No Significant Direct Causal Association Between TNF Pathway Biomarkers and Hip Fracture Risk: A Study Based on...

Hip fracture is a common and serious condition in elderly individuals, often associated with altered TNF-α signaling. However, few studies have explored whether changes in TNF pathway biomarkers contribute to the risk of hip fracture. In this study, adverse events related to hip fracture reported for five TNF inhibitors were analyzed using data from the first quarter of 2014 to the fourth quarter of 2023. After data standardization and cleaning, four disproportionality methods, including the reporting odds ratio, proportional reporting ratio, multi-item gamma Poisson shrinker, and Bayesian confidence propagation neural network, were applied to assess the association between TNF inhibitor exposure and hip fracture outcomes. Complementary mendelian randomization analyses were further conducted using TNF-α, sTNFR1, and sTNFR2 as exposures and hip fracture as the outcome. Pharmacovigilance analyses revealed no significant association between TNF inhibitor exposure and hip fracture-related adverse events across the four algorithms. Mendelian randomization analyses identified no significant direct causal association between genetically predicted TNF-α and hip fracture risk, and additional analyses of sTNFR1 and sTNFR2 yielded consistent results. These findings suggest that TNF pathway biomarkers are unlikely to act as independent direct determinants of hip fracture risk and may provide a useful basis for future mechanistic studies and prevention strategies.