Bone mineral density (BMD) measured at the femoral neck (FN) is the most important risk phenotype for osteoporosis and has been used as a reference standard for describing osteoporosis. The specific genes influencing FN BMD remain largely unknown. To identify such genes, we first performed a genome-wide association (GWA) analysis for FN BMD in a discovery sample consisting of 983 unrelated white subjects. We then tested the top significant single-nucleotide polymorphisms (SNPs; 175 SNPs with p<5×10-4) for replication in a family-based sample of 2557 white subjects. Combing results from these two samples, we found that two genes, parathyroid hormone (PTH) and interleukin 21 receptor (IL21R), achieved consistent association results in both the discovery and replication samples. The PTH gene SNPs, rs9630182, rs2036417, and rs7125774, achieved p values of 1.10×10-4, 3.24×10-4, and 3.06×10-4, respectively, in the discovery sample; p values of 6.50×10-4, 5.08×10-3, and 5.68×10-3, respectively, in the replication sample; and combined p values of 3.98×10-7, 9.52×10-6, and 1.05×10-5, respectively, in the total sample. The IL21R gene SNPs, rs8057551, rs8061992, and rs7199138, achieved p values of 1.51×10-4, 1.53×10-4, and 3.88×10 -4, respectively, in the discovery sample; p values of 2.36×10-3, 6.74×10-3, and 6.41×10 -3, respectively, in the replication sample; and combined p values of 2.31×10-6, 8.62×10-6, and 1.41×10 -5, respectively, in the total sample. The effect size of each SNP was approximately 0.11 SD estimated in the discovery sample. PTH and IL21R both have potential biologic functions important to bone metabolism. Overall, our findings provide some new clues to the understanding of the genetic architecture of osteoporosis. © 2010 American Society for Bone and Mineral Research.