Aging Biomarkers in Osteoporosis: A Systematic Review of Molecular Mechanisms, Biological Aging, and Population Evidence.

While chronological age is an important risk factor for osteoporosis, biological aging measures may better capture nuances in systemic and bone-tissue aging among same-age individuals. This review aims to summarize the associations between DNA methylation/telomere(definition) dysfunction (mainly telomere shortening) and bone health. We searched for human epidemiological studies that examined the associations between blood-based epigenetic aging clocks or leukocyte telomere length (LTL) and osteoporosis-related outcomes on PubMed and Embase. Five epigenetic aging-related studies and 14 LTL-related studies were eventually included, from which data on study design, population, bone health-related outcomes, and statistically significant effect estimates were extracted. Risk of bias was assessed using the Newcastle-Ottawa Scale for observational studies. Findings were summarized narratively due to heterogeneity in study design, biomarkers, and outcome definitions. This review concludes that while laboratory-based studies often provide evidence of aging biomarkers' association with bone outcomes, population-level epidemiological studies provide inconclusive evidence, highlighting limited studies on epigenetic aging clocks and bone health, and inconsistent findings regarding the association between LTL and bone health. Challenges many of the human studies faced include small sample sizes, inadequate study designs, non-diverse cohorts, and heterogeneity in epigenetic clock(definition) selection and/or bone health outcomes. Future research should focus on conducting prospective studies with larger, independent cohort sizes and comprehensive adjustment for intervening factors to paint a clearer picture of the biological aging markers' associations with osteoporosis and provide guidance on their potential clinical relevance in bone health.