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Submitted on February 18, 2005
Accepted on April 28, 2005
INSERM Research Unit 403, Lyon France; Synarc, Lyon, France
* To whom correspondence should be addressed. E-mail: patrick.garnero{at}synarc.com.
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), while their effect on fracture remains uncertain.
Objective: To investigate the relationships between VDR genotypes and fracture risk
Design: Prospective population-based cohort
Subjects: 589 postmenopausal (mean age 62 yr) followed prospectively during a median (IQ) of 11 yr (1.1).
Main outcome: Incident vertebral and non-vertebral fractures
Results: VDR allele B was significantly and dose dependently over represented in women who fractured, including 34 and 86 women with first incident vertebral and non vertebral fragility fractures, respectively. This corresponded to an odds-ratio (OR) of 1.5 (95% CI: 0.95-2.40) for heterozygous carriers (bB: n = 286) and 2.10 (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, sex hormone binding globulin, insulin-like growth factor I, intact parathyroid hormone 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.
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