Date Published: May 30, 2012
Publisher: Hindawi Publishing Corporation
Author(s): Carlo Perisano, Emanuele Marzetti, Maria Silvia Spinelli, Cinzia Anna Maria Callà, Calogero Graci, Giulio Maccauro.
β-thalassemia major (βTM) or Cooley anemia is characterized by significantly reduced or absent synthesis of β-globin chains, which induces important pathologic consequences including hemolytic anemia, altered erythropoiesis, and bone marrow overstimulation. The pathogenesis of bone changes in patients with βTM is not yet completely understood. However, an unbalance in bone mineral turnover resulting from increased resorption and suppression of osteoblast activity has been detected in βTM patients. The abnormal regulation of bone metabolism may be related to hormonal and genetic factors, iron overload and iron chelation therapy, nutritional deficits, and decreased levels of physical activity. Here, we review the most recent findings on the physiopathology of bone abnormalities in βTM. Clinical presentation and radiological features of βTM-related bone changes are also discussed.
β-thalassemia, firstly described by Cooley and Lee , comprises a group of inherited, autosomal, recessive, and hematologic disorders characterized by decreased or absent synthesis of β-globin chains. The mature hemoglobin (Hb) molecule is a tetramer composed of two α-globin and two β-globin chains, along with a heme prosthetic group. β-globin synthesis is controlled by one gene located on each chromosome 11 . Defects are usually secondary to point mutations and rarely occur as a consequence of deletions . In β-thalassemia, β-globin chain production can range from near to normal to completely absent, leading to varying degrees of excess α-globin chains and disease severity . β-thalassemia trait (minor), resulting from heterozygosity for β-thalassemia, is clinically asymptomatic and manifests with microcytosis and mild anemia. β-thalassemia intermedia comprises a clinically and genotypically heterogeneous group of disorders, ranging in severity from the asymptomatic carrier state to severe, transfusion-dependent disease. β-thalassemia major (βTM) or Cooley anemia is characterized by severely reduced or absent synthesis of β-globin chains from both genes, with symptoms and signs beginning at about six months of age (abdominal swelling, growth retardation, irritability, jaundice, pallor, skeletal abnormalities, and splenomegaly) .
The worldwide prevalence of α- and β-thalassemia trait is 1.7% . Males and females are equally affected. The incidence of thalassemia trait is 4.4 per 10,000 live births . β-thalassemia in its various presentations is more common in the Mediterranean area, Africa, and Southeastern Asia.
The pathogenesis of bone changes in βTM patients is not yet completely understood . In spite of the improved treatment of the hematologic disorder and its complications, β-thalassemia patients exhibit an unbalance in bone mineral turnover with increased resorptive rates and suppression of osteoblast activity, resulting in diminished bone mineral density (BMD) more evident in the lumbar spine [8, 9]. Putative mechanisms involved in the pathogenesis of bone abnormalities in βTM are discussed in the following subsections.
Bone marrow expansion and extramedullary hemopoiesis can result in the classical enlargement of cranial and facial bones with mongoloid appearance, as originally described by Cooley [1, 3]. Novel transfusion regimens and early iron-chelating therapy have improved the survival of βTM patients  and have substituted the marked bone abnormalities previously described  with less severe skeletal lesions. Yet, sequelae of osteopenia and severe osteoporosis represent the leading cause of morbidity in βTM patients [14, 22]. Indeed, the prevalence of osteoporosis in these patients is as high as 50%, with higher rates in males [23, 24].
In βTM patients, the most evident radiological changes are those caused by intense marrow hyperplasia . Such abnormalities include bone cortex thinning and widening of intratrabecular spaces, usually seen in hands, but also in the pelvis and ribs . Extramedullary hemopoietic tissue sometimes grows beneath the periosteum, producing a scalloped cortex edge in hands, feet, tibiae, fibulae, knees, radii, and ulnae. In other cases, extramedullary hemopoietic tissues can appear as large intrathoracic masses, simulating paravertebral tumors. In the skull, significant thickening of the cranium can take place, and overgrowth of the facial bones can impede pneumatization of sinuses .
Bone changes are frequent in βTM patients and occur as a consequence of the hematological disorder and its complications as well as iron overload, iron-chelation therapy, nutritional deficits, and sedentarism. The sequalae of osteoporosis, especially vertebral and long bone fractures, represent a major cause of morbidity in these patients. A better understanding of the pathogenetic mechanisms underlying bone abnormalities in βTM is needed to develop targeted treatments. As of now, the early detection of osteoporosis and the eventual institution of bisphosphonate treatment are the most effective strategies to reduce the incidence and severity of skeletal complications. The use of new-generation iron chelators may avoid the negative effects of deferoxamine on bone metabolism. Finally, the identification and correction of nutritional and hormonal deficits and the engagement in physical training programs should be pursued in βTM patients to reduce the incidence of osteoporosis and increase overall bone strength.