Bone Diseases in Thalassemia

R E V I E W
Bone Disease in Thalassemia: A Molecular and

Clinical Overview
Phillip Wong, Peter J. Fuller, Matthew T. Gillespie, and Frances Milat

Department of Endocrinology (P.W., P.J.F., F.M.), Monash Health, Clayton, Victoria 3168, Australia; Hudson Institute
of Medical Research (P.W., P.J.F., F.M.), Clayton, Victoria 3168, Australia; Faculty of Medicine (P.W., P.J.F., M.T.G.,
Downloaded from https://academic.oup.com/edrv/article-abstract/37/4/320/2567096 by guest on 01 December 2019

F.M.), Nursing and Health Sciences, Monash University, Clayton, Victoria 3168, Australia
Thalassemia bone disease is a common and severe complication of thalassemia—an inherited blood disorder due to
mutations in the ␣ or ␤ hemoglobin gene. In its more severe form, severe anemia is present, and treatment with
frequent red blood cell transfusion is necessary. Because the body has limited capacity to excrete iron, concomitant
iron chelation is required to prevent the complications of iron overload. The effects of chronic anemia and iron
overload can lead to multiple end-organ complications such as cardiomyopathy, increased risks of blood-borne
diseases, and liver, pituitary, and bone disease. However, our understanding of thalassemia bone disease is incom-
plete and is composed of a complex piecemeal of risk factors that include genetic factors, hormonal deficiency,
marrow expansion, skeletal dysmorphism, iron toxicity, chelators, and increased bone turnover. The high prevalence
of bone disease in transfusion-dependent thalassemia is seen in both younger and older patients as life expectancy
continues to improve. Indeed, hypogonadism and GH deficiency contribute to a failure to achieve peak bone mass
in this group. The contribution of kidney dysfunction to bone disease in thalassemia is a new and significant com-
plication. This coincides with studies confirming an increase in kidney stones and associated accelerated bone loss in
the thalassemia cohort. However, multiple factors are also associated with reduced bone mineral density and include
marrow expansion, iron toxicity, iron chelators, increased bone turnover, GH deficiency, and hypogonadism. Thala-
ssemia bone disease is a composite of not only multiple hormonal deficiencies but also multiorgan diseases. This
review will address the molecular mechanisms and clinical risk factors associated with thalassemia bone disease and
the clinical implications for monitoring and treating this disorder. (Endocrine Reviews 37: 320–346, 2016)
I. Introduction J. Calcium and vitamin D

II. Thalassemia K. Bone turnover markers
A. Classification and diagnosis of thalassemia VI. The Assessment of Bone Structure, Bone Mineral Den-
III. Iron Overload sity, and Body Composition in Thalassemia
A. Iron chelators A. Bone biopsy
IV. Epidemiology of Thalassemia Bone Disease B. Dual-energy x-ray absorptiometry
A. Low bone mass and strength C. Peripheral quantitative computer tomography
B. Fractures D. Body composition using dual-energy x-ray
V. Mechanisms of Bone Loss in Thalassemia absorptiometry
A. Genetic factors E. Bone deformity
B. Bone biology (RANK-ligand and WNT/␤-catenin VII. Treatment
signalling) A. Overview
C. Iron overload in vitro and in vivo studies B. Bisphosphonates
D. Iron overload clinical studies C. Sex steroid therapy
E. Bone marrow expansion D. Others (zinc, teriparatide, strontium ranelate, de-
F. Hypogonadism nosumab, and romosozumab)
G. GH and IGF-1 VIII. Perspectives and Conclusion
H. Hypoparathyroidism
I. Renal-bone dysfunction
Abbreviations: AFF, atypical femoral fracture; BMD, bone mineral density; CI, confi-
dence interval; DXA, dual-energy x-ray absorptiometry; FE, fractional excretion;
ISSN Print 0163-769X ISSN Online 1945-7189 FGF-23, fibroblast growth factor 23; HbE, hemoglobin E; HRT, hormone replacement
Printed in USA therapy; MRI, magnetic resonance imaging; 25(OH) vitamin D, 25-hydroxyvitamin D;
Copyright © 2016 by the Endocrine Society OPG, osteoprotegerin; QCT, quantitative computed tomography; RANK, receptor ac-
Received September 20, 2015. Accepted June 6, 2016. tivator of nuclear factor ␬; RANKL, RANK ligand; TBS, trabecular bone score; VDR,
First Published Online June 16, 2016 vitamin D receptor.
320 press.endocrine.org/journal/edrv Endocrine Reviews, August 2016, 37(4):320 –346 doi: 10.1210/er.2015-1105
doi: 10.1210/er.2015-1105 press.endocrine.org/journal/edrv 321
I. Introduction in phenotypes with varying severities of anemia. The ma-

jor clinical distinction between the thalassemias is the need
halassemia is derived from the Greek words thalassa
T meaning “sea” and haema meaning “of blood.” In-
deed, it was first described in people who lived around the
for red blood cell transfusion. The need for transfusion
therapy is highly associated with mortality and treatment-
related complications in thalassemia (3).
Mediterranean. The condition is highly prevalent in Med-
The common feature of all thalassemia syndromes de-
iterranean countries, the Middle East, and Southeast Asia.
rives from an imbalanced production of either the ␣ or ␤
However, due to widespread migration, thalassemia can globin chain (4). When produced in excess, damage to red
now be found across the globe (Figure 1). blood cell precursors and mature red blood cells leads to
The clinical spectrum of thalassemia encompasses the anemia. This leads to a compensatory increase in the ex-

asymptomatic carriers to the severe thalassemia major pa- pansion of the ineffective marrow with deleterious effects
tients who require lifelong blood transfusions and iron on bone formation and growth. The need for regular red
chelation. The optimal control of iron overload im- blood cell transfusions can be associated with severe iron
proves mortality, but this increased longevity is associ- overload (5). The major cause of morbidity and mortality
ated with a higher burden of complications. Thalasse- is the effect of iron deposition in the endocrine organs,
mia is associated with multiple endocrine complications liver, and heart, which results not only from transfusion
involving the pituitary, thyroid, pancreas, gonads, therapy but also from increased intestinal absorption of
parathyroid, and bone (1). iron (5, 6).
Thalassemia bone disease is a common but poorly un-
derstood disease that affects both younger and relatively
A. Classification and diagnosis of thalassemia
older patient cohorts. The multiple contributing factors to
The hemoglobinopathies describe a broad range of
bone loss present diagnostic and therapeutic challenges in
diseases of the red blood cell and include: structural he-
thalassemia but also emphasize the importance of an in-
moglobinopathies (hemoglobins with altered abnormal
tegrated approach to management between the hematol-
amino acid sequences), hereditary persistence of high lev-
ogist and other specialty units.
els of fetal hemoglobin, acquired hemoglobinopathies (eg,
met- or sulfhemoglobin due to toxic exposures), and the
thalassemias (7). The thalassemias are broadly separated
II. Thalassemia
into mutations of either the ␣ or ␤ globin chains, ie, ␣ or
Thalassemia is an autosomal recessive disorder and is the ␤ or thalassemic variants, where structurally abnormal
most common monogenic disorder worldwide (2). The hemoglobin is associated with coinherited thalassemic
mutation occurs in either the ␣ or ␤ globin gene, resulting phenotypes, eg, hemoglobin E (HbE) (4).
Figure 1. 1. ␣-Thalassemia
The ␣-thalassemia syndromes are
primarily caused by gene deletions
on chromosome 16 of the ␣ chain
and are usually inherited in an auto-
somal recessive manner (4). The four
clinical subtypes of ␣-thalassemia
syndromes are classified according
to the number of gene deletions, and
this corresponds to their clinical se-
verity (8).
Silent ␣-thalassemia carriers or
trait (deletion of one or two genes)
may have a slight reduction in mean
cell hemoglobin or mean cell vol-
ume. Hydrops fetalis, which repre-
sents the most severe form of
␣-thalassemia (four gene deletions)
is not compatible with life. The He-
Figure 1. Global prevalence of thalassemia (World Health Organization, 2011). moglobin H shows ragged inclusion
322 Wong et al Bone Disease in Thalassemia Endocrine Reviews, August 2016, 37(4):320 –346
bodies due to precipitation of hemoglobin H along with transportation into cells (15). The labile iron pool de-
hypochromia and anisopoikilocytosis on blood film. scribes the reservoir of free iron available for cellular iron
exchange and is localized primarily in the cytosol (5, 16).
2. ␤-Thalassemia Under conditions of iron overload, the labile iron pool is
The ␤-thalassemia is characterized by a defect in pro- increased, whereby free iron is able to promote the pro-
duction of the ␤ globin chain, which is found on chromo- duction of free radicals through the Fenton reaction (14,
some 11 (4, 9). The major and intermedia forms are in- 16). Free radicals are highly unstable and reactive due to
herited in an autosomal recessive pattern. ␤-Thalassemia the presence of unpaired electrons. They can react with
major is characterized by the inheritance of two abnormal and modify proteins, nucleic acids, and fatty acids in cell
␤-globin genes leading to severe anemia and a need for red membranes and plasma lipoproteins (14, 17). Without

