• Manuel R Blum, Douglas C Bauer, Tinh-Hai Collet, Howard A Fink, Anne R Cappola, Bruno R da Costa, Christina D Wirth, Robin P Peeters, Bjørn O Åsvold, Wendy P J den Elzen, Robert N Luben, Misa Imaizumi, Alexandra P Bremner, Apostolos Gogakos, Richard Eastell, Patricia M Kearney, Elsa S Strotmeyer, Erin R Wallace, Mari Hoff, Graziano Ceresini, Fernando Rivadeneira, André G Uitterlinden, David J Stott, Rudi G J Westendorp, Kay-Tee Khaw, Arnuf Langhammer, Luigi Ferrucci, Jacobijn Gussekloo, Graham R Williams, John P Walsh, Peter Jüni, Drahomir Aujesky, Nicolas Rodondi, and Thyroid Studies Collaboration.
• Department of General Internal Medicine, Inselspital, Bern University Hospital, Bern, Switzerland.
• JAMA. 2015 May 26; 313 (20): 205520652055-65.

ImportanceAssociations between subclinical thyroid dysfunction and fractures are unclear and clinical trials are lacking.ObjectiveTo assess the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures.Data Sources And Study SelectionThe databases of MEDLINE and EMBASE (inception to March 26, 2015) were searched without language restrictions for prospective cohort studies with thyroid function data and subsequent fractures.Data ExtractionIndividual participant data were obtained from 13 prospective cohorts in the United States, Europe, Australia, and Japan. Levels of thyroid function were defined as euthyroidism (thyroid-stimulating hormone [TSH], 0.45-4.49 mIU/L), subclinical hyperthyroidism (TSH <0.45 mIU/L), and subclinical hypothyroidism (TSH ≥4.50-19.99 mIU/L) with normal thyroxine concentrations.Main Outcome And MeasuresThe primary outcome was hip fracture. Any fractures, nonspine fractures, and clinical spine fractures were secondary outcomes.ResultsAmong 70,298 participants, 4092 (5.8%) had subclinical hypothyroidism and 2219 (3.2%) had subclinical hyperthyroidism. During 762,401 person-years of follow-up, hip fracture occurred in 2975 participants (4.6%; 12 studies), any fracture in 2528 participants (9.0%; 8 studies), nonspine fracture in 2018 participants (8.4%; 8 studies), and spine fracture in 296 participants (1.3%; 6 studies). In age- and sex-adjusted analyses, the hazard ratio (HR) for subclinical hyperthyroidism vs euthyroidism was 1.36 for hip fracture (95% CI, 1.13-1.64; 146 events in 2082 participants vs 2534 in 56,471); for any fracture, HR was 1.28 (95% CI, 1.06-1.53; 121 events in 888 participants vs 2203 in 25,901); for nonspine fracture, HR was 1.16 (95% CI, 0.95-1.41; 107 events in 946 participants vs 1745 in 21,722); and for spine fracture, HR was 1.51 (95% CI, 0.93-2.45; 17 events in 732 participants vs 255 in 20,328). Lower TSH was associated with higher fracture rates: for TSH of less than 0.10 mIU/L, HR was 1.61 for hip fracture (95% CI, 1.21-2.15; 47 events in 510 participants); for any fracture, HR was 1.98 (95% CI, 1.41-2.78; 44 events in 212 participants); for nonspine fracture, HR was 1.61 (95% CI, 0.96-2.71; 32 events in 185 participants); and for spine fracture, HR was 3.57 (95% CI, 1.88-6.78; 8 events in 162 participants). Risks were similar after adjustment for other fracture risk factors. Endogenous subclinical hyperthyroidism (excluding thyroid medication users) was associated with HRs of 1.52 (95% CI, 1.19-1.93) for hip fracture, 1.42 (95% CI, 1.16-1.74) for any fracture, and 1.74 (95% CI, 1.01-2.99) for spine fracture. No association was found between subclinical hypothyroidism and fracture risk.Conclusions And RelevanceSubclinical hyperthyroidism was associated with an increased risk of hip and other fractures, particularly among those with TSH levels of less than 0.10 mIU/L and those with endogenous subclinical hyperthyroidism. Further study is needed to determine whether treating subclinical hyperthyroidism can prevent fractures.

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