MR analysis reveals no causal association between mitochondrial DNA copy number and osteoporosis

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. 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. 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). 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.