cell transfusion in the first few years of life (3, 10). Thala- adequate treatment, the deposition of excessive iron leads
ssemia intermedia is less clearly defined because patients to multiple end-organ damage including cardiomyopathy,
may tolerate anemia reasonably well with signs and symp- liver dysfunction, anterior pituitary hormonal deficits,
toms of anemia appearing in later childhood or early adult and parathyroid, pancreatic, and bone disease (3).
life. ␤-Thalassemia minor results from the inheritance of Whereas cardiac, liver, and pituitary failure is easily
only one defective ␤ globin gene and leads to a mild ane- recognizable, assessing the degree of iron overload is more
mia. The clinical heterogeneity of ␤-thalassemia therefore complicated. There are different validated and standard-
encompasses the major form, which is characterized by ized methods for assessing iron overload that include se-
severe anemia and dependence on chronic transfusion rum ferritin, monitoring transfusion quantity, quantifying
therapy, and the relatively asymptomatic ␤-thalassemia liver iron using biopsy, and magnetic resonance imaging
trait (9). (MRI) assessment of cardiac and liver iron (18). The serum
␤-Thalassemia major can be diagnosed clinically on the ferritin level is the simplest and most widely available mea-
basis of severe anemia and clinical signs of severe eryth- sure of iron overload. It correlates with total body iron, is
ropoiesis, ie, hepatosplenomegaly and bone deformity. a useful measure of iron chelation treatment adequacy,
However, the noninvasive prenatal diagnosis of thalasse- and is an accurate prognostic indicator of survival in trans-
mia major using fetal DNA in maternal plasma is highly fusion-dependent thalassemia (19). Assessment of iron
accurate (11). The laboratory abnormalities are charac- overload in the liver and particularly the heart is important
terized by a severe hypochromic microcytic anemia and in the management of thalassemia because iron-mediated
elevated levels of fetal hemoglobin, Hemoglobin A2, or cardiac toxicity remains one of the leading causes of death
both. in transfusion-dependent thalassemia (5, 20 –22). MRI is
increasingly used for the assessment of liver and cardiac
iron because MRI images darken at a rate proportional to
III. Iron Overload the iron concentration, with the half-life of this darkening
defined as T2*. The change in MRI image darkening can
The body has limited capacity to excrete iron, and iron in be accurately quantified to reflect tissue iron concentra-
excess can lead to long-term damage to tissue. Iron is re- tion (18).
quired for many essential and basic cellular functions, but The life expectancy of patients with transfusion-depen-
its major role in mammals is to carry oxygen as part of dent thalassemia is inversely proportional to iron levels
hemoglobin. Normal body iron stores are 3– 4 g; an excess and has improved dramatically since the introduction of
of iron of 20 g or more can lead to organ damage (5). Iron iron chelation therapy (22, 23). The major causes of mor-
overload is a universal complication of transfusion-depen- tality are cardiac disease (22), followed by infection, liver
dent thalassemia (3, 12). Increased intestinal absorption of disease, and malignancy (24). The prognosis for survival
iron occurs in response to ineffective erythropoiesis and without cardiac disease is excellent when serum ferritin
chronic anemia. Each unit of transfused red blood cells concentrations remain below 2500 ng/L with chelation
contains 200 –250 mg of iron, and because the body has no therapy (19). Indeed, survival has improved dramatically
mechanism for excreting excess iron, iron overload readily over the past half century. In a large Italian cohort of
occurs in patients after 10 to 20 transfusions (13). Exces- thalassemia major, at the age of 15 years, the Kaplan-
sive body iron can lead to increased free iron, which is Meier estimate of survival after the first decade of life was
highly toxic to cells (14). 80.6% for subjects born in 1960 – 64, 84.2% for those
Iron is tightly bound to various proteins and enzymes in born in 1965– 69, and 96.9% for those born in 1970 –74
the body. Ferritin, and to a lesser extent hemosiderin, is the (24). However, mortality has decreased and survival has
major storage form of iron, and transferrin binds iron for improved not only due to improvements in iron chelation
Table 1. Iron Chelator Therapies for Use in Thalassemia

Property Deferoxamine Deferiprone Deferasirox
Chelator: iron binding 1:1 3:1 2:1
Route of administration Subcutaneous or iv Oral Oral
Usual dosage, mg/kg/d 25–50 75 20 –30
Schedule Over 8 –24 h, 5–7 days per week Three times a day Daily
Adverse effects Local reactions Agranulocytosis Gastrointestinal disturbance
Ophthalmological Gastrointestinal disturbance Transaminase elevation
Auditory Transaminase elevation Rise in serum creatinine
Bone abnormalities Arthralgia Proteinuria
Pulmonary Rash

Neurological
Allergic reactions
Advantages Long-term data available May be superior in removal of cardiac iron High patient compliance
Disadvantages Poor compliance Variable efficacy in removing liver iron Long-term data lacking;
efficacy at cardiac iron
removal not established
Special monitoring Long bone films in children Weekly complete blood count Monthly renal, creatinine, and
Annual ophthalmic and hepatic transaminase levels
audiology assessment
Adapted from J. L. Kwiatkowski: Management of transfusional iron overload - differential properties and efficacy of iron chelating agents. J Blood Med. 2011;2:135–
149 (25), with permission. © Dove Press Ltd.
but also due to the development and implementation of bile (29). The most common side effects include rash,
dedicated, integrated, multidisciplinary, skilled centers gastrointestinal disturbances, and mild nonprogressive
worldwide and the development of evidence-based stan- increases in serum creatinine (28, 30). However, testing
dardized protocols for the management of anemia and for renal tubulopathy, and in particular hypercalciuria,
iron overload. was not routinely performed in these early pivotal stud-
ies. Increasing and worrying reports of renal tubular
A. Iron chelators dysfunction including hypercalciuria have emerged
Chronic transfusion leads to iron overload and the nec- with deferasirox (31, 32), but this has not been exam-
essary use of iron chelators to reduce the toxicity of iron ined systematically. Recently, studies have confirmed
on tissues (25). There are three major types of iron chela- that deferasirox, when used in therapeutic doses, leads
tors available (Table 1 and Figure 2). to dose-dependent hypercalciuria (33).
Deferoxamine is the most studied of the available Deferiprone is an alternative oral iron chelator excreted
iron chelators. The effective use of deferoxamine in re- predominantly through the kidney; it is the only iron
ducing total body iron stores leads to improved survival chelator that crosses the blood– brain barrier (34). Defer-
and morbidity from cardiac, liver, and endocrine com- iprone is mainly absorbed from the stomach and is sus-
plications of iron overload (23). Deferoxamine is char- ceptible to food-drug interactions or other gastric factors
acterized by poor oral bioavailability and is rapidly that affect absorption (30). Wide variation in the metab-
cleared by the kidney. The deferoxamine-iron complex olism and clearance of deferiprone among patients has
in serum is eliminated chiefly by the kidneys and to a been observed and is dependent on the degree of iron over-
lesser extent by the liver, where it is excreted into the bile load and availability of chelatable iron (30). The utility of
(26). Rapid clearance by the kidney requires continuous this medication has been limited by its narrow therapeutic
sc or iv administration. The invasive route of adminis- index and safety concerns, including a risk of agranulo-
tration and discomfort at the site of sc infusion con- cytosis (35).
tributes to the poor treatment compliance associated
with deferoxamine therapy (27).
The oral iron chelator deferasirox is well absorbed IV. Epidemiology of Thalassemia Bone Disease
from the gastrointestinal tract and was a much welcome
alternative to deferoxamine. The phase III trials, com- Thalassemia bone disease includes a heterogeneous
pleted in 2006, confirmed the efficacy of deferasirox in group of conditions that includes bone deformity, pain,
the treatment of iron overload in thalassemia major marrow expansion, reduced bone density, and fractures
(28). The deferasirox-iron complexes are excreted pre- (36). The characteristics of thalassemia bone disease are
dominantly through the hepatobiliary system into the unique compared to those of the more typical idiopathic
Figure 2. for osteoporosis when deciding on

an appropriate therapeutic strategy
A for patients.
A. Low bone mass and strength

The morbidity associated with low
bone mass and fragility fracture is of
increasing importance as survival rates
for transfusion-dependent thalasse-
B C
mia improve. Multiple risk factors are
implicated in bone loss and have been

previously described (49, 50). There
have been many studies describing the
prevalence of reduced bone mass in
thalassemia, but direct comparison of
individual studies is difficult (49, 51–
53). The problem lies in the inconsis-
tent use of the DXA Z score, T score,
Figure 2. Molecular structure of iron chelators: deferoxamine (A), deferasirox (B), and deferiprone (C). and areal BMD to describe patient
cohorts. Moreover, it is necessary to
make appropriate adjustments when
osteoporosis seen in the general community. The dif- using DXA in the relatively young (age, 20 –30 years) thala-
ference lies in the relatively young age of patients (pre- ssemic patient population. In general, the BMD Z score is the
dominantly in their 20s to 30s), the multitude of risk most appropriate descriptive parameter of bone density in
factors for bone loss (many of which are unique to pa- the young thalassemia cohort. However, apart from age and
tients with thalassemia), the epidemiology of fractures, gender, changes to body size and bone size also need to be
and the response to treatment with bone-preserving considered (54).
agents. These factors contribute to the complex pa- In a small study of 18 children (age, 5.8 ⫾ 1.5 years)
thophysiology and management of thalassemia bone with ␤-thalassemia major who received hypertransfusion
disease. and chelation therapy, Z scores were noted to be ⬍⫺2.5
Our understanding of thalassemia bone disease is in 22.2% of children, between ⫺1 and ⫺2.5 in 38.8%, and
incomplete, given the complex piecemeal collection of ⬎1 in 38.8% (55). Adolescent patients with transfusion-
risk factors, which includes hormonal deficiency, mar- dependent thalassemia had suboptimal BMD, with 61.3%
row expansion, iron toxicity, chelator toxicity, and in- of patients demonstrating a Z score of ⬍⫺2 and 22.6%
creased bone turnover (37– 40). These risk factors having a Z score between ⫺1 and ⫺2 (56). In contrast, in
also impact on pubertal growth, nutrition, and exercise a study of children and adolescents (age, 5–20 years) with
and can lead to important changes in body composition ␤-thalassemia major who received regular transfusion and
and the inter-relationship between bone, fat, and chelation therapy, Z scores were within the normal range
muscle (41). for all subjects, with a mean Z score of 0.42 for females
The prevalence of osteoporosis in transfusion-depen- and ⫺0.41 for males (P ⫽ .018) (57).
dent thalassemia has been well characterized, but studies Adolescence is a critical period of bone accrual when clin-
examining the longitudinal change in bone mineral den- ical and lifestyle factors including nutrition, exercise, and
sity (BMD) have been small and of relative short duration endocrinopathies (principally sex hormones and GH) play
(42, 43). Similarly, data on fracture burden have been an integral role in optimizing bone health and achieving peak
mainly self-reported in most studies and cross-sectional bone mass (58). The need to adjust for bone size when em-
in design (44, 45). The relationship between BMD and ploying DXA in a skeleton undergoing rapid growth can also
fracture is a well-established concept in osteoporosis (46, make comparisons of bone density in adolescent patients
47). However, fracture risk is a composite of multiple fac- difficult (59). The major determinant of BMD in young
tors, many of which will lead to significant deterioration adults and beyond is dependent on the peak bone mass
in bone microarchitecture, without a concomitant reduc- achieved and the rate of bone loss thereafter. The ability to
tion in areal BMD as measured by dual-energy x-ray ab- achieve peak bone mass is compromised in patients with
sorptiometry (DXA) (48). The difficulty, of course, lies in transfusion-dependent thalassemia (49, 60). The different
assessing the relative contribution of multiple risk factors transfusion and chelation treatment protocols in thalassemia
units worldwide account for differences not only in mortality occur more frequently in the upper extremities (53.3% of
but also in skeletal health. all fractures), whereas spine and pelvic fractures occurred
The impact of gender on bone mass in thalassemia is in 10.6% (45). A clear gradation of fracture risk with
dependent on gonadal hormone sufficiency, but other fac- worsening BMD as measured by DXA is less clear in pe-
tors are likely to be implicated (61). The age at which peak diatric metabolic bone disease compared to osteoporosis
bone mass is reached has been reported to occur at 22.4 in postmenopausal women (54). In a retrospective study,
years (95% confidence interval [CI], 19.0 –31.8) in fe- the average BMD Z and T scores were 0.85 SD lower
males and 29.8 years (95% CI, 23.5–34.0) in males (49). among patients with a history of fractures where the mean
The contribution of hypogonadism to BMD in severe Z/T score was ⫺2.78 vs ⫺1.93 (95% CI, ⫺0.49 to ⫺1.22;
thalassemia in both genders is important (61), with hypo- P ⫽ .02) (67).

