As a valuable blood glucose measurement, HemoglobinA1c (HbA1c) is of great clinical value for diabetes. However, in previous observational studies, studies on its effect on bone mineral density (BMD) have different results. This study aimed to use Mendelian randomization (MR) to assess the effect of HbA1c on bone mineral density and fracture risk, and try to further explore whether this association was achieved through glycemic or non-glycemic factors.

Take HbA1c measurement as exposure, and BMD estimated from quantitative heel ultrasounds (eBMD) and bone fractures as outcomes. Two-Sample MR Analysis was conducted to assess the causal effect of HbA1C on heel BMD and risk fracture. Then, we performed the analysis using two subsets of these variants, one related to glycemic measurement and the other to erythrocyte indices.

Genetically increased HbA1C was associated with the lower heel eBMD [odds ratio (OR) 0.91 (95% CI 0.87, 0.96) per %-unit, P = 3 × 10−4(IVW)]. Higher HbA1C was associated with lower heel eBMD when using only erythrocytic variants [OR 0.87 (0.82, 0.93), P=2× 10−5(IVW)]; However, when using only glycemic variants, this casual association does not hold. In further MR analysis, we test the association of erythrocytic traits with heel eBMD.

Our study revealed the significant causal effect of HbA1c on eBMD, and this causal link might achieve through non-glycemic pathways (erythrocytic indices).

糖化血红蛋白（HbA1c）作为一种有价值的血糖测量指标，对糖尿病具有重要的临床价值。然而，在以往的观察性研究中，关于其对骨密度（BMD）影响的研究却有不同的结果。本研究旨在使用孟德尔随机化 (MR) 来评估 HbA1c 对骨密度和骨折风险的影响，并试图进一步探讨这种关联是通过血糖因素还是非血糖因素实现的。

以 HbA1c 测量作为暴露，以定量足跟超声 (eBMD) 和骨折作为结果估计 BMD。进行双样本 MR 分析以评估 HbA1C 对足跟骨密度和骨折风险的因果影响。然后，我们使用这些变体的两个子集进行了分析，一个与血糖测量相关，另一个与红细胞指数相关。

基因增加的 HbA1C 与较低的足跟 eBMD [比值比 (OR) 0.91 (95% CI 0.87, 0.96) 每 %-单位，P = 3 × 10−4(IVW)] 相关。当仅使用红细胞变体时，较高的 HbA1C 与较低的足跟 eBMD 有关 [OR 0.87 (0.82, 0.93)，P=2× 10-5(IVW)]；然而，当仅使用血糖变体时，这种偶然关联并不成立。在进一步的 MR 分析中，我们测试了红细胞特征与足跟 eBMD 的关联。

我们的研究揭示了 HbA1c 对 eBMD 的显着因果关系，并且这种因果关系可能通过非血糖途径（红细胞指数）实现。