Bone disease and skeletal complications in patients with β thalassemia major

Bone 48 (2011) 425–432

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Bone j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / b o n e

Review

Bone disease and skeletal complications in patients with β thalassemia major Rachid Haidar a,⁎, Khaled M. Musallam b, Ali T. Taher b a b

Division of Orthopedic Surgery, Department of Surgery, American University of Beirut Medical Center, Beirut, Lebanon Division of Hematology & Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon

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a b s t r a c t Increased survival in patients with β thalassemia major (TM) allowed for several complications of the disease and its treatment to manifest, one of which is bone disease. Osteoporosis in this patient population results from a variety of genetic and acquired factors. Early diagnosis and prevention are essential and several measures have been evaluated for management including bisphosphonates. Fracture prevalence in TM patients seems to be clustered in mid adulthood, and is related to vitamin D deficiency and low bone mineral density. Fracture healing in patients with TM does not seem to be different from that in normal individuals. Bone and joint pain are a common manifestation of the underlying pathophysiology or may be related to iron chelator intake. Intervertebral disc changes are seen in patients who are heavily iron overloaded or those who are chelated with deferoxamine. Spinal deformity is common in TM, yet the prognosis is benign with spontaneous resolution frequently observed. Further research is warranted to evaluate the mechanisms, clinical implications, and optimal management of bone disease in this patient population. © 2010 Elsevier Inc. All rights reserved.

Article history: Received 4 May 2010 Revised 7 September 2010 Accepted 20 October 2010 Available online 28 October 2010 Edited by: Felicia Cosman Keywords: Bone Thalassemia major Osteoporosis Fractures Spine

Contents Introduction . . . . . . . . . . . Osteopenia and osteoporosis . . . Pathogenesis . . . . . . . . . Management . . . . . . . . . Fractures . . . . . . . . . . . . Pain . . . . . . . . . . . . . . . Intervertebral disc changes . . . . Spinal deformity . . . . . . . . . Summary and concluding remarks Conflict of interest . . . . . . . . References . . . . . . . . . . . .

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Introduction The thalassemias, a group of inherited disorders of hemoglobin synthesis, are the most common monogenetic disease worldwide [1]. In β thalassemia, mutations of the β globin gene lead to various degrees of defective β chain production, an imbalance in globin chain synthesis, ineffective erythropoiesis, and a spectrum of anemia [1]. β thalassemia major (TM) refers to those patients whose clinical course ⁎ Corresponding author. Clinical Orthopedic Surgery, Division of Orthopedic Surgery, Department of Surgery, American University of Beirut Medical Center, P.O. Box 11-0236, Riad El Solh 1107 2020, Beirut, Lebanon. Fax: + 961 1 366384. E-mail address: [email protected] (R. Haidar). 8756-3282/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.bone.2010.10.173

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is characterized by profound anemia, who present to medical attention in the first year of life, and who subsequently require regular blood transfusions for survival [1]. Repeated blood transfusions, however, do not come without their own side effect as iron overload inevitably manifests resulting in multiple organ damage, notably the heart, liver, and endocrine glands [2]. Iron chelation therapy is attained by the use of subcutaneous deferoxamine pumps; or more recently, through the use of the oral iron chelators deferiprone and deferasirox [3,4]. The introduction of safe blood transfusion practices and iron chelation therapy surely translated into prolonged survival and enhanced quality of life for patients with TM [5]. The increased life span in these patients, however, allowed for several morbidities of the disease and its treatment to unfold,