gonadism present in 34% of females and 38% of males The major limitation in the assessment and optimal
(49). However, even in eugonadal subjects with ␤-thala- management of thalassemia bone disease is the lack of
ssemia major, males had lower Z scores than females (Z large longitudinal studies examining fracture incidence.
score, ⫺3.0 in males, ⫺2.0 in females; P ⫽ .004) (62). The studies reporting fracture incidence are few in num-
Furthermore, in a risk model of bone density where po- ber, and they have small sample sizes and short follow-up
tential confounders of gender, endocrinopathies, and iron duration. In a 2-year prospective study of 105 patients, 14
overload were taken into account, male subjects with (13.3%) patients sustained a total of 28 fractures, seven
thalassemia still had reduced BMD compared to their fe- patients sustained more than one fracture, and two-thirds
male counterparts (62). The implication that male patients of these fractures were caused by trivial trauma (69). In a
appeared to be at greater risk of bone loss is clinically smaller study of 38 patients over a 5-year period, the in-
significant. Young males are also more likely to engage in cidence of fractures was 21% (70).
higher risk activities and thereby increase their risk of trau- The incidence of fractures in the general community is
matic fractures. partly dependent on gender and age. The incidence is uni-
form in women until the menopause when fracture inci-
B. Fractures dence accelerates; in males, the incidence is high in young
Fractures were highly prevalent (up to 50%), multiple, men and falls until the age of 60, when it increases again
and frequently healed with resultant deformity in patients (71). Studies examining fracture prevalence in thalassemia
with ␤-thalassemia major before the introduction of ef- patients younger than 20 years of age report relatively
fective transfusion and chelation therapy (44, 63, 64). In reduced fracture rates, presumably due to decreased phys-
a study of 62 patients between 10 and 32 years of age, one ical activity associated with chronic disease (45, 67). The
in three had sustained fractures and one in five had mul- prevalence of fractures is often derived from self-reported
tiple or recurrent fractures (63). Moreover, deformities cases (49, 67, 68) and therefore lacks the integrity and
were often caused by the premature fusion of the epiphyses objectivity of radiologically confirmed fractures. Because
of the long bones in patients and occurred at sites involving spinal x-rays were not routinely performed, this may also
the lower tibia and fibula, upper humeral, and lower fem- account for the relatively reduced rate of vertebral frac-
oral epiphyses (63). tures. Risk factors for fracture in thalassemia include the
The introduction of red blood cell transfusion and con- need for regular transfusion as in ␤-thalassemia major (49,
comitant iron chelation therapy has led to improved bone 67, 68), increasing age (45, 67), male gender (45, 68), low
health through various mechanisms. It leads to a reduction body mass index (68), a history of sex hormone replace-
in medullary expansion and cortical bone thinning, the ment (67), and lower BMD (67) (Figure 3).
reduced incidence of hypogonadism, and a reduction in
other endocrine complications such as hypoparathyroid-
ism and metabolic disorders that predispose to low bone V. Mechanisms of Bone Loss in Thalassemia
density and fractures (65, 66). In a retrospective study of
702 patients with thalassemia, the overall prevalence of The major mechanisms that account for bone loss in the
fracture was 12.1% with near equal distribution in males general community are also relevant to those with thala-
(12.7%) and females (11.5%) (67). Fractures occurred ssemia. In particular, deficiencies in sex and growth hor-
more frequently in thalassemia major (16.6%) and thala- mones are important contributing factors to bone loss, in
ssemia intermedia (12.2%) compared to hemoglobin E-␤ addition to risk factors that are unique to the thalassemia
thalassemia (7.4%) and ␣-thalassemia (2.3%) (67). Other cohort. These risk factors are related to the long-term com-
studies have reported the prevalence of fractures to be plications of anemia and its treatments, resulting in mar-
roughly 36% (49, 68). Fractures have been described to row expansion and skeletal deformity together with iron
Figure 3. nants of bone mass. In a small study

of thalassemia major, VDR and
calcitonin receptor gene polymor-
phisms were not found to be associ-
ated with osteoporosis (75). In con-
trast, another study examining VDR
polymorphisms (FokI, TaqI, and
Bsml) related to low BMD were
shown to be significantly correlated
with lower BMD at the lumbar spine

(74). The relationship between VDR
polymorphism and low BMD had
also been demonstrated in another
study among patients with the BB
VDR genotype (79).
The question of whether poly-
morphism in the VDR influences
the response to treatment in thala-
ssemia bone disease has been ex-
amined (80, 81). In a small study of
40 patients with thalassemia ma-
jor, Bsml polymorphism was asso-
ciated with an improved response
in BMD to treatment with alendro-
nate therapy (81).
The identification of multiple
polymorphic gene markers in the
VDR underlies the complex and
multifactorial contribution and in-
teraction between the gene and envi-
ronmental factors in thalassemia
bone disease. However, larger epide-
Figure 3. Fractures and marrow expansion in ␤-thalassemia major. There is osseous expansion miological studies followed by ap-
and low T1 signal throughout the marrow consistent with extramedullary hematopoiesis.
propriate interventional studies are
Compression fractures are also seen (arrows).
required before a causal relationship
between VDR, BMD, and the re-
and chelator toxicity. The contribution of kidney dysfunc-
sponse to antiresorptive medications can be established.
tion to bone disease in thalassemia also requires further
study because increasing reports of renal tubular dysfunc-
B. Bone biology (RANK-ligand and
tion including hypercalciuria have emerged with the use of
WNT/␤-catenin signaling)
the oral iron chelator, deferasirox (Figure 4).
The receptor activator of nuclear factor ␬ (RANK)/
A. Genetic factors RANK ligand (RANKL) osteoprotegerin (OPG) system is a
Genetic factors account for up to 70% of the variance key mediator of osteoclast differentiation and formation
in BMD in the general population (72). (82). OPG acts as a natural decoy receptor to RANK by
A polymorphism in the vitamin D receptor (VDR) has binding to RANKL and leading to reduced osteoclast for-
been found to be associated with skeletal and nonskeletal mation and differentiation (83). Thalassemic patients show
parameters in thalassemia major. It has been associated with no differences in plasma levels of OPG compared with con-
short stature (73) and BMD in thalassemia major (74, 75). trols and significantly higher plasma levels of RANKL, with
Moreover, an association with an increased risk of renal tu- a consequent significantly lower OPG/RANKL ratio (84).
bular dysfunction has also been demonstrated (76). This may partly account for the enhanced osteoclastic bone
The collagen type I ␣ 1 gene locus (77) as well as poly- resorption and bone loss characteristics of these patients
morphism of the VDR gene (78) are promising determi- (84). Moreover, RANKL had a significant negative correla-
Figure 4. not lead to a reduction in sclerostin

levels in postmenopausal women
with osteoporosis (92) but leads to
further increases to baseline levels of
Dickkopf-1 (93). The use of teripa-
ratide after bisphosphonate therapy
in thalassemia major has been shown
to increase BMD at the total hip and
femoral neck in case reports (94).

