Treatment options for thalassemia patients with osteoporosis

A N N A L S O F T H E N E W Y O R K A C A D E M Y O F S C I E N C E SIssue: Cooley’s Anemia: Ninth Symposium Treatment options for thalassemia patients with
osteoporosis
Evangelos Terpos1 and Ersi Voskaridou21Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece. 2Thalassemia Center, LaikonGeneral Hospital, Athens, Greece Address for correspondence: Evangelos Terpos, Department of Clinical Therapeutics, University of Athens School ofMedicine, Alexandra General Hospital, 80 Vas. Sofias Avenue, 11528 Athens, Greece. eterpos@hotmail.com Osteoporosis represents a prominent cause of morbidity in patients with thalassemia. The delay in sexual maturation,
the presence of diabetes and hypothyroidism, the parathyroid gland dysfunction, the progressive marrow expansion,
the iron toxicity on osteoblasts, the iron chelators, and the deficiency of growth hormone or insulin growth factors
have been identified as major causes of osteoporosis in thalassemia. Adequate hormonal replacement, effective
iron chelation, improvement of hemoglobin levels, calcium and vitamin D administration, physical activity, and
smoking cessation are the main to-date measures for the management of the disease. During the last decade, novel
pathogenetic data suggest that the reduced osteoblastic activity, which is believed to be the basic mechanism of bone
loss in thalassemia, is accompanied by a comparable or even greater increase in bone resorption. Therefore, the
role of bisphosphonates, potent inhibitors of osteoclast activation, arises as a major factor in the management of
osteoporosis in thalassemia patients.
Keywords: thalassemia; osteoporosis; bisphosphonates; therapy; pathogenesis
Introduction
dysfunction, the accelerated hemopoiesis with pro-gressive marrow expansion, the direct iron toxicity Thalassemia major (TM) is a hereditary hemolytic on osteoblasts and the deficiency of growth hor- anemia caused by a defect in the ability of erythrob- mone (GH) or insulin growth factor I (IGF-I) have lasts to synthesize the ␤ chain of adult hemoglobin.
been indicated as possible causes for thalassemia- Several bone abnormalities are present in patients induced osteoporosis.1–3 Furthermore, iron chela- with TM, including the enlargement of the cranial tion has correlated with growth failure and bone and facial bones, spinal deformities, scoliosis, nerve abnormalities, and high desferrioxamine dosage has compression, spontaneous fractures, and bone loss.
been associated with cartilage alterations.4,5 More The incidence of osteopenia or osteoporosis in well- puzzling, however, is the observation that, despite treated TM patients has been found to be approx- the normalization of hemoglobin levels, adequate imately 40–50%, and therefore osteoporosis repre- hormone replacement, and effective iron chela- sents a prominent cause of morbidity in TM patients tion, patients continue to show an unbalanced bone of both genders.1 The pathogenesis of osteoporo- turnover with an increased resorptive phase result- sis in TM is very complicated and differs from the ing in seriously diminished bone mineral density pathogenesis of bone deformities characteristically found in nontransfused patients (thalassemia inter-media; TI), who develop bone distortion mainly due Pathogenesis of osteoporosis in
to accelerated hemopoiesis and progressive marrow thalassemia
expansion. Several genetic and acquired factors areimplicated in bone destruction in TM. The typi- According to the Word Health Organization, os- cal delay in sexual maturation, the presence of di- teoporosis is a disease characterized by low bone abetes and hypothyroidism, the parathyroid gland mass and microarchitectural deterioration of bone Ann. N.Y. Acad. Sci. 1202 (2010) 237–243 c 2010 New York Academy of Sciences.
tissue, leading to enhanced bone fragility and a are needed to exact final conclusion for the associa- consequential increase in fracture risk.8 The cut-off tion between gene polymorphisms and bone mass in of 2.5 standard deviations below the normal mean TM patients, COLIA 1 gene polymorphisms seem to in BMD for the respective age is used for the defini- be of importance in the pathogenesis of thalassemia- tion of osteoporosis, whereas the decrease of BMD between 1.5 and 2.5 standard deviations below thenormal mean for the respective age is defined as osteopenia.9 The most important factors that are Endocrine complications. Hypothyroidism, hy-
implicated in the pathogenesis of bone loss in tha- poparathyroidism, diabetes mellitus, and mainly lassemia patients are described later.
