title: Higher serum undercarboxylated osteocalcin and other bone turnover markers are associated with reduced diabetes risk and lower estradiol concentrations in older men.
abstract: BACKGROUND
  In mice, undercarboxylated osteocalcin (ucOC) modulates insulin secretion and sensitivity and increases testosterone (T) secretion from Leydig cells, but human data are lacking. We hypothesized that ucOC is associated with diabetes risk and modulates sex hormone concentrations in older men, distinct from other bone turnover markers.
  
  
  METHODS
  PARTICIPANTS were community-dwelling men aged 70 to 89 years resident in Perth, Western Australia.
  
  
  METHODS
  Serum total osteocalcin (TOC), N-terminal propeptide of type I collagen (P1NP), and collagen type I C-terminal cross-linked telopeptide (CTX) were measured by immunoassay, and ucOC by hydroxyapatite binding. Plasma total T, DHT, and estradiol (E2) were assayed by mass spectrometry.
  
  
  RESULTS
  Excluding men with osteoporosis or conditions affecting sex hormones or on bisphosphonates, glucocorticoids, or warfarin, 2966 men were included. In multivariate analyses, higher ucOC was associated with reduced diabetes risk (odds ratio [OR] per 1 SD increase = 0.55, P < .001). Similar results were seen for TOC (OR = 0.60, P < .001), P1NP (OR = 0.64, P < .001), and CTX (OR = 0.60, P < .001) but not ucOC/TOC. When all 4 markers were included in the fully adjusted model, higher ucOC (OR = 0.56, P < .001) and CTX (OR = 0.76, P = .008) remained associated with reduced diabetes risk. E2 was inversely associated with ucOC (coefficient -0.04, P = .031), TOC (-0.05, P = .001) and CTX (-0.04, P = .016); and positively with ucOC/TOC (0.05, P = .002). DHT was inversely associated with ucOC/TOC (-0.04, P = .040). T was not associated with bone turnover.
  
  
  CONCLUSIONS
  Higher bone remodeling rates are associated with reduced diabetes risk in older men. Higher ucOC is both a marker of bone remodeling and an independent predictor of reduced diabetes risk. E2 is inversely associated with bone turnover markers. We found no evidence ucOC modulates circulating T in older men.
authors.affiliation: Schools of Medicine and Pharmacology (B.B.Y., S.A.P.C., L.F.) and Surgery (P.E.N.) and Western Australian Centre for Health and Ageing (L.F.), Centre for Medical Research, University of Western Australia, Perth, Western Australia 6009, Australia; Department of Endocrinology and Diabetes (B.B.Y., R.G.), Fremantle and Fiona Stanley Hospitals, Perth, Western Australia 6160, Australia; School of Public Health (H.A.), Curtin University, Perth, Western Australia 6102, Australia; PathWest Laboratory Medicine (S.A.P.C., J.P.B.), Fremantle, Royal Perth and Sir Charles Gairdner Hospitals, Perth, Western Australia 6160, Australia; Department of Medicine (P.R.E.), School for Clinical Sciences, Monash University, Melbourne, Victoria 3800, Australia; ANZAC Research Institute (D.J.H.), University of Sydney, Sydney, New South Wales 2139, Australia; Monash Institute of Medical Research (C.A.A.), Prince Henry's Research Institute, Melbourne, Victoria 3168, Australia; and Department of Medicine (M.G.), Austin Health, University of Melbourne, Melbourne, Victoria, 3084 Australia.
authors.forename: Bu B
authors.initials: BB
authors.lastname: Yeap
authors.forename: Helman
authors.initials: H
authors.lastname: Alfonso
authors.forename: S A Paul
authors.initials: SA
authors.lastname: Chubb
authors.forename: Richard
authors.initials: R
authors.lastname: Gauci
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Byrnes
authors.forename: John P
authors.initials: JP
authors.lastname: Beilby
authors.forename: Peter R
authors.initials: PR
authors.lastname: Ebeling
authors.forename: David J
authors.initials: DJ
authors.lastname: Handelsman
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Allan
authors.forename: Mathis
authors.initials: M
authors.lastname: Grossmann
authors.forename: Paul E
authors.initials: PE
authors.lastname: Norman
authors.forename: Leon
authors.initials: L
authors.lastname: Flicker
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D015519:Bone Density; D024042:Collagen Type I / Q000097:blood; D003922:Diabetes Mellitus, Type 1 / Q000097:blood*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D013196:Dihydrotestosterone / Q000097:blood; D004958:Estradiol / Q000097:blood*; D006801:Humans; D008297:Male; D015675:Osteocalcin / Q000097:blood*; D010446:Peptide Fragments / Q000097:blood; D010455:Peptides / Q000097:blood; D011347:Procollagen / Q000097:blood; D012307:Risk Factors; D013739:Testosterone / Q000097:blood
chemical_list: D015415:Biomarkers; D024042:Collagen Type I; D010446:Peptide Fragments; D010455:Peptides; D011347:Procollagen; C052929:collagen type I trimeric cross-linked peptide; C047202:procollagen Type I N-terminal peptide; D013196:Dihydrotestosterone; D015675:Osteocalcin; D013739:Testosterone; D004958:Estradiol