The causal association between bone mineral density and risk of osteoarthritis: A Mendelian randomization study

Objectives The causal direction and magnitude of the association between total body bone mineral density (TB-BMD) and osteoarthritis (OA) risk is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. The study aimed to explore the relationships between TB-BMD concentration and OA using Mendelian randomization (MR). Methods In this study, we used two-sample MR to obtain unconfounded estimates of the effect of TB-BMD on hip and knee OA. Single nucleotide polymorphisms (SNPs) strongly associated with TB-BMD in a large genome-wide association study (GWAS) were identified and selected as instrumental variables (IVs). In addition to the main analysis using inverse-variance weighted (IVW) method, we applied 2 additional methods to control for pleiotropy(MR-Egger regression, weighted median estimator) and compared the respective MR estimates. Results MR analyses suggested that genetically predicted higher TB-BMD is associated with risks of hip OA (For IVW: OR=1.199, 95%CI: 1.02-1.42, P =0.032; for WM: OR=1.257, 95%CI: 1.09-1.45, P =0.002). There was no evidence that the observed causal effect between TB-BMD and the risk of hip OA was affected by genetic pleiotropy( P =0.618). Additionally, our study didn’t support causal effects of a genetically increased TB-BMD risk on knee OA risk(OR=1.121, 95%CI: 0.99-1.28, P =0.084 using IVW; OR=1.132, 95%CI: 0.99-1.29, P =0.068 using WM; OR=1.274, 95%CI: 0.88-1.85, P =0.217 using MR-Egger). Conclusions Our findings support a causal effect that a genetic predisposition to systematically higher TB-BMD was associated with the risk of OA. And, TB-BMD likely exerts an effect on the risk of hip OA not knee OA.