Beta-thalassemia major (β-TM) is a common cause of skeletal morbidity and increased bone fracture risk in thalassemic patients1. Its pathogenesis is multifactorial and mainly includes bone marrow expansion, endocrine dysfunction and iron overload [2, 3]. In this study, we investigated the DPD, beta-CTX, OPG and RANKL values of our patients diagnosed with β-TM. We compared these values with DEXA and hormonal changes to observe whether there was a correlation between them.
OPG levels were significantly decreased in thalassemic patients, although no significant difference was detected between the serum RANKL levels of the groups. The most important result of this finding is an increased RANKL/OPG ratio in thalassemic children. Morabito et al. [10] reported that thalassemic patients showed no differences in plasma levels of OPG compared with controls and significantly higher plasma levels of RANKL, with a consequent significantly lower OPG/RANKL ratio (which is equal to a higher RANKL/OPG ratio) in an adult study. These results indicate that low bone mass can be associated with decreased osteoblastic activity in children despite increased osteoclastic activity in adults [10]. Our findings are correlated with Morabito’s study. Ozdemir et al. [11] reported that vitamin menaquinone-7 and calcitriol have beneficial effects on thalassemic osteopathy.
Alfaqih et al. [12] reported that plasma RANKL level was the most significant marker for bone resorption and strongly correlated with the N-terminal propeptide of type 1 collagen; lower in individuals with thalassemia intermedia.
Osteoblasts and osteoclasts are responsible for bone remodelling at the cellular level. In adult thalassemic patients, RANK/RANKL-OPG system disorder increases in favour of osteoclasts. Many studies have noted that the RANKL/OPG ratio increases in patients with thalassemia major, and this situation shows the role of this system in the pathogenesis of osteoporosis [13,14,15]. Toumba and Skordis [6] reported that in thalassemia patients, progressive “ageing” of the bone starts even in childhood by the gradual development of an imbalance between augmented osteoclastic resorption and insufficient osteoblastic bone formation. We suggest that osteoblastic dysfunction is the dominant mechanism of osteopenia in prepubertal children.
We did not find any association with sex steroids, OPG, RANKL and DEXA, which agrees with different studies from Italy and Greece [16, 17].
Several studies have shown that PTH acts by enhancing the production of RANKL and by inhibiting the synthesis of OPG [18, 19]. However, we detected a positive correlation between PTH and OPG levels in this study. These results may be attributed to the unique characteristics of the growing bones and the high rate of bone turnover in childhood. There were no other significant correlations between the markers of bone turnover and PTH in this study.
In a study of 42 patients diagnosed with thalassemia major, the rate of osteoporosis by DEXA was 81%. β-CTX and PTH levels were high, but vitamin D levels were low in the same group [16]. This study similarly shows high levels of PTH and alkaline phosphatase and an increased ratio of RANKL/OPG in the thalassemic group. Although the difference was not statistically significant, the mean β-CTX levels of the thalassemic patients were higher than those in our study’s control group. These biochemical markers serve as a signal in the development of osteoporosis in patients with beta-thalassemia major.
It is not clear whether sex differences influence bone diseases [20]. Some studies report that sex differences have a role in developing osteoporosis syndrome in thalassemia and affect its severity. Males are more frequently and severely affected by osteopenia and osteoporosis than females, and some others report that sex differences are not significant [20, 21]. In a study conducted on patients with sickle cell anaemia, the mean lumbar spine Z score was significantly lower in prepubertal girls than in boys. However, there was no significant difference in the pubertal group [22]. When the prepubertal thalassemic patients in this study were evaluated according to sex, the mean spine DEXA Z score results were higher in females than males. In contrast, the mean femur Z score was higher in males than females.
Iron accumulation has a negative effect on bone mineralisation. BMD was significantly influenced by noneffective chelation in children with beta-thalassemia major [23]. According to the results of this study, it was confirmed that DEXA Z scores similarly decreased with increasing levels of ferritin.
Limitations
One of the most important limitations of the study is that the participants were not homogeneous in terms of the duration of thalassemia disease. This may affect the degree of osteoporosis in these patients, and thus the correlation between osteoporosis and the potential markers studied. The inability to perform DEXA examination in healthy controls is another important limitation. The possibility of osteoporosis among these patients may confound the comparisons between patients with β-TM and healthy controls. Therefore, there is a need for larger-scale studies comparing the results of a more homogeneous study group in terms of disease duration and a control group that is proven to be free of osteoporosis.