Thalassaemia: a problem of bones and stones

Thalassaemia describes a group of inherited blood disorders with mutations in the α or β haemoglobin gene. In its more severe form severe anaemia is present and treatment with frequent red blood cell transfusion is necessary. As the body has limited capacity to excrete iron, concomitant iron chelation is required to prevent the complications of iron overload. The effects of chronic anaemia and iron-overload can lead to multiple end-organ complications such as cardiomyopathy, increased risks of blood-borne diseases, liver, pituitary and bone disease. However, our understanding of thalassaemia bone disease is incomplete and composed of a complex piecemeal of risk factors which include hormonal deficiency, marrow expansion, skeletal dysmorphism, iron toxicity and chelators and increased bone turnover. The contribution of kidney dysfunction to bone disease in thalassaemia also requires further study, as increasing reports of renal tubular dysfunction including hypercalciuria have emerged with the use of the oral iron chelator, deferasirox. The aim of this thesis was to investigate the clinical risk factors associated with bone disease and the effect of renal dysfunction on the renal-bone axis in thalassaemia major. This thesis has confirmed that hypogonadism is highly prevalent in patients with transfusion- dependent thalassaemia. This work indicates that hypogonadism attenuated the strength of the muscle–bone relationship in males but strengthened the positive correlation of skeletal muscle mass and fat mass in female subjects with thalassaemia. In a 19 year longitudinal analysis, this work confirmed male subjects had a greater reduction in bone mineral density (BMD) and increased fractures compared to females. The femoral neck was confirmed to be the most consistent site for BMD follow-up. Furthermore, there was an accelerated loss of BMD in the last 5 years of follow-up which coincided with the use of deferasirox. Deferasirox is an oral iron chelator widely used in the treatment of iron overload since 2007. This work has confirmed renal phosphate wasting and a dose-dependent hypercalciuria occurs at therapeutic doses of deferasirox. Furthermore, there was an increased risk of kidney stones with associated reduction in femoral neck Z scores in patients treated with deferasirox. The prevalence of urolithiasis was extremely high at 59%. Kidney stones as determined using dual energy computer tomography (DECT) were of complex pathophysiology and affected patients generally had multiple stones, often with more than one component: struvite (33.3%), calcium oxalate (31.3%) and cysteine (21.6%) stones were prevalent. Hypercalciuria was present in 77.8% of subjects and calcium-containing urolithiasis was associated with reduced hip BMD. In summary, this body of work confirms the complex nature and multiple contributing factors associated with thalassaemia bone disease. The femoral neck should be the preferred site for BMD follow up compared to the lumbar spine. Increased vigilance for hypercalciuria, kidney stones and bone loss is required in those treated with deferasirox. In the presence of urolithiasis and/or loss of significant BMD, consideration should be given where possible to either reducing the dose of deferasirox or switching to an alternative iron chelator. The clinical sequelae and reversibility of hypercalciuria in patients exposed to deferasirox needs to be confirmed in a prospective longitudinal study.