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amongst which is bone disease. In fact, skeletal complications in patients with TM were noted when the disease was first described. Cooley described peculiar bone changes with mongoloid appearance caused by the enlargement of the cranial and facial bones [6]. Today, a great deal of knowledge has been attained on the imbalance in bone remodeling in patients with TM [7]. A spectrum of bone abnormalities including osteopenia/osteoporosis, pain, fractures, and spinal complications continue to be observed. We herein present a comprehensive overview of bone disease in patients with TM aiming to orient the practitioner from various medical and surgical disciplines to this potentially disabling complication. Osteopenia and osteoporosis Osteopenia and osteoporosis represent prominent causes of morbidity in children and adults of both genders with TM [8–13]. Despite normalization of hemoglobin levels, adequate hormone replacement, and effective iron chelation therapy patients continue to show an unbalanced bone turnover with an increased resorptive phase resulting in seriously diminished bone mineral density (BMD) [14–16]. In well treated TM patients, the reported frequency of osteoporosis is approximately 40–50% [12,17–19]. Of note, recent evidence indicates that individual values of BMD measured by traditional Dual energy X-ray absorptiometry (DEXA) are lower than those determined by quantitative computed tomography in TM patients. Thus, the prevalence of bone demineralization in TM appears to be frankly lower in studies performed with quantitative computed tomography. The reason for this discrepancy is still a matter of debate; likewise, which technique is superior in determining the overall vertebral strength in this clinical condition remains to be evaluated [20,21]. Pathogenesis Several genetic factors have been implicated in the pathogenesis of thalassemia-induced osteoporosis. The polymorphism at the Sp1 site of the collagen type Ia1 (COLIA 1) gene has been associated with severe osteoporosis and pathologic fractures of the spine and the hip in TM patients both in the heterozygote and homozygote states [22–25]. The vitamin D receptor (VDR) BsmI and FokI polymorphisms were found to constitute a risk factor for bone mineral damage, low BMD, and short stature in prepubertal and pubertal patients with TM [26,27]. Acquired factors include the primary disease itself causing ineffective hematopoiesis with progressive marrow expansion, and several secondary factors such as delay in sexual maturation, presence of diabetes and hypothyroidism, parathyroid gland dysfunction, deficiency of growth hormone (GH) or insulin growth factor I (IGF-I), direct iron toxicity on osteoblasts, deferoxamine toxicity, calcium, zinc and vitamin D deficiencies, and inadequate physical activity (Table 1) [12,18,22,28–50]. Most acquired factors act mainly through the inhibition of osteoblastic activity. Histomorphometry studies have revealed that increased osteoid thickness, increased osteoid maturation and mineralization lag time, and defective mineralization are present in children and adolescents with TM [50]. In addition, iron deposits appeared along mineralization fronts and osteoid surfaces, whereas focal thickened osteoid seams were found together with focal iron deposits [50,51]. Dynamic bone formation histomorphometry studies have also established reduced bone formation rate in TM patients [50]. This reduced bone formation is thought to-date to be mainly the result of iron poisoning in osteoblasts and/or the result of reduced function of GH and IGF-1 axis in TM patients [52]. Morabito et al. [53] have shown decreased levels of serum osteocalcin, a protein produced by osteoblasts, in patients with TM. However, other studies failed to confirm such an association [54]. More recently, Voskaridou et al. found increased serum levels of Dickkopf-1, a soluble inhibitor of

Table 1 Acquired factors involved in the pathogenesis of osteoporosis in thalassemia major. Factor

Effects

• Marrow expansion causes mechanical interruption of bone formation, leading to cortical thinning, increased distortion and fragility of the bones. Endocrine complications⁎ • Low estrogen and progesterone levels lead to a decrease in inhibition of osteoclast activity and bone formation. • Low testosterone levels lead to a decrease in its direct stimulatory effects on osteoblast proliferation and differentiation. • Defective GH–IGF axis leads to low IGF-I and the corresponding binding protein (IGFBP-III) levels and subsequent decrease in osteoblast proliferation and bone matrix formation and increase in activation of osteoclasts leading to bone loss. Iron overload and iron chelation • Iron deposition in bone impairs osteoid therapy (deferoxamine) maturation and inhibits mineralization locally, resulting in focal osteomalacia. • Incorporation of iron into crystals of calcium hydroxyapatite, affecting the growth of hydroxyapatite crystals and reducing the bone metabolism unit tensile strength. • Deferoxamine inhibits DNA synthesis, osteoblast and fibroblast proliferation, osteoblast precursors differentiation, and collagen formation • Deferoxamine enhances osteoblast apoptosis, especially in patients who receive inappropriately high doses. Vitamin deficiencies • Vitamin C deficiency in iron overloaded induces the risk of osteoporotic fractures. • Vitamin D deficiency affects the regulatory effect of vitamin D on both osteoclasts and osteoblasts. Decreased physical activity • Reduced physical activity due to the complications of the disease and the overprotection by their parents who do not encourage muscle activity. • Leads to destruction of bone by increasing the osteoclast function and/or reducing the osteoblast activity. Ineffective erythropoiesis and bone marrow expansion

GH = growth hormone; IGF = insulin growth factor; DNA = deoxyribonucleic acid. ⁎ Hypothyroidism, hypoparathyroidism, diabetes mellitus, and mainly hypogonadism secondary to hemosiderosis of the pituitary gonadotrophic cells and iron deposition in the testes and ovaries.

