Genetically Predicted Sex Hormone-Binding Globulin and Bone Mineral Density: A Mendelian Randomization Study

Previous observational studies have identified various risk factors associated with the development of osteoporosis, including sex hormone-binding globulin (SHBG). The aim of this study was to determine the potential causal effects of circulating SHBG concentrations on bone mineral density (BMD). Two-sample Mendelian randomization (MR) approach was applied in analyses. From summary-level data of genome-wide association studies (GWAS), we selected 11 single-nucleotide polymorphisms (SNPs) associated with SHBG levels as instrumental variable, and used summary statistics for BMD at forearm (FA) (n = 8143), femoral neck (FN) (n = 32,735), lumbar spine (LS) (n = 28,498) and heel (HL) (n = 394,929), and total-body BMD of different age-stages (15 or less, 15-30, 30-45, 45-60, 60 or more years old) (n = 67,358). Inverse causal associations was observed between SHBG levels and FA BMD (Effect = - 0.26; 95% CI - 0.49 to - 0.04; P = 0.022), HL eBMD (Effect = - 0.09; 95% CI - 0.12 to - 0.06; P = 3.19 × 10^-9), and total-body BMD in people aged 45-60 years (Effect = - 0.16; 95% CI - 0.31 to - 2.4 × 10^-3; P = 0.047) and over 60 years (Effect = - 0.19; 95% CI - 0.33 to - 0.05; P = 0.006). Our study demonstrates that circulating SHBG concentrations are inversely associated with FA and HL eBMD, and total-body BMD in people aged over 45 years, suggesting that the role of SHBG in the development of osteoporosis might be affected by chronological age of patients and skeletal sites.