ArticleInternational journal of women's health2026
Causal Effects of Female Reproductive and Hormonal Factors on Osteoporosis, Bone Mineral Density, and Osteoarthritis: A Two-Sample Mendelian Randomization Study.
Article in International journal of women's health, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Purpose: The causal links between female reproductive and hormonal factors and bone diseases remain uncertain, partly due to conflicting observational evidence and potential reverse causation. We used two-sample Mendelian randomization (MR) to clarify these relationships. Methods: Using large-scale genome-wide association studies (GWAS), predominantly from individuals of European ancestry, we analyzed 12 reproductive and hormonal exposures, including reproductive milestones, fertility history, and hormonal interventions, against 7 bone-related outcomes. Genetically predicted causal effects were estimated using inverse-variance weighted (IVW) MR after removing pleiotropic outliers via the MR-PRESSO test. Heterogeneity and pleiotropy were assessed using MR-Egger, Steiger directionality, and leave-one-out analyses. Results: After FDR correction (FDR < 0.05), genetically predicted effects showed that later age at menarche was associated with higher osteoporosis risk (OR: 1.59) and lower bone mineral density (BMD) (OR: 0.88), whereas later age at menopause was associated with reduced osteoporosis risk (OR: 0.74) and, after outlier removal, higher BMD in women aged 45-60 years (OR: 1.17). Ever use of hormone replacement therapy was also associated with higher mid-life BMD in women aged after outlier correction (OR: 0.71). Longer menstrual cycles were associated with lower BMD (OR: 0.83), and later age at last oral contraceptives (OCP) use showed a modest association with lower BMD (OR: 0.65). Regarding osteoarthritis, later age at first and last live birth was associated with lower risk (OR: 0.81 and 0.75, respectively), and later age at starting OCP was associated with reduced osteoarthritis risk (OR: 0.88). Conclusion: This study provides genetic evidence for the protective role of a longer reproductive lifespan on bone health. Hormonal factors exert distinct causal effects on osteoporosis and osteoarthritis, which is critical for informing targeted prevention strategies.
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