C. Iron overload in vitro and
in vivo studies
The osteoblast is derived from
mesenchymal stem cells and is the
principal cell responsible for bone
formation. It is primarily responsible
for the laying down of bone matrix
and mineralization (95). In cell stud-
ies, ferritin leads to down-regulation
Figure 4. Potential mechanisms of bone loss in thalassemia. The causes of bone loss are of osteoblast specific genes (96 –98)
multifactorial and multisystem in nature in transfusion-dependent thalassemia.
and is attributed to the ferroxidase
tion with T and estradiol levels in male and female thalasse- activity of ferritin (96).
mic subjects (84). This suggests that increasing sex hormone Chronic iron overload increases the total labile iron
treatment may reduce RANKL and reduce the increase in pool in the body. Free iron that is not chelated may pro-
bone resorption. There was no relationship between mote the production of free radicals through the Fenton
RANKL and OPG levels with BMD in thalassemia (84, 85), reaction (Figure 6) in patients with severe thalassemia. In
although this relationship has also been found to be incon- a murine model, reactive oxygen species had been shown
sistent in the normal population (86, 87). Iron toxicity can to accumulate in the bone marrow as a consequence of
also lead to altered bone remodeling. In a mouse model of ovariectomy and lead to bone loss (99). Increased oxida-
iron overload, reactive oxygen species generated from tive stress in MC3T3-E1 cells (mouse cell line for the study
the Fenton reaction was associated with increased markers of in vitro osteoblast differentiation) has been shown to
of bone resorption and deterioration in bone micro- inhibit the differentiation of osteoblastic cells (100). Iron also
architecture, which was reversed after treatment with anti- promotes RANKL-induced osteoclast formation via oxida-
oxidants (88). tive stress in RAW 264.7 cells (mouse leukemic monocyte
Sclerostin, a Wnt signaling inhibitor that is produced by macrophage cell line), and this effect was attenuated by the
osteocytes and inhibits osteoblast function, was found to administration of an antioxidant (101). In an iron-over-
be elevated in subjects with thalassemia (89) (Figure 5). loaded mouse model, increased reactive oxidative stress led
Moreover, sclerostin levels were significantly correlated to increased bone resorption and trabecular and cortical
with BMD at the lumbar spine, femoral neck, and radius thinning of bone (88). In contrast, bone histomorphometry
(89). These findings suggest that a high sclerostin level may in iron-loaded pigs showed reduced bone apposition and
serve as a marker of increased osteocyte activity in thala- formation consistent with reduced osteoblast recruitment
ssemia patients. but intact osteoclast resorption surfaces (102).
Dickkopf-1 is an inhibitor of Wnt signaling (90) and
plays an important role in osteoblast differentiation. In 66 D. Iron overload clinical studies
patients with thalassemia major who received therapy Iron overload can lead to loss of bone mass through
with zoledronic acid in a placebo-controlled, randomized direct toxicity on bone, pituitary and/or gonadal dysfunc-
trial, baseline levels of Dickkopf-1 were increased and cor- tion leading to hypogonadism, and chronic liver disease
related with increased bone turnover markers and reduced (103). In patients with hemochromatosis, osteoporosis
BMD at the lumbar spine and the distal radius (91). In- was detected in 25% and osteopenia in 41%, but BMD
terestingly, treatment with zoledronic acid did not reduce was also independently associated with alkaline phospha-
the high baseline levels of sclerostin (89) but did lead to a tase (a marker of liver function), hypogonadism, and se-
reduction in levels of Dickkopf-1 (91). Teriparatide does rum ferritin (104). Indeed, higher ferritin levels have also
Figure 5.

Figure 5. The role of RANKL and WNT/␤-catenin signaling in thalassemia bone disease. Increased osteoclast activity can be mediated through sex
hormone and GH deficiency, leading to increased bone resorption through elevation of the RANKL/OPG ratio. High levels of sclerostin and DKK-1
lead to reduced bone formation. The actions of elevation of the RANKL/OPG ratio or enhanced sclerostin/DKK-1 result in low bone mass with
enhanced capacity for bone fragility. DKK-1, Dickkopf-1.
been shown to correlate with lower BMD and accelerated ter adjusting for confounding factors. Moreover, ferritin
bone loss in the general community (105). as a measure of iron overload changes dynamically in
The relationship between serum ferritin and BMD is response to chelation therapy and blood transfusion.
less clear in subjects with transfusion-dependent thalas- Chronic iron overload is associated with deficits in
semia. In cross-sectional studies of thalassemia bone dis- pituitary function leading to hypogonadism and GH de-
ease, serum ferritin levels were not found to be signifi- ficiency; hypoparathyroidism is found in up to 14.6% of
cantly associated with BMD (49, 106). Similarly, there thalassemia subjects receiving transfusion (108, 109).
was no significant association between serum ferritin or Therefore, quantitating the effect of iron on BMD is a
BMD in a large 19-year longitudinal study of thalassemia composite of multiple risk factors.
bone disease (107). The failure to show a statistically sig-
E. Bone marrow expansion
nificant association between serum ferritin and BMD in
Blood transfusion not only provides a source of normal
thalassemia may be due to several reasons. Serum ferritin
red blood cells for oxygen transport but also reduces the
is one of many competing risk factors for bone loss in
degree of marrow expansion (66). The vertebrae is an im-
thalassemia, making it difficult to demonstrate statistical
portant site for marrow expansion, and significant cortical
significance in univariate or multivariate analysis even af-
thinning and disruption of trabecu-
Figure 6. lar bone can occur (66, 110). In con-
trast, the relative absence of bony de-
formity, red marrow activity, and
overlying soft tissue artifact at the
femoral neck enables a more accu-
rate assessment of BMD using DXA
in longitudinal analysis (111).
Supporting the concept that mar-
row expansion can lead to reduced
BMD, a longitudinal study showed a
significant positive correlation be-
tween hemoglobin levels and BMD
(111). In a cross-sectional analysis,
hemoglobin was found to be posi-
Figure 6. Fenton reaction. Iron can catalyze the Fenton reaction leading to the formation of free tively correlated with BMD in
oxygen radicals, and this can cause oxidative stress and damage to cells. ␤-thalassemia (66). A recent study
had confirmed increased erythropoiesis in males compared of GH on bone metabolism in GH-deficient adults is
to females with ␤-thalassemia major after adjusting for he- 2-fold: it stimulates bone resorption (126, 127) and bone
moglobin levels (112). This may account for the greater loss formation (127, 128). GH initially increases bone resorp-
of BMD seen with male thalassemia even after adjusting for tion with a concomitant bone loss that is followed by a
confounding factors (107). Moreover, it raises the impor- phase of increased bone formation, with a net increase in
tant clinical question of whether transfusing patients (par- bone mass occurring after 6 months and lasting for up to
ticularly males) to a higher hemoglobin concentration might 12–18 months of GH treatment (123). Vitamin D has also
lead to reduced bone loss (111). been shown to have a positive correlation with circulating
IGF-1 and IGF binding protein-3 in the normal population
F. Hypogonadism (129), although this has not been consistently demon-

Hypogonadism in transfusion-dependent thalassemia strated in the thalassemia cohort (60).
results primarily from pituitary failure (113–115) and to The true prevalence of GH deficiency in thalassemia is
a lesser extent gonadal failure (115). It is secondary to iron uncertain due to the variability of the diagnostic criteria
overload and is the most common endocrine complication employed, ie, clinical, baseline, and provocative hormonal
(115). The prevalence of hypogonadism in thalassemia has testing. In a multicenter questionnaire of 3817 ␤-thalas-
been reported to be between 22.9 and 54.7% (22, 116, semia major patients, GH deficiency was documented in
117). The difference between the thalassemia cohort and 7.9% of males and 8.8% of females (1). In a study of 28
the general population is the higher prevalence and adult patients with thalassemia major, GH deficiency was
younger age of onset of hypogonadism in thalassemia. present in 32.1% of subjects as demonstrated using an
This has longer term implications for growth, fertility, and arginine plus GHRH stimulation test (130). In a cross-
osteoporosis, particularly because most patients will not sectional study, increased ferritin concentrations, male
have achieved peak bone mass (49). gender, and the presence of hypogonadism were all asso-
The decline in BMD due to estrogen deficiency is dra- ciated with lower serum IGF-1 and IGF binding protein-3
matic and characterizes the transition from the eugonadal concentrations (60).
to menopausal state (118). Indeed, whereas males do not In patients with ␤-thalassemia major, growth retarda-
experience a similar precipitous drop in BMD at midlife, tion is a common complication, and treatment with re-
the critical role of estradiol in regulating bone resorption combinant human GH for 2 years resulted in an increase
in males is well established (119). Hypogonadism is asso- in height growth velocity (131). Although the results of
ciated with lower BMD in patients with thalassemia (61). short-term GH therapy are encouraging, the impact of
In a cross-sectional study of thalassemia, hypogonadal treatment on the final height of non-GH-deficient short
subjects receiving regular transfusion therapy had the thalassemic children remains uncertain (132). In addition,
most severe reduction in BMD; this was associated with an growth failure in adolescent thalassemic patients can be
increase in markers of bone resorption whereas bone for- due to poor nutrition, iron overload, the toxic effects of
mation markers remained normal (38). deferoxamine, or hypogonadism (133).
In adequately treated hypogonadal subjects with thala- In patients with transfusion-dependent thalassemia,
ssemia, there was no significant reduction in BMD based subjects with GH deficiency had reduced BMD (134, 135)
on cross-sectional (37, 61) and preserved BMD was also but showed an unbalanced bone turnover with increased
seen in the non-thalassemia population (107). However, bone resorption relative to bone formation indices com-
treatment of hypogonadism in thalassemia does not compared to normal controls (135, 136). The presence of in-
pletely address the deficiency in BMD (120), and in eu- creased bone turnover and reduced BMD in thalassemia,
gonadal thalassemia patients, GH may have an important despite adequately treated hypogonadism, suggests that
role in the maintenance of bone health (121, 122). reduced IGF-1 in these patients may play an important role
in bone loss (135). In prepubertal GH-deficient children
G. GH and IGF-1 with thalassemia major, GH treatment for 1 year was able
GH is important in the regulation of bone growth (123, to increase but not normalize bone turnover (134). How-
124). It increases bone formation in two ways: via a direct ever, it is likely that longer treatments with GH may lead
interaction with GH receptors on osteoblasts, and via an to larger and more sustained increases in BMD.
induction of endocrine and autocrine/paracrine IGF-1
(123). The anabolic effect of intermittent PTH adminis- H. Hypoparathyroidism
tration in bone appears to be mediated through IGF-1- Hypoparathyroidism is a condition of reduced PTH
dependent mechanisms (125). GH treatment also results secretion. The biochemical abnormalities include hy-
in increased osteoclast formation (126). Thus, the action pocalcemia, hyperphosphatemia, and reduced PTH levels
Figure 7. pocalcemia has been reported in

