This study aimed to examine the association between sex hormone-binding globulin (SHBG) and osteoporosis through a cross-sectional study and a two-sample bidirectional Mendelian randomization (MR). We used the National Health and Nutrition Examination Survey (NHANES) 2013–2014 and 2015–2016 data, with exposure as serum SHBG and outcome as osteoporosis and performed multivariate logistic regression to test the correlation between SHBG and osteoporosis. To determine the causal relationship between SHBG and osteoporosis, a two-sample bidirectional MR was employed. The genome-wide association study (GWAS) dataset for SHBG (n = 189,473) was obtained from the IEU database, and the GWAS dataset for osteoporosis (n = 212,778) was obtained from the FinnGen bioBank. The principal MR technique was inverse-variance weighting (IVW). In MR analyses, the MR-Egger intercept and Cochran Q test were used to detect multiple validity and horizontal heterogeneity. 1249 older adult participants (age ≥ 60) were involved in the cross-sectional study, including 113 osteoporosis cases. We identified a significant relationship between circulating SHBG concentration and osteoporosis risk [OR 3.963, 95% CI (2.095–7.495), P < 0.05]. Subgroup analysis indicated that SHBG was closely linked to the risk of osteoporosis in the female population [OR 1.008, 95% CI (1.002–1.013), P = 0.005] but not in males (P = 0.065). In addition, The IVW approach suggested a causal connection between SHBG and increased osteoporosis risk [OR 1.479, 95% CI (1.144–1.912), P = 0.003], and the MR-Egger intercept and the Cochran Q test validated the consistency of the MR results. Finally, the reverse MR analysis declined to identify a causal relation between SHBG and osteoporosis. Our research demonstrates a significant causal connection between circulating SHBG levels and increased osteoporosis risk. These results indicate that high SHBG may be associated with the risk of osteoporosis in postmenopausal women, but more research is needed.

本研究旨在通过横断面研究和两样本双向孟德尔随机化 (MR) 来探讨性激素结合球蛋白 (SHBG) 与骨质疏松症之间的关联。我们使用 2013-2014 年和 2015-2016 年国家健康和营养检查调查 (NHANES) 数据，以血清性激素结合球蛋白 (SHBG) 暴露和骨质疏松症结果为结果，并进行多变量逻辑回归来测试性激素结合球蛋白 (SHBG) 与骨质疏松症之间的相关性。为了确定性激素结合球蛋白 (SHBG) 与骨质疏松症之间的因果关系，采用了两个样本的双向 MR。SHBG 的全基因组关联研究 (GWAS) 数据集 ( n  = 189,473) 从 IEU 数据库获得，骨质疏松症的 GWAS 数据集 ( n  = 212,778) 从 FinnGen bioBank 获得。主要的 MR 技术是逆方差加权 (IVW)。在 MR 分析中，使用 MR-Egger 截距和 Cochran Q 检验来检测多重有效性和水平异质性。1249 名老年参与者（年龄≥60 岁）参与了这项横断面研究，其中包括 113 例骨质疏松病例。我们发现循环 SHBG 浓度与骨质疏松风险之间存在显着关系 [OR 3.963, 95% CI (2.095–7.495), P  < 0.05]。亚组分析表明，女性人群中性激素结合球蛋白（SHBG）与骨质疏松风险密切相关[OR 1.008，95% CI（1.002-1.013），P  = 0.005]，但男性人群中则不然（P  = 0.065）。此外，IVW 方法表明 SHBG 与骨质疏松风险增加之间存在因果关系 [OR 1.479，95% CI (1.144–1.912)，P  = 0.003]，MR-Egger 截距和 Cochran Q 检验验证了磁共振结果。最后，反向 MR 分析未能确定 SHBG 与骨质疏松症之间的因果关系。我们的研究表明循环性性激素结合球蛋白水平与骨质疏松症风险增加之间存在显着的因果关系。这些结果表明，高性激素结合球蛋白（SHBG）可能与绝经后女性骨质疏松症的风险相关，但还需要更多的研究。