Abstract: BACKGROUND: Many clinical research observations have indicated a close association between rheumatoid arthritis and osteoporosis as well as bone mineral density (BMD). However, it remains unclear whether there is a causal genetic relationship between rheumatoid arthritis and the development of osteoporosis and alterations of BMD.
OBJECTIVE: To assess the potential causal relationship between rheumatoid arthritis and osteoporosis as well as BMD using a two-sample Mendelian randomization approach, provide meaningful insights from a genetic perspective into the underlying mechanisms and offer a reference for early prevention of osteoporosis and improvement in the progression of the disease.
METHODS: We conducted a study using data from publicly available genome-wide association studies databases to identify single nucleotide polymorphisms associated with rheumatoid arthritis as instrumental variables (P < 5×10-8). The main outcomes of the study included osteoporosis and BMD at five different sites, including total body BMD, lumbar spine BMD, femoral neck BMD, heel BMD, and forearm BMD. The inverse variance-weighted method was used as the primary analysis method to evaluate causal effects. Weighted median, simple median, weighted mode and MR-Egger regression were used as supplementary analyses. Causal relationships between rheumatoid arthritis and the risk of osteoporosis and BMD were assessed using odds ratios (OR) and 95% confidence intervals (CI). Heterogeneity was assessed using Cochran’s Q test and horizontal pleiotropy was evaluated using MR-Egger intercept tests.
RESULTS AND CONCLUSION: The inverse variance-weighted analysis demonstrated a positive association between genetically predicted rheumatoid arthritis and osteoporosis (OR=1.123, 95% CI: 1.077-1.171; P=4.02×10-8). Heterogeneity test (P=0.388) indicated no significant heterogeneity among the single nucleotide polymorphisms. MR-Egger intercept (P=0.571) tests did not detect horizontal pleiotropy, and sensitivity analysis showed no evidence of bias in the study results. There was no causal relationship between rheumatoid arthritis and BMD at the five different sites. The total body BMD (OR=1.000, 95% CI: 0.988-1.012; P=0.925), lumbar spine BMD (OR=0.999, 95% CI: 0.982-1.016; P=0.937), femoral neck BMD (OR=1.001, 95% CI: 0.986-1.016; P=0.866), heel BMD (OR=0.996, 95% CI: 0.989-1.004; P=0.419), and forearm BMD (OR=1.063, 95% CI: 0.970-1.031; P=0.996) indicated no significant association. MR-Egger intercept analysis did not detect potential horizontal pleiotropy (total body BMD: P=0.253; lumbar spine BMD: P=0.638; femoral neck BMD: P=0.553; heel BMD: P=0.444; forearm BMD: P=0.079). Rheumatoid arthritis may contribute to the development of osteoporosis through the interaction between chronic inflammation and bone formation, resorption, and absorption. Additionally, the use of glucocorticoids and the presence of autoantibodies (such as anti-citrullinated protein antibody) in patients with rheumatoid arthritis showed associations with osteoporosis. Future research should focus on monitoring systemic inflammatory markers, standardized use of glucocorticoids, and regular screening for osteoporosis risk in patients with rheumatoid arthritis.

Key words: osteoporosis, rheumatoid arthritis, bone mineral density, Mendelian randomization, single nucleotide polymorphism, causal association, genome-wide association study, instrumental variable