Insulin-like Growth Factor-1, Bone Mineral Density, and Fracture: A Mendelian Randomization Study

CONTEXT: The associations of circulating insulin-like growth factor-1 (IGF-1) levels with bone mineral density and fracture risk are inconclusive in observational studies. OBJECTIVE: We conducted a mendelian randomization study to assess the associations of serum IGF-1 levels with estimated bone mineral density (eBMD) and fracture. METHODS: Genetic instruments for IGF-1 were selected at the genome-wide significance level (P < 5 × 10(–8)) from a genome-wide association study including 358 072 individuals of European ancestry. Summary-level data for eBMD (426 824 individuals) and fracture (53 184 fracture cases and 373 611 noncases) were obtained from the UK Biobank study. Univariable and multivariable mendelian randomization analyses methods were used to estimate the associations of IGF-1 with eBMD and fracture. The main outcome measure included the change of eBMD and odds ratio of fracture per genetically predicted 1-SD increase of serum IGF-1 levels. RESULTS: For 1-SD increase in IGF-1, the change of eBMD levels was 0.04 g/cm(2) (95% CI, 0.01-0.07; P = .011) and the odds ratio of fracture was 0.94 (95% CI, 0.91-0.98; P = .003). The associations persisted with similar magnitude after adjustment for height. The association was consistent for fracture but not for eBMD after excluding genetic instruments that might directly influence these outcomes. The association between IGF-1 and fracture was somewhat attenuated after adjustment for eBMD (odds ratio 0.96; 95% CI, 0.92-0.99; P = .012). CONCLUSION: The present study supports a role for IGF-1 in preventing fracture, possibly and partly mediated by greater bone mineral density.