Rheumatoid arthritis and the risk of fracture: A Mendelian randomization study

Observational epidemiological studies indicate a higher fracture incidence in rheumatoid arthritis (RA) patients compared to the general population. However, the causal relationship between RA and fracture risk, particularly traumatic and osteoporotic fractures, is not well established. We performed Mendelian randomization (MR) analysis to evaluate the causal relationship between RA and fracture risk. We performed a MR analysis using summary statistics from genome-wide association studies to investigate the causal association between RA and the risk of traumatic fractures at 9 sites and 3 types of osteoporotic fractures. The primary analysis used inverse-variance weighting, supplemented by MR-Egger regression and other methods to assess causal relationships and sensitivity analyses, including heterogeneity and pleiotropy assessments, using R software with appropriate packages. The inverse-variance weighting results demonstrated a causal relationship between genetically predicted RA and an elevated risk of fractures, particularly traumatic fractures of the long bones and osteoporotic fractures, including fractures of shoulder and upper arm (odds ratio [OR] = 1.041, 95% confidence interval [CI]: 1.020-1.062, P = 9.06e-05), fractures of forearm (OR = 1.026, 95% CI: 1.007-1.044, P = .006), fracture of femur (OR = 1.036, 95% CI: 1.009-1.064, P = .009), fractures of lower leg, including joint (OR = 1.031, 95% CI: 1.016-1.047, P = 6.38e-05), fractures of rib(s), sternum, and thoracic vertebrae (OR = 1.041, 95% CI: 1.018-1.064, P = 4.08e-04), osteoporotic with pathological features (OR = 1.128, 95% CI: 1.071-1.188, P = 5.54e-06), postmenopausal osteoporotic with pathological features (OR = 1.060, 95% CI: 1.002-1.123, P = .044), and drug-induced osteoporotic with pathological features (OR = 1.255, 95% CI: 1.124-1.400, P = 5.02e-05). This study highlights the genetic causal link between RA and an increased risk of traumatic and osteoporotic fractures, presenting a new direction for future exploration of the mechanisms underlying RA-related fractures.