osteoblast differentiation, in TM patients that correlated with reduced BMD of the lumbar spine and the distal radius. High Dickkopf-1 also correlated with increased bone resorption and reduced bone formation markers [55]. Although osteoblast dysfunction is thought to be the major pathogenetic mechanism for osteoporosis in TM, there is also evidence of increased osteoclast activation in these patients. Patients with TM and osteoporosis have elevated markers of bone resorption, such as urinary levels of N-telopeptides of collagen type I (NTX), which is a specific marker of bone resorption, and increased serum levels of tartrate resistant acid phosphatase isoform 5b (TRACP-5b), an enzyme that is produced only by activated osteoclasts [27,56–58]. Both NTX and TRACP-5b levels correlated with BMD of the lumbar spine in these patients [27,57–59]. Pyridinoline and deoxypyridinoline, other markers of bone resorption, were also found to be increased in patients with TM and osteoporosis compared with normal controls [53,54,58,60]. An increase of circulating pro-osteoclastogenic cytokines (IL-1α, IL-6, TNF-α) and their associations with several markers of impaired bone turnover has also been documented in TM patients [61]. The receptor activator of the nuclear factor-kappa B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) pathway has been recently recognized as the final, dominant mediator of osteoclast proliferation and activation [62–64]. Mice that lack either RANKL or RANK or that

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over-express OPG develop osteopetrosis because of decreased osteoclast activity. Conversely, OPG knockout mice are osteoporotic, develop multiple fractures and have decreased trabecular bone volume and numerous osteoclasts, since OPG cannot inhibit RANKL activity [62–64]. Thus, it is the balance between the expression of RANKL and OPG that determines the extent of bone resorption, and hence, the ratio of RANKL to OPG regulates the formation and activity of osteoclasts. The ratio of RANKL/OPG was increased in TM patients compared to controls [53,57–59,61,65]. This explained the uncoupling on bone turnover observed in TM patients. A negative correlation was found between RANKL and free testosterone in male TM patients and with 17-β estradiol in female TM patients, which suggests that the RANKL/OPG system may be involved in mediating the action of sex steroids on bone [53]. Furthermore, a correlation between the RANKL/ OPG ratio and erythropoietin levels was also documented, which represents a mechanism through which anemia, by continuously stimulating the erythropoietin synthesis and determining bone marrow hyperplasia, may increase bone resorption through enhanced RANKL levels [53]. A recent study, however, failed to confirm these findings [44]. All these data support the complex pathogenesis of osteoporosis in TM and reflect the difficulties in the management of this complication of TM. Fig. 1 summarizes systemic and local factors that may be involved in abnormal bone remodeling in patients with TM. Management The lack of early diagnosis and intervention leads to common occurrences such as pain, fractures, and spinal deformities [18]. As such, early detection, prevention and treatment are essential for effective control of this potentially debilitating morbidity in TM. Annual follow-up of BMD, starting in adolescence, is considered crucial. Physical activity must always be encouraged, wherein moderate and high impact activities are to be supported. Smoking should be discouraged. Adequate calcium (500 mg–1 g/day orally) and zinc intake during skeletal development can increase bone mass

Fig. 1. Factors involved in regulation of bone remodeling that may be altered in patients with thalassemia major leading to decreased osteoblasts and/or increased osteoclasts activity (PTH= parathyroid hormone; T4 =thyroxine; PDGF =platelet-derived growth factor; BMPs=bone morphogenetic proteins; FGFs=fibroblast growth factors, IGFs=insulin-like growth factors; TGF-β=transforming growth factor-beta; IL=interleukin; M-CSF=macrophage colony-stimulating factor; RANKL=receptor activator of nuclear factor-kappa B ligand; OPG=osteoprotegerin; IFN=interferon).

