Exploring the Causal Relationship Between Osteoporosis and Rheumatoid Arthritis: A Bidirectional Mendelian Randomization Study

Abstract

Objective: Osteoporosis and rheumatoid arthritis (RA) are commonly associated, but whether there is a causal genetic relationship between them remains unclear. This study used a two-sample Mendelian randomization (MR) approach to investigate this causal relationship.

Methods: Genetic instruments for osteoporosis and RA were obtained from published genome-wide association studies (GWAS). We selected SNPs with genome-wide significance (p < 5×10-8) and independent variation (r2 < 0.001). Causality was assessed using the inverse variance weighted (IVW) method, and heterogeneity, pleiotropy, and robustness were tested using Cochran's Q test, MR-Egger intercept, and leave-one-out sensitivity analysis.

Results: The MR analysis revealed a causal effect of decreased bone mineral density (BMD) on RA risk (TB-BMD: OR = 1.094, 95% CI = 1.023-1.170, P = 0.009; FA-BMD: OR = 1.159, 95% CI = 1.019-1.320, P = 0.025; LS-BMD: OR: 1.175, 95% CI = 1.070-1.291, P = 0.001). Osteoporosis at different sites and age groups significantly influenced RA, while RA did not significantly affect osteoporosis. Sensitivity analyses confirmed the robustness of the results.

Conclusion: Our study suggests a potential causal relationship between osteoporosis and RA, suggesting that osteoporosis may predispose individuals to RA. Further research is needed to understand the mechanisms and to confirm these findings across diverse populations.

Keywords: GWAS; Mendelian randomization; osteoporosis; rheumatoid arthritis.

Figure 1

The MR design, guided by strict assumptions. Assumption 1: Genetic variants (instrumental variables) must be strongly associated with the risk factor. Assumption 2: These genetic variants should not be linked to confounding factors. Assumption 3: The variants should influence the outcome solely through the risk factor, not via other pathways. MR reduces confounding and reverse causation, enhancing causal inference because genetic variants are randomly allocated at conception, minimizing bias.

Figure 2

Effect of Bone Mineral Density at Different Sites on RA.

Figure 3

Effect of Bone Mineral Density at Different Ages on RA.

Figure 4

Effect of RA on Bone Mineral Density at Different Sites.

Figure 5

Effect of RA on Bone Mineral Density at Different Ages.