Pain in Thalassemia—An Emerging Complication

Abstract

Many thalassemia subjects both transfused Major (TM) and nontransfused Intermedia (TI) suffer from longstanding bone disease, reduced or low bone mass (osteopenia or osteoporosis), fractures and bone pain. Unexpected musculoskeletal disease occurs despite longstanding hypertransfusion and new iron chelation strategies. Conditions which have been implicated in its pathogenesis include the massive ineffective erythropoiesis, chronic hypoxia associated with anemia, the local metabolic dysfunction from hemochromatosis, iron chelation toxicity, trace mineral deficiencies such as zinc deficiency, low vitamin D concentrations, the effect of endocrine dysfunction such as hypoparathyroidism, hypogonadism and growth hormone deficiency from hemochromatosis and the chronic inflammatory state induced by iron excess. The pathogenesis of bone disease has been attributed to the underlying marrow expansion of medullary bone caused by the massive ineffective erythropoiesis and subsequent cortical thinning. The process of normal bone health is maintained by a metabolic interplay of several hormonal factors including growth hormone, estrogen, testosterone, parathyroid hormone all of which can be diminished by iron overload in Thalassemia. Trace metals and vitamins including calcium, copper, zinc or vitamin C can also be deficient from iron excess or iron chelation which are also important contributors to bone metabolism. Indeed toxicities of iron chelation itself on bone development in the growing child associated with zinc deficiency, high Deferoxamine dosing and low iron burdens or the collagenous joint disease associated with deferiprone chelation have further contributed to the current musculoskeletal disease of Thalassemias. Decreased spinal height, vertebral flattening and scoliosis have also been reported. Magnetic Resonance Imaging (MRI) of adolescent and adult β Thalassemia Major and Intermedia patients with osteoporosis and pain have assisted in defining the associated musculoskeletal pathology. The outcomes of the TCRN cross sectional observational study of low bone mass revealed the nature of bone disease across all ages and thalassemia syndromes and identified the prevalence and history of fractures and observed pain. Longstanding osteopenia and osteoporosis existed in the majority of subjects across all thalassemia syndromes. The TCRN Bone Study showed high prevalence of low BMD, fractures and bone pain in Thalassemia. A strong association between low bone mass and fractures was identified factors that may contribute to the pathogenesis of bone disease in Thalassemia. Bone mass was reduced even in children; 55% of 6–10 year olds had osteopenia or osteoporosis. Low vitamin D levels were also associated with increased pain in Thalassemia Major (p = 0.010). Pain has been associated with vitamin D deficiency and vitamin D abnormalities are prevalent in Thalassemia compared to the general population. Musculoskeletal disease of thalassemia may be related to the underlying disease, the consequences of iron excess, associated inflammatory mechanisms or iron chelator effects. Further studies are needed to identify its etiology and improve treatment strategies and prevent the emerging progressive osteoporotic disease process in thalassemia associated with high risk of fractures and musculoskeletal pain disrupting quality of life causing anxiety and depression into adolescence and adulthood.