Investigating the relationship between osteoporosis and rheumatoid arthritis: prospective cohort study and genetic analyses

Background: The co-occurrence of osteoporosis (OP) and rheumatoid arthritis (RA) has long been observed; their intrinsic link, however, has not been fully understood. Objectives: We aimed to inform the importance of integrated care targeting both diseases by investigating the phenotypic as well as the genetic relationships underlying OP and RA. Design: This is a prospective cohort study and genome-wide cross-trait analysis. Methods: We evaluated phenotypic associations using longitudinal follow-up data from the UK Biobank ( N = 472,050). We investigated genetic relationships by leveraging summary statistics from the largest genome-wide association study in European ancestry conducted for RA ( N case/control = 22,350/74,823), seropositive RA ( N case/control = 17,221/74,823), and a reliable proxy of OP—the heel estimated bone mineral density (eBMD; N = 426,824). Results: Observational analysis suggested a bidirectional relationship (OP → RA: hazard ratio (HR) = 1.59, 95% confidence interval (CI) = 1.28–1.97; RA → OP: HR = 2.94, 95% CI = 2.59–3.35). A negative overall genetic correlation was observed for eBMD with RA ( = −0.06, p = 1.37 × 10 −5 ) and with its seropositive subtype ( r g = −0.06, p = 9.15 × 10 −6 ). Cross-trait meta-analysis replicated 96 previously reported trait-associated loci and discovered three novel pleiotropic loci (rs72836346, rs2613812, and rs76458888). Transcriptome-wide association study revealed 23 shared genes. Mendelian randomization analysis suggested a putative causal effect of eBMD on RA (odds ratio (OR) = 0.90, 95% CI = 0.84–0.96), but not of RA on eBMD. Conclusion: Our work demonstrates a significant biological pleiotropy as well as a putative causal relationship between OP and RA, emphasizing an intrinsic link underlying the pronounced phenotypic association. These findings highlight the possibility of preventing and predicting RA development by monitoring and interfering with bone loss in preclinical high-risk individuals.