Thalassaemia-induced osteoporosis

Introduction
Osteoporosis is a prominent cause of morbidity in patients with thalassemia major (TM). According to the World Health Organization, osteoporosis is characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequential increase in fracture risk. The cut-off of 2.5 standard deviations below the normal mean in bone mineral density (BMD) for the respective age is used for the definition of osteoporosis, whereas the decrease of BMD between 1.5 and 2.5 standard deviations below the normal mean for the respective age is defined as osteopenia. The incidence of osteopenia or osteoporosis in well treated TM patients has been found to be approximately 40–50%.

Genetic factors
These factors have been implicated in the pathogenesis of postmenopausal osteoporosis, as regulator genes of BMD. The polymorphism at the Sp1 site of the collagen type Ia1 (COLIA 1) gene (collagen type I is the major bone matrix protein) has been associated with reduced BMD in postmenopausal osteoporosis, and predisposes women to osteoporotic fractures. In a study by Wonke et al, approximately 30% of the TM patients were heterozygotes (Ss) and 4% were homozygotes (SS) for the Sp1 polymorphism. The authors concluded that male patients with TM carrying the Sp1 mutation may develop severe osteoporosis of the spine and the hip more frequently than patients who do not carry this mutation. Other genetic factors that have been reported to correlate with low BMD in adult patients with TM include the vitamin D receptor (VDR) Bsml BB polymorphism, the loss of- function mutations in the gene of the vitamin D receptor, the sequence variation of 713-8delC of transforming growth factor-β1, the presence of restriction fragment length polymorphisms for the calcitonin receptor gene, estrogen receptor and interleukin-6 gene loci.

Endocrine complications
Hypothyroidism, hypoparathyroidism, diabetes mellitus, and mainly hypogonadism (as delayed puberty and/or secondary hypogonadism) are considered as major causes of osteopenia/osteoporosis in TM. Hemosiderosis of the pituitary gonadotrophic cells and iron deposition in the testes and ovaries are involved in the pathogenesis of hypogonadism in TM.

Iron overload and desferrioxamine
Iron deposition in the bone impairs osteoid maturation and inhibits mineralization locally, resulting in focal osteomalakia. The mechanism by which iron overload interferes in osteoid maturation and mineralization includes the incorporation of iron into crystals of calcium hydroxyapatite, which consequently affects the growth of hydroxyapatite crystals and reduces the bone metabolism unit tensile strength. Desferrioxamine inhibits DNA synthesis, osteoblast, and fibroblast proliferation, osteoblast precursors differentiation, and collagen formation, although enhances osteoblast apoptosis, especially in patients who receive inappropriately high doses of desferrioxamine.



Bone marrow expansion
Bone marrow expansion, which is a typical finding in patients with TM, has been considered as a major cause of bone destruction.

Vitamin deficiencies
Vitamin C deficiency in iron overload patients with low levels of serum ascorbic acid induces the risk of osteoporotic fractures. Vitamin D deficiency is also implicated in the pathogenesis of osteoporosis in TM patients due to the regulatory effect of vitamin D in both osteoclasts and osteoblasts.

Physical activity
Patients with TM have reduced physical activity due to the complications of the disease and the overprotection by their parents who do not encourage muscle activity, predisposing for osteoporosis. These factors can lead to the destruction of bone in thalassemia patients by increasing the osteoclast function and/or reducing the osteoblast activity.

Increased osteoclast function in thalassemic patients with osteoporosis
Patients with TM and osteoporosis have elevated markers of bone resorption, such as N-terminal cross-linking telopeptide of collagen type-I (NTX) and tartrate-resistant acid phosphatase type 5b (TRACP-5b) that correlated with BMD of the lumbar spine in these patients. This increased osteoclast activity seems to be at least partially due to an imbalance in the receptor–activator of nuclear factor-kappa B ligand (RANKL)/osteoprotegerin (OPG) system, which is of great importance for the activation and proliferation of osteoclast precursors, and the overproduction of cytokines that are involved in the osteoclast differentiation and function. The ratio of sRANKL/OPG in the serum as well as IL-1α, TNF-α, IL-6 and TGF-β are increased in thalassemia patients with osteopenia/osteoporosis, suggesting their involvement in the pathogenesis of TM osteoporosis ( Figure 1). Activin-A, a member of the TGF-β superfamily that promotes osteoclastic activity in vitro is also elevated in the serum of patients with TM and correlates with low BMD.

