MR Analysis Reveals No Causal Association Between Mitochondrial DNA Copy Number and Osteoporosis

Objectives : Observational studies have suggested a connection between mitochondrial DNA copy number (mtDNA-CN) and osteoporosis, but the causal role of mtDNA-CN remains uncertain. This study aimed to elucidate the causal association between mtDNA-CN and osteoporosis using a two-sample Mendelian randomization (MR) approach. Materials and Methods: Genome-wide association studies (GWAS) summary data were utilized. Four MR methods—inverse-variance weighted (IVW), weighted median, weighted mode, and MR-Egger—were applied, with IVW as the primary analysis. Sensitivity analyses included the MR-PRESSO test to assess pleiotropy and heterogeneity. Outcomes comprised bone mineral density (BMD) measurements at total body, lumbar spine, femoral neck, and forearm. Results: No significant causal relationship was observed between mtDNA-CN and osteoporosis. IVW results showed odds ratios (ORs) of 0.97 (95% CI: 0.89–1.05, P = 0.427) for total BMD, 1.00 (95% CI: 0.87–1.15, P = 0.977) for lumbar spine BMD, 1.00 (95% CI: 0.89–1.12, P = 0.988) for femoral neck BMD, and 0.90 (95% CI: 0.70–1.16, P = 0.421) for forearm BMD. Sensitivity analyses confirmed robustness, with no evidence of horizontal pleiotropy (MR-Egger intercept P > 0.05) or outliers (MR-PRESSO P > 0.05). Conclusions: This MR study found no causal effect of mtDNA-CN on osteoporosis risk across multiple skeletal sites. The null association challenges prior observational hypotheses, suggesting mtDNA-CN may not be a primary determinant of osteoporosis. Further research is warranted to explore alternative mechanisms.