Journal of Shandong University (Health Sciences) ›› 2026, Vol. 64 ›› Issue (6): 94-103.doi: 10.6040/j.issn.1671-7554.0.2025.1276

• Public Health and Preventive Medicine • Previous Articles    

Causal associations of lipid-lowering drugs with skeletal diseases: a transethnic drug-target Mendelian randomization analysis

YU Haorui1,2, CHEN Changhai1,2, ZHANG Xiumei1,2, YUAN Zhongshang1,2   

  1. 1. Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China;
    2. National Institute of Health and Medical Big Data, Jinan 250003, Shandong, China
  • Published:2026-06-29

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Abstract: Objective To assess the causal associations of five lipid-lowering drug classes—statins, cholesterol absorption inhibitors, proprotein convertase subtilisin/kexin type 9(PCSK9)inhibitors, ATP citrate lyase(ACL)inhibitors, and angiopoietin-like 3(ANGPTL3)inhibitors—with the risk of osteoporosis and osteoarthritis using a drug-target Mendelian randomization approach. Methods Summary statistics from publicly available genome-wide association studies were used. Five lipid-lowering drug classes were considered as exposures, and osteoporosis and osteoarthritis as outcomes. Drug-target Mendelian randomization analyses were conducted using inverse-variance weighting as the primary method, supplemented by seven additional methods. The false discovery rate(FDR)method was applied to correct for multiple comparisons. Heterogeneity tests, pleiotropy tests, and leave-one-out analyses were performed to assess robustness. Results PCSK9 inhibitor use showed a positive causal association with increased osteoporosis risk in both European(OR=1.169, 95%CI: 1.025-1.332, PFDR=0.040)and East Asian populations(OR=1.370, 95%CI: 1.115-1.683, PFDR=0.008). PCSK9 inhibitor use was also positively associated with osteoarthritis risk in the European population(OR=1.183, 95%CI: 1.102-1.271, PFDR=1.46×10-5). The causal association between statin use and osteoarthritis exhibited population heterogeneity: a positive association in the European population(OR=1.128, 95%CI: 1.01-1.259, PFDR=0.040)and a negative association in the East Asian population(OR=0.440, 95%CI: 0.253-0.765, PFDR=0.010). Cholesterol absorption inhibitor use was causally associated with reduced osteoarthritis risk in the European population(OR=0.723, 95%CI: 0.544-0.962, PFDR=0.043). Conclusion PCSK9 inhibitor use increases the risk of osteoporosis in both European and East Asian populations, while the effect of statins on osteoarthritis is population-specific. These findings suggest that skeletal safety evaluation of lipid-lowering drugs should consider target specificity and population heterogeneity.

Key words: Mendelian randomization, Proprotein convertase subtilisin/kexin type 9 inhibitors, Statins, Osteoporosis, Osteoarthritis

CLC Number: 

  • R681
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