Causal relationships between sex hormone traits, lifestyle factors, and osteoporosis in men: A Mendelian randomization study

Although observational studies have explored factors that may be associated with osteoporosis, it is not clear whether they are causal. Osteoporosis in men is often underestimated. This study aimed to identify the causal risk factors associated with bone mineral density (BMD) in men. Single nucleotide polymorphisms (SNPs) associated with the exposures at the genome-wide significance (p < 5x10(-8)) level were obtained from corresponding genome-wide association studies (GWASs) and were utilized as instrumental variables. Summary-level statistical data for BMD were obtained from two large-scale UK Biobank GWASs. A Mendelian randomization (MR) analysis was performed to identify causal risk factors for BMD. Regarding the BMD of the heel bone, the odds of BMD increased per 1-SD increase of free testosterone (FT) (OR = 1.13, P = 9.4 x 10(-17)), together with estradiol (E2) (OR = 2.51, P = 2.3 x 10(-4)). The odds of BMD also increased with the lowering of sex-hormone binding globulin (SHBG) (OR = 0.87, P = 7.4 x 10(-8)) and total testosterone (TT) (OR = 0.96, P = 3.2 x 10(-2)) levels. Regarding the BMD of the lumbar spine, the odds of BMD increased per 1-SD increase in FT (OR = 1.18, P = 4.0 x 10(-3)). Regarding the BMD of the forearm bone, the odds of BMD increased with lowering SHBG (OR = 0.75, P = 3.0 x 10(-3)) and TT (OR = 0.85, P = 3.0 x 10(-3)) levels. Our MR study corroborated certain causal relationships and provided genetic evidence among sex hormone traits, lifestyle factors and BMD. Furthermore, it is a novel insight that TT was defined as a disadvantage for osteoporosis in male European populations.