thalassemia major (142, 143). Sev-
eral case series have also reported ex-
tensive cerebral calcification (144,
145), which may increase the risk of
seizures and subsequent fracture in
thalassemia.
I. Renal-bone dysfunction
The intimate relationship be-

tween bone structure and kidney
dysfunction is evident in renal osteo-
dystrophy (146). The kidney plays
an essential role in regulating cal-
cium and phosphate directly and
indirectly through PTH, 1,25-hy-
droxyvitamin D, and fibroblast
growth factor 23 (FGF-23), an im-
Figure 7. The renal-bone axis in thalassemia. Excessive urine phosphate wasting and
portant regulator of phosphate ho-
hypercalciuria predispose to kidney stone and loss of bone mass. meostasis (147). FGF-23 is secreted
by osteocytes and osteoblasts in re-
(137). The effect of PTH on bone is complex, but hyper- sponse to oral phosphate loading or
parathyroidism is a clinical entity of high bone turnover as increased serum 1,25-dihydroxyvitamin D levels (147).
opposed to hypoparathyroidism, which is one of low bone Iron infusion has been shown to induce hypophos-
turnover. Therefore, the effect of hypoparathyroidism on phatemia through elevation in FGF-23 (148). This is par-
the skeleton is one of relative increase in BMD Z scores, ticularly pertinent in the context of iron overload and the
particularly at the lumbar spine (138, 139). Patients with increasing number of reports of urine phosphate wasting
sporadic idiopathic hypoparathyroidism have increased in thalassemia (149). More recently, therapeutic doses of
BMD at the lumbar spine and hip but not in the forearm, deferasirox have been shown to cause dose-dependent hy-
compared to normal, healthy matched controls (139). The percalciuria in thalassemia major (33). Increased urine
increase in BMD appears to be related to the duration of phosphate and calcium loss in association with defera-
the disease rather than the serum calcium levels (139). The sirox may therefore be an important risk factor for the
nonskeletal manifestations of hypoparathyroidism are development of osteomalacia in thalassemia. Multiple
secondary to the deposition of calcium-phosphate depos- other factors are also likely to contribute to the renal-bone
its in the basal ganglia and other tissues (140). dysfunction seen in thalassemia (Figure 7).
Hypoparathyroidism is a recognized complication of The presence of kidney dysfunction is a relatively recent
chronic iron overload in patients with transfusion-dependent but potentially concerning complication associated with
thalassemia. The prevalence of hypoparathyroidism has thalassemia. Deferasirox, the oral iron-chelating agent, is
been reported to be between 13.5 and 14.6% (108, 109) in known to cause a reversible increase to serum creatinine
severe thalassemia. Consistent with its effect on BMD in gen- (28); other abnormalities of renal function have been de-
eral, BMD was greater in the thalassemic patients with hy- scribed in thalassemia subjects, mainly through case re-
poparathyroidism compared to normal thalassemic patients ports (150). Abnormal elevated levels of renal tubular
(Z score ⫽ ⫺1.975 ⫾ 0.89 vs 2.246 ⫾ 0.97), although the markers have been detected in subjects with thalassemia
difference was not statistically significant (109). Despite the major on deferoxamine. These markers include urinary
tendency for higher BMD, its impact on longer term fracture N-acetyl ␤-D-glucosaminidase (35.9%), fractional excre-
risk has not been established in thalassemia. Indeed, in a tion (FE)-Na (29.1%), FE-K⫹ (7.8%), FE-uric acid
group of non-thalassemic patients with surgical hypopara- (52.4%), urine protein creatinine ratio (0.3%), and urine
thyroidism, there was an increased frequency of morpho- calcium to creatinine ratio (22.3%) (151). These renal dis-
metric vertebral fractures (141). orders occurred in greater frequency with age, increased
Several nonskeletal manifestations of hypoparathy- duration of transfusion, and deferoxamine usage (151). In
roidism have been reported. Exacerbation of cardiac fail- particular, an elevated urine phosphate and calcium loss in
ure in the setting of hypoparathyroidism-induced hy- association with deferasirox may therefore be an impor-
tant risk factor for the development of osteomalacia in thalassemia major (33); this is an area deserving of further
thalassemia. Multiple other factors are also likely to con- research.
tribute to the renal-bone dysfunction seen in thalassemia.
Urine calcium to creatinine ratio was found to be present J. Calcium and vitamin D
in 32.2% of transfusion-dependent thalassemia patients, Vitamin D plays an important role in calcium homeo-
with most of these patients on deferoxamine or defer- stasis and musculoskeletal health. The definition of what
iprone (32). constitutes optimal 25-hydroxyvitamin D [25(OH) vita-
Cases of renal failure and Fanconi syndrome have also min D] levels is not clear (156). The circulating 25(OH)
been described with deferasirox (152). Fanconi syndrome vitamin D level needed to suppress serum PTH concen-
leads to reduced absorption of glucose, amino acids, phos- tration had been proposed, but levels have varied widely

phate, and bicarbonate by the proximal renal tubule. The between 30 and 99 nmol/L (157, 158). Expert opinion
Fanconi syndrome secondary to deferasirox is generally suggests that the optimal serum 25(OH) vitamin D level
reversible on cessation of therapy but can occur on rechal- for bone health is between 50 and 80 nmol/L (156). The
lenge of the drug (153). The loss of urine phosphate can prevalence of suboptimal 25(OH) vitamin D has been well
lead to impaired bone mineralization and osteomalacia. described worldwide, and in an Australian cohort,
Osteomalacia secondary to renal phosphate wasting with 25(OH) vitamin D levels ⬍28 nmol/L were present in
deferasirox therapy, which was reversible on cessation of 11.3% of subjects, and 43.2% of the subjects had levels
deferasirox, has also been reported (149). ⬍50 nmol/L (159).
The pathogenic mechanism(s) leading to renal impair- In thalassemia patients, 12.8% had 25(OH) vitamin D
ment with deferasirox has not been fully elucidated but is concentrations ⬍27 nmol/L, and 82% had levels ⬍75
likely to be multifactorial. The kidney tubule is likely to be nmol/L, with 25(OH) vitamin D levels being lowest in
already compromised by the long-term effects of chronic adolescence (60). Other studies have shown 25(OH) vi-
iron overload and anemia, which are present in all patients tamin D levels to be inversely proportional to age (160). In
with transfusion-dependent thalassemia (154). Iron can thalassemia major patients, the 25(OH) vitamin D levels
catalyze the Fenton reaction, leading to the formation of were negatively correlated with age (P ⬍ .05) and with
free oxygen radicals, and this can cause oxidative stress serum ferritin (P ⬍ .05). Thalassemia major patients who
and damage to cells. The effect of oxidative stress can also had lower 25(OH) vitamin D levels ⬍17.8 ng/mL had
be exacerbated by anemia. Deferasirox is particularly li- higher serum ferritin levels (P ⬍ .01) and higher PTH (P ⬍
pophilic and can enter cells freely and form complexes .05) compared to those with normal 25(OH) vitamin D
with potentially toxic elements such as iron (152). These (160). Despite the high prevalence of low vitamin D status
intracellular complexes are less lipophilic and remain among thalassemia major patients, the association be-
trapped within the cytoplasm, leading to toxicity. This tween low 25(OH) vitamin D levels and reduced BMD has
insult can lead to lipid peroxidation, cell damage, and been inconsistent (161, 162). Moreover, no studies have
dysfunction. been able to demonstrate that vitamin D supplementation
Kidney stones are a recognized complication of hyper- independently increases BMD in thalassemia. In the ab-
calciuria and are associated with reduced BMD and in- sence of interventional studies of vitamin D therapy on
creased fracture risk in the general community (155). BMD or fractures, adoption of appropriate vitamin D tar-
Apart from case reports and anecdotal experience, the gets as in the general population is most appropriate in the
prevalence of kidney stones and its associated effect on the thalassemia cohort.
skeleton was largely unappreciated in thalassemia. In a
retrospective study of subjects with transfusion-depen- K. Bone turnover markers
dent thalassemia, the prevalence of asymptomatic kidney Biochemical markers of bone turnover are a noninva-
stones was found to be 18.1% (111). These stones were sive way of assessing whole-body bone remodeling (163).
more prevalent in male subjects and associated with re- These markers can include products produced by oste-
duced femoral neck BMD and an increased risk of frac- oclasts and osteoblasts or osteoclast-generated degrada-
tures among male stone formers. Of significance, stone tion products of bone matrix. In clinical practice, changes
formers in this study cohort were found to have higher in bone turnover are an independent risk factor for frac-
serum creatinine and lower ferritin levels, suggesting a ture and are also useful in monitoring the effect of osteo-
possible causative role for deferasirox (111). The recent porosis therapy (163, 164).
finding that deferasirox leads to dose-dependent hyper- Patients with thalassemia bone disease have evidence of
calciuria provides a biological mechanism for both in- increased bone resorption, but normal levels of bone for-
creased kidney stones and accelerated bone loss in mation markers have also been reported (38, 136, 165–
166). This inconsistency may reflect the different treat- mote osteoclast activity (102) and reduce osteoblast
ment protocols among thalassemia units worldwide and function (97); animal models of iron overload have
their impact on these markers. The increase in bone re- demonstrated a reduction in parameters of bone for-
sorption markers is particularly pronounced in untreated mation (102). In patients with thalassemia, stainable
hypogonadal subjects with thalassemia (167) and is con- iron was negatively correlated with trabecular bone vol-
sistent with changes in bone resorption seen in normal ume. However, iron overload showed no changes to
menopausal women (168). Indeed, of all the multiple risk osteoid volume, thickness, or osteoblast surface (172).
factors for bone loss, the suboptimal treatment of hypo- On balance, iron toxicity in thalassemia may exert its
gonadism in thalassemia is likely to be the major contrib- effect on bone indirectly through an increased risk of
uting factor for reduced BMD. In the eugonadal patient hypogonadism and IGF-1.

