Using multivariable Mendelian randomization to estimate the causal effect of bone mineral density on osteoarthritis risk, independent of body mass index

ObjectivesObservational analyses suggest that high Bone Mineral Density (BMD) is a risk factor for osteoarthritis (OA); its unclear whether this represents a causal effect or shared aetiology and whether these relationships are body mass index (BMI)-independent. We performed bidirectional Mendelian randomization (MR) to uncover the causal pathways between BMD, BMI and OA. MethodsOne-sample (1S)MR estimates were generated by two-stage least-squares regression. Unweighted allele scores instrumented each exposure. Two-sample (2S)MR estimates were generated using inverse-variance weighted fixed-effects meta-analysis. Multivariable MR (MVMR), including BMD and BMI instruments in the same model, determined the BMI-independent causal pathway from BMD to OA. Latent causal variable (LCV) analysis, using weight-adjusted FN-BMD and hip/knee OA summary statistics, determined if genetic correlation explained the causal effect of BMD on OA. Results1SMR provided strong evidence for a causal effect of eBMD on hip and knee OA (ORhip =1.28[1.05,1.57],p=0.02, ORknee =1.40[1.20,1.63],p=3x10-5, OR per SD increase). 2SMR effect sizes were consistent in direction. Results suggested that the causal pathways between eBMD and OA were bidirectional ({beta}hip=1.10[0.36,1.84],p=0.003, {beta} knee =4.16[2.74,5.57],p=8x10-9, {beta}=SD increase per doubling in risk). MVMR identified a BMI-independent causal pathway between eBMD and hip/knee OA. LCV suggested that genetic correlation (i.e. shared genetic aetiology) did not fully explain causal effects of BMD on hip/knee OA. ConclusionsThese results provide evidence for a BMI-independent causal effect of eBMD on OA. Despite evidence of bidirectional effects, the effect of BMD on OA did not appear to be fully explained by shared genetic aetiology, suggesting a direct action of bone on joint deterioration.