The role of inflammatory cytokines and blood metabolites in osteoporosis: A Mendelian randomization study on pathways and therapeutic targets

The precise mechanisms underlying the development of osteoporosis (OP) remain unclear, but evidence suggests that inflammatory cytokines and blood metabolites play a significant role. We aim to investigate, as a strictly genomic study based on genome-wide association studies (GWAS) summary statistics, the causal relationships between inflammatory cytokines, blood metabolites, and OP by using Mendelian randomization (MR) analysis and uncover potential therapeutic targets. We utilized inflammatory cytokines from a GWAS summary containing 8293 healthy participants, 1400 blood metabolites from GWAS Catalog, and OP data from the FinnGen repository, all of which are sourced from the largest GWAS conducted to date. Employing bidirectional MR analyses, we investigated the causal relationships between inflammatory cytokines and OP. Additionally, we conducted 2 mediation analyses, two-step MR and multivariable MR (MVMR), to identify potential mediating metabolites. Three inflammatory cytokines were causally associated with OP, while OP did not have a significant causal effect on them. In the two-step MR analysis, CTACK and TRAIL, along with metabolites Spermidine to (N(1) + N(8))-acetylspermidine ratio, Oxalate, 2,4-di-tert-butylphenol, Phosphate to linoleoyl-arachidonoyl-glycerol (18:2-20:4) ratio, Trans 3,4-methyleneheptanoate and X-11478, were all significantly associated with OP (all P < .05). MVMR analysis revealed that the associations between CTACK and OP were mediated by Spermidine to (N(1) + N(8))-acetylspermidine ratio (-15.6%, P = .001), Oxalate (7.8%, P = .014), and 2, 4-di-tert-butylphenol (-15.6%, P = .005). The present MR study offers evidence supporting the causal relationships between several specific inflammatory cytokines and OP, as well as identifying potential mediating metabolites.