with thalassemia, reduced IGF-1 levels were correlated The variability seen on bone histomorphometry in
with increased markers of bone resorption and reduced transfusion-dependent thalassemia is not entirely surpris-
bone formation, and this may be an important interme- ing; the many competing factors associated with deterio-
diary for bone loss in thalassemia (122, 135), although an ration in bone quality and different treatment protocols
association between increased circulating levels of pro- associated with each thalassemia unit most likely account
resorptive cytokines such as IL-1␣, IL-6, and TNF␣ may for this (Figure 8).
be implicated (169).
B. Dual-energy x-ray absorptiometry
DXA is the most widely used modality for the as-
VI. The Assessment of Bone Structure, sessment of bone mineralization in clinical practice. It
Bone Mineral Density, and Body Composition serves to identify those patients at greatest risk of fra-
in Thalassemia gility fractures, to guide decisions regarding treatment,
and to monitor the response to therapy (46). The rela-
A. Bone biopsy tively low cost per study and radiation exposure, in the
Bone histomorphometry provides an important visual range of 2–5 mrem (173), has made it a safe and acces-
overview of the complex and competing factors involved sible tool for use in the management of osteoporosis.
in thalassemia bone disease. In a study of 18 eugonadal The precision of DXA, expressed as a coefficient of vari-
subjects with ␤-thalassemia/HbE, Domrongkitchaiporn ation, has been reported to be as low as 0.48% for the
et al (122) examined bone histomorphometry after tetra- lumbar spine and 0.85% for the femoral neck (174).
cycline double labeling. The most striking abnormality This enables reliable long-term follow-up of patients
was the reduction in trabecular bone volume over total with reduced BMD.
volume in these subjects in the presence of relatively pre- Multiple large prospective studies have confirmed the
served measures of other bone parameters on biopsy. Bone accuracy of DXA in predicting fracture risk. In postmeno-
volume over total volume was positively correlated with pausal women, for each standard deviation reduction in
IGF-1 and BMD at the total hip but not the lumbar spine femoral neck bone density, the age-adjusted risk of hip
(122). These patients had normal bone turnover markers fracture was increased 2.6-fold (175). BMD at the femoral
and low 25 (OH) vitamin D and 1,25 (OH) vitamin D neck was also a better predictor of hip fracture than mea-
levels, although no evidence of abnormal osteoid volume surements of BMD at the spine or radius (175). However,
was seen. The lack of osteomalacia was also characteristic non-BMD risk factors for fractures such as gender, age,
of other studies where changes in cortical bone were most family history of osteoporosis, glucocorticoid use, and hy-
severe with cortical bone fissures and focal mineralization pogonadism are important factors in both the general and
defects (170). thalassemia population (36, 50, 176). This is in addition
However, the increased prevalence of renal tubular dys- to the thalassemia-specific risk factors such as marrow
function, and in particular hypercalciuria (32, 150), in expansion, iron overload, and kidney stones that are
many thalassemia major patients may show defects in sec- known to reduce BMD and are associated with fracture
ondary mineralization of osteoid seams (171). Interest- risk (111).
ingly, in a study of 17 children (mean age, 13.4 years) with There are several limitations to the use of DXA that
␤-thalassemia/HbE and thalassemia major who were sub- are particularly relevant to the thalassemia population.
optimally transfused, focal osteomalacia was the predom- BMD, as measured by DXA, corrects BMD for the area
inant bone abnormality. (height and width) but not for the volume (height,
The contribution of iron toxicity on bone is unclear. width, and thickness) of bone. Therefore, if two people
In vitro models have shown that iron toxicity can pro- with identical “true” volumetric bone density are com-
Figure 8. The lumbar spine and femoral

neck are the two most common sites
for measurement of BMD using
DXA. The presence of multiple de-
generative changes at the spine can
impact on the accuracy of DXA. In a
study of women between 40 and 84
years of age, numerous pathologies
were demonstrated that could im-
pact on BMD. Osteophytes were

present in 45.8%, osteochondrosis
in 21.5%, vascular calcification in
24.3%, and scoliosis in 22.2%
(178). The spine in patients with
thalassemia is also a site of signifi-
cant bone deformity secondary to
significant marrow expansion and
deferoxamine-induced bone dyspla-
sia (179, 180). Therefore, the preci-
sion of DXA in monitoring BMD
changes at the spine in transfusion-
dependent thalassemia may be sig-
nificantly affected by these morpho-
logical changes. The femoral neck is
also the most accurate site for
monitoring the longitudinal changes
in BMD in patients with thalassemia
(107).
An assessment of bone quality can
be derived through the use of the tra-
becular bone score (TBS), which is
Figure 8. Bone biopsy of a male patient with thalassemia major. Thick osteoid is seen on some derived from the spine through DXA
surfaces with areas of thinner osteoid. The seam between the older bone and the osteoid is and is a predictor of fracture risk
distinct, consistent with the sharp tetracycline label, suggesting that this is not an osteomalacia (181, 182). TBS has been shown to
type of effect, with slow commencement of mineralization, but that mineralization has
effectively stopped suddenly. (Image courtesy of A/Prof Natalie Sims.)
be lower in patients with thalassemia
compared to controls and to also
correlate with BMD, but an associ-
pared, the shorter person will have a lower BMD than ation between TBS and fracture is yet to be established
the taller one (59, 177). Controversy persists about the (183).
optimal method for adjusting for variations in bone
size, body composition, and maturity; ideally, the ad- C. Peripheral quantitative computer tomography
justment method should prove to be a stronger predic-
The bone loss that occurs in thalassemia is unlikely to
tor of fracture (177). Thalassemia bone disease is still
affect cortical and trabecular bone in equal measure. This
very much a problem of young adults. The high prev-
presents obvious limitations for DXA, which is a two-
alence of GH deficiency and hypogonadism, com-
pounded with the significant impact of anemia and the dimensional measure of bone density and therefore en-
need for chronic transfusion, contributes to reduced capsulates cortical and trabecular components of bone
skeletal size and a failure to reach peak bone mass in into a single parameter.
severe thalassemia (49). Indeed, nutrition, physical ac- Quantitative computed tomography (QCT) is a three-
tivity, pubertal stage, disease severity, patient and fam- dimensional technique for quantifying BMD at the spine,
ily fracture history, and medication exposure need to be proximal femur, forearm, and tibia. This diagnostic mo-
considered in the assessment of pediatric bone disease. dality has a number of advantages over conventional
DXA: cortical and trabecular bone can be separated, tra- sexual dimorphism of body composition and bone density
becular volumes of interest are largely independent of de- in patients with transfusion-dependent thalassemia.
generative changes in the spine, and three-dimensional Whereas the effect of hypogonadism on BMD and body
geometric parameters can be determined (184). composition has been well described in the general pop-
A number of small studies have investigated skeletal ulation, the influence of hypogonadism on body compo-
status in thalassemia employing QCT. In a study of 48 sition in adult transfusion-dependent thalassemia is un-
patients, the correlation coefficient between DXA BMD certain. In a pediatric cohort, hypogonadism was not
and QCT trabecular BMD was 0.545 (P ⬍ .001). The correlated with measures of body composition in subjects
classification of patients into normal, osteopenia, and os- with transfusion-dependent thalassemia (41). In a cross-
teoporotic categories, using QCT Z scores, was in better sectional study of transfusion-dependent thalassemia, hy-

agreement with the assignment based on trabecular num- pogonadism attenuates the strength of the muscle-bone
ber (k ⫽ 0.209; P ⫽ .053) than the classification using relationship in males but strengthens the positive correla-
DXA Z scores (k ⫽ 0.145; P ⫽ .12) (185). Another study tion of skeletal muscle mass and fat mass in female sub-
employing peripheral QCT showed lower tibial trabecular jects (190).
volumetric BMD, cortical area, cortical bone mineral con- The effect of reduced lean muscle mass on falls risk,
tent, cortical thickness, periosteal circumference, and sec- BMD, and fractures has been described in the general
tion modulus Z scores in thalassemic patients compared to population (191). Low grip strength is associated with
controls (52). reduced BMD (192), falls, and fractures in the general
Although there have been relatively few studies em- population (193). In a cross-sectional study of patients
ploying QCT techniques to assess thalassemia bone dis- with thalassemia, the plasma level of klotho protein was
ease, this technique appears to have significant advantages found to be lower in patients with thalassemia major com-
over conventional DXA in assessing bone status in the pared to healthy controls and was correlated with hand-
pediatric cohort and at the spine. The question of whether grip strength, and these patients had a higher probability
QCT parameters are superior to DXA measures in pre- of fragility fractures (194).
dicting fracture risk remains to be answered. Exploring the inter-relationship between fat mass, lean
tissue mass, and BMD in the hypogonadal thalassemic
D. Body composition using dual-energy
x-ray absorptiometry
cohort may provide insights into the effect of sex hormone
The study of body composition is concerned with the per- replacement, nutrition, and exercise on BMD. GH therapy
centage and distribution of fat and lean tissue in the body. results in increased muscle mass and reduced fat mass
This can be derived from most DXA machines after a total (195). There have been no studies examining the effect of
body density study, but despite its availability, the assessment hypogonadism or GH deficiency on body composition in
of body composition using DXA is an underutilized tool. subjects with transfusion-dependent thalassemia.
The study of body composition is particularly relevant Many studies have reported inconsistent findings in de-
in thalassemia with its impaired growth, poor nutritional scribing the relationship between fat, muscle, and bone.
status, and delayed skeletal and sexual maturation. How- One reason may be the failure to account for the multi-
ever, the nature of associated body composition deficits collinearity between body weight, fat, lean tissue, and
has been poorly studied. In the general population, body other covariates with BMD (196). Collinearity is a com-
composition is influenced by many factors including age, mon but important statistical problem in multiple regres-
gender, gonadal status, nutrition, exercise, and hormonal sion analysis and can be seen in many analyses of body
factors (186). Lean tissue mass has been shown to be composition (196). It can occur when the correlations
highly correlated with BMD up to middle age, and fat mass among the independent variables, ie, weight, fat, and lean
begins to account for a larger variance in BMD thereafter tissue, are highly correlated in a multiple regression anal-
(187–189). ysis where BMD is the dependent variable. When two or
The need for chronic transfusion in severe thalassemia more variables are highly correlated, they convey essen-
may have significant long-term consequences on nutri- tially the same information from a statistical perspective.
tion, physical activity, and growth (41). Hepatospleno- This can lead to the paradoxical situation where the over-
megaly is an important complication of ineffective eryth- all statistical model is significant, but none of the inde-
ropoiesis and will lead to an overestimation of total lean pendent variables that were adjusted in the multiple re-
tissue mass if measured by DXA. The need to account for gression model are significant (197). Therefore, it makes
multiple confounding factors in such an analysis is chal- some variables statistically insignificant where they oth-
lenging. These factors and others may be implicated in the erwise should be, and vice versa.
E. Bone deformity sociated with hormonal complications such as hypogo-

