartis, had no role in the
design and conduct of the study; collection,
management, analysis, and interpretation of the
data; preparation, review, or approval of the
manuscript; and decision to submit the manuscript
for publication.
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Previous Presentations: Preliminary results of this
research were presented at the American Society of
Bone Mineral Research Annual Meeting; October 5,
2013; Baltimore, Maryland. The research was also
presented at the American Geriatrics Society
Annual Meeting; May 15, 2014; Orlando, Florida.
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920 JAMA Internal Medicine June 2015 Volume 175, Number 6 (Reprinted) jamainternalmedicine.com

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Invited Commentary

Osteoporosis Treatment and Fracture Outcomes

Robert Lindsay, MB, ChB, PhD

In this issue of JAMA Internal Medicine, Greenspan and
colleagues1 present intriguing data on zoledronic acid, one
of the most potent drugs in the bisphosphonate family
if not the most potentapproved for treatment of osteo-
porosis. In a study of frail
elderly women liv ing in
Related article page 913
nursing homes, the authors
suggest that a single 5-mg infusion of zoledronic acid, while
producing the expected effects on surrogate outcomes (re-
ducing bone remodeling and increasing bone mineral den-
sity [BMD]), failed to reduce the incidence of fractures over a
2-year period. The study deserves careful evaluation and
interpretation before any modifications to clinical practice
can be recommended.
First, this study includes 181 participants rather than the
thousands usually involved in fracture studies. However, the
included population represents those at greatest risk of frac-
ture, in no small measure related to sarcopenia and accompa-
nying frailty.
The study recorded 14 incident vertebral fractures using
lateral dual x-ray absorptiometry technology and 19 nonver-
tebral fractures confirmed by record and radiographs. The un-
adjusted odds ratio (OR) for vertebral fractures was 0.76 (95%
CI, 0.25-2.28; P = .62) and for all fractures was 1.30 (95% CI, 0.61-
2.78; P = .52); the OR for nonvertebral fractures was not spe-
cifically reported but clearly favors placebo.
As the authors point out, the study was not designed as a
fracture study. Power was defined using reasonable criteria for
BMD change in the spine and femoral neck, which requires a
much smaller sample size than would be required for a frac-
ture study even in a high-risk population. While the positive
but nonsignificant effect on vertebral fractures is comfort-
ing, the lack of effect on nonvertebral fractures deserves at-
tention. In this regard, other studies perhaps supply addi-
tional support. We know that nursing home residents have a
high prevalence of nonskeletal risk factors. 2 Data in the
literature3 suggest that a high prevalence of these features that
increase falling risk tend to negate the positive effects of bone-
active drugs on clinical fracture outcomes even in noninsti-
tutionalized individuals. In a population of 80-year-old par-
ticipants, recruited based on nonskeletal features, risedronate
failed to reduce hip fracture risk, although there was a signifi-

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