Role of hypogonadism in development of bone alterations in thalassemic patients: HRT effects on bone mass deficiency

Because this important role of hypogonadism, we should expect that hormonal replacement therapy (HRT) corrects or prevents bone mass deficiency in adult TM patients. Conflicting results have been presented with some studies indicating a clear improvement and other giving doubtful results. In our recent study, we found that female TM patients treated with HRT still have reduced bone mass and increased bone turnover compared to normal women of similar age. However, patients who started the HRT in younger age had better results than patients who started the treatment later. Maybe, it is important to start the treatment early, at the pubertal age. On the other hand, it cannot be excluded that HRT is not sufficient because other factors contribute to the bone mass deficiency of TM patients. Consistent with our results, Lasco et al. found that bone mass, measured by DEXA, was lower in all TM patients than in controls, but the difference was more marked in patients who didn't receive HRT. We can conclude that HRT is an important 
part of the treatment of bone mass deficiency in adult TM patients but that the treatment has to be started early and that often alone is not sufficient to normalize bone mass. Because of the disappointing results of HRT on bone mass in adult TM patients, it has been suggested to associate HRT and bisphosphonates. Limited experience is available but the results of our group and of other authors suggest that the results may be better than with HRT alone.

Role of hypogonadism in development of bone alterations in thalassemic patients: Causes of hypogonadism in adult TM patients

It has been suggested that in TM patients the hypothalamus and the pituitary are damaged by the iron overload. In fact the pituitary gland is very sensitive to iron and also a modest deposition may impair its functionality. Histological studies have confirmed the damage of the pituitary gland by iron overload in TM patients and MRI has shown a signif-icantly smaller anterior pituitary volume. Other studies have shown that iron overload may also directly damage the gonads. Therefore, it may be assumed that the hypogo- nadism of adult TM patients is mainly a consequence of the iron deposit.

Some authors have reported higher ferritin levels in subjects who had hypogonadism compared to those with normal go- nadal function. Ferritin is the protein that stores iron intra- cellularly and when its capability is exceeded an excess of active iron is released and catalyses the formation of free radicals. Free radicals may damage membrane lipids, leading to mitochondrial and lysosomal damage and finally to cell death. Because of these findings it has been suggested that improvement of chelation treatments may prevent or reduce the appearance of hypogonadism in TM patients. While it may be probable, other studies did not find such correlations and our normogonadic patients had the same transfusion and chelation treatment than hypogonadic patients. Moreover, while hypogonadic patients had slightly higher ferritin circulating levels, the difference with normogonadic patients was not significant.

Role of hypogonadism in development of bone alterations in thalassemic patients

Beta thalassemia major (TM) is an important health concern in many countries, mostly in the Mediterranean area, in the Middle East, India, East Asia. In 1988 a report from the WHO documented that almost 50000 children per year were born with TM.

In the last decades, improved programs of transfusional and chelation therapy have permitted to TM patients to survive until their forties or fifties and to get a better quality of life. However, several complications progressively arise and in particular endocrine alterations are common with diabetes, hypothyroidism, hypoparathyroidism, and hypogonadism being well known complications of adult thalassemia major. More recently, in adult TM patients, bone mass deficiency has been recognised as a major problem that may cause pathologic fractures and limb deformities and greatly worsen the quality of life of these patients. The etiology of bone mass deficiency in thalassemia is still unclear and many factors have been suggested as possible causes, including IGF-I deficiency, low vitamin D levels, alterations of genes related to collagen synthesis, bone cortical thinning because of bone marrow expansion and altered levels of some oligoelements such as zinc and copper. However, a main role is probably played by hypogonadism that is a hallmark of adult TM patients. In this brief review, we will examine the characteristics of hypogonadism in TM patients and the possible link between hypogonadism and bone mass deficiency. Finally, we will discuss the role of the hormonal substitutive therapy in the prevention and treatment of bone mass deficiency in TM.