The cellular hypoxia that results from the more severe nadism further contributes to reduced peak bone mass and
forms of thalassemia results in increased erythropoietin long-term reduction in BMD. Randomized control studies
production (198). High levels of erythropoietin lead to investigating the effect of sex steroids on BMD are lacking;
significant marrow expansion in sites of extramedullary this adds to the uncertainty regarding what constitutes the
erythropoiesis. This leads to deformities of the skull, face, most appropriate dose and route for sex hormone replace-
vertebrae, and long bones with skeletal consequences of ment in thalassemia bone disease.
disfigurement and increased risk of fracture (199) (Figure Calcium and vitamin D replacement is common in
9, A and B). Indeed the BMD at the total body, femoral thalassemia, but evidence of improvement in BMD and/or
neck, and lumbar spine was found to be negatively cor- fractures is lacking, as is the case in the normal population.

related with serum transferrin receptor levels, a marker of The experience with pharmacological treatment of osteo-
erythropoietic activity (66). porosis in thalassemia is mainly confined to the bisphos-
Chronic back pain is common in transfusion-depen- phonates. There is minimal experience with teriparatide,
dent thalassemia. In those with thalassemia major and denosumab, and strontium ranelate showing improve-
intermedia, extensive, severe, and multilevel lumbar disc ments in BMD, but fracture endpoints are lacking.
degeneration has been described (200). Scoliosis is also
more common and is associated with lower hematocrit B. Bisphosphonates
levels (201). Moreover, the incidence, evolution, and eti- Bisphosphonates are potent inhibitors of bone resorp-
ology of scoliosis in ␤-thalassemia differs from that of tion and are widely used in the treatment of osteoporosis,
idiopathic scoliosis, suggesting that scoliosis in ␤-thalas- myeloma, and metastatic bone disease. The newer gener-
semia represents a distinct entity (202). The vertebrae are ation bisphosphonates interfere with the mevalonate
also characterized by cortical thickening and have a stri- pathway by inhibiting farnesyl diphosphate synthase,
ated appearance resulting from preservation and thicken- thereby blocking prenylation of GTP-binding proteins
ing of the vertical trabeculae (203) (Figure 10). (208). The effect is decreased osteoclast recruitment, dif-
Deferoxamine use is also associated with bone dys- ferentiation, activity, and survival, resulting in reduced
plasia, leading to reduced final height (199, 204), wid- bone resorption. This can be seen through a reduction in
ening of the growth plate, biconvex contours of verte- bone turnover markers and an increase in BMD, with a
bral end-plates, and platyspondyly with decreased reduction in the risk of fracture (208).
vertebral body height (179, 199). The age at which de- Table 2 summarizes the published randomized control
feroxamine therapy is initiated appears to influence the studies of bisphosphonates in thalassemia to date (209 –
risk of bone deformity. In a retrospective study, defer- 213). These studies were between 12 and 24 months in
oxamine therapy initiated after 3 years of age, and only duration, with the largest study enrolling 118 subjects
after iron overload has been established, did not lead to (213). The randomized design of these studies is their ma-
compromised longitudinal growth (205). Patients with jor strength, but there are several limitations. The small
thalassemia major have short stature, which can be sec- number of patients and the short duration of treatment
ondary to disproportionate truncal shortening; the mean there is insignificant power to detect fracture inci-
causes are multifactorial, but hypogonadism and iron dence. Despite the mean age of study participants being
chelation therapy may be implicated (206). ⬍50 years, only one study reported DXA Z scores (209);
The presence of spinal dysmorphism may compromise the other studies reported areal BMD and T scores (210 –
the accuracy of measuring lumbar spine BMD using DXA. 213). It is also important to stress that the zoledronic acid
This is an important factor that has yet to be investigated used in these trials was given at a dose of 4 mg every 3 to
in clinical studies of thalassemia bone disease. 6 months for up to 2 years (211, 212), in contrast to the
more common dose of 5 mg once a year in the non-thala-
ssemia population. A recent Cochrane review of random-
ized control studies of thalassemia major patients treated
VII. Treatment
with bisphosphonate therapy concluded that treatment
A. Overview resulted in an increase to BMD (214).
The severe anemia and the complications related to its Treatment with zoledronic acid, alendronate, and
treatment underlie the unique set of risk factors that char- neridronate was associated with a significant increase in
acterize thalassemia bone disease. Optimal transfusion BMD, but clodronate was not associated with a significant
and chelation therapy undoubtedly reduce the severity of increase in BMD despite achieving a significant reduction
bone fragility and deformity (207). Skeletal morbidity as- in bone turnover markers (210). A direct comparison be-
Figure 9. continuation of treatment (216).

This also raises the question of
whether a yearly dose of zoledronic
acid at 5 mg, rather than a 3- to
6-monthly regimen of zoledronic
acid as used in some trials (211, 212),
is effective in improving BMD in
thalassemia major.
Incident fractures, particularly of
the vertebrae, are key efficacy end-

points in bisphosphonate trials. De-
spite demonstrating an increase in
BMD and a reduction in turnover
markers, antifracture efficacy data
are lacking from bisphosphonate tri-
als in patients with thalassemia. The
lack of fracture efficacy data in this
cohort is due mainly to small study
size and short study duration. In ad-
dition, fractures may be dependent
on extrinsic factors such as high risk-
taking activity in young subjects.
Back pain in transfusion-dependent
thalassemia is common and may be
due to spinal deformity or, more fre-
quently, to bone marrow expansion
(36). The effect on bone pain with
bisphosphonate treatment was as-
sessed objectively in two randomized
trials in thalassemia and showed a
significant improvement as early as 3
months after treatment with zole-
dronic acid (211, 213).
The use of zoledronic acid was as-
sociated with a “flu-like” reaction in a
small proportion of thalassemia sub-
jects with the first infusion, but this
Figure 9. Bone deformity due to severe medullary expansion. A, A female patient with
was absent with subsequent treat-
thalassemia major with significant marrow expansion of the skull. B, A male patient with
thalassemia major with severe marrow expansion of the maxilla. ments (211, 212). The clinical con-
cerns related to bisphosphonate-asso-
tween BMD is not possible in these trials, given the dif- ciated osteonecrosis of the jaw and atypical femoral
ferent treatment agents and baseline risk of osteoporosis in fractures (AFFs) have not been described in clinical trials in
each study. A significant increase in BMD was associated thalassemia patients. However, a recent case series has con-
with a concomitant significant reduction in bone resorp- firmed three cases of bisphosphonate-associated osteone-
tion markers in these studies, except for the study by Gil- crosis of the jaw in thalassemia major patients taking alen-
fillan et al (212). The iv bisphosphonates have the advan- dronate (217). Dental examination should be considered
tage of being able to be administered after the patient’s before the use of potent antiresorptive medications. There
regular blood transfusion. Furthermore, treatment with iv have been four reported cases of AFFs in patients with thala-
zoledronic acid overcomes problems of compliance be- ssemia who have received bisphosphonates (218 –219). The
cause bone effects last for at least 12 months (215). The relationship between bisphosphonate use and AFF cannot
effect of zoledronic acid on BMD in thalassemia major is be considered to be causal yet, but alterations in the material
enduring, with improvements seen 24 months after dis- properties of bone resulting from low bone turnover may be
Figure 10. with thalassemia must therefore in-

clude a careful risk assessment that
accounts for the severity of bone dis-
ease, history of fracture, plans for
pregnancy, and other skeletal co-
morbidities. This highlights the need
for experienced clinical judgment
and for treatment to be considered
on a case-by-case basis. Future stud-
ies will need to address the optimal

frequency and duration of bisphos-
phonate treatment. The concept of
bisphosphonate holidays has been
well described in postmenopausal
osteoporosis, but whether this can be
extrapolated to the thalassemia ma-
jor population is uncertain and re-
quires further investigation (222).
C. Sex steroid therapy