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in adult life and, in combination with the administration of low doses of vitamin D (1000–1500 IU/day orally), may prevent bone loss and fractures [14,66,67]. Furthermore, adequate iron chelation may prevent iron toxicity in the bone and sufficient blood transfusions may inhibit uncontrolled bone marrow expansion. Since an association between deferoxamine therapy and bone disease has been observed, the more novel oral iron chelators may be an alternative. Prevention of hypogonadism seems to be the most effective way for preventing osteoporosis and other bone deformities in TM patients [12,66]. Continuous hormonal replacement therapy with transdermal estrogen for females or human chorionic gonadotrophin for males improves bone density parameters [32]; although some studies failed to document such benefit and sideeffects of hormone replacement therapy remain a concern [15]. However, despite the aforementioned measures patients with TM still continue to lose bone mass [14,15]. Calcitonin, a potent inhibitor of osteoclasts, was found to decrease bone pain, radiological findings of osteoporosis, and the number of fractures in TM patients [68]. In thalassemia-induced osteoporosis, almost all generations of bisphosphonates have been used in an attempt to increase the BMD and improve the abnormal bone remodeling. Clodronate reduced bone resorption markers, deoxypyridinoline and pyridinoline, and inhibited bone loss but it was unable to increase BMD at all studied sites [69,70]. Daily treatment with alendronate normalized the rate of bone turnover, and resulted in a rise in BMD of the spine and the hip. This increment was statistically significant at the femoral neck, whereas at the lumbar spine the gain was less marked [69]. Pamidronate, a second generation aminobisphosphonate, has been given intravenously in patients with TM and osteoporosis. A significant improvement in BMD was observed in most patients [39]. Administration of 30 to 60 mg of pamidronate resulted in a significant increase of the BMD of the lumbar spine in all patients, but not the BMD of the femoral neck and the forearm. Administration was also followed by a clear decrease in the markers of bone resorption (NTX, and TRACP-5b), OPG, and osteocalcin. Furthermore, most patients who complained of severe bone pain had a significant reduction of pain after treatment period. No severe adverse-events were reported [57]. Zoledronic acid, the most potent third generation bisphosphonate to-date, was evaluated in TM patients at a dose of 1 mg intravenously every 3 months over a 12month period. Administration of zoledronic acid was followed by a clear increase in the BMD of the lumbar spine, as well as by a significant decrease in IGF-1, NTX, and osteocalcin, and a significant increase in OPG serum levels. No treatment-related side-effects were observed; however, the risk of hypocalcemia that may be associated with intravenous zoledronic acid administration remains a concern in the TM patient with coexisting hypoparathyroidism [71,72]. The efficacy and safety of zoledronic acid, 4 mg intravenously every 3 months, was also assessed in a phase II trial on 18 TM patients with osteoporosis over a period of 12 months. Patients taking zoledronic acid had a significant increase in their lumbar spine, femoral neck, trochanter, and total hip BMD measurements over the 12-month period. There was a significant change in the levels of osteocalcin and bone alkaline phosphatase over the 12-month follow-up period. There was also a significant decrease in the number of painful sites experienced by the patients. Treatment was also well-tolerated [73]. The same authors found no association between VDR polymorphisms and response to treatment [74]. Two randomized, double-blind, placebo-controlled trials confirmed the efficacy and safety of zoledronic acid in this setting for up to two years of treatment [75–77]. Zoledronic acid resulted in a significant increase the lumbar spine BMD, dramatic reductions in bone pain, markers of bone resorption, and Dickkopf-1 [55,75–77]. A recent meta-analysis found that zoledronic acid (4 mg given every 3 months) improves the baseline BMD in TM patients by 0.69 standard deviations—an effect that was more pronounced when BMD was measured at the lumbar

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spine [78]. However, evidence-based guidelines on the use of bisphosphonates in the management of TM-induced osteoporosis are lacking. Most of the above trials included heterogenous or small groups of patients; thus, larger prospective studies are warranted before true benefit is established and wide use is recommended. More importantly, although some studies observed improvement in BMD, markers of bone resorption, or the rate of pain episodes with the use of bisphosphonates, the effect on decreasing fracture rate has not been evaluated and long-term studies are thus called for. Lastly, reports have shown that bone marrow transplantation, the only curative treatment for patients with TM, is associated with reversal of metabolic bone disease in TM patients, as evaluated by DEXA, serum concentrations of osteocalcin, bone-specific alkaline phosphatase, and urinary deoxypyridinoline [79].