Reduced osteoblast function in thalassemic patients with osteoporosis
There is evidence of reduced osteoblast function in TM mainly due to iron poisoning in osteoblasts and/or the result of reduced function of GH and IGF-1 axis. However, novel molecules seem to be implicated in osteoblast dysfunction in TM. Wnt signaling inhibitors dickkopf-1 (Dkk-1) and sclerostin which block inhibit the osteoblast differentiation and function are increased in the serum of TM patients with osteoporosis and inversely correlate with BMD.

Prevention and general principles
Prevention and treatment of early bone loss make the best policy.
 * Annual checking of BMD starting in adolescence is considered indispensable.
 * Physical activity must always be encouraged. Smoking should be discouraged.
 * Adequate calcium intake during skeleton development can increase bone mass in adult life and in combination with administration of low doses of vitamin D may prevent bone loss and fractures.
 * Early diagnosis and treatment of diabetes mellitus
 * Adequate iron chelation may prevent iron toxicity in the bone and sufficient blood transfusions may inhibit uncontrolled bone marrow expansion.

Hormonal replacement
Prevention of hypogonadism seems to be the most effective way for preventing osteoporosis and other bone deformities in thalassemia patients. Continuous hormonal replacement therapy with transdermal estrogen for females or human chorionic gonadotrophin for males improves bone density parameters.

Calcitonin
Parenteral and intranasal instillations of calcitonin, a potent inhibitor of osteoclasts, are available. Calcitonin reliefs bone pain, improves radiological findings of osteoporosis, decreases the number of fractures with no important side effects.

Bisphosphonates
Bisphosphonates are potent inhibitors of osteoclastic bone resorption. They inhibit osteoclastic recruitment and maturation, prevent the development of monocyte precursors into osteoclasts, induce osteoclast apoptosis and interrupt their attachment to the bone. Almost all generations of bisphosphonates have been used in an attempt to increase the BMD In thalassemia induced osteoporosis. Oral administration of alendronate but not intramascular clodronate normalizes the rate of bone turnover, and results in a rise in BMD of the spine and the hip. Pamidronate, a second-generation aminobisphosphonate, has been given intravenously in patients with TM and osteoporosis with a significant improvement in BMD in most patients, a clear decrease of markers of bone resorption (NTX and TRACP-5b), and significant reduction of pain Zoledronic acid is the most potent third generation bisphosphonate to-date and has been found to be extremely efficacious in increasing BMD in TM patients, that continues to act after its discontinuation. However, more trials must be conducted to clarify the exact role of each biphosphonate, the long-term benefit and side effects as well as the effects of the combination of bisphosphonates with other effective agents, such as hormonal replacement, in thalassemia-induced osteoporosis.

Other novel agents
Teriparatide, a recombinant peptide fragment of parathyroid hormone, and strontium ranelate, a second anabolic agent, that seem to prevent osteoporotic fractures in postmenopausal women, are being studied but their effects in TM-induced osteoporosis remains to be proven. Antibodies against RANKL, such as denosumab, which has just been licensed by FDA for the treatment of postmenopausal osteoporosis, and antibodies against Dkk-1 or against sclerostin may be future agents for the effective management of this difficult complication of thalassemia. Sotatercept, a chimeric protein containing the extracellular domain of the activin receptor 2A (ActRIIA) inhibits activin-A, increasing bone mineral density as well as haemoglobin levels in TM patients.