Bone Metabolic Biochemical Markers, Bone Mineral Density, and the Risk of Osteonecrosis of the Femoral Head: A Mendelian Randomization Study

Abstract

Abstract Background Alterations in bone metabolism may potentially exert a significant influence in the early stages of femoral head necrosis; however, the causal relationship has hitherto remained unelucidated. This study employs a two-sample Mendelian randomization (MR) approach to investigate the causal associations between biochemical indicators of bone metabolism, bone mineral density, and the occurrence of femoral head necrosis. Methods This study utilizes publicly accessible genome-wide association study (GWAS) datasets and validated single nucleotide polymorphisms (SNPs) linked to exposure variables (25OHD, serum Ca, and ALP) as well as indicators of bone mineral density (lumbar spine, heel, femoral neck, and total body). The two-sample Mendelian randomization method is employed, including techniques such as inverse variance weighting (IVW), MR-Egger regression, and weighted median estimation (WM), with the odds ratio (OR) as the evaluation criterion. Additionally, the effectiveness of the results is assessed through sensitivity testing. Results A total of 934 SNPs were included in this study. The MR analysis results indicate that the IVW analysis of 25OHD, serum Ca, and ALP did not reach statistical significance (25OHD OR = 1.006, 95%CI: 0.69–1.47, P = 0.975; serum Ca OR = 0.856, 95%CI: 0.43–1.70, P = 0.657; ALP OR = 1.022, 95%CI: 0.86–1.21, P = 0.801). However, bone density, including heel, lumbar spine, and total body bone density, showed a protective causal relationship with the onset of ONFH, while the results for femoral neck bone density did not reach statistical significance (lumbar spine BMD OR = 0.662, 95%CI: 0.48–0.91, P = 0.010; heel BMD OR = 0.726, 95%CI: 0.62–0.85, P < 0.001; total body BMD OR = 0.726, 95%CI: 0.62–0.85, P < 0.001; femoral neck BMD OR = 0.748, 95%CI: 0.53–1.05, P = 0.096). Cochran’s Q statistic for IVW and MR-Egger methods indicated no intergenic heterogeneity for all exposure outcomes' SNPs, and the tests for pleiotropy suggested a low likelihood of pleiotropy in all causal analyses. Conclusions This study does not support the hypothesis that 25OHD, serum Ca, and ALP reduce the risk of ONFH. However, heel, lumbar spine, and total body bone mineral density can be considered protective factors for the occurrence of ONFH. There is no genetic causality between femoral neck bone mineral density and ONFH development.