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Subclinical Thyroid Dysfunction and the Risk for Fractures: A Systematic Review and Meta-analysisSubclinical Thyroid Dysfunction and the Risk for Fractures

Christina D. Wirth, MD; Manuel R. Blum, MD; Bruno R. da Costa, PhD; Christine Baumgartner, MD; Tinh-Hai Collet, MD; Marco Medici, MD, MSc; Robin P. Peeters, MD, PhD; Drahomir Aujesky, MD, MSc; Douglas C. Bauer, MD; and Nicolas Rodondi, MD, MAS
[+] Article and Author Information

From University of Bern, Bern, Switzerland; University Hospital of Lausanne, Lausanne, Switzerland; Erasmus Medical Center, Rotterdam, the Netherlands; and University of California, San Francisco, San Francisco, California.

Acknowledgment: The authors thank Professor Richard Eastell and Dr. Judith Finigan (University of Sheffield, Sheffield, United Kingdom); Dr. Avantika Waring (University of California, San Francisco, San Francisco, California); Dr. Stephanie Litwack-Harrison (San Francisco Coordinating Center, California Pacific Medical Center Research Institute, San Francisco, California); Professor Graham Leese and Dr. Robert W. Flynn (Ninewells Hospital and Medical School, Dundee, Scotland, United Kingdom); Dr. Anders Svare (Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway); Professor Howard Fink (Geriatric Research Education and Clinical Center, Minneapolis Veterans Affairs Medical Center, and Department of Medicine, University of Minnesota School of Medicine, Minneapolis, Minnesota); and Professor Anne R. Cappola (Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania) for supplying additional data from their studies.

Financial Support: By the Swiss National Science Foundation (grant SNSF 320030-138267 [Dr. Rodondi]; salary support [Drs. Wirth, Blum, and Baumgartner]; and grant PBLAP3-145870 for salary support [Dr. Collet]) and in part by the Swiss Heart Foundation (Dr. Rodondi).

Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-0125.

Requests for Single Reprints: Nicolas Rodondi, MD, MAS, Department of General Internal Medicine, Inselspital, Bern University Hospital, 3010 Bern, Switzerland; e-mail, Nicolas.Rodondi@insel.ch.

Current Author Addresses: Drs. Wirth, Blum, Baumgartner, Aujesky, and Rodondi: Department of General Internal Medicine, Inselspital, Bern University Hospital, 3010 Bern, Switzerland.

Dr. da Costa: Nicole Wertheim College of Nursing & Health Sciences, Florida International University, Modesto A. Maidique Campus, AHC 3, 11200 SW 8th Street, Miami, FL 33199.

Dr. Collet: Service of Endocrinology, Diabetes and Metabolism, University Hospital of Lausanne, rue du Bugnon 46, 1011 Lausanne, Switzerland.

Drs. Medici and Peeters: Rotterdam Thyroid Center, Department of Internal Medicine, Erasmus Medical Center, Dr. Molewaterplein 50, 3015 GE, Rotterdam, the Netherlands.

Dr. Bauer: Departments of Medicine and Epidemiology & Biostatistics, University of California, San Francisco, 185 Berry Street, San Francisco, CA 94143.

Author Contributions: Conception and design: C.D. Wirth, M.R. Blum, B.R. da Costa, D.C. Bauer, N. Rodondi.

Analysis and interpretation of the data: C.D. Wirth, M.R. Blum, B.R. da Costa, C. Baumgartner, T. Collet, M. Medici, R.P. Peeters, D.C. Bauer, N. Rodondi.

Drafting of the article: C.D. Wirth, N. Rodondi.

Critical revision of the article for important intellectual content: C.D. Wirth, M.R. Blum, B.R. da Costa, C. Baumgartner, T. Collet, M. Medici, R.P. Peeters, D. Aujesky, D.C. Bauer, N. Rodondi.

Final approval of the article: C.D. Wirth, B.R. da Costa, T. Collet, M. Medici, R.P. Peeters, D. Aujesky, D.C. Bauer, N. Rodondi.

