Hyperthyroidism and Bone Mineral Density

Dissecting the Causal Association With Mendelian Randomization Analysis

Harshal Deshmukh; Maria Papageorgiou; Mo Aye; James England; Mohammed Abdalla; Thozhukat Sathyapalan

Disclosures

Clin Endocrinol. 2021;94(1):119-127. 

In This Article

Abstract and Introduction

Abstract

Introduction: 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.

Methods: 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/m2) 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.

Results: 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.

Conclusion: 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.

Introduction

Hyperthyroidism, characterized by excess thyroid hormone synthesis and secretion from the thyroid gland, affects approximately 1 in 100 individuals.[1–3] Graves' disease and multinodular goitre are the most common causes of hyperthyroidism in young/middle-aged and older individuals, respectively.[2,3] Untreated overt hyperthyroidism has well-documented skeletal consequences including low bone mineral density (BMD), secondary osteoporosis and increased fragility fracture risk, which result from high and more frequent initiation of bone turnover (i.e. simultaneous increases in bone formation and resorption).[4–11] Impaired bone health has also been shown among patients with subclinical hyperthyroidism (TSH concentrations below the normal reference range and free T3 and T4 levels within the normal reference range)[12–14] and euthyroid individuals with relatively low TSH and relatively high free T4 levels, albeit within the reference range.[15,16] The treatment options for hyperthyroidism commonly include antithyroid drugs, radioactive iodine therapy and near-total or total thyroidectomy.[1,17] Although some studies have shown increases in bone formation, improvements in BMD and reduction in fracture risk,[5,17–20] others suggest persistent, low BMD even after treatment, especially in populations at risk of osteoporosis such as postmenopausal women.[17,21,22]

Current guidelines for the diagnosis and management of osteoporosis (National Institute for Clinical Excellence NICE) clinical guideline CG146, ESCEO and IOF,[23] Scientific Advisory council of osteoporosis Canada,[24] American Association of Clinical Endocrinologists/American College of Endocrinology[25] recommend estimation of the absolute risk of the fracture using the FRAX score. The clinical risk factors included in the FRAX score do not consider patients treated for hyperthyroidism, and hence, these patients are likely to obtain a low FRAX score. As a result, patients who have received or are currently receiving treatment for hyperthyroidism are unlikely to be offered routine screening (i.e. a dual-energy X-ray absorptiometry [DXA] scan) for monitoring changes in BMD and osteoporosis status. As such, it is critical to understand whether populations with imbalances in thyroid hormones are susceptible to ongoing bone loss, once they have definitive treatment for their hyperthyroidism. Whilst available population-based studies have shown at least partial BMD recovery,[5,17–22] these are often limited by low statistical power, cross-sectional design or short-term follow-up and are confounded by factors such as age, sex, body mass index (BMI), presence of other endocrine disorders, lifestyle factors (e.g. physical activity, smoking and alcohol consumption) or concurrent use of medications, which can affect BMD. These confounding factors can be overcome to some extent by Mendelian randomization analysis,[26] which can uncover causal relationships between selected thyroid disorders and BMD, whilst avoiding reverse causality (i.e. the disease cannot affect genotype) by using Mendel's Laws of Inheritance.[27] This law postulates that alleles segregate randomly from parents to offspring[28] and thus, offspring genotypes are randomly distributed in the population and are unlikely to be associated with confounders. An assessment of the association of excess genetic risk for hyperthyroid states such as Graves' with BMD and fractures will help in understanding if these states have a direct causal role in lowering of the BMD and increasing risk of fractures. If such an association exists, it will support careful monitoring of BMD and periodic basement of fracture susceptibility in these patients. However, if there is no such association, it would support the current NICE guidelines.

The aim of the present investigation was to assess the effects of genetic susceptibility to hyperthyroidism on BMD and history of fragility fractures using the UK Biobank data and data from the GEnetic Factors for OSteoporosis (GEFOS) Consortium.[29]

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