Zhang Chao, Yu Hao, Miao Yulin, Wei Biaofang
Guangzhou University of Chinese Medicine, Guangzhou, China.
Linyi People's Hospital, Linyi, China.
J Transl Med. 2025 Feb 25;23(1):226. doi: 10.1186/s12967-024-06030-9.
Osteonecrosis (ON) is a debilitating orthopedic condition characterized by bone cell death due to impaired blood supply, leading to structural changes and disability. Osteoporosis (OP), a systemic skeletal disease, results in reduced bone density and quality, making bones fragile and prone to fractures. Although distinct, OP and ON share several risk factors such as corticosteroid use and smoking. This study aims to investigate the causal relationships between OP, bone mineral density (BMD), and ON using a bidirectional two-sample Mendelian randomization (MR) approach.
This study utilized genome-wide association study (GWAS) data for OP from the FinnGen database, and BMD data for the lumbar spine and femoral neck from the Genetic Factors for Osteoporosis (GEFOS) consortium. ON data were also obtained from the FinnGen database. All participants were of European descent. Genetic instruments were selected based on genome-wide significance, linkage disequilibrium, and strength (F-statistic). Bidirectional MR analysis was performed using inverse-variance weighted (IVW), MR-Egger regression, and weighted median methods to assess causality. Sensitivity analyses, including Cochran's Q test and MR-PRESSO, were conducted to evaluate heterogeneity and pleiotropy.
MR analysis demonstrated a positive causal effect of OP on ON using the IVW method, with an odds ratio (OR) of 1.223 (95% CI: 1.026-1.459, P = 0.025). The weighted median method also confirmed this result with an OR (95% CI) 1.290 (1.021-1.630), P = 0.033. No significant causal effects were found between BMD (lumbar spine and femoral neck) and ON. Furthermore, ON did not exhibit a causal effect on OP or BMD. Sensitivity analyses confirmed the robustness of the results, showing no evidence of heterogeneity or pleiotropy.
This study provides evidence of a unidirectional causal relationship between OP and ON, suggesting that individuals with a genetic predisposition to OP have an increased risk of developing ON. These findings highlight the importance of early OP detection and management to potentially reduce ON incidence. The lack of a significant causal relationship between BMD and ON indicates that factors other than bone density, such as vascular health, may play a crucial role in ON development. Future research should explore these mechanisms further to inform clinical interventions.
骨坏死（ON）是一种使人衰弱的骨科疾病，其特征是由于血液供应受损导致骨细胞死亡，进而引起结构变化和功能障碍。骨质疏松症（OP）是一种全身性骨骼疾病，会导致骨密度和质量降低，使骨骼变得脆弱且易于骨折。尽管OP和ON有所不同，但它们有一些共同的风险因素，如使用皮质类固醇和吸烟。本研究旨在使用双向双样本孟德尔随机化（MR）方法研究OP、骨矿物质密度（BMD）和ON之间的因果关系。
本研究利用了来自芬兰基因数据库的OP全基因组关联研究（GWAS）数据，以及来自骨质疏松症遗传因素（GEFOS）联盟的腰椎和股骨颈BMD数据。ON数据也来自芬兰基因数据库。所有参与者均为欧洲血统。基于全基因组显著性、连锁不平衡和强度（F统计量）选择遗传工具。使用逆方差加权（IVW）、MR-Egger回归和加权中位数方法进行双向MR分析以评估因果关系。进行了敏感性分析，包括 Cochr an's Q检验和MR-PRESSO，以评估异质性和多效性。
MR分析使用IVW方法证明OP对ON有正向因果效应，优势比（OR）为1.223（95%置信区间：1.026 - 1.459，P = 0.025）。加权中位数方法也证实了这一结果，OR（95%置信区间）为1.290（1.021 - 1.630），P = 0.033。未发现BMD（腰椎和股骨颈）与ON之间存在显著因果效应。此外，ON对OP或BMD也未表现出因果效应。敏感性分析证实了结果的稳健性，未显示异质性或多效性的证据。
本研究提供了OP与ON之间单向因果关系的证据，表明具有OP遗传易感性的个体发生ON的风险增加。这些发现凸显了早期检测和管理OP对于潜在降低ON发病率的重要性。BMD与ON之间缺乏显著因果关系表明，除骨密度外的其他因素，如血管健康，可能在ON的发生中起关键作用。未来的研究应进一步探索这些机制，为临床干预提供依据。
