Leng Pengyuan, Qiu Ying, Zhou Mengxue, Zhu Yuhang, Yin Na, Zhou Mingming, Wu Weili, Liu Min
Department of Orthopedics, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Postgraduate Training Base Alliance of Wenzhou Medical University (The Third Affiliated Hospital of Wenzhou Medical University), Ruian, Zhejiang, China.
Front Med (Lausanne). 2024 Nov 1;11:1453502. doi: 10.3389/fmed.2024.1453502. eCollection 2024.
BACKGROUND: Observational studies have demonstrated a correlation between thyroid dysfunction and osteoporosis (OP); however, the underlying causality has yet to be fully elucidated. METHODS: The necessary dataset was sourced from public databases. Initially, instrumental variables (IVs) were selected based on three primary hypotheses. Subsequently, Cochran's Q test was employed to exclude IVs exhibiting heterogeneity. The MR-PRESSO test and the leave-one-out sensitivity test were further applied to detect potential pleiotropy. Inverse variance was utilized for the analysis. This study primarily utilized the inverse variance weighted (IVW) model for Mendelian analysis. Since Type 1 diabetes mellitus can also contribute to the development of osteoporosis, this study additionally employed multivariate Mendelian analysis. Furthermore, 249 circulating metabolites were selected for mediation analysis in the Mendelian randomization framework. RESULTS: In this study, the two-sample Mendelian randomization (MR) analysis primarily employed the random-effects IVW model and demonstrated a causal relationship between hypothyroidism (OR = 1.092, 95% CI: 1.049-1.137, < 0.001) and hyperthyroidism (OR = 1.080, 95% CI: 1.026-1.137, = 0.003) with the risk of OP. No causal relationships were identified between FT3, FT4, TSH, and the risk of OP ( > 0.05). The results of the multivariate Mendelian randomization (MVMR) analysis indicated that hyperthyroidism was no longer a risk factor for OP (OR = 0.984, 95% CI: 0.918-1.055, = 0.657), whereas hypothyroidism persisted as a risk factor (OR = 1.082, 95% CI: 1.021-1.147, = 0.008). The mediated Mendelian randomization analysis revealed that hypothyroidism may exert an indirect effect on OP via triglycerides in large VLDL, mediating approximately 2.47% of the effect. CONCLUSION: This study identifies a potential link between hypothyroidism and OP, possibly mediated indirectly via triglyceride levels in large VLDL. Further investigations are required to elucidate the direct or indirect causal mechanisms underlying this association.
背景：观察性研究已证明甲状腺功能障碍与骨质疏松症（OP）之间存在关联；然而，潜在的因果关系尚未完全阐明。 方法：必要的数据集来自公共数据库。最初，基于三个主要假设选择工具变量（IVs）。随后，采用 Cochr an's Q检验排除表现出异质性的IVs。进一步应用MR - PRESSO检验和留一法敏感性检验来检测潜在的多效性。采用逆方差进行分析。本研究主要利用逆方差加权（IVW）模型进行孟德尔分析。由于1型糖尿病也可能导致骨质疏松症的发生，本研究还采用了多变量孟德尔分析。此外，在孟德尔随机化框架中选择了249种循环代谢物进行中介分析。 结果：在本研究中，两样本孟德尔随机化（MR）分析主要采用随机效应IVW模型，结果显示甲状腺功能减退（OR = 1.092，95%CI：1.049 - 1.137，P < 0.001）和甲状腺功能亢进（OR = 1.080，95%CI：1.026 - 1.137，P = 0.003）与OP风险之间存在因果关系。未发现FT3、FT4、TSH与OP风险之间存在因果关系（P > 0.05）。多变量孟德尔随机化（MVMR）分析结果表明，甲状腺功能亢进不再是OP的危险因素（OR = 0.984，95%CI：0.918 - 1.055，P = 0.657），而甲状腺功能减退仍然是危险因素（OR = 1.082，95%CI：1.021 - 1.147，P = 0.008）。中介孟德尔随机化分析显示，甲状腺功能减退可能通过大极低密度脂蛋白中的甘油三酯对OP产生间接影响，介导约2.47%的效应。 结论：本研究确定了甲状腺功能减退与OP之间的潜在联系，可能通过大极低密度脂蛋白中的甘油三酯水平间接介导。需要进一步研究以阐明这种关联背后的直接或间接因果机制。
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