Assessing the Casual Association between Sex Hormone Levels and Fracture Risk: A Two‐Sample Mendelian Randomization Study

OBJECTIVE: Prior observational studies have reported that levels of sex hormones constitute a risk factor for the fracture. The aim of this study was to ascertain whether there is a causal relationship between the levels of sex hormones and the risk of fracture through Mendelian randomization (MR). METHODS: Single‐nucleotide polymorphisms (SNPs) associated with two indicators of sex hormone levels, circulating sex hormone‐binding globulin (SHBG) and bioavailable testosterone levels, as exposures were selected from a large genome‐wide association study (GWAS) from UK Biobank. The summary statistics for 11 different types of fracture as outcomes from the FinnGen consortium. This study employed the two‐sample MR approach. For the main analysis, the inverse‐variance‐weighted (IVW) method was utilized. To assess the heterogeneity of MR results, the IVW method and MR–Egger method were utilized. To evaluate potential pleiotropy, MR–Egger regression was conducted. Additionally, a leave‐one‐SNP‐out test was performed to assess the robustness of MR results to the exclusion of any individual SNP. RESULTS: The MR analyses demonstrated a conspicuous impact of SHBG on the risk of pathological fracture with osteoporosis (OP). We found that an increase of one standard deviation (SD) in SHBG correspondingly increased the risk of pathological fracture with OP [odds ratio (OR) 2.42, 95% confidence interval (CI), 1.52–3.85; p = 1.93 × 10(−4)]. The bioavailable testosterone showed the negative casual genetic associations with fractures of foot and forearm. An increase of one SD in the genetically predetermined bioavailable testosterone was associated with a reduction of 37% in the risk of fracture of foot (OR 0.63, 95% Cl 0.49 to 0.81; p = 3.37 × 10(−4)), as well as a 39% decrease in the risk of fracture of forearm (OR 0.61, 95% Cl 0.50 to 0.76; p = 5.40 × 10(−6)). CONCLUSIONS: Our study confirms that individuals experiencing elevated SHBG concentrations showed a major causal effect on pathological fracture with OP. High bioavailable testosterone levels play an important role in preventing the fractures of foot and forearm. Although increasing bioavailable testosterone and decreasing SHBG levels had no casual effect on most fractures in the general population, they are likely to have the most clinically relevant effect on certain fracture risk reduction.