Division of Bone Diseases, Department of Academic Diabetes, Endocrinology and Metabolism, Hull York Medical School, University of Hull, Hull, UK.
Department of Internal Medicine Specialties, Faculty of Medicine, Geneva University Hospital, Geneva, Switzerland.
Clin Endocrinol (Oxf). 2021 Jan;94(1):119-127. doi: 10.1111/cen.14330. Epub 2020 Sep 28.
Untreated hyperthyroidism is associated with accelerated bone turnover, low bone mineral density (BMD) and increased susceptibility to fragility fractures. Although treatment appears to improve or even reverse some of these adverse skeletal effects, there is limited guidance on routine BMD assessment in hyperthyroid patients following treatment. By using Mendelian randomization (MR) analysis, we aimed to assess the causal association of hyperthyroid thyroid states with BMD and fractures using the UK Biobank.
This MR analysis included data from 473 818 participants (women: 54% of the total sample, the median age of 58.0 years (IQR = 50-63 years), median body mass index (BMI) of 26.70 (IQR + 24.11-29.82 kg/m ) as part of the UK Biobank study. The study outcomes were heel BMD assessed by quantitative ultrasound of the heel and self-reported fractures. Beta-weighted genetic risk score analysis was performed using 19 single nucleotide polymorphisms (SNPs) for Graves' disease, 9 SNPs for hyperthyroidism and 11 SNPs for autoimmune thyroiditis. Since the unadjusted risk score MR is equivalent to the inverse-variance weighted method, the genetic risk score analysis was adjusted for age, gender and BMI. Sensitivity analyses were conducted using the Mendelian randomization-Egger (MR-Egger) and the inverse-variance weighted estimate methods. Replication analysis was performed using the GEnetic Factors for Osteoporosis (GEFOS) consortium data.
MR analysis using beta-weighted genetic risk score showed no association of genetic risk for Graves' disease (Beta = -0.01, P-value = .10), autoimmune thyroiditis (Beta = -0.006 P-value = .25) and hyperthyroidism (Beta = -0.009, P-value = .18) with heel ultrasound BMD. MR-Egger and inverse-variance MR methods in UK Biobank and GEFOS consortium confirmed these findings. The genetic risk for these hyperthyroid conditions was not associated with an increased risk of fractures.
Our study shows that excess genetic risk for Graves' autoimmune thyroiditis and hyperthyroidism does not increase the risk for low BMD and is not associated fractures in the Caucasian population. Our findings do not support routine screening for osteoporosis following definitive treatment of hyperthyroid states.
未经治疗的甲状腺功能亢进症与骨转换加速、骨密度降低（BMD）和脆性骨折易感性增加有关。尽管治疗似乎可以改善甚至逆转这些不良的骨骼影响，但对于治疗后甲状腺功能亢进症患者的常规 BMD 评估，目前还缺乏指导。通过使用孟德尔随机分析（MR），我们旨在使用英国生物库评估甲状腺功能亢进症状态与 BMD 和骨折的因果关系。
本 MR 分析包括英国生物库 473818 名参与者的数据（女性占总样本的 54%，中位年龄为 58.0 岁（IQR=50-63 岁），中位体重指数（BMI）为 26.70（IQR+24.11-29.82kg/m ）。研究结果为足跟骨密度，通过足跟定量超声检查和自我报告的骨折进行评估。使用 19 个格雷夫斯病的单核苷酸多态性（SNP）、9 个甲状腺功能亢进症的 SNP 和 11 个自身免疫性甲状腺炎的 SNP 进行加权遗传风险评分分析。由于未经调整的风险评分 MR 等同于逆方差加权方法，因此遗传风险评分分析调整了年龄、性别和 BMI。使用孟德尔随机化- Egger（MR-Egger）和逆方差加权估计方法进行敏感性分析。使用 GEFOS 联盟数据进行复制分析。
使用加权遗传风险评分的 MR 分析显示，格雷夫斯病的遗传风险（Beta=-0.01，P 值=0.10）、自身免疫性甲状腺炎（Beta=-0.006，P 值=0.25）和甲状腺功能亢进症（Beta=-0.009，P 值=0.18）与足跟超声 BMD 无关联。英国生物库和 GEFOS 联盟的 MR-Egger 和逆方差 MR 方法证实了这些发现。这些甲状腺功能亢进症的遗传风险与增加的 BMD 风险无关，也与骨折无关。
我们的研究表明，格雷夫斯自身免疫性甲状腺炎和甲状腺功能亢进症的遗传风险增加并不会增加低 BMD 的风险，也不会增加白种人群的骨折风险。我们的研究结果不支持在甲状腺功能亢进症状态得到明确治疗后常规筛查骨质疏松症。
