No Significant Direct Causal Association Between TNF Pathway Biomarkers and Hip Fracture Risk: A Study Based on Real-World Data

Peng Xiao; Bingqi Wei; Guilong Zhang; Desheng Liu; Yufan Zhang; Jiahui Sun; Hejia Wan; Yipin Heng; Shiyu Zhou; Yijing Li; Xingyue Ren; Zhiheng Sun; Yong Huang; Xiaoqin Fu

doi:10.3791/70376

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Research Article

No Significant Direct Causal Association Between TNF Pathway Biomarkers and Hip Fracture Risk: A Study Based on Real-World Data

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DOI:

10.3791/70376

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June 5th, 2026

Peng Xiao^*¹ , Bingqi Wei^*² , Guilong Zhang^*¹ , Desheng Liu^*³ , Yufan Zhang⁴ , Jiahui Sun² , Hejia Wan⁵ , Yipin Heng² , Shiyu Zhou² , Yijing Li² , Xingyue Ren² , Zhiheng Sun¹ , Yong Huang¹ , Xiaoqin Fu⁶

¹International Department of Orthopedics, Hospital of Chengdu University of Traditional Chinese Medicine, ²School of Orthopedics, Henan University of Chinese Medicine, ³Emergency Department, Hospital of Chengdu University of Traditional Chinese Medicine, ⁴School of Traditional Chinese Medicine, Hubei University of Chinese Medicine, ⁵School of Nursing, Henan University of Chinese Medicine, ⁶Department of Orthopedics, Hospital of Chengdu University of Traditional Chinese Medicine

^* These authors contributed equally

Summary

This study integrates FAERS pharmacovigilance with Mendelian randomization to assess associations between TNF pathway biomarkers and hip fracture risk. Combining real-world adverse-event surveillance with genetic causal inference, the workflow offers a reproducible approach for evaluating biomarker–outcome relationships when randomized trials are unavailable, impractical, or ethically difficult to conduct in practice.

Abstract

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.

Introduction

Hip fracture is a common and serious clinical condition in elderly individuals, and its clinical manifestations are usually characterized by hip pain and dysfunction¹. Hip fracture not only has a serious impact on patients but also imposes a heavy burden on families and society. For patients, hip fracture is often accompanied by a long period of hospitalization and rehabilitation, which has a great impact on the physical and mental health of elderly patients²^,³^,⁴. At the family level, patients usually require long-term care from family members, which c....