Provision of study materials or patients: M.R. Blum, R.P. Peeters, N. Rodondi.

Statistical expertise: B.R. da Costa, M. Medici, N. Rodondi.

Obtaining of funding: N. Rodondi.

Administrative, technical, or logistic support: M.R. Blum, R.P. Peeters, D. Aujesky, D.C. Bauer, N. Rodondi.

Collection and assembly of data: C.D. Wirth, M.R. Blum, C. Baumgartner, T. Collet, D.C. Bauer, N. Rodondi


Ann Intern Med. 2014;161(3):189-199. doi:10.7326/M14-0125
Text Size: A A A

Background: Data on the association between subclinical thyroid dysfunction and fractures conflict.

Purpose: To assess the risk for hip and nonspine fractures associated with subclinical thyroid dysfunction among prospective cohorts.

Data Sources: Search of MEDLINE and EMBASE (1946 to 16 March 2014) and reference lists of retrieved articles without language restriction.

Study Selection: Two physicians screened and identified prospective cohorts that measured thyroid function and followed participants to assess fracture outcomes.

Data Extraction: One reviewer extracted data using a standardized protocol, and another verified data. Both reviewers independently assessed methodological quality of the studies.

Data Synthesis: The 7 population-based cohorts of heterogeneous quality included 50 245 participants with 1966 hip and 3281 nonspine fractures. In random-effects models that included the 5 higher-quality studies, the pooled adjusted hazard ratios (HRs) of participants with subclinical hyperthyroidism versus euthyrodism were 1.38 (95% CI, 0.92 to 2.07) for hip fractures and 1.20 (CI, 0.83 to 1.72) for nonspine fractures without statistical heterogeneity (P = 0.82 and 0.52, respectively; I2 = 0%). Pooled estimates for the 7 cohorts were 1.26 (CI, 0.96 to 1.65) for hip fractures and 1.16 (CI, 0.95 to 1.42) for nonspine fractures. When thyroxine recipients were excluded, the HRs for participants with subclinical hyperthyroidism were 2.16 (CI, 0.87 to 5.37) for hip fractures and 1.43 (CI, 0.73 to 2.78) for nonspine fractures. For participants with subclinical hypothyroidism, HRs from higher-quality studies were 1.12 (CI, 0.83 to 1.51) for hip fractures and 1.04 (CI, 0.76 to 1.42) for nonspine fractures (P for heterogeneity = 0.69 and 0.88, respectively; I2 = 0%).

Limitations: Selective reporting cannot be excluded. Adjustment for potential common confounders varied and was not adequately done across all studies.

Conclusion: Subclinical hyperthyroidism might be associated with an increased risk for hip and nonspine fractures, but additional large, high-quality studies are needed.

Primary Funding Source: Swiss National Science Foundation.

Figures

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Appendix Figure 1.

Summary of evidence search and selection.

Studies evaluated for inclusion in the meta-analysis (adapted from PRISMA Statement flow diagram [43]).

* Until 16 March 2014.

† From key articles in the field and contact with the authors (44).

‡ Exclusion criteria included records unrelated to the association between subclinical thyroid dysfunction and fractures or studies without prospective design and thyroid measurement.

§ For list of excluded full-text articles, see the Appendix Table.

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Figure.

Forest plots for subclinical hyperthyroidism.

CHS = Cardiovascular Health Study; HUNT2 = Nord Trøndelag Health Study 2; MrOS = Osteoporotic Fractures in Men Study; NR = not reported; SOF = Study of Osteoporotic Fractures; TEARS = Thyroid Epidemiology Audit and Research Study. Top. Risk for hip fractures. Bottom. Risk for nonspine fractures.

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Appendix Figure 2.

Forest plots for subclinical hypothyroidism.

CHS = Cardiovascular Health Study; HUNT2 = Nord Trøndelag Health Study 2; MrOS = Osteoporotic Fractures in Men Study; NR = not reported; TEARS = Thyroid Epidemiology Audit and Research Study. Top. Risk for hip fractures. Bottom. Risk for nonspine fractures.

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