Bone Histomorphometry in Children and Adolescents with β-Thalassemia Disease: Iron-Associated Focal Osteomalacia

Abstract

Thalassemia/hemoglobinopathy is a hereditary disease that causes chronic anemia and increased erythropoiesis. Consequently, an expansion of bone marrow spaces may contribute to osteopenia/osteoporosis. However, the pathogenesis of bone changes is not yet known. We, therefore, carried out the study on bone histomorphometry and biochemical and hormonal profiles in children and adolescents with suboptimally treated beta-thalassemia disease with the hope of gaining some new insight into the cellular and structural alterations of thalassemic bone. Seventeen patients underwent iliac crest bone biopsy for histomorphometric analyses. Bone mineral density (BMD) measurements were performed by dual energy x-ray absorptiometry. Most patients had growth retardation and delayed bone age. BMD was low especially at the lumbar spine. Serum IGF-I levels were almost always low. Bone histomorphometry revealed increased osteoid thickness, osteoid maturation time, and mineralization lag time, which indicate impaired bone matrix maturation and defective mineralization. In addition, iron deposits appeared along mineralization fronts and osteoid surfaces. Moreover, focal thickened osteoid seams were found together with focal iron deposits. Dynamic bone formation study revealed reduced bone formation rate. These findings indicate that delayed bone maturation and focal osteomalacia are the pathogenesis of bone disease in suboptimally blood-transfused thalassemics with iron overload. Iron deposits in bone and low circulating IGF-I levels may partly contribute to the above findings.

Bone Disease in Haemoglobin Disorders

“…In addition, iron deposits appeared along mineralization fronts and osteoid surfaces, whereas focal thickened osteoid seams were found together with focal iron deposits (33,43). Finally, dynamic bone formation histomorphometry studies established reduced bone formation rate in TM patients (33). 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.…”

“…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 (33). Furthermore, 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 (34).…”

“…Bone marrow expansion, which is a typical finding in patients with TM, has been considered as a major cause of bone destruction (33). Transferrin receptor studies have demonstrated increased bone marrow activity even in patients with low reticulocyte count or marrow hypoplasia (35).…”

“…There is evidence of reduced osteoblast function in TM. Histomorphometry studies have revealed that increased osteoid thickness, increased osteoid maturation and min-eralization lag time, which indicate impaired bone matrix maturation, and defective mineralization is present in children and adolescents with TM (33). In addition, iron deposits appeared along mineralization fronts and osteoid surfaces, whereas focal thickened osteoid seams were found together with focal iron deposits (33,43).…”

Response of biochemical markers of bone turnover to oral glucose load in diseases that affect bone metabolism

“…The pathogenesis of thalassemia-induced bone disease is multifactorial and includes bone marrow expansion, endocrine dysfunction, and iron overload, as well as genetic susceptibility to attainment of low peak bone mass (17,18). At tissue level, it has been demonstrated that there is an osteoblast dysfunction together with increased osteoclast activity leading to imbalanced bone turnover in favor of bone resorption (19)(20)(21).…”