Context: Osteoporosis is a systemic disease with a strong genetic component. Vitamin D receptor (VDR) gene polymorphisms explain only a small part of the genetic influence on the level of bone mineral density (BMD), whereas their effect on fracture remains uncertain.

Objective: The objective of this study was to investigate the relationships between VDR genotypes and fracture risk

Design: A prospective population-based cohort was studied.

Subjects: A total of 589 postmenopausal women (mean age, 62 yr) were followed prospectively during a median (interquartile) of 11 (1.1) yr.

Main Outcome Measure: The study measured incidents of vertebral and nonvertebral fractures.

Results: VDR allele B was significantly and dose dependently overrepresented in women who fractured, including 34 and 86 women with first incident vertebral and nonvertebral fragility fractures, respectively. This corresponded to an odds ratio of 1.5 (95% confidence interval, 0.95–2.40) for heterozygous carriers (bB, n = 286) and 2.10 (95% confidence interval, 1.16–3.79) for homozygous carriers (BB, n = 90) of the B allele, compared with women with the bb genotype (n = 213). VDR genotype groups did not differ for demographics, physical activity, grip strength, personal and maternal history of fracture, and calcium intake. The association was independent of BMD of the spine, hip, and radius, and of the BMD loss at the radius. The relationship between VDR polymorphisms and fracture risk was not altered after adjustment for baseline circulating levels of bone turnover markers, estradiol, dehydroepiandrosterone sulfate, SHBG, IGF-I, intact PTH, and 25 hydroxyvitamin D.

Conclusion: VDR genotypes are associated with the risk of fracture in postmenopausal women independently of BMD, rate of postmenopausal forearm BMD loss, bone turnover, and endogenous hormones. The mechanisms by which VDR genotypes influence bone strength remain to be determined.