Genetic Perspective on the Relationship between Female Reproductive Traits, Exercise, and Bone Health Outcomes: Evidence from a National Database

Abstract

Abstract Introduction Female reproductive traits influence bone mineral density (BMD) and fracture risks through estrogen exposure. However, these causal relationships remain unclear due to confounding. Understanding these relationships is crucial for osteoporosis prevention strategies. This study aimed to investigate the causal impact of age at natural menopause (ANM) and age at menarche (AAM) on BMD and osteoporosis risk, and to explore gene-exercise interactions influencing bone health in East Asian women. Methods We conducted two-sample Mendelian randomization (MR) using 15 genetic variants for AAM and 36 variants for ANM in 51,049 women from the Taiwan Biobank, split into discovery (n = 25,549) and validation (n = 25,500) cohorts. Outcomes were BMD Z scores, T scores, and clinical osteoporosis. We performed univariable and multivariable MR, followed by regression analyses, focusing on exercise effects on BMD and genetic predisposition scores for AAM and ANM. Results In multivariable MR, genetically determined later ANM was associated with higher BMD Z scores (β = 0.045, 95% confidence interval [0.021, 0.069]), higher T scores (β = 0.046, [0.020, 0.072]), and lower osteoporosis risk (β = −0.106, [−0.154, −0.058]). No consistent causal effect was observed for AAM due to genetic pleiotropy. ANM polygenic risk score and regular exercise were independently associated with improved BMD Z- and T scores and reduced risk of osteoporosis. Specific gene-exercise interactions were identified in which the AAM polygenic risk score interacted significantly with gymnastics, while the ANM polygenic risk score interacted with lower-limb exercise and swimming. Conclusion Late ANM provides causal protection against osteoporosis in East Asian women, while the effects of AAM remain insignificant. Exercise benefits bone health with activity-specific genetic interactions. These findings support personalized osteoporosis prevention strategies incorporating both genetic risk assessment and targeted exercise recommendations, particularly for women with early menopause predisposition.