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Systemic Inflammatory Regulators Associated with Osteoporosis: A Bidirectional Mendelian Randomization Study

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Abstract

To elucidate the precise upstream and downstream regulatory mechanisms of inflammatory factors in osteoporosis (OP) progression and to establish a causal relationship between inflammatory factors and OP. We conducted bidirectional Mendelian randomization (MR) analyses using data for 41 cytokines obtained from three independent cohorts comprising 8293 Finnish individuals. Estimated bone mineral density (eBMD) data were derived from 426,824 UK Biobank White British individuals (55% female) and fracture data from 416,795 UK Biobank participants of European ancestry. The inverse variance-weighted method was the primary MR analysis approach. We employed other methods as complementary approaches for mutual corroboration. To test for pleiotropy and heterogeneity, we used the MR-Egger regression, MR-pleiotropy residual sum and outlier global test, and the Cochrane Q test. Macrophage inflammatory protein (MIP)-1α and interleukin (IL)-12p70 expression associated negatively and causally with eBMD (β = −0.017 [MIP-1α], β = −0.011 [IL-12p70]). Conversely, tumor necrosis factor-related apoptosis-inducing ligand was associated with a decreased risk of fractures (Odds Ratio: 0.980). Additionally, OP influenced the expression of multiple inflammatory factors, including growth-regulated oncogene-α, interferon-gamma, IL-6, beta nerve growth factor, and IL-2. Finally, we discovered complex bidirectional causal relationships between IL-8, IL-10, and OP. Specific inflammatory factors may contribute to OP development or may be causally affected by OP. We identified a bidirectional causal relationship between certain inflammatory factors and OP. These findings provide new perspectives for early prediction and targeted treatment of OP. Larger cohort studies are necessary in the future to further validate these findings.

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Acknowledgements

We would like to express our gratitude to all genetics consortiums for opening up the genome-wide association studies (GWAS) summary data.

Funding

This research is supported by Shanxi Province Science and Technology Research Project (Grant Number 20150313004–6) and Shanxi Province Science and Technology Cooperation and Exchange Special Project (Grant Number 202204041101027).

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  1. Lei Xu and Hui Li have contributed equally to this work.

Authors and Affiliations

  1. Department of Orthopedics, The First Hospital of Shanxi Medical University, Taiyuan, 030000, China

    Lei Xu, Hui Li, Bin Liu, Xiaoqiang Han & Haibiao Sun

  2. The First Clinical Medical College, Shanxi Medical University, Taiyuan, 030000, China

    Lei Xu, Hui Li & Bin Liu

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Contributions

Manuscript writing: LX and HS; data collection and collation: BL and HL; statistical analysis: LX and XH; methodological quality assessment: HS and XH; key revisions of important knowledge content: LX and HS; all authors accepted the final version.

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Correspondence to Haibiao Sun.

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Lei Xu, Hui Li, Bin Liu, Xiaoqiang Han, Haibiao Sun declare that they have no conflict of interest.

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All data were derived from published studies or publicly available GWAS abstract data in which ethical approval and informed consent were provided. No separate ethical approval was required for this study.

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All data were derived from published studies or publicly available GWAS abstract data in which ethical approval and informed consent were provided. No separate ethical approval was required for this study.

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Xu, L., Li, H., Liu, B. et al. Systemic Inflammatory Regulators Associated with Osteoporosis: A Bidirectional Mendelian Randomization Study. Calcif Tissue Int 114, 490–501 (2024). https://doi.org/10.1007/s00223-024-01200-9

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