Genetic Variation in the RANKL/RANK/OPG Signaling Pathway Is Associated With Bone Turnover and Bone Mineral Density in Men

Research output: Contribution to journalArticle


The aim of this study was to determine if single-nucleotide polymorphisms (SNPs) in RANKL, RANK, and OPG influence bone turnover and bone mineral density (BMD) in men. Pairwise tag SNPs (r(2) >= 0.8) were selected for RANKL, RANK, and OPG and their 10-kb flanking regions. Selected tag SNPs plus five SNPs near RANKL and OPG, associated with BMD in published genome-wide association studies (GWAS), were genotyped in 2653 men aged 40 to 79 years of age recruited for participation in a population-based study of male aging, the European Male Ageing Study (EMAS). N-terminal propeptide of type I procollagen (PINP) and C-terminal cross-linked telopeptide of type I collagen (CTX-I) serum levels were measured in all men. BMD at the calcaneus was estimated by quantitative ultrasound (QUS) in all men. Lumbar spine and total-hip areal BMD (BMDa) was measured by dual-energy X-ray absorptiometry (DXA) in a subsample of 620 men. Multiple OPG, RANK, and RANKL SNPs were associated with bone turnover markers. We also identified a number of SNPs associated with BMD, including rs2073618 in OPG and rs9594759 near RANKL. The minor allele of rs2073618 (C) was associated with higher levels of both PINP (beta = 1.83, p = .004) and CTX-I (beta = 17.59, p = 4.74 x 10(-4)), and lower lumbar spine BMDa (beta = -0.02, p = .026). The minor allele of rs9594759 (C) was associated with lower PINP (beta = -1.84, p = .003) and CTX-I (beta = -27.02, p = 6.06 x 10(-8)) and higher ultrasound BMD at the calcaneus (beta = 0.01, p = .037). Our findings suggest that genetic variation in the RANKL/RANK/OPG signaling pathway influences bone turnover and BMD in European men. (c) 2010 American Society for Bone and Mineral Research.


  • Delnaz Roshandel
  • Kate L. Holliday
  • Stephen R. Pye
  • Steven Boonen
  • Herman Borghs
  • Dirk Vanderschueren
  • Ilpo T. Huhtaniemi
  • Judith E. Adams
  • Kate A. Ward
  • Gyorgy Bartfai
  • Felipe Casanueva
  • Joseph D. Finn
  • Gianni Forti
  • Thang S. Han
  • Krzysztof Kula
  • Michael E. Lean
  • Neil Pendleton
  • Margus Punab
  • Alan J. Silman
  • Frederick C. Wu
  • Wendy Thomson
  • Terence W. O'Neill
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Obstetrics, Gynecology and Reproductive Medicine


Original languageEnglish
Pages (from-to)1830-1838
JournalJournal of Bone and Mineral Research
Issue number8
Publication statusPublished - 2010
Publication categoryResearch