hypogonadism (as delayed puberty and/or sec-ondary hypogonadism) are considered as ma- jor causes of osteopenia/osteoporosis in TM.1–3,5 Genetic factors seem to play a role in the develop- Hemosiderosis of the pituitary gonadotrophic cells ment of low bone mass and osteoporotic fractures.
and iron deposition in the testes and ovaries are in- These factors have been implicated in the pathogen- volved in the pathogenesis of endocrine complica- esis of postmenopausal osteoporosis, as regulator tions in TM.14 Hypogonadism is a well-recognized genes of BMD, but have not been studied thor- cause of osteoporosis and osteopenia not only in oughly in thalassemia-induced osteoporosis. The patients with TM but also in the general population polymorphism at the Sp1 site of the collagen type Ia1 and is characterized by high bone turnover with (COLIA 1) gene (collagen type I is the major bone enhanced resorptive phase.15 Estrogen and proges- matrix protein) was studied by Wonke and col- terone appear to inhibit osteoclast activity and pro- leagues,10 who found that approximately 30% of the mote bone formation, whereas testosterone has a TM patients were heterozygotes (Ss) and 4% were direct stimulatory effect on osteoblast proliferation homozygotes (SS) for the Sp1 polymorphism. The and differentiation.3 IGFs play also an important authors have concluded that male patients with TM role in bone remodeling. Low-serum IGF levels de- carrying the Sp1 mutation may develop severe os- crease osteoblast proliferation and bone matrix for- teoporosis of the spine and the hip more frequently mation and reduce the activation of osteoclasts.16 than patients who do not carry this mutation. The Several studies have demonstrated a positive corre- COLIA 1 polymorphism has been associated with lation between the BMD of the lumbar spine and the reduced BMD in postmenopausal osteoporosis, and IGF-I concentration.17 It is well documented that predisposes women to osteoporotic fractures.11 The the GH–IGF axis is defective in TM. Thalassemia genes encoding collagen types Ia1 and Ia2 (COLIA patients have significantly lower circulating levels 1 and COLIA 2, respectively) are also important of IGF-I and the corresponding binding protein candidates for the genetic regulation of BMD, as (IGFBP-III) than normal individuals; thus, leading mutations that affect the coding regimens of these to increased bone resorption, decreased bone for- genes are implicated in the pathogenesis of osteo- mation, and finally to bone loss.18,19 genesis imperfecta and osteoarthritis.12 The studyof COLIA 1 polymorphism may help in identify- Iron overload and desferrioxamine. Iron deposi-
ing thalassemia patients who are at higher risk to tion in the bone impairs osteoid maturation and develop osteoporosis and pathologic fractures.13 inhibits mineralization locally, resulting in focal os- Other genetic factors that have been reported to teomalakia. The mechanism by which iron overload correlate with bone mineral damage in adult pa- interferes in osteoid maturation and mineralization tients with ␤-thalassemia include the vitamin D includes the incorporation of iron into crystals of receptor (VDR) Bsml BB polymorphism, the loss- calcium hydroxyapatite, which consequently affects of-function mutations in the gene of the vitamin the growth of hydroxyapatite crystals and reduces D receptor, the sequence variation of 713-8delC of the bone metabolism unit tensile strength.20 Fur- transforming growth factor-␤1, the presence of re- thermore, desferrioxamine inhibits DNA synthesis, striction fragment length polymorphisms for the osteoblast, and fibroblast proliferation, osteoblast calcitonin (CT) receptor gene, estrogen receptor and precursors differentiation, and collagen formation, interleukin-6 gene loci.1,13 Although further studies although enhances osteoblast apoptosis, especially Ann. N.Y. Acad. Sci. 1202 (2010) 237–243 c 2010 New York Academy of Sciences.
