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

作者：Lingli Qiu, Wenqiang Zhang, Zhixin Tan, Xuan Wu, Yutong Wang, Min Tang, Lin Chen, Yanqiu Zou, Yunjie Liu, B W Lei, Xiaofeng Ma, Di Zhang, Wenzhi WANG, Yiping Jia, Qiurong He, Li Sun, Lu Wang, Jian Xu, Yao Chen, Mengyu Fan, Jiayuan Li, Ben Li Zhang, Xiaoling Wen, Xia Jiang · 发表于：Therapeutic Advances in Musculoskeletal Disease · 年份：2026 · DOI：10.1177/1759720x251412846 · 研究领域：Rheumatoid Arthritis Research and Therapies、Genetic Associations and Epidemiology、Bone health and osteoporosis research

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 sugge...