INTRODUCTION: 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. METHODS: Pair-wise tag SNPs (r(2)>/=0.8) were selected for RANKL, RANK and OPG, and their 10 kb flanking regions. Selected tag SNPs plus 5 SNPs near RANKL and OPG, associated with BMD in published genome-wide association studies (GWAS), were genotyped in 2653 men aged 40-79 years, recruited for participation in a population-based study of male aging, the European Male Ageing Study (EMAS). N-terminal propeptide of type I procollagen (P1NP) and C-terminal cross-linked telopeptide of type I collagen (CTX-1) serum levels were measured in all men. BMD at calcaneus was estimated by quantitative ultrasound (QUS) in all men. Lumbar spine and total hip areal BMD (BMD(a)) was measured by dual energy X-ray absorptiometry (DXA) in a subsample of 620 men. RESULTS: 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 P1NP (beta=1.83, p=0.004) and CTX-1 (beta=17.59, p=4.74x10(-4)), and lower lumbar spine BMD(a) (beta=-0.02, p=0.026). The minor allele of rs9594759 (C) was associated with lower P1NP (beta=-1.84, p=0.003) and CTX-1 (beta=-27.02, p=6.06x10(-8)), and higher ultrasound BMD at calcaneus (beta=0.01, p=0.037). CONCLUSION: 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.