More than half of the patients in this cohort had thalassemia-associated osteoporosis (55%). The prevalence of osteoporosis in this study was comparable to the previous studies in adult thalassemia patients.17–19 Advanced age and high GDF15 levels were associated with an increased risk of osteoporosis, whereas high pre-transfusion hemoglobin levels were associated with a decreased risk of osteoporosis. Because osteoporosis is a time-dependent complication, aging is well established as a significant risk factor. This study discovered that a 10-year increase in age significantly increased the risk of osteoporosis, with an AOR of 1.6 (p-value = 0.005).
Growth differentiating factor-15 is a biomarker of ineffective erythropoiesis found in high levels in thalassemia patients. Furthermore, high GDF15 levels are also associated with clinical severity in NTDT patients. 6 GDF15 levels were found to be significantly higher in thalassemia patients with osteoporosis compared to those without osteoporosis. Moreover, high GDF15 levels (per 10,000 pg/mL increase) in these thalassemia patients were associated with an increased risk of osteoporosis (AOR = 1.3, p-value = 0.001). This finding could be correlated to high GDF15 levels in these patients, which suppresses hepcidin functions. Xu et al. found that hepcidin protects against iron overload-induced bone loss. Low hepcidin levels contribute to osteoporosis by inhibiting osteoblast functions and increasing osteoclast activity, resulting in low bone mineral density. 14 As a result, high GDF15 levels had a negative correlation with bone mass in thalassemia patients. High GDF15 levels may represent the underlying ineffective erythropoiesis in individual thalassemia patients. Ineffective erythropoiesis may be one of the primary causes of osteoporosis in thalassemia patients. The ROC in Fig. 2 demonstrated that GDF15 levels performed well in predicting the development of osteoporosis. Using the cut-off level of GDF15 ≥ 20,000 pg/mL, the sensitivity and specificity were 90.2% and 60.3% in predicting osteoporosis. This finding suggested that GDF15 levels in thalassemia patients could be used as one of the predictive biomarkers of osteoporosis.
Anti-GDF15 antibodies inhibit osteoclast activity, preventing bone loss, according to a preclinical study. 11 Sotatercept is a soluble activin-receptor type 2A (ActRIIa) IgG-Fc fusion protein. It works as a ligand trap for TGF-β superfamily ligands including GDF15. Sotatercept has been shown in clinical studies to increase biomarkers of bone formation and hemoglobin levels in postmenopausal women. 20,21 Similarly, Luspatercept, a soluble activin-receptor type 2B (ActRIIb) IgG-Fc fusion protein, acts as a ligand trap for TGF-β superfamily ligands, inhibiting the Smad-signaling pathway. A recent phase III study of Luspatercept in patients with transfusion-dependent beta-thalassemia showed that it can increase Hb levels while decreasing the red blood cell transfusion burden. 22 The activin-receptor ligand traps may not only raise Hb levels but also improve bone metabolism in thalassemia patients. Further research into the role of these agents in preventing or improving osteoporosis in thalassemia patients is needed.
Chronic anemia in thalassemia patients is caused by ineffective erythropoiesis, chronic hemolysis, and decreased globin production. As a result, chronic anemia causes bone marrow expansion and low bone mass in these patients. This study found that increasing Hb levels reduces the risk of osteoporosis in thalassemia patients (AOR = 0.6, p-value = 0.017). This finding suggests that adequate red blood cell transfusion may help thalassemia patients avoid bone loss and the development of osteoporosis.
Endocrine disorders are well established as a significant risk factor for osteoporosis and fractures in the individual with thalassemia.3,23−25 The univariate analysis showed that endocrinopathies are strongly associated with osteoporosis (OR = 3.5, p-value = 0.03). In multivariate analysis, however, endocrine disorders did not show a statistically significant with osteoporosis. These findings may be due to the majority of the enrolled patients being young adults, and the number of endocrine disorders in this cohort was small. Other risk factors that have been indicated as risk factors for osteoporosis, i.e., menopause, and smoking were not significantly associated with osteoporosis in this study due to the limited number of events.
The current finding must be interpreted in the context of several potential strengths and weaknesses. Endocrine disorders were diagnosed in this study, primarily based on medical history and physical examinations, and completed investigations of hypogonadism and growth retardation were not performed in all cases. As a result, the prevalence of these endocrine disorders could be understated. To the best of the authors’ knowledge, this was the first study to show the relationship between GDF15 levels and osteoporosis in adult thalassemia patients. This study enrolled a variety of thalassemia genotypes with different clinical severities. Further research in distinct genotypes of thalassemia, however, is needed to determine the utility of this biomarker in predicting osteoporosis.
Finally, thalassemia-associated osteoporosis is common in adult thalassemia patients. Advanced age and high GDF15 levels were both significant risk factors for osteoporosis. A higher hemoglobin level is associated with a lower risk of osteoporosis. These findings could have clinical implications for using the GDF15 levels as a predictive biomarker to assess the risk of osteoporosis in thalassemia patients. Furthermore, adequate RBC transfusion and GDF15 inhibition may prevent or improve this complication.