Fractures Fracture prevalence in iron-overloaded patients with TM ranged between 38% and 41% in two large studies in the US where selfreporting methodology was used [80–82]. Over half of the reported fractures were from a fall, whereas less than a quarter occurred during recreational activities. This was attributed to the fact that severe anemia leads to decreased physical activity and fewer opportunities for recreational fractures. The most frequently reported fracture site was the upper extremity, whereas a much smaller percentage of all fractures (10%) was reported in the spine, hip and pelvis [81]. In one study, the majority of TM patients suffered at least one iron overload-related endocrinopathy, which was highly related to the prevalence of fracture [81]. In another, fracture prevalence was related to low bone mass and sex hormone replacement therapy, but not to the presence of other endocrinopathies [80,82]. Patients with TM were more likely to have multiple fractures and the strongest determinant of a new fracture was a previous fracture [81]. Moreover, male subjects with TM seemed to fracture more than females, especially as they were more likely to be hypogonadal [81,83]. The peak age of fracture was in the mid to late 30s. Interestingly, the percentage of subjects who remained fracture free by the age of 18 years was significantly higher than population estimates of healthy children without hemoglobinopathies [84]. There did not appear to be an increase in fracture prevalence during the adolescent growth spurt or surrounding the initiation of menstruation, as is typically observed in healthy reference cohorts. This may be attributed to the anemia which leads to decreased physical activity and fewer opportunities for recreational fractures, the decreased time available for sports and physical activity as these patients spend a significant amount of their time at health care centers, or overprotection from parents and care takers. In summary, these findings confirm that the epidemiology of fracture in TM remains unique, as it is not mainly correlated with risk taking behavior but is mainly due to vitamin D deficiency or low BMD which become more severe with age in this cohort of patients [81]. Estimates of time for fracture healing in TM patients have been controversial [9]. Some reports have showed slow bone healing in this patient population [85,86]. Scott et al. noted that prolonged time to bone union is seen after osteotomy in TM patients [86]. Dines et al. reported on 75 TM patients with 47 fractures in whom the hemoglobin was kept above 5.5 g/dl. Most of the fractures involved long bones. They found that casting combined with early ambulation, lead to slow healing, many deformities, and frequent refractures [85]. However, utilizing a similar management approach, Finserbush et al. reported that 30 TM patients' fractures healed within normal time limits [87]. Moreover, another report on 7 TM patients observed that 6 patients managed nonoperatively healed in the expected time. The only patient that had prolonged time to healing was found to be vitamin C deficient [9].

Pain Bone- and joint-related pains in thalassemic patients are common symptoms. In one study 30% of patients were found to suffer from arthralgia while 25% complained of low back pain [88]. Although arthralgia has been mainly attributed to iron overload or use of iron chelators [89,90], back pain is mainly associated with osteoporosis, compression fractures, and intervertebral disc degeneration [7,91]. In a recent study by the Thalassemia Clinical Research Network (TCRN) young adults with thalassemia experienced pain comparable to the general population, whereas older adults (aged 35+) experienced greater pain. There was an association of pain with low vitamin D level, and a trend toward increased pain with lower bone density and bisphosphonate use, suggestive of a possible relationship in a subset of patients. Patients with osteopenia and osteoporosis often complained of pain secondary to fractures, particularly back pain associated with compression fractures of the vertebrae [92]. Deferiprone was the first orally active iron chelator introduced for the management of iron overload in TM patients. Among its notable side-effects was arthropathy. The frequency of arthropathy varied greatly between studies, from as low as 4.5% at one year [93] to 15% after four years [90] in a predominantly European patient group, and as high as 33–40% in a study of patients in India [94]. It is not yet clear whether these differences reflect environmental or genetic differences, or differences in iron overload between populations at the start of treatment. Symptoms range from mild non-progressive arthropathy, typically in the knees, controllable with non-steroidal antiinflammatory drugs to (more rarely) severe erosive arthropathy that may progress even after treatment is stopped. Cases involving other joints, such as wrists, ankles and elbows, and hips, have also been described. Intervertebral disc changes Desigan et al. reviewed the appearances of the intervertebral discs in TM patients compared with age- and sex-matched controls, with both cohorts complaining mainly of back pain. A significant difference in disc degeneration severity has been shown between TM patients and controls on MRI and radiographs [91]. The pattern of disc degeneration was different in TM patients as they exhibited multilevel disease with all levels of the lumbar spine involved (Fig. 2). Findings of intranuclear gas and calcification within discs, platyspondyly, and endplate irregularity were more common in TM patients [91]. Although no clear mechanism has been suggested for the development of disc changes in TM patients, an underlying metabolic basis has been suggested. Degeneration of intervertebral discs results in part from weakening of the annulus fibrosus. The chelating agent deferoxamine commonly used in patients with TM has been proposed to deleteriously affect the integrity and strength of the annulus fibrosus fibers [91]. It has also been implicated in endplate deformation causing platyspondyly and osseous defects of ventral upper and lower edges of vertebrae, either by chelating other minerals or trace elements and thus interfering with enchondral ossification, or possibly, by direct toxicity [95–100]. In Desigan et al.'s study there was a trend within the case group toward lower disc degeneration severity scores in TM patients who did not receive deferoxamine [91]. Hartkamp et al., in their study of spinal deformities in deferoxamine-treated TM patients, described a tendency toward disc-space narrowing. The study also noted intervertebral disc calcification in two of 22 patients [98]. Alternatively, the injurious effect of iron overload is also postulated as a factor. Iron overload in TM causes tissue damage by free radical generation [101]. Free radical generation is recognized as a cause of arthropathy in joints from studies performed mainly on animal models, and may exacerbate disc degeneration [89]. The possibility of disc fluid and nutrition compromise by the vertebral

