Thalassemia is the most common cause of inherited anemia worldwide1. The two main forms of the disease include defects in the α- (α-thalassemia) and β-globin synthesis (β-thalassemia)1 with the former being the most common form1, 2, 3. The prevalence of α-thalassemia is highest among people of Southeast Asia, Middle East, Mediterranean and Central Africa regions, with the reported variant frequency ranging from 5-68%2,3. As compared to deletional α-thalassemia (i.e., hemoglobin [Hb] H disease), individuals with non-deletional α-thalassemia, such as Hb H-Constant Spring (CS), typically have more severe clinical phenotypes (including lower Hb concentration, impaired growth, craniofacial changes and marked hepatosplenomegaly) and require frequent blood transfusion3,4. As a result, iron overload-induced endocrine complications commonly occur in these individuals4. However, the prevalence and extent of these complications are less well characterized as compared to β-thalassemia.

Osteoporosis is one of the major endocrine complications in long-term care of thalassemia. The pathogenesis of thalassemia-associated osteoporosis (TAO) is complex with anemia and iron overload being the major determinants. Other factors include bone marrow expansion, physical inactivity, decreased sun exposure, renal dysfunction, hormone deficiencies and the toxic effect of iron chelators on the bone5,6. Individuals with thalassemia are at higher risk for osteoporosis than the general population7 with 12-18% of individuals with β-thalassemia major (β-TM), 7-12% of β-thalassemia intermedia (β-TI) and 2.4-4% of α-thalassemia8,9 affected by osteoporotic fracture. Low bone mineral density (BMD), a strong predictor for fractures, is also very common in this patient population. Whereas many studies have demonstrated high prevalence of low BMD in children (20-67%)8,10 and adults (50-90%)8,10 with β-thalassemia, these data are limited in all forms of α-thalassemia. Moreover, such data are lacking in adolescence, a critical period of bone mass acquisition11.

In addition to BMD, a growing body of research has explored the use of bone biomarkers, such as the Wnt signaling pathway inhibitors sclerostin and dickkopf-1 (Dkk-1), in TAO. Dkk-1, an osteogenic cell-derived glycoprotein, inhibits Wnt signaling pathway in osteoblasts through preventing the binding of Wnt to cell surface receptors (frizzled receptor and its coreceptor low-density lipoprotein receptor-related protein [LRP]-5 or 6), thereby inhibiting bone formation12. Further, Dkk-1 also enhances receptor activator of NF-kB (RANK) ligand expression, and limits osteoprotegerin expression leading to increased bone resorption12. An increase in serum concentrations of sclerostin13,14 and Dkk-115 has been observed in adults with β-thalassemia and TAO, which are associated with a decrease in lumbar spine (LS) BMD13, 14, 15 similar to that observed in postmenopausal osteoporosis16. These data suggest that Dkk-1 has the potential to serve as a bone biomarker in TAO. Therefore, in this study, we sought to evaluate the prevalence of low BMD in adolescents with non-deletional Hb H disease (NDHbH). We also aimed to determine the association between Dkk-1 and BMD in this patient population.