Causal effect between systemic inflammatory cytokines and osteoporotic pathological fractures: A bidirectional Mendelian randomization study

Osteoporosis is a prevalent metabolic bone disorder that significantly impairs patients' quality of life. Mounting evidence suggests a close relationship between systemic inflammation and bone metabolism, yet the causal nature of this association remains unclear. This study aims to elucidate potential causal links between circulating inflammatory factors and osteoporotic pathological fractures. We employed a bidirectional 2-sample Mendelian randomization (MR) approach, utilizing large-scale genetic data from the FinnGen biobank (1822 osteoporosis cases and 3,11,210 controls) and the genome-wide association study catalog to analyze 91 circulating inflammatory factors. Instrumental variables were selected using a threshold of P < 1 × 10-5, followed by stringent linkage disequilibrium pruning (R2 < 0.001). The inverse variance weighted method served as the primary analytical tool, supplemented by MR-Egger, weighted median, and mode-based estimator methods. Sensitivity analyses, including leave-one-out analysis, Mendelian Randomization Pleiotropy RESidual Sum and Outlier, and Cochran's Q test, were conducted to assess the robustness of the results. Forward MR analysis identified potential causal associations between 7 inflammatory factors and the risk of osteoporotic pathological fractures. Notably, Artemin levels were negatively correlated with fracture risk (OR = 0.7954, P = .0167), while elevated levels of β-nerve growth factor (OR = 1.2375, P = .0398), C-X-C motif chemokine 10 (OR = 1.2675, P = .0183), CXCL6 (OR = 1.2623, P = .0026), interleukin-10 receptor α subunit (OR = 1.2828, P = .0204), interleukin-10 receptor β subunit (OR = 1.1463, P = .0386), and latency-associated peptide transforming growth factor β1 (OR = 1.2481, P = .0206) were associated with increased fracture risk. Reverse MR analysis suggested that fractures might lead to decreased levels of C-X-C motif chemokine 11 (OR = 0.9574, P = .0104), interleukin-1α (OR = 0.9591, P = .0263), and thymic stromal lymphopoietin (OR = 0.9625, P = .0439), as well as elevated levels of tumor necrosis factor-β (OR = 1.0519, P = .0111). This study unveils a complex bidirectional relationship between circulating inflammatory factors and osteoporotic pathological fractures. These findings provide novel insights into the pathogenesis of osteoporosis and offer important clues for potential preventive, diagnostic, and therapeutic strategies.