Objective: Integrin alphavbeta3 is essential for mature osteoclast function and therefore important for the development of osteoporosis and osteoporotic fractures. Integrin alphavbeta3 antagonists have antiresorptive effects in bone. We tested the hypothesis that the Leu33Pro polymorphism in the integrin beta3-subunit associates with risk of hip fracture.
Methods: We included 9233 men and women selected at random to represent the Danish general population as participants in the Copenhagen City Heart Study. First-ever hip fractures (n=267) were registered during 25 years follow-up. Log-rank statistics and Cox regression were used to compare fracture incidences and risk estimates between genotypes.
Results: Genotyping rendered 69.9% noncarriers, 27.3% heterozygotes and 2.7% homozygotes. Incidence of hip fracture was 2.8 and 1.5 per 1000 person-years in homozygotes and noncarriers (log-rank: P=0.02), respectively. Multifactorial adjusted Cox regression revealed a hazard ratio of 2.0 (95% confidence interval: 1.1-3.5) for hip fracture in homozygotes versus noncarriers. After stratification by sex, equivalent hazard ratios were 2.0 (1.0-4.1) in women and 2.0 (0.8-5.0) in men. In the 2193 postmenopausal women, hazard ratio for hip fracture in homozygotes versus noncarriers after additional adjustment for age at menopause and use of hormone replacement therapy was 2.6 (1.2-5.3). Hazard ratio for hip fracture in heterozygotes versus noncarriers did not differ from 1.0.
Conclusions: Individuals homozygous for the integrin beta3 Leu33Pro polymorphism have a two-fold risk of hip fracture, mainly confined to postmenopausal women. Integrin beta3 Leu33Pro homozygosity could prove a useful marker for risk of future hip fracture and may contribute to pharmacogenetic variation in effects of integrin alphavbeta3 antagonists.