Mendelian randomization study reveals the causal effect of sex hormone binding globulin on osteoporosis

TL;DR

This study uses genetic data to show that higher SHBG levels are linked to lower bone density, suggesting a potential target for osteoporosis treatment.

Contribution

The study provides causal evidence using Mendelian randomization that SHBG negatively affects bone mineral density.

Findings

Higher SHBG levels are inversely linked to bone mineral density at multiple skeletal sites.

The relationship between SHBG and bone density is independent of BMI and T2DM.

Reverse causality between bone density and SHBG is not supported by the data.

Abstract

Multiple observational studies have reported the relationship between circulating SHBG level and bone health. However, their results were inconclusive, in this research we aim to exam the relationship by two-sample Mendelian randomization. Several quality control steps were taken in our analysis to select eligible instrumental SNPs strongly associated with circulating SHBG level. Our analysis employed several robust analytical methods (inverse-variance weighting, weighted median, MR-Egger regression and MR.RAPS method) to enhance the reliability of causal inferences. To assess the horizontal pleiotropy, heterogeneities and stability of these genetic variants on BMD, MR-Egger intercept test, Cochran’s Q test and “leave-one-out” sensitivity analysis were performed during analysis. To reduce heterogeneity and the effect of horizontal pleiotropy, outlier variants identified by MR-PRESSO outlier test were excluded. Multivariable MR analysis was performed to control for potential horizontal pleiotropy acting via BMI or T2DM. Reverse MR analysis was performed to guard against the possibility of reverse causality. Our two-sample Mendelian randomization analyses with two groups of exposure (circulating SHBG) GWAS summary statistics and four groups of outcome (BMD of different skeletal sites) GWAS summary statistics suggests an inverse link between circulating SHBG level and BMDs of different skeletal sites. Results of multivariable MR analysis demonstrates that the inverse link between circulating SHBG level and BMDs is independent of BMI and T2DM. Reverse MR analyses demonstrates no reverse link between TB-BMD and circulating SHBG level. Our result can be helpful for researchers to identify new treatment target for osteoporosis, or reminding clinicians of taking measures and concerted efforts to prevent or intervene with bone loss when patients are diagnosed as high circulating SHBG level.

The online version contains supplementary material available at 10.1186/s12891-025-08956-7.

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