Nicola Dalbeth, Ruth Topless, Tanya Flynn, Murray Cadzow, Mark J Bolland, Tony R Merriman

In observational studies, serum urate concentrations are positively associated with bone mineral density (BMD) and reduced risk of fragility fractures, raising the possibility that urate is a direct mediator of bone density. We used Mendelian randomisation analysis to examine whether urate has a causal effect on BMD. Methods We analysed data from the Generation 3 cohort in the Framingham Heart Study (FHS) (n=2501 total; 1265 male, 1236 female). A weighted genetic urate score was calculated using the SLC2A9, ABCG2, SLC17A1, SLC22A11 and SLC22A12 SNPs that explain 3.4% of the variance in serum urate. Mendelian randomisation analysis was done using the two-stage least squares method, with >80% power at α=0.05 to detect an effect size equivalent to that observed in the ordinary least squares analysis between serum urate and total femur BMD. Results A strong association between serum urate and BMD was observed in the crude ordinary least squares analysis (total femur crude beta=0.47, P=1.7E-51). In the two-stage least squares analysis using the weighted genetic urate score as the instrumental variable, no significant relationship was observed between serum urate and BMD (total femur crude beta -0.36, P=0.06). Similar findings were observed in both the male and female subgroups, and there was no evidence for causality when individual SNPs were analysed. Conclusion Serum urate is strongly associated with BMD. However, controlling for confounders by Mendelian randomisation analysis does not provide evidence that increased urate has a causal effect on increasing BMD. This article is protected by copyright. All rights reserved.