Exploring causality between bone mineral density and frailty: A bidirectional Mendelian randomization study

The bidirectional correlation between low bone mineral density (BMD) and frailty, despite its extensive documentation, still lacks a conclusive understanding. The objective of this Mendelian randomization (MR) study is to investigate the bidirectional causal relationship between BMD and frailty.

We utilized summary statistics data for BMD at different skeletal sites-including heel BMD (e-BMD, N = 40,613), forearm BMD (FA-BMD, N = 8,143), femoral neck BMD (FN-BMD, N = 32,735), and lumbar spine BMD (LS-BMD, N = 28,489), alongside frailty index (FI, N = 175,226) data in participants of European ancestry. MR analysis in our study was conducted using well-established analytical methods, including inverse variance weighted (IVW), weighted median (WM), and MR-Egger approaches.

We observed negative causal estimates between genetically predicted e-BMD (IVW β = - 0.020, 95% confidence interval (CI) = - 0.038, - 0.002, P = 0.029) and FA-BMD (IVW β = -0.035, 95% CI = -0.066, -0.004, P = 0.028) with FI. However, the results did not reach statistical significance after applying the Bonferroni correction, with a significance threshold set at P < 0.0125 (0.05/4). There was no causal effect of FN-BMD (IVW β = - 0.024, 95% CI = -0.052, 0.004, P = 0.088) and LS-BMD (IVW β = - 0.005, 95% CI = -0.034, 0.024, P = 0.749) on FI. In the reverse Mendelian randomization (MR) analysis, we observed no causal effect of FI on BMD at various skeletal sites.

Our study provides support for the hypothesis that low BMD may be a potential causal risk factor for frailty, but further research is needed to confirm this relationship. However, our findings did not confirm reverse causality.