Circulating osteoprotegerin and receptor activator of NF-κB ligand system in patients with β-thalassemia major

Abstract

Osteoporosis represents an important cause of morbidity in patients with beta-thalassemia major, and its etiology is multifactorial. Thus, the aim of this study was to characterize the possible role of the osteoprotegerin (OPG) and receptor activator of the NF-kappaB ligand (RANKL) system in thalassemia-related bone loss. Serum concentrations of OPG, soluble RANKL (s-RANKL), markers of bone turnover, and lumbar spine bone mineral density (BMD) were measured in random samples of males (n = 29; mean age +/- SEM, 24.26 +/- 1.29 years; range, 13-41 years) and females (n = 31; age, 24.59 +/- 0.95 years; range, 12-34 years) with beta-thalassemia major and in 30 healthy age-, height-, and weight-matched subjects. Thalassemic patients had significantly lower levels of OPG compared with controls (2.54 +/- 0.12 vs. 3.25 +/- 0.122, respectively; P < 0.05) and higher, albeit not statistically significantly, serum levels of s-RANKL (0.350 +/- 0.03 vs. 0.295 +/- 0.046, respectively; P < 0.05). s-RANKL correlated negatively with age (r = -0.3, P < 0.05), and OPG correlated positively with the duration of the interval between the onset of transfusions and chelation therapy (r = 0.52, P < 0.001). Regarding markers of bone metabolism, plasma values of osteocalcin correlated positively with s-RANKL (r = 0.40, P < 0.05) and negatively with OPG/s-RANKL ratio (r = -0.55, P < 0.01). In multiple regression analysis only cross-linked N-teleopeptide of type I collagen (NTX) significantly accounted for BMD. Although the OPG/RANKL system may have some clinical usefulness as a marker of bone turnover in beta-thalassemia, conventional markers of bone turnover more accurately represent changes in the BMD of these patients.

Association of osteoprotegerin and rankl levels with insulin resistance in pubertal obese children

“…Browner has reported the association between serum OPG levels with diabetes and cardiovascular mortality, however OPG levels were not correlated with either baseline BMD or the risk of stroke or fracture [6]. In their study on beta-thalassemia patients, Angelopoulos NG et al demonstrated the clinical effectiveness of the OPG/RANKL system as a marker of bone turnover [23]. In our study, we failed to demonstrate a significant correlation between OPG or BMD levels of obese children and control group.…”

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

“…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.…”

“…The pathogenesis of thalassemia-induced bone disease is multifactorial and includes bone marrow expansion, endocrine dysfunction, and iron overload, as well as genetic susceptibility to attainment of low peak bone mass (17,18). At tissue level, it has been demonstrated that there is an osteoblast dysfunction together with increased osteoclast activity leading to imbalanced bone turnover in favor of bone resorption (19)(20)(21).…”

Anabolic therapy in b-thalassaemia major induced osteoporosis: case report and literature review

“…Una bassa DMO è associata, nei T, alla cardiomiopatia, al diabete, all'epatite cronica, all'incremento delle transaminasi, all'amenorrea (31) ed alla mancata terapia ormonale sostitutiva nei casi di ipogonadismo ipogonadotropo (29)(30)(31). A carico del tessuto osseo, in corso di ST si determina: -basso valore del rapporto osteoprotegerina (OPG)/ RANKL con (a) livelli di OPG sovrapponibili (39) o diminuiti (40,41) e (b) netto aumento del RANKL rispetto alla popolazione generale (39); -alti livelli di cross-links del piridinio e di N-telopeptidi urinari (39,(41)(42)(43); -livelli diminuiti di osteocalcina, fosfatasi alcalina ossea e C telopeptide del procollagene I (40, 43); -riduzione della attività osteoblastica a causa dei depositi di ferro (44); -ridotta 25-idrossilazione della vitamina D a causa della emosiderosi epatica e della possibile presenza di epatite post-trasfusionale (33, 34); -ridotta secrezione di GH con conseguente ridotta proliferazione degli OB (9, 45) e, da parte di questi ultimi, ridotta secrezione di insulinlike growth factor I (IGF-I) (39) e di Insulin-like growth factor binding protein-3 (IGFBP-3) (29); -correlazione statisticamente significativa dei diminuiti livelli di IGF-I con la diminuizione della DMO (41); -correlazione inversa tra l'aumento del RANKL ed i livelli di testosterone libero e 17-b-estradiolo (39).…”