Osteoprotegerin and RANKL in the Pathogenesis of Thalassemia-Induced Osteoporosis: New Pieces of the Puzzle

Abstract

Osteoporosis represents an important cause of morbidity in adult thalassemic patients, and its pathogenesis has not, as yet, been completely clarified. In our study, we observed that thalassemic patients showed a significantly lower OPG/RANKL ratio than normal subjects. These data are extremely important for the possible therapeutic use of RANKL antagonists such as OPG in thalassemia-induced osteoporosis.Introduction: Osteoporosis represents an important cause of morbidity in adult thalassemic patients who display increased fracture risk. The etiology of this bone disease is multifactorial, but it is thought that the main role is played by hypogonadism. The mechanisms by which the skeletal effects of sex steroids are mediated are still not fully understood. Recently, two new cytokines, osteoprotegerin (OPG) and RANKL, have been implicated in the pathogenesis of postmenopausal osteoporosis and other metabolic bone diseases. Thus, the aim of this study was to characterize the possible role of the OPG/RANKL system in thalassemia-related bone loss. Materials and Methods: We measured, in 30 thalassemic patients and in 20 healthy control subjects, serum OPG and RANKL levels, and determined their correlations with bone turnover markers, BMD, sex steroid levels, erythropoietin, and hemoglobin. Results: Thalassemic patients had an unbalanced bone turnover with an increased resorption phase (shown by high levels of pyridinium cross-links) and a decreased neoformation phase (shown by the slightly low levels of osteocalcin). Moreover, they displayed lower BMD values than controls both at the lumbar and femoral level. As far as the OPG/RANKL system is concerned, 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. Conclusions: Our data suggest that, in thalassemic patients, an altered modulation of the OPG/RANKL system, resulting in increased expression of RANKL by stromal or osteoblastic cells, could contribute to the enhanced osteoclastic bone resorption and bone loss characteristic of these patients.

Response of biochemical markers of bone turnover to oral glucose load in diseases that affect bone metabolism

“…In addition, P1NP but not osteocalcin was also found increased in these patients, reflecting increased bone turnover. This would be considered to be in contrast with the study by Morabito et al (25) who have shown decreased serum osteocalcin levels in patients with thalassemia major, suggesting decreased osteoblast activity. However, osteocalcin accounts for only a minor fraction of bone proteins, compared with collagen type 1, which constitutes 90% of bone matrix.…”

“…Several genetic factors, such as COLIA1 and VDR polymorphisms, and acquired factors due to primary disease itself (defective erythropoiesis and bone marrow expansion), iron overload, or toxicity due to iron chelation therapy have all been implicated in thalassemia-induced bone loss (17,18). At molecular level, although osteoblast dysfunction is considered to be the main pathogenetic mechanism (19), recent evidence has demonstrated that anemia, through stimulation of erythropoietin and subsequent bone marrow expansion, also increases expression of RANKL and thus promotes activation of osteoclast activity (21,25). In accordance with previous studies (20,26) bone resorption marker b-CTX was found significantly increased at baseline compared with the control group.…”

“…Data of bone turnover markers in hypothyroid patients have presented inconclusive results reporting low or normal levels, although BMD is usually within normal limits (8,29). In histomorphometry studies, however, the bone remodeling cycle was found significantly prolonged associated with decreased bone turnover rate (25,30). In addition, large population studies have shown a two-to three-fold increase in fracture risk even after 10 years following initial diagnosis of hypothyroidism (8,31).…”

Bone Disease in Haemoglobin Disorders

“…It is well documented that the GH-IGF axis is defective in TM. Thalassemia patients have significantly lower circulating levels of IGF-I and the corresponding binding protein (IGFBP-III) than normal individuals; thus, leading to increased bone resorption, decreased bone formation, and finally to bone loss (31)(32).…”

Iron overload causes osteoporosis in thalassemia major patients through interaction with transient receptor potential vanilloid type 1 (TRPV1) channels

“…[14][15][16] The increased osteoclast activity seems to be at least partially a consequence of an imbalance in the receptor-activator of the nuclear factor-kappa B ligand (RANKL)/osteoprotegerin system, and the overproduction of cytokines involved in osteoclast differentiation and function. [17][18][19][20][21] However, no correlation has been found between RANKL or osteoprotegerin levels and bone The pathogenesis of bone resorption in b-thalassemia major is multifactorial and our understanding of the underlying molecular and cellular mechanisms remains incomplete. Considering the emerging importance of the endocannabinoid/endovanilloid system in bone metabolism, it may be instructive to examine a potential role for this system in the development of osteoporosis in patients with b-thalassemia major and its relationship with iron overload and iron chelation therapy.…”