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Fig. 3. An anteroposterior roentgenogram of the spine of a 23-year-old woman with thalassemia major with right-sided lumbar scoliosis. With permission from reference [106].

Fig. 2. Sagittal (a) T1, and (b) T2-weighted magnetic resonance images through the lumbar spine of a 34-year-old female patient with thalassemia major showing changes of degenerative disc disease involving all lumbar discs; and sagittal (c) T1, and (d) T2-weighted magnetic resonance images from a corresponding age- and sex-matched control. With permission from reference [91].

changes of TM also needs to be considered as a possible reason for increased disc degeneration [91]. Lastly, Hall-Craggs et al. have described the use of ultrashort echo time (UTE) MRI in the assessment of the thalassemic spine. UTE MRI pulse sequences known to be sensitive to short T2 relaxation components such as iron deposition were utilized, and showed high signal intensity bands parallel to the vertebral end plates in the upper lumbar and lower thoracic spine, prominent in the most degenerate spine. The technique may indeed be a helpful contribution to the assessment of TM patients with back pain and in detecting early degenerative disease [102]. Spinal deformity An increased incidence of scoliosis associated with TM has been described since 20 years ago (Fig. 3) [103–106]. The authors demonstrated an increased prevalence of frontal curves of at least 5° in 67% of the patients with TM. However, scoliosis curvatures of more than 10° and less than 14° were observed in 21.7% of the examined patients [103–106]. It seemed that location, direction, and pattern of the curvatures, age of onset, gender, and rate of progression of this type of scoliosis associated with TM differed from those in patients with idiopathic scoliosis [103–106]. Papanastasiou et al. studied the natural history of untreated scoliosis associated with TM over a 10-year period [107]. The prevalence of frontal curves of at least 5° in 43 TM patients was approximately 80%. Scoliosis of at least 10°

and not more than 19° was revealed in 28% to 35% of patients. The most common scoliosis curve pattern was the S-shaped (right thoracic, left lumbar). The prevalence of scoliosis was not genderrelated, irrespective of age and curve magnitude. Progression of scoliosis in the 10-year period was only detected in four (12%) of 34 patients with scoliosis of 5° to 14°, a rate much lower than that reported in patients with idiopathic scoliosis. Only one patient (2.9%) developed scoliosis of 65° that progressed to 85°, and no other patient developed scoliosis curves that required bracing or operative treatment. No correlation was shown between scoliosis progression and any of growth potential, curve pattern, gender, or curve magnitude [107]. Progression was mainly attributed to anemia, hemosiderosis, iron chelation therapy, and associated hormonal disorders previously described in patients with TM [103–106]. Around 24% of curves showed spontaneous resolution, this was equally distributed among all but the right thoracic curve patterns. Left lumbar and thoracolumbar scoliosis improved at a rate of 22% and 33%, respectively. However, most of the curves showed a magnitude of less than 10°. This remarkable absence of progression and spontaneous resolution in small curves depicts the unique etiology of scoliosis in this hematologic condition. Of note, thoracic kyphosis increased with the age of the patients, whereas lumbar lordosis decreased with age and followed the changes of thoracic kyphosis. The ‘junction’ thoracolumbar kyphosis increased with the age of the patients but independently from thoracic kyphosis and lumbar lordosis. However, neither scoliosis magnitude nor progression was correlated to thoracic kyphosis [107]. Summary and concluding remarks Current evidence suggests that abnormalities of bone remodeling in patients with TM are multifactorial, with several genetic and acquired factors so far identified. Osteoporosis is a progressive disease; thus prevention and early diagnosis are very important. Adequate hormonal replacement, effective blood transfusion and iron