The relationship between hypo-
gonadism and sex hormone replace-
ment with BMD and fractures is
clearly defined in the non-thalasse-
mic population (223). The paucity of
longitudinal studies and the variable
dose and route of administration of
sex hormone replacement in thalas-
semia has made it difficult to quan-
titate the effect of hypogonadism
and its treatment on BMD. In a pro-
spective study of 67 patients with
thalassemia major, the effect of hy-
pogonadism and sex hormone re-
placement regimens on BMD was
assessed; lumbar spine BMD was
30% lower than controls, those with
untreated hypogonadism had the
lowest BMD, and females on contin-
uous topical hormone replacement
therapy (HRT) achieved the highest
BMD (61). The optimal dose of HRT
Figure 10. Scoliosis and trabecular thickening of the vertebrae. A male patient with thalassemia for skeletal health in thalassemia
major with mild scoliosis and trabecular thickening of the vertebrae. remains a matter of debate. The in-
consistency between sex hormone
an important pathogenic factor (220, 221). Increased clini- replacement and improvement in BMD in some published
cal vigilance for both osteonecrosis of the jaw and AFF is studies (37) reflects the retrospective nature of these stud-
required of clinicians treating bone disease in thalassemia. ies with limited numbers and heterogeneous hormone
The other clinical concern relates to the use of very preparations. Chatterjee et al (120) conducted a prospec-
potent bisphosphonates in a patient cohort that is relative study of treated hypogonadal females that included
tively young, typically in their third or fourth decade. The individuals with thalassemia major and non-thalassemia.
decision to commence bisphosphonate therapy in patients Although BMD improved in both groups, the non-thala-
Table 2. Summary of Randomized Control Studies of Bisphosphonates in Thalassemia Published to Date

First Author (Ref.) Morabito (209) Pennisi (210) Voskaridou (211) Gilfillan (212) Forni (213)
No. of patients 25 30 66 23 118
Study design Randomized, Randomized Double-blinded, Double-blinded, Randomized
placebo-controlled controlled randomized, randomized, controlled
placebo-controlled placebo-controlled
Active treatment I Alendronate 10 mg Clodronate 300 mg ZA 4 mg ZA 4 mg iv 3 monthly Neridronate 100 mg
oral daily iv 3 weekly iv 6 monthly iv 3 monthly
Active treatment II Clodronate 100 mg None ZA 4 mg iv 3 monthly None None
im every 10 d
Study duration, y 2 2 1 2 1

Patient type TM TM TM/TI TM TM
Baseline BMD
(placebo)
Lumbar spine Z score, ⫺2.66 T score, ⫺2.71 T score, ⫺2.5 T score, ⫺2.91 BMD, 0.721 g/cm2
Femoral neck Z score, ⫺1.97 T score, ⫺1.92 T score, ⫺2.0 T score, ⫺1.45 BMD, 0.651 g/cm2
Baseline BMD
(active treatment)
Lumbar spine Z score, ⫺2.75 T score, ⫺2.66 T score, ⫺3.3 T score, ⫺2.86 BMD, 0.734 g/cm2
(alendronate) (ZA 6 monthly)
Z score, ⫺2.74 T score, ⫺2.9
(clodronate) (ZA 3 monthly)
Femoral neck Z score, ⫺2.25 T score, ⫺1.64 T score, ⫺1.9 T score, ⫺1.55 BMD, 0.656 g/cm2
(Alendronate) (ZA 6 monthly)
Z score, ⫺2.26 T score, ⫺1.5
(Clodronate) (ZA 3 monthly)
Percentage change in
BMD in active
group
Lumbar spine Placebo, ⫺4.9 Not available 5.8 ( ZA 6 monthly) 10.2a 3.6a
(but nonsignificant)
Alendronate, 2.88a 15.2 (ZA 3 monthly)a
Clodronate, 0.12
Femoral neck Placebo, ⫺7.4 Not available 4.8 (ZA 6 monthly) 5.2a 1.4a
(but nonsignificant)
Alendronate, 5.64a 11.3 (ZA 3 monthly)a
Clodronate, 1.39
Abbreviations: TM, thalassemia major; TI, thalassemia intermedia; ZA, zoledronic acid.
a
Statistically significant compared to placebo (P ⬍ .05).
ssemic group had a greater increase in spinal T scores in thalassemia, and zinc deficiency is widespread in this
contrast to the thalassemia major patients (120). There are cohort (225, 226).
currently no studies investigating the effect of hypogonad- Teriparatide leads to an increase in BMD and reduction
ism and its treatment with HRT on fracture outcomes in in fractures in men (227) and postmenopausal women
thalassemia. (228). The clinical use of teriparatide in thalassemia major
The current literature supports the benefits of sex hor- leads to an increase in BMD, although the experience is
mone replacement in optimizing skeletal health. However, limited to case reports, and therefore its use should be
important clinical questions pertaining to dose, route of considered strictly on an individual basis (94, 229). The
administration, and the impact of treatment on fracture use of teriparatide as a follow-on treatment after pro-
endpoints in thalassemia remain unanswered. longed or failed bisphosphonate therapy appears clinically
justified and sound in thalassemia major. However, severe
D. Others (zinc, teriparatide, strontium ranelate, extramedullary erythropoiesis can lead to spinal cord
denosumab, and romosozumab) compression and treatment with radiation therapy in
The use of zinc in patients with thalassemia was as- transfusion-dependent thalassemia; teriparatide therapy
sociated with an increase in total body bone mineral would be contraindicated in these cases given the potential
content but no significant change in bone mass or BMD concerns of bone malignancy.
at the hip or spine (214, 224). Zinc appears to be an Strontium ranelate leads to an increase in BMD and a
important nutrient for growth and development in reduction in fractures (230), although concerns regarding
increased cardiovascular risks have surfaced more re- Moreover, the optimal frequency and duration of bispho-
cently (231). In a small study of 24 patients with thalas- sphonate administration is not known. The role of ana-
semia major, treatment with strontium ranelate improved bolic therapies such as teriparatide and, in the near future,
BMD and normalized bone turnover markers, as well as the antisclerostin antibody romosozumab needs to be
lowering serum sclerostin levels (232). However, the use studied. The optimal dose and route of application of sex
of strontium ranelate will require caution, given the in- hormone therapy for bone preservation also remain to be
creased baseline risk of thromboembolism (233) and car- established.
diac iron overload in transfusion-dependent thalassemia. Important questions remain regarding the mechanism
Denosumab is a fully human monoclonal antibody to underlying the increased prevalence of kidney stones and
RANKL and a potent antiresorptive used in the treatment associated bone loss in thalassemia. Whether or not this

of osteoporosis. In a small study of 30 subjects with thala- defect in renal tubular dysfunction is secondary to the
ssemia major, denosumab administered every 6 months underlying thalassemia condition, the role of iron over-
for 1 year was associated with a 9.2% and 6.0% increase load and iron chelators needs to be clarified. Moreover,
in BMD at the lumbar spine and femoral neck, respectively the clinical sequelae of renal tubular dysfunction such as
(234). The most common side effect was pain in the hypercalciuria or phosphate wasting leading to acceler-
back and extremities (12%) and nausea (10%), whereas ated bone loss and kidney stones also need to be confirmed
hypocalcemia occurred in 7% (234). The risk of hypocal- in longitudinal studies.
cemia is a potential concern in thalassemia, given the
predilection for low serum calcium secondary to hypo-
parathyroidism (108, 109) and renal impairment associ-
Acknowledgments
ated with the use of deferasirox (28). Thus, the use of
denosumab in thalassemia major will require increased We thank Prof Donald Bowden, Head of Thalassemia at Monash Health,
vigilance for associated hypocalcemia. Melbourne, for his encouragement and clinical insight; A/Prof Natalie
Sims at St Vincent’s Institute, Melbourne, for providing the bone histo-
Romosozumab is a monoclonal antibody that binds
morphometry image; and Ms Sue Panckridge and Dr Vicky Kartsogi-
and inhibits sclerostin. Romosozumab increases bone for-
annis at Hudson Institute of Medical Research, for graphical support and
mation and has been shown to increase BMD in post- constructive discussions, respectively.
menopausal women (235). Thalassemia patients have
been found to have higher baseline levels of sclerostin (89). Address all correspondence and requests for reprints to: Dr Phillip Wong,
The corollary is that the use of a specific antisclerostin Hudson Institute of Medical Research, 27–31 Wright Street, Clayton 3168,
Victoria, Australia. E-mail: phillip.wong@hudson.org.au.
antibody, such as romosozumab, may be beneficial in P.W. was supported by an Australian Postgraduate Award and Royal
treating reduced BMD in patients with thalassemia. How- Australian College of Physicians / Osteoporosis Australia Scholarship.
ever, the efficacy and safety profile of this drug in the P.J.F. is supported by a National Health and Medical Research Council
(Australia) Senior Principal Research Fellowship. Hudson Institute of
treatment of low BMD and fractures in thalassemia re-
Medical Research is supported by the Victorian Government’s Opera-
mains to be established. tional Infrastructure Support Program.
Disclosure Summary: The authors have nothing to declare.
VIII. Perspectives and Conclusion

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R E V I E W

Bone Disease in Thalassemia: A Molecular and

Phillip Wong, Peter J. Fuller, Matthew T. Gillespie, and Frances Milat

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I. Introduction J. Calcium and vitamin D

I. Introduction in phenotypes with varying severities of anemia. The ma-

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Table 1. Iron Chelator Therapies for Use in Thalassemia

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Figure 2. for osteoporosis when deciding on

A. Low bone mass and strength

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Figure 3. nants of bone mass. In a small study

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Figure 4. not lead to a reduction in sclerostin

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Figure 7. pocalcemia has been reported in

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Figure 8. The lumbar spine and femoral

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E. Bone deformity sociated with hormonal complications such as hypogo-

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Figure 9. continuation of treatment (216).

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Figure 10. with thalassemia must therefore in-

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C. Sex steroid therapy

Table 2. Summary of Randomized Control Studies of Bisphosphonates in Thalassemia Published to Date

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VIII. Perspectives and Conclusion

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144. Karimi M, Habibzadeh F, De Sanctis V. Hypoparathyroid- of vitamin D deficiency in transfusion-dependent thalas-

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