Zhu Junyu, Zhou Shijie, Jiang Mingqi, Wang Wenying, Yan Jun
Department of Orthopedics, Third Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China.
Department of Orthopedics, The Daping Hospital, Chongqing, China.
Medicine (Baltimore). 2025 Aug 29;104(35):e44153. doi: 10.1097/MD.0000000000044153.
Studies show excessive cortisol is linked to osteoporosis (OP). However, the impact of mild cortisol excess (MCE) on bone mineral density (BMD) remains unclear. Sarcopenia may play a key role in this, particularly in aging or stress contexts. To investigate the association between MCE and OP outcomes and the proportion of this association that is mediated through SP using Mendelian randomization (MR). MR study using summary statistics with traits were obtained from publicly available genome-wide association studies (GWAS) of OP and sarcopenia-related traits. Three single-nucleotide polymorphisms (SNPs) associated with plasma cortisol concentrations in the CORtisol NETwork consortium were used as instrumental variables. All participants were of European ancestry. Random-effect inverse-variance weighted (IVW) method was used as the main analysis of MR, and a series of sensitivity analyses were performed to detect heterogeneity and horizontal pleiotropy. A 2-step MR approach was used to investigate whether the mediating pathway from MCE to OP was mediated by sarcopenia-related traits. Cortisol increases OP risk in the femoral neck (FN, OR = 0.874, 95% CI: 0.786-0.973, P = .0138), while reducing it in the lumbar spine (LS, OR = 1.140, 95% CI: 1.008-1.291, P = .037) and heel (OR = 1.027, 95% CI: 1.000-1.054, P = .047). The mediation analysis via 2-step MR showed that sarcopenia mediates up to 8.4% of the cortisol-induced osteoporosis risk in the LS. This MR analysis suggests that MCE primarily increases OP risk in the FN, rather than affecting the body systemically. It also shows that SP mediates up to 8.4% of the cortisol-induced OP risk in the lumbar spine, highlighting the importance of muscle-strengthening exercises in preventing OP.
研究表明，皮质醇过多与骨质疏松症（OP）有关。然而，轻度皮质醇过量（MCE）对骨密度（BMD）的影响仍不清楚。肌肉减少症可能在其中起关键作用，尤其是在衰老或应激情况下。为了使用孟德尔随机化（MR）研究MCE与OP结局之间的关联以及通过肌肉减少症（SP）介导的这种关联的比例。使用从公开可用的OP和肌肉减少症相关性状的全基因组关联研究（GWAS）中获得的汇总统计数据进行MR研究。来自皮质醇网络联盟的与血浆皮质醇浓度相关的三个单核苷酸多态性（SNP）用作工具变量。所有参与者均为欧洲血统。随机效应逆方差加权（IVW）方法用作MR的主要分析，并进行了一系列敏感性分析以检测异质性和水平多效性。采用两步MR方法研究从MCE到OP的中介途径是否由肌肉减少症相关性状介导。皮质醇增加了股骨颈（FN）的OP风险（OR = 0.874，95% CI：0.786 - 0.973，P = 0.0138），而在腰椎（LS）（OR = 1.140，95% CI：1.008 - 1.291，P = 0.037）和足跟（OR = 1.027，95% CI：1.000 - 1.054，P = 0.047）中则降低了OP风险。通过两步MR进行的中介分析表明，肌肉减少症介导了LS中皮质醇诱导的骨质疏松症风险的8.4%。该MR分析表明，MCE主要增加FN的OP风险，而不是全身性地影响身体系统。它还表明，SP介导了腰椎中皮质醇诱导的OP风险的8.4%，突出了加强肌肉锻炼在预防OP中的重要性。
