Female reproductive factors, genetic susceptibility and incident osteoporosis risk

Osteoporosis risk is shaped by both reproductive factors and genetic predisposition, yet their combined effects remain insufficiently studied.
A total of 49,885 women from the UK Biobank were analyzed, excluding those with baseline osteoporosis or missing reproductive data. Reproductive factors included age at menarche, menopause time/status, history of stillbirth, hysterectomy, oophorectomy and oral contraceptive (OC) use. Genetic susceptibility was assessed using the polygenic risk score (PRS). Cox models estimated associations, with restricted cubic splines testing non-linear trends. Kaplan–Meier curves and sensitivity analyses were performed.
Late menarche, premature ovarian insufficiency, menopausal status, stillbirth, hysterectomy and oophorectomy were linked to higher osteoporosis risk, while OC use was protective. Women with high PRS combined with adverse reproductive histories had the greatest risk. Additive interactions were evident between genetic risk and menopause, stillbirth, hysterectomy and oophorectomy, whereas other factors acted largely independently. Sensitivity analyses supported robustness.
Both reproductive history and genetic susceptibility contribute to osteoporosis risk in women. Joint assessment of these factors may enhance risk stratification and inform personalized prevention.
Osteoporosis is a condition that weakens bones and increases fracture risk, especially in women, and both life-long hormonal factors and genetics may contribute to its development. Hormonal milestones such as the timing of first menstruation and menopause, along with reproductive events including stillbirth or surgeries involving the uterus or ovaries, can influence bone strength, but how these factors interact with genetic susceptibility has been unclear. We studied nearly 50,000 women from the UK Biobank over an average follow-up of 12 years and found that women with later first menstruation, premature ovarian insufficiency, or a history of stillbirth, hysterectomy, or ovary removal had a higher risk of developing osteoporosis, whereas use of oral contraceptives was associated with a slightly lower risk. Importantly, women who had both high genetic risk and adverse reproductive factors showed the greatest likelihood of osteoporosis, indicating that genes and reproductive history can reinforce each other. These findings suggest that considering both genetic background and reproductive history may improve osteoporosis risk assessment in women, support earlier identification of high-risk individuals, and help guide personalized prevention strategies such as targeted screening, lifestyle modification, or preventive treatment to protect bone health later in life.