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chelation, calcium and vitamin D administration, physical activity, and cessation of smoking, are currently the main measures for the management of the disease. Bisphosphonates seem to be valuable in the management of osteoporosis in TM. Zoledronic acid was effective in increasing the BMD without causing any severe side-effects in these patients; however, the long-term benefit especially on the rate of fractures requires evaluation. Moreover, unlike healthy individuals in whom fractures are common in adolescence with increased recreational activity, patients with TM experience fractures in adulthood, that are mainly attributed to vitamin D deficiency and low BMD. Although reports remain scarce, fracture healing in patients with TM does not seem to be different from that in normal individuals. Although bone pain has been designated as a manifestation of thalassemia-induced osteoporosis, joint pain is mainly observed in those patients treated with the oral chelator deferiprone. Intervertebral disc changes are seen in patients who are heavily iron overloaded or those who are chelated with deferoxamine. The newest iron chelator deferasirox is not known to have any skeletal adverse effects, and may thus provide a more suitable alternative in those patients suffering from bone disease. Finally, although spinal deformity is not uncommon in patients with TM, the prognosis seems favorable with many patients showing spontaneous resolution without the need for intervention. This diverse nature of bone disease in patients with TM highlights the importance of multidisciplinary care, involving a team of endocrinologists and orthopedists alongside the thalassemia specialists. Collaborative efforts should be made to control the associated physical and psychological morbidity, and to initiate prospective trials that evaluate the mechanisms, clinical implications, and optimal management of bone disease in this patient population. Conflict of interest None to disclose. This study did not receive external funding. References [1] Weatherall DJ, Clegg JB. The thalassaemia syndromes. 4th ed. Oxford: Malden, MA: Blackwell Science; 2001. [2] Taher AT, Musallam KM, Inati A. Iron overload: consequences, assessment, and monitoring. Hemoglobin 2009;33(Suppl 1):S46–57. [3] Cappellini MD, Musallam KM, Taher AT. Overview of iron chelation therapy with desferrioxamine and deferiprone. Hemoglobin 2009;33(Suppl 1):S58–69. [4] Cappellini MD, Taher A. Deferasirox (Exjade) for the treatment of iron overload. Acta Haematol 2009;122:165–73. [5] Borgna-Pignatti C, Rugolotto S, De Stefano P, Zhao H, Cappellini MD, Del Vecchio GC, Romeo MA, Forni GL, Gamberini MR, Ghilardi R, Piga A, Cnaan A. Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica 2004;89:1187–93. [6] Cooley TB, Witwer ER, Lee P. Anemia in children with splenomegaly and peculiar changes in the bones. Am J Dis Child 1927;34:347–63. [7] Voskaridou E, Terpos E. New insights into the pathophysiology and management of osteoporosis in patients with beta thalassaemia. Br J Haematol 2004;127: 127–39. [8] Pootrakul P, Hungsprenges S, Fucharoen S, Baylink D, Thompson E, English E, Lee M, Burnell J, Finch C. Relation between erythropoiesis and bone metabolism in thalassemia. N Engl J Med 1981;304:1470–3. [9] Michelson J, Cohen A. Incidence and treatment of fractures in thalassemia. J Orthop Trauma 1988;2:29–32. [10] Johanson NA. Musculoskeletal problems in hemoglobinopathy. Orthop Clin North Am 1990;21:191–8. [11] Orvieto R, Leichter I, Rachmilewitz EA, Margulies JY. Bone density, mineral content, and cortical index in patients with thalassemia major and the correlation to their bone fractures, blood transfusions, and treatment with desferrioxamine. Calcif Tissue Int 1992;50:397–9. [12] Jensen CE, Tuck SM, Agnew JE, Koneru S, Morris RW, Yardumian A, Prescott E, Hoffbrand AV, Wonke B. High prevalence of low bone mass in thalassaemia major. Br J Haematol 1998;103:911–5. [13] Vichinsky EP. The morbidity of bone disease in thalassemia. Ann NY Acad Sci 1998;850:344–8. [14] Lasco A, Morabito N, Gaudio A, Buemi M, Wasniewska M, Frisina N. Effects of hormonal replacement therapy on bone metabolism in young adults with betathalassemia major. Osteoporos Int 2001;12:570–5.

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