Causal relationship between aging-related biomarkers and osteoporosis: A bidirectional two-sample Mendelian randomization study

Objective The potential causal role of molecular biomarkers of biological aging in osteoporosis remains uncertain. This study aimed to evaluate whether genetically predicted levels of aging-related traits are causally associated with the risk of osteoporosis. Methods In this study, we selected eight exposures: telomere length, mitochondrial DNA copy number, insulin-like growth factor 1 levels, DNA methylation PhenoAge acceleration, leucine, isoleucine, valine, and Dickkopf-related protein 1. A bidirectional two-sample Mendelian randomization analysis was conducted among the European population. The inverse-variance weighted method served as the primary analysis, complemented by Mendelian randomization–Egger, weighted median, mode-based methods, Cochran's Q test, the Mendelian randomization–Egger intercept, and leave-one-out analysis to assess robustness, heterogeneity, and pleiotropy. Results The inverse-variance weighted analysis showed nominal associations (p < 0.05) between genetically predicted higher insulin-like growth factor 1 (odds ratio = 0.910, 95% confidence interval: 0.840 to 0.985, p = 0.019) and isoleucine (odds ratio = 0.780, 95% confidence interval: 0.618 to 0.984, p = 0.036) with a lower risk of osteoporosis and elevated Dickkopf-related protein 1 (odds ratio = 1.195, 95% confidence interval: 1.043 to 1.368, p = 0.010) with a higher risk of osteoporosis; however, none remained significant after Bonferroni correction (p > 0.00625). Sensitivity analyses suggested a statistically significant association for Dickkopf-related protein 1 (weighted median and mode, p < 0.00625), whereas no significant causal effects were observed for any of the other biomarkers. Reverse Mendelian randomization revealed no evidence that osteoporosis influenced any of the biomarkers. Conclusions In this study, no robust causal effects were identified between the eight aging biomarkers and osteoporosis in the European population. However, the nominal associations observed for insulin-like growth factor 1, isoleucine, and Dickkopf-related protein 1 warrant further investigation into the aging-skeleton axis.