Observational studies have demonstrated the relations of homocysteine (HCY) with bone mineral density (BMD) and bone fracture risk, but yielding contradictory results. The present study was conducted to evaluate whether the genetically predicted plasma HCY levels were causally associated with the change of BMD and the risk of bone fracture.

Genetic summary statistics were extracted from genome-wide association study (GWAS) meta-analysis of plasma HCY levels (n = 44,147), GWAS meta-analyses of measured forearm (FA), femoral neck (FN) and lumbar spine (LS) BMD (n = up to 32,735), UK Biobank estimated heel BMD (eBMD) (n = 426,824) and fracture (n = 426,795) GWAS data. Two Sample Mendelian Randomization (TSMR) analysis was performed to assess the causal effects of genetically determined plasma HCY on the BMD and bone fractures.

The MR analysis indicated that, genetically decreased plasma HCY was associated with the increased FA-BMD based on the inverse variance weighting (IVW) method (standard deviation [SD] = 0.348, 95% CI: 0.146 to 0.550, P = 7 × 10−4). However, there were no significant associations of genetically decreased plasma HCY with FN-BMD, LS-BMD, eBMD and the risk for bone fracture (SD = −0.041, 95% CI: −0.189 to 0.106, P = 0.582; SD = −0.053, 95% CI: −0.238 to 0.131, P = 0.572; SD = −0.030, 95% CI: −0.090 to 0.030, P = 0.328, odds ratio [OR]: 1.03, 95% CI: 0.94 to 1.13, P = 0.562, respectively). Moreover, the results also found that genetically determined HCY increase was not correlated with the changes of BMD and the risk for bone fracture.

Our study revealed that genetically decreased plasma HCY was associated with increase of FA-BMD.