Genetic Insights Into the Relationship Between Menstrual Factors and Site‐/Age‐Specific Bone Mineral Density

Backgrounds Observational studies have suggested possible links between reproductive factors and bone mineral density (BMD) and osteoporosis (OP), but the causal impact of menstrual factors on BMD remains obscure. Objectives This study is aimed at inferring causal associations between key menstrual factors and site‐/age‐specific BMD. Methods Genetic variants associated with age at menarche (AAM), last menstrual period (LMP), and length of menstrual cycle (LMC) were obtained from genome‐wide association studies (GWASs). The site‐/age‐specific BMD genetic data were derived from the Genetic Factors for OP Consortium (GEFOS). Causal associations were evaluated using a two‐sample Mendelian randomization (MR) approach and a multivariable MR (MVMR) model. Results LMP was causally associated with increased estimated heel BMD (eBMD) (beta = 0.055; 95% CI: 0.020, 0.089; P FDR = 0.001) and lumbar spine BMD (LS‐BMD) (beta = 0.103; 95% CI: 0.031, 0.175; P FDR = 0.039). LMC was inversely associated with TB‐BMD in both discovery (beta = −0.207; 95% CI: −0.323, −0.091; P FDR = 0.001) and replication cohorts (beta = −0.211; 95% CI: −0.335, −0.087; P FDR = 0.002). LMP was negatively associated with TB‐BMD among individuals aged 15–30 but was positively associated in those aged 45–60. Additional MVMR analysis supported direct causal relationships of LMP and LMC with site‐specific BMD (eBMD and TB‐BMD) and age‐specific BMD (age 45–60). Conclusions Our study observes the causal effects of LMP and LMC on BMD, with variations across anatomical sites and age groups. These findings enhance our understanding of the relationship between menstrual factors and bone health, providing evidence to inform targeted prevention strategies for OP.