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Meta-Analysis
. 2018 Jan;283(1):56-72.
doi: 10.1111/joim.12688. Epub 2017 Oct 16.

Association between subclinical thyroid dysfunction and change in bone mineral density in prospective cohorts

D Segna  1 , D C Bauer  2 , M Feller  1 , C Schneider  1 , H A Fink  3   4 , C E Aubert  1 , T-H Collet  5 , B R da Costa  6 , K Fischer  7   8 , R P Peeters  9 , A R Cappola  10 , M R Blum  1 , H A van Dorland  1 , J Robbins  11 , K Naylor  12 , R Eastell  12 , A G Uitterlinden  9 , F Rivadeneira Ramirez  9 , A Gogakos  13 , J Gussekloo  14 , G R Williams  13 , A Schwartz  2 , J A Cauley  15 , D A Aujesky  1 , H A Bischoff-Ferrari  7   8 , N Rodondi  1   6 ; Thyroid Studies Collaboration
Affiliations
Meta-Analysis

Association between subclinical thyroid dysfunction and change in bone mineral density in prospective cohorts

D Segna et al. J Intern Med. 2018 Jan.

Abstract

Background: Subclinical hyperthyroidism (SHyper) has been associated with increased risk of hip and other fractures, but the linking mechanisms remain unclear.

Objective: To investigate the association between subclinical thyroid dysfunction and bone loss.

Methods: Individual participant data analysis was performed after a systematic literature search in MEDLINE/EMBASE (1946-2016). Two reviewers independently screened and selected prospective cohorts providing baseline thyroid status and serial bone mineral density (BMD) measurements. We classified thyroid status as euthyroidism (thyroid-stimulating hormone [TSH] 0.45-4.49 mIU/L), SHyper (TSH < 0.45 mIU/L) and subclinical hypothyroidism (SHypo, TSH ≥ 4.50-19.99 mIU/L) both with normal free thyroxine levels. Our primary outcome was annualized percentage BMD change (%ΔBMD) from serial dual X-ray absorptiometry scans of the femoral neck, total hip and lumbar spine, obtained from multivariable regression in a random-effects two-step approach.

Results: Amongst 5458 individuals (median age 72 years, 49.1% women) from six prospective cohorts, 451 (8.3%) had SHypo and 284 (5.2%) had SHyper. During 36 569 person-years of follow-up, those with SHyper had a greater annual bone loss at the femoral neck versus euthyroidism: %ΔBMD = -0.18 (95% CI: -0.34, -0.02; I2 = 0%), with a nonstatistically significant pattern at the total hip: %ΔBMD = -0.14 (95% CI: -0.38, 0.10; I2 = 53%), but not at the lumbar spine: %ΔBMD = 0.03 (95% CI: -0.30, 0.36; I2 = 25%); especially participants with TSH < 0.10 mIU/L showed an increased bone loss in the femoral neck (%Δ BMD = -0.59; [95% CI: -0.99, -0.19]) and total hip region (%ΔBMD = -0.46 [95% CI: -1.05, -0.13]). In contrast, SHypo was not associated with bone loss at any site.

Conclusion: Amongst adults, SHyper was associated with increased femoral neck bone loss, potentially contributing to the increased fracture risk.

Keywords: bone density; bone loss; hyperthyroidism; hypothyroidism; prospective studies; thyroid disease.

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Conflict of interest statement

Conflict of interest

Dr. Rodondi and Dr. Gussekloo report funding for a randomized controlled trial on subclinical hypothyroidism (TRUST trial) from the European Commission FP7-HEALTH-2011, Specific Programme “Cooperation” – Theme “Health” Investigator-driven clinical trials for therapeutic interventions in elderly populations (Proposal No: 278148-2). Dr. Peeters reports lecture and/or advisory board fees from Genzyme B.V., EISAI, IPSEN, and Goodlife Fertility; and grant support from Veracyte, all outside of the submitted work. Dr. Eastell reports grants and personal fees from Amgen, grants from Department of Health, grants from AstraZeneca, grants, personal fees and non-financial support from Immunodiagnostic Systems, grants from ARUK/MRC Centre for Excellence in Musculoskeletal Ageing Research, grants from National Institute for Health Research, grants from MRC/AZ Mechanisms of Diseases Call, grants from MRC, grants and personal fees from Alexion, grants and other from National Osteoporosis Society, grants, personal fees and other from Roche, personal fees and other from Eli Lilly, other from European Calcified Tissue Society, other from IOF CSA, other from IBMS, other from ASBMR, personal fees from D-STAR, personal fees from GSK Nutrition, outside the submitted work; Dr Robbins reports funding from NHLBI during the conduct of the study. Dr Collet reports grants from Swiss National Science foundation during the conduct of the study.

Figures

Appendix Figure 1
Appendix Figure 1. Flow chart of study selection
BMD: bone mineral density, fT4: free thyroxine, IPD: individual participant data, n= number of studies
Appendix Figure 2
Appendix Figure 2. Subclinical Hyperthyroidism and Annualized Percentage Change in Femoral Neck Bone Mineral Density Compared to Euthyroid Individuals
Multivariable adjustment for age, sex, bone mass index, smoking and menopausal status, history of diabetes. Values presented as mean difference in annualized percentage change in BMD (%ΔBMD), as compared to euthyroid controls. Abbreviations: I2: I2 statistics; p = p for heterogeneity; 95%CI: 95% confidence intervals
Figure 1
Figure 1. Annualized Percentage Change in Hip Bone Mineral Density Stratified by Cohort-Specific fT4 Quartiles
Multivariable adjustment for age, sex, bone mass index, smoking and menopausal status, history of diabetes. Values presented as mean difference in annualized percentage change in BMD (%ΔBMD). 95%CI: 95% confidence intervals; fT4: free thyroxine; quartiles obtained from each cohort, p for difference in %ΔBMD between the highest and lowest fT4 quartile.
See this image and copyright information in PMC

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