Corrigenda

Abstract

Context:The role and importance of circulating sclerostin is poorly understood. High bone mass (HBM) caused by activating LRP5 mutations has been reported to be associated with increased plasma sclerostin concentrations; whether the same applies to HBM due to other causes is unknown.Objective:Our objective was to determine circulating sclerostin concentrations in HBM.Design and Participants:In this case-control study, 406 HBM index cases were identified by screening dual-energy x-ray absorptiometry (DXA) databases from 4 United Kingdom centers (n = 219 088), excluding significant osteoarthritis/artifact. Controls comprised unaffected relatives and spouses.Main measures:Plasma sclerostin; lumbar spine L1, total hip, and total body DXA; and radial and tibial peripheral quantitative computed tomography (subgroup only) were evaluated.Results:Sclerostin concentrations were significantly higher in both LRP5 HBM and non-LRP5 HBM cases compared with controls: mean (SD) 130.1 (61.7) and 88.0 (39.3) vs 66.4 (32.3) pmol/L (both P < .001, which persisted after adjustment for a priori confounders). In combined adjusted analyses of cases and controls, sclerostin concentrations were positively related to all bone parameters found to be increased in HBM cases (ie, L1, total hip, and total body DXA bone mineral density and radial/tibial cortical area, cortical bone mineral density, and trabecular density). Although these relationships were broadly equivalent in HBM cases and controls, there was some evidence that associations between sclerostin and trabecular phenotypes were stronger in HBM cases, particularly for radial trabecular density (interaction P < .01).Conclusions:Circulating plasma sclerostin concentrations are increased in both LRP5 and non-LRP5 HBM compared with controls. In addition to the general positive relationship between sclerostin and DXA/peripheral quantitative computed tomography parameters, genetic factors predisposing to HBM may contribute to increased sclerostin levels.

Genome-wide association study of extreme high bone mass: Contribution of common genetic variation to extreme BMD phenotypes and potential novel BMD-associated genes

“…NPR3 may be the target gene regulated by rs9292469, as our human osteoblast eQTL data do not support an alternative target, and we and others have shown Npr3 expression in the mouse skeleton [ 48 ]. Previous findings in our unexplained HBM population have shown that although adult height is no different from controls, trabeculae are thicker increasing trabecular density [ 57 , 58 ], possibly recapitulating observations in Npr3 -mutant mice [ 47 , 49 ]. Our previous analyses suggested unexplained HBM protects against age-associated declines in trabecular BMD [ 57 ].…”

“…Spon1 knockout mice have a skeletal phenotype consistent with HBM, with Spon1 −/− mice at 6 months age having 60% higher bone volume, bone volume/total volume, cortical area and trabecular number with reduced trabecular spacing [ 59 ]. Increased trabecular density and reduced endosteal expansion is seen in human HBM [ 57 , 58 ]. Serum CTX-1 and TRAP levels are normal in Spon1 −/− mice; however, TGF-β1 levels are reduced compared with WT mice, whilst SMAD 1/5 activation is enhanced in both osteoblasts and chondrocytes [ 59 ].…”

High Serum Sclerostin Levels Are Associated with a Better Outcome in Haemodialysis Patients

“…However, Szulc et al [27] found a similar relationship in male patients with normal renal function, and this association has been reported in post-menopausal women without CKD [28]. Moreover, individuals with genetically high bone mass have higher serum sclerostin levels than controls [29]. This could be in apparent contradiction with the known impact of sclerostin on post-menopausal osteoporosis [30].…”

Idiopathic Acquired Osteosclerosis in a Middle-Aged Woman With Systemic Lupus Erythematosus

“…(26-28) Hence, our patient's hypersclerostinemia could seem paradoxical. In the high-bone-mass disorder due to activating mutations within LRP5 causing increased WNT signalling, (29) circulating SOST levels are normal (29-30) or increased. (31) For our patient, mutation analysis was negative for SOST, LRP5, LRP4, and osteopetrosis genes.…”