Abstract
Osteoporosis is driven by skeletal aging and increases the risk of fragility fractures. Skeletal aging is influenced by epigenetic mechanisms; however, the link to the epigenetic clocks, that is, the suggested biomarkers of biological aging intensively studied within aging research, remains largely unexplored. We investigated the association of eight epigenetic clocks-Horvath, IEAA, Hannum, EEAA, PhenoAge, GrimAge, DunedinPoAm, DunedinPACE-and methylation-based telomere length (mTL) measured at intake (1997, 2007, or 2008-11) with register-based incident fracture and osteoporosis diagnoses in 310 (Discovery cohort), and 777 (Replication cohort) twins, derived from nationwide population-based surveys (end-of-follow-up: 2022). For the 288 youngest twins, bone mineral density (BMD), and bone turnover markers C-terminal telopeptide (CTX) and amino pro-collagen type 1 N-terminal propeptide (P1NP) were available. Analyses were conducted at both the individual and twin-pair levels, reducing genetic and environmental confounding. A consistent pattern emerged: increased epigenetic age, faster pace of aging, and shorter mTL associated with a higher risk of fractures, or osteoporosis. Notably, DunedinPoAm, DuninPACE, and GrimAge demonstrated the most robust associations. DuninPACE displayed the largest effects; hazard ratios ranging from 1.29 to 3.17, reflecting a 29%-217% increased hazard for diagnosis pr. one standard deviation increase in DuninPACE. The same directions of effects were seen for decreasing CTX and P1NP levels, suggesting bone remodeling impairment for individuals with higher biological age. Lastly, sex- and age-specific analysis of BMD indicated the same direction of effect for DunedinPoAm, and GrimAge in older females. These findings suggest that epigenetic clocks may serve as biomarkers for bone aging.