Pain in thalassemia - an emerging complication

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. 许多地中海贫血患者，无论得了需输血的重型（TM）贫血病或不需输血的中间型贫血病，都会长期患骨病，导致骨质减少或骨质降低（骨质疏松）、骨断裂和骨痛。 尽管采取了高量输血和新铁螯合疗法，肌骨病也会突然产生。 发病机制中反应出的症状有：大量红血球生成无效、贫血伴随慢性缺氧、血色病导致局部新陈代谢机能失调、铁螯合具毒性、微量矿物质缺乏，如缺锌、低维生素D浓度、内分泌失调造成甲状旁腺功能减退、血色病导致性腺功能减退和生长激素缺乏以及铁过量促使慢性发炎。 大量红血球生成无效和皮质变薄引起骨髓的潜在膨胀，进而产生骨病。 骨质健康通过几种激素因子（包括生长激素、雌激素、睾丸激素和甲状旁腺素）新陈代谢的相互作用来保持。这几种激素因子会因地中海贫血患者的铁过载而减少。 微量金属元素和维生素，包括钙、铜、锌或维生素C，也会因铁过量或铁螯合而减少。铁过量和铁螯合也是骨代谢的重要促成因素。 确实，由于缺锌儿童骨发育过程中铁螯合具毒性、高去铁胺剂量、低铁负载、去铁酮螯合伴随的胶原关节病等原因，进一步引发了地中海贫血肌骨病。 脊髓高度降低、椎骨变平和脊柱侧凸等症状也有报告。 伴随骨质疏松症和疼痛的青少年和成年B型地中海重型和中间型患者，可通过磁共振成像(MRI)检查来辅助确定肌骨病的发病机理。 地中海贫血临床研究网络（TCRN）观察研究了低骨质截面，结果显示出各年龄阶段骨病和地中海贫血综合症的类型，并且确定了骨断裂的发病率和历史和观察到的疼痛。 大多数地中海贫血综合症病人都患有长期骨质疏松。 TCRN骨研究显示低骨质密度、骨断裂和骨痛具有高发病率。 低骨质密度和骨断裂有较强的联系，这种联系构成地中海贫血骨病的促发因子。 儿童的骨质也都减少了；6 – 10岁儿童中有55%的患儿得了骨质疏松症。 维生素D含量减少也与重型地中海贫血疼痛加重有关(P = 0.010)。 与大众比较，在地中海贫血患者中，由于维生素D缺乏和异常导致疼痛，这种情况很普遍。 地中海贫血肌骨病可能与潜在疾病、铁过量、相关发炎机制或铁络合剂作用有关。 为确定伴随骨断裂和肌骨疼痛高发风险的地中海贫血肌骨病的病原学和改善治疗策略并防止出现渐进式骨质疏松病，需要开展更多的研究， 以免影响生活质量、让青少年和成年人产生焦虑和沮丧的心情。