Inflammation and Bone Health: A Causal Link Unveiled Through Mendelian Randomization

Objective: Relevant studies have indicated a close relationship between inflammatory cytokines and osteoporosis, but the causal relationship between them remains incompletely understood. This study aims to employ a two-sample Mendelian randomization approach to explore the potential causal relationship between circulating inflammatory cytokines and osteoporosis. Methods: This study extracted corresponding exposure and outcome data from the Genome-Wide Association Study (GWAS) database. Subsequently, a two-sample Mendelian randomization analysis was performed on these data. The inverse variance weighted (IVW) method was used as the primary analysis method to assess causal effects, while the weighted median method, MR- Egger regression method, simple median method, and weighted mode method were also used for supplementary analysis. To provide a more comprehensive analysis, this study also utilized MR-Egger Intercept and MR-PRESSO analysis methods for pleiotropy testing, Cochran's Q test to check for heterogeneity, and the leave-one-out method to assess the stability of the results. Results: The IVW results showed that GCST90274779 (OR=1.100, 95% CI: 1.002-1.209, P=0.045), GCST90274781 (OR=1.150, 95%CI: 1.043-1.268, P=0.005), GCST90274803 (OR=1.087, 95% CI: 1.004-1.176, P=0.040), and GCST90274839 (OR=1.108, 95% CI: 1.002-1.226, P=0.046) were positively associated with osteoporosis. Conversely, GCST90274760 (OR=0.895, 95% CI: 0.819-0.979, P=0.015) was negatively associated with osteoporosis. Supplementary analysis methods further verified the consistency of the direction and magnitude of the research results. Sensitivity analysis results indicated that the data were reliable and unbiased. Conclusion: By employing the Mendelian randomization method, this study confirmed a clear causal relationship between circulating inflammatory factors and osteoporosis. Specifically, inflammatory cytokines such as CXCL1, CXCL11, IL-17C, and TWEAK were identified as important risk factors for osteoporosis. In contrast, ARTN plays a positive protective role in maintaining bone health and resisting the progression of osteoporosis.