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.

先前的观察性研究已经确定了与骨质疏松症发展相关的各种风险因素，包括性激素结合球蛋白 (SHBG)。本研究的目的是确定循环 SHBG 浓度对骨矿物质密度 (BMD) 的潜在因果影响。在分析中应用了两样本孟德尔随机化 (MR) 方法。从全基因组关联研究 (GWAS) 的汇总数据中，我们选择了 11 个与 SHBG 水平相关的单核苷酸多态性 (SNP) 作为工具变量，并使用了前臂 BMD (FA) 的汇总统计数据 ( n  = 8143)，股骨颈 (FN) ( n  = 32,735)、腰椎 (LS) ( n  = 28,498) 和脚跟 (HL) ( n = 394,929），以及不同年龄阶段（15 岁或以下、 15-30、30-45、45-60、60岁或以上）的全身 BMD（n = 67,358）。在 SHBG 水平和 FA BMD（效应 = − 0.26；95% CI − 0.49 至 − 0.04；P  = 0.022）、HL eBMD（效应 = − 0.09；95% CI − 0.12 至 − 0.06；P  = 3.19 × 10 ^–9 )，以及 45–60 岁人群的全身 BMD（效应 = − 0.16；95% CI − 0.31 至 − 2.4 × 10 ^–3；P  = 0.047）和 60 岁以上（效应 = − 0.19；95% CI − 0.33 至 − 0.05；P = 0.006）。我们的研究表明，循环 SHBG 浓度与 FA 和 HL eBMD 以及 45 岁以上人群的全身 BMD 呈负相关，这表明 SHBG 在骨质疏松症发展中的作用可能受患者实际年龄和骨骼部位的影响.