title: Elevated circulating Sclerostin concentrations in individuals with high bone mass, with and without LRP5 mutations.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
authors.affiliation: Musculoskeletal Research Unit (C.L.G., J.H.T.), School of Clinical Sciences, University of Bristol, Bristol BS10 5NB, United Kingdom; Medical Research Council (MRC) Lifecourse Epidemiology Unit (C.L.G.), University of Southampton, Southampton, SO16 6YD United Kingdom; Department of Medicine (K.E.S.P.), University of Cambridge, Cambridge, CB2 0SP United Kingdom; Metabolic Bone Centre (E.V.M.), Sheffield University, Sheffield, S3 7HF United Kingdom; Human Genetics Group (E.L.D.), University of Queensland Diamantina Institute, Brisbane, Australia; Department of Endocrinology (E.L.D), Royal Brisbane and Women's Hospital, Brisbane, Australia; Institute of Aerospace Medicine (J.R.), German Aerospace Center (Deutschen Zentrums fuür Luft- und Raumfahrt), Cologne, Germany; Institute for Biomedical Research into Human Movement and Health Research Institute (J.R.), Manchester Metropolitan University, Manchester, M1 5GD United Kingdom; Department of Medicine (W.D.F.), Norwich Medical School, University of East Anglia, Norwich, NR4 7TJ United Kingdom; and MRC Integrative Epidemiology Unit (G.D.S.), School of Social and Community Based Medicine, University of Bristol, Bristol, BS8 2BN United Kingdom.
authors.forename: Celia L
authors.initials: CL
authors.lastname: Gregson
authors.forename: Kenneth E S
authors.initials: KE
authors.lastname: Poole
authors.forename: Eugene V
authors.initials: EV
authors.lastname: McCloskey
authors.forename: Emma L
authors.initials: EL
authors.lastname: Duncan
authors.forename: Jörn
authors.initials: J
authors.lastname: Rittweger
authors.forename: William D
authors.initials: WD
authors.lastname: Fraser
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Tobias
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015519:Bone Density / Q000235:genetics; D019485:Bone Morphogenetic Proteins / Q000097:blood*; D016022:Case-Control Studies; D005260:Female; D005819:Genetic Markers; D006801:Humans; D015576:Hyperostosis / Q000097:blood* / Q000453:epidemiology / Q000235:genetics; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010009:Osteochondrodysplasias / Q000097:blood* / Q000453:epidemiology / Q000235:genetics; D013576:Syndactyly / Q000097:blood* / Q000453:epidemiology / Q000235:genetics; D006113:United Kingdom / Q000453:epidemiology; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C422903:SOST protein, human