in patients who receive inappropriately high doses function.26 The RANK/RANKL/OPG pathway is of great importance for the activation and prolifera-tion of osteoclast precursors. We and others have Bone marrow expansion. Bone marrow expan-
shown that the ratio of sRANKL/OPG in the serum sion, which is a typical finding in patients with was increased in thalassemia patients with osteope- TM, has been considered as a major cause of bone nia/osteoporosis, providing evidence for the role of destruction.20 Transferrin receptor studies have RANKL/OPG system in the pathogenesis of osteo- demonstrated increased bone marrow activity even porosis in thalassemia.26–28 Serum levels of IL-1␣, in patients with low reticulocyte count or marrow TNF-␣, IL-6, and TGF-␤, that are able to increase hypoplasia.22 However, there was found no direct osteoclast function, were elevated in TM and cor- correlation between serum levels of soluble trans- related with bone resorption and lumbar BMD,29 ferrin receptor and the severity of osteoporosis.10 suggesting their involvement in the pathogenesis of Vitamin deficiencies. Vitamin C deficiency in iron-
TM osteoporosis and supporting the role of the im- overload patients with low levels of serum ascorbic acid induces the risk of osteoporotic fractures.23 Vi-tamin D deficiency is also implicated in the patho- Reduced osteoblast function in thalassemic pa-
genesis of osteoporosis in TM patients due to the tients with osteoporosis. There is evidence of re-
regulatory effect of vitamin D in both osteoclasts duced osteoblast function in TM. Histomorphom- and osteoblasts. Adequate calcium intake and small etry studies have revealed that increased osteoid amounts of vitamin D administration during skele- thickness, increased osteoid maturation and min- ton development can increase bone mass in adoles- eralization lag time, which indicate impaired bone cents and decrease bone loss in adult life. However, matrix maturation, and defective mineralization is most studies have failed to show reduced serum lev- present in children and adolescents with TM.20 In els of 25-hydroxyvitamin D in TM patients.
addition, iron deposits appeared along mineral-ization fronts and osteoid surfaces, whereas focal Physical activity. Patients with TM have reduced
thickened osteoid seams were found together with physical activity due to the complications of the focal iron deposits.20,30 Finally, dynamic bone for- disease and the overprotection by their parents who mation histomorphometry studies established re- do not encourage muscle activity. Thus, the lack of duced bone formation rate in TM patients.20 This physical activity is another predisposing factor for reduced bone formation is thought to-date to be osteoporosis in TM patients and muscle activity has mainly the result of iron poisoning in osteoblasts and/or the result of reduced function of GH These factors can lead to the destruction of bone and IGF-1 axis in TM patients.1 However, novel in thalassemia patients by increasing the osteoclast molecules seem to be implicated in osteoblast dys- function and/or reducing the osteoblast activity.
function in TM. Dickkopf-1 (Dkk-1) is a Wnt sig- Increased osteoclast function in thalassemic pa-
naling inhibitor, which inhibits the osteoblast differ- tients with osteoporosis. During the last decade,
entiation and function. We have recently shown that there was sufficient data supporting that increased serum levels of Dkk-1 were increased in TM patients osteoclast activation is present in TM patients.
with osteoporosis and correlated with lumbar spine Patients with TM and osteoporosis have elevated and wrist BMD. Interestingly, when zoledronic acid markers of bone resorption, such as N-terminal (ZA) was given in these patients there was a reduc- cross-linking telopeptide of collagen type-I (NTX) tion in Dkk-1 levels, which was not observed in the and tartrate-resistant acid phosphatase type 5b placebo group of this randomized trial.31 (TRACP-5b)24,25 that correlated with BMD of the Management of thalassemia-associated
lumbar spine in these patients.25,26 This increased osteoporosis
osteoclast activity seems to be at least partially dueto an imbalance in the receptor–activator of nuclear Prevention and general principles. Prevention
factor-kappa B ligand (RANKL)/osteoprotegerin and treatment of early bone loss make the best pol- (OPG) system and the overproduction of cytokines icy. Annual checking of BMD starting in adoles- that are involved in the osteoclast differentiation and cence is considered indispensable. Physical activity Ann. N.Y. Acad. Sci. 1202 (2010) 237–243 c 2010 New York Academy of Sciences.
