Adverse Childhood Experiences, Genetic Susceptibility, and the Risk of Osteoporosis: A Cohort Study.

Emerging evidence indicates that individuals exposed to adverse childhood experiences (ACEs) face elevated risks for various chronic illnesses. However, the association between ACEs and osteoporosis risk remains underexplored, particularly regarding potential modifications by genetic susceptibility. This prospective cohort study aims to examine the relationship of ACEs with incident osteoporosis and investigate interactions with polygenic risk score (PRS). This study analyzed 124,789 UK Biobank participants initially free of osteoporosis. Cumulative ACE burden (emotional neglect, emotional abuse, physical neglect, physical abuse, sexual abuse) was ascertained through validated questionnaires. Multivariable-adjusted Cox proportional hazards models assessed osteoporosis risk during a median follow-up of 12.8 years. Moderation analysis examined genetic susceptibility interactions using a standardized PRS incorporating osteoporosis-related SNPs. Among 2474 incident osteoporosis cases, cumulative ACEs showed dose-response associations with osteoporosis risk (adjusted hazard ratio [HR] = 1.07, 95% confidence interval [CI] 1.04-1.11; high ACEs [≥3 types] vs. none: HR = 1.26, 1.10-1.43). Specifically, emotional neglect (HR = 1.14, 1.04-1.25), emotional abuse (HR = 1.14, 1.03-1.27), physical abuse (HR = 1.17, 1.05-1.30), and sexual abuse (HR = 1.15, 1.01-1.31) demonstrated comparable effect sizes. Sex-stratified analysis revealed stronger associations in women. Joint exposure to high ACEs/high PRS tripled osteoporosis risk (HR = 3.04, 2.46-3.76 vs. low ACEs/low PRS) although G × E interaction was nonsignificant (P-interaction = 0.10). These results suggest that ACEs conferred incremental osteoporosis risk independent of genetic predisposition. These findings support the inclusion of ACE screening in osteoporosis prevention strategies and highlight the need for targeted bone health interventions for youth exposed to ACEs.