Luo Zhixiong, Feng Anping, Tyurin Anton, Cui Qingmei, Rita Khusainova, Xie Zhaomin, Ildar Minniakhmetov, An Ran, Chen Siqi, Zhang Yidan, Dai Lingyan, Madsen Tracy E, Liu Simin, Li Jie
School of Medicine, South China University of Technology, Guangzhou, 510006, China.
Global Health Research Centre, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China.
Osteoporos Int. 2025 Jul 15. doi: 10.1007/s00198-025-07620-z.
Both observational and factorial Mendelian randomization analysis revealed that the combined exposure to higher TT and lower SHBG was associated with decreased risk of fracture. These findings suggest that considering both TT and SHBG-rather than focusing on testosterone alone-may improve fracture risk assessment.
Lower total testosterone (TT) levels have been associated with increased fracture risk in aging men, yet the benefits of testosterone supplementation remain uncertain. This study aimed to assess the joint contributions of TT and sex hormone-binding globulin (SHBG) to fracture risk using both observational and genetic approaches.
We included 162,786 men from the UK Biobank, with baseline serum TT and SHBG measurements and genetic data. Cox proportional hazards models were used to estimate associations of TT and SHBG with incident fractures. A 2 × 2 factorial Mendelian randomization (MR) analysis was conducted to evaluate the combined genetic effects of increased TT and decreased SHBG on fracture risk.
The median age at baseline was 59.0 years, and 7493 men experienced fractures during 13.3 years follow-up. The association between serum TT levels and incident fracture was significantly affected by adjustment for SHBG. Compared to the lowest quintile of Bio-T levels, the adjusted hazard ratio (HR) for total fracture in the highest quintile was 0.72 (95% CI: 0.67, 0.78). In factorial MR analysis, men with genetically higher TT and lower SHBG had significantly lower odds of total fracture (OR: 0.87, 95% CI: 0.80-0.95) compared to those with genetically lower TT and higher SHBG. No association was observed in groups with only high TT or only low SHBG.
Our findings suggest that the interplay between TT and SHBG is important in determining fracture risk, highlighting the potential clinical value of jointly assessing them to improve fracture risk stratification in men.
观察性和析因孟德尔随机化分析均显示，较高的总睾酮（TT）和较低的性激素结合球蛋白（SHBG）联合暴露与骨折风险降低相关。这些发现表明，综合考虑TT和SHBG，而不是仅关注睾酮，可能会改善骨折风险评估。
较低的总睾酮（TT）水平与老年男性骨折风险增加有关，但睾酮补充的益处仍不确定。本研究旨在使用观察性和基因方法评估TT和性激素结合球蛋白（SHBG）对骨折风险的联合作用。
我们纳入了来自英国生物银行的162786名男性，他们有基线血清TT和SHBG测量值以及基因数据。使用Cox比例风险模型估计TT和SHBG与新发骨折的关联。进行了2×2析因孟德尔随机化（MR）分析，以评估TT升高和SHBG降低对骨折风险的联合遗传效应。
基线时的中位年龄为59.0岁，在13.3年的随访期间，7493名男性发生了骨折。血清TT水平与新发骨折之间的关联在调整SHBG后受到显著影响。与生物T水平最低的五分位数相比，最高五分位数的总骨折调整风险比（HR）为0.72（95%CI：0.67，0.78）。在析因MR分析中，与基因TT较低和SHBG较高的男性相比，基因TT较高和SHBG较低的男性总骨折的几率显著较低（OR：0.87，95%CI：0.80 - 0.95）。在仅TT高或仅SHBG低的组中未观察到关联。
我们的研究结果表明，TT和SHBG之间的相互作用在确定骨折风险方面很重要，突出了联合评估它们以改善男性骨折风险分层的潜在临床价值。