must always be encouraged. Moderate and high Bisphosphonates. The increased bone resorption
impact activities are to be supported. Exercise has observed in patients with thalassemia-induced os- additional benefits: it improves cardiovascular sys- teoporosis has led to the use of bisphosphonates in tem, reduces the risk of diabetes, and prevents de- the management of osteoporosis in this cohort of pression. Smoking should be discouraged. Adequate patients. Bisphosphonates are potent inhibitors of calcium intake during skeleton development can osteoclastic bone resorption. They act by inhibiting increase bone mass in adult life and in combina- osteoclastic recruitment and maturation, prevent- tion with administration of low doses of vitamin ing the development of monocyte precursors into D may prevent bone loss and fractures.32 Early di- osteoclasts, inducing osteoclast apoptosis and inter- agnosis and treatment of diabetes mellitus is also rupting their attachment to the bone. In thalassemia important, as the association between diabetes and osteoporosis, almost all generations of bisphospho- low bone mass in TM patients has been well docu- nates have been used in an attempt to increase the mented.1 Furthermore, adequate iron chelation may BMD and improve the abnormal bone remodeling.
prevent iron toxicity in the bone and sufficient blood Morabito and colleagues scheduled a randomized, transfusions may inhibit uncontrolled bone marrow placebo-controlled study to investigate the effects of 2 years daily oral administration of alendronateor intramascular administration of clodronate on Hormonal replacement. Prevention of hypogo-
BMD, bone turnover markers, safety, and tolera- nadism seems to be the most effective way for pre- bility in 25 thalassemia patients with osteoporo- venting osteoporosis and other bone deformities sis.37 Patients were randomized to receive placebo in thalassemia patients.1–3,5,32 Anapliotou and col- (eight patients) or 100 mg of clodronate, i.m., every leagues recommended that continuous hormonal 10 days (eight patients) or 10 mg of alendronate per replacement therapy with transdermal estrogen for os daily (nine patients). All patients also received females or human chorionic gonadotrophin for 500 mg of elemental calcium and 400 IU cholecal- males improves bone density parameters.33 How- ciferol daily. After 2 years of follow-up, the lumbar ever, despite hormonal replacement, calcium and spine and femoral neck BMD had decreased signif- vitamin D administration, effective iron chelation, icantly in the placebo group. Clodronate reduced and normalization of hemoglobin levels, patients bone resorption markers, deoxypyrydinoline, and with TM continue to lose bone mass.6,7 pyrydinoline, and inhibited bone loss but it was un- Calcitonin. Canatan and colleagues have evaluated
able to increase BMD at all studied sites. Daily treat- the effect of calcitonin (CT), a potent inhibitor of ment with alendronate normalized the rate of bone osteoclasts, on bone mass in 14 patients with TM.
turnover, and resulted in a rise in BMD of the spine One hundred IU of CT were administered, three and the hip. This increment was statistically signif- times a week, for 1 year in combination with daily icant at the femoral neck, whereas at the lumbar administration of 250 mg of calcium. At the end spine the gain was less marked. Alendronate caused of treatment period, bone pain had disappeared, few adverse effects, including upper gastrointestinal radiological findings of osteoporosis had been im- symptoms, but no patient discontinued the study.37 proved, and the number of fractures had been de- The ineffectiveness of clodronate was established in creased in the treatment group but not in controls.
another randomized, placebo-controlled trial.38 CT had no important side effects.34 Both parenteral Pamidronate, a second-generation aminobispho- and intranasal instillations are available.
sphonate, has been given intravenously in patientswith TM and osteoporosis. First, Wonke evalu- Hydroxyurea. Ten patients with TM were given hy-
ated the effect of 15 mg of pamidronate on BMD.
droxyurea (HU), at a dose of 1.5 g p.o. daily, in an Pamidronate was given in a 40 min infusion, at attempt to reduce marrow hyperplasia diagnosed by monthly intervals. A significant improvement in MRI. HU improved bone pain and MRI findings.35 BMD was observed in most patients.10 Our group However, in another study, the administration of compared the effects of two different doses of HU for at least 2 years did not manage to show any pamidronate, 30 mg versus 60 mg, on BMD of the improvement of the BMD compared with patients lumbar spine, femoral neck, and forearm and on markers of bone remodeling and osteoclast function Ann. N.Y. Acad. Sci. 1202 (2010) 237–243 c 2010 New York Academy of Sciences.
in 26 patients with thalassemia and osteoporosis.
groups A and B and for 12 months for group C (pa- Thirteen patients with TM and five patients with TI tients of group C received ZA, 4 mg every 3 months, were given pamidronate at a dose of 30 mg in a 2 h i.v.
i.v., for 12 months after their placebo 12-month ad- infusion, once a month for 12 months; another eight ministration). We found, interestingly, that at the patients (four with TM and four with TI) received 36th month, patients of group B continued to show a dose of 60 mg/month, in an attempt to explore an increase in the BMD of all studied sites despite whether increasing the dose of pamidronate might the discontinuation of ZA. Furthermore, patients of have any additional effect. Both groups included pa- groups A and C showed a dramatic increase in BMD tients with comparable degrees of osteoporosis and of all studied sites compared with baseline values (P hypogonadism. All patients were also receiving cal- < 0.01) The increase of BMD observed in groups A cium and vitamin D supplement prior and during and C was accompanied by a comparable reduction the 12-month follow-up period of the study. Ad- in bone resorption marker CTX at the 36th month, ministration of 30 mg of pamidronate resulted in a which had not reported at the 12th month; on the significant increase of the BMD of the lumbar spine contrary in group C there was an increase in CTX in all patients, but not the BMD of the femoral neck at the 12th month. These observations suggest that and the forearm. The 60 mg of pamidronate group ZA continues to act after its discontinuation.39 showed a similarly significant increase in the BMD In another recent study, we confirmed that the of the lumbar spine in both transfusion-dependent increase of erythropoietic activity in TI, which con- and transfusion-independent patients. Administra- tinues irrespectively of the improvement of BMD tion of both doses of pamidronate was also followed produced by ZA, seems to be a major cause of bone by a clear decrease of markers of bone resorption loss in this hemoglobinopathy. Soluble transferrin (NTX and TRACP-5b), OPG, and osteocalcin that receptor (sTfR) and erythropoietin (Epo) serum was similar in patients of both treatment groups.
levels are increased in TI but we showed for the first Furthermore, most patients complaining for severe time in the literature that this elevation was further bone pain at the onset of the study had a significant increased by time, although BMD was improved by reduction of pain after treatment period. No severe adverse-events were reported in this study.25 All described studies confirm the effectiveness of Zoledronic acid is the most potent third genera- bisphosphonates in the treatment of thalassemia- tion bisphosphonate to-date and has been found to induced osteoporosis. Alendronate, pamidronate, be extremely efficacious in increasing BMD in TM and ZA seem to have the greater efficacy. How- patients. We reported the results of a randomized, ever, more trials must be conducted to clarify the placebo-controlled trial of ZA in 66 thalassemia exact role of each biphosphonate, the long-term patients with osteoporosis. The patients were ran- benefit and side effects as well as the effects of domized to receive 4 mg ZA intravenously every the combination of bisphosphonates with other ef- fective agents, such as hormonal replacement, in 3 months (21 patients; group B), or to receive placebo every 3 months (22 patients; group C), for Conclusion and future perspectives
a period of 1 year. Patients of group B had a sig-nificant increase in their lumbar spine BMD, which Thalassemia-associated osteoporosis is multifacto- was accompanied by dramatic reductions in bone rial and, therefore, very difficult in its management.
pain, and bone markers. Patients in placebo group Osteoporosis is a progressive disease; thus, preven- showed no alteration in BMD of any studied site tion and early diagnosis are very important. Ade- or in bone pain scores; on the contrary, they had quate hormonal replacement, effective iron chela- an aggravation in bone resorption. Therefore, this tion, improvement of hemoglobin levels, calcium study confirmed that ZA is an effective treatment and vitamin D administration, physical activity, for increasing BMD and reducing bone resorption and smoking cessation are the main to-date mea- in thalassemia-induced osteoporosis with no serious sures for the management of the disease. However, side effects.28 As the duration of ZA therapy had not novel pathogenetic data suggest that the reduced been evaluated in any trial, we followed-up our pa- osteoblastic activity, which is believed to be the ba- tients for 24 months after discontinuation of ZA for sic mechanism of bone loss in TM, is accompanied Ann. N.Y. Acad. Sci. 1202 (2010) 237–243 c 2010 New York Academy of Sciences.
by a comparable or even greater increase in bone What are the criteria by which a densitometric diagnosis resorption. Therefore, the role of bisphosphonates of osteoporosis can be made in males and non-Caucasians? arises as major in the management of osteoporo- J. Clin. Densitom. 5(Suppl.): 19–27.
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