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Subclinical Thyroid Dysfunction and Fracture Risk: A Meta-analysis
Open accessAbstract
IMPORTANCE: Associations between subclinical thyroid dysfunction and fractures are unclear and clinical trials are lacking. OBJECTIVE: To assess the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures. DATA SOURCES AND STUDY SELECTION: The 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 EXTRACTION: Individual 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 MEASURES: The primary outcome was hip fracture. Any fractures, nonspine fractures, and clinical spine fractures were secondary outcomes. RESULTS: Among 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 RELEVANCE: Subclinical 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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“Therefore, the data reported in the available prospective cohort studies suggest an increased risk of hip fractures and non-spine fractures in SHyper, with the risk of fractures being greater in adults with grade 2 SHyper [108, 109] .”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [109]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Grade 2 SHyper was associated with higher fracture rates with an HR of 1.61 (95% CI: 1.21-2.15;47 events in 510 participants) for hip fracture, 1.98 (95% CI: 1.41-2.78;44 events in 212 participants) for any fracture, 1.61 (95% CI: 0.96-2.71;32 events in 185 participants) for non-spine fracture and 3.57 (95% CI: 1.88-6.78;8 events in 162 participants) for spine fracture [109] .”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [109]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Although these meta-analyses do not show evidence that treatment is effective in improving the risks associated with untreated SHyper, they demonstrate that SHyper is a potentially life-threatening condition.”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [109]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Recent data, however, indicate that subclinical hyperthyroidism is associated with low bone mineral density (BMD) and an increased risk of fracture.”
From Thyroid diseases and bone health (2018) · cites this paper as [28]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Overall, subclinical hyperthyroidism was associated with bone loss and fracture, particularly in individuals with endogenous disease [28].”
From Thyroid diseases and bone health (2018) · cites this paper as [28]
Experimental — accuracy not yet measured
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Large-scale cohort studies and meta-analyses have reported an increased risk of osteoporosis and osteoporotic fractures, so there is much convincing evidence that asymptomatic endogenous hyperthyroidism adversely affects bones (14,39).”
From Effect of TSH Suppression Therapy on Bone Mineral Density in Differentiated Thyroid Cancer: A Systematic Review and Meta-analysis (2021) · cites this paper as [39]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“A very recent meta-analysis, including IPD from 13 prospective cohorts, confirmed that Endo SHyper is associated with an increased risk of fractures with an HR 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 [109].”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [109]
The cited source says what the claim attributes to it.
In the citing paper
“A very recent meta-analysis, including IPD from 13 prospective cohorts, confirmed that Endo SHyper is associated with an increased risk of fractures with an HR 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 [109].”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [109]
The cited source says what the claim attributes to it.
In the citing paper
“Grade 2 SHyper was associated with higher fracture rates with an HR of 1.61 (95% CI: 1.21-2.15;47 events in 510 participants) for hip fracture, 1.98 (95% CI: 1.41-2.78;44 events in 212 participants) for any fracture, 1.61 (95% CI: 0.96-2.71;32 events in 185 participants) for non-spine fracture and 3.57 (95% CI: 1.88-6.78;8 events in 162 participants) for spine fracture [109] .”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [109]
The cited source says what the claim attributes to it.
In the citing paper
“Grade 2 SHyper was associated with higher fracture rates with an HR of 1.61 (95% CI: 1.21-2.15;47 events in 510 participants) for hip fracture, 1.98 (95% CI: 1.41-2.78;44 events in 212 participants) for any fracture, 1.61 (95% CI: 0.96-2.71;32 events in 185 participants) for non-spine fracture and 3.57 (95% CI: 1.88-6.78;8 events in 162 participants) for spine fracture [109] .”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [109]
The cited source says what the claim attributes to it.
In the citing paper
“Grade 2 SHyper was associated with higher fracture rates with an HR of 1.61 (95% CI: 1.21-2.15;47 events in 510 participants) for hip fracture, 1.98 (95% CI: 1.41-2.78;44 events in 212 participants) for any fracture, 1.61 (95% CI: 0.96-2.71;32 events in 185 participants) for non-spine fracture and 3.57 (95% CI: 1.88-6.78;8 events in 162 participants) for spine fracture [109] .”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [109]
The cited source says what the claim attributes to it.
In the citing paper
“A very recent meta-analysis, including IPD from 13 prospective cohorts, confirmed that Endo SHyper is associated with an increased risk of fractures with an HR 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 [109].”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [109]
The cited source says what the claim attributes to it.
In the citing paper
“Grade 2 SHyper was associated with higher fracture rates with an HR of 1.61 (95% CI: 1.21-2.15;47 events in 510 participants) for hip fracture, 1.98 (95% CI: 1.41-2.78;44 events in 212 participants) for any fracture, 1.61 (95% CI: 0.96-2.71;32 events in 185 participants) for non-spine fracture and 3.57 (95% CI: 1.88-6.78;8 events in 162 participants) for spine fracture [109] .”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [109]
The cited source says what the claim attributes to it.
In the citing paper
“A very recent meta-analysis, including IPD from 13 prospective cohorts, confirmed that Endo SHyper is associated with an increased risk of fractures with an HR 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 [109].”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [109]
The cited source says what the claim attributes to it.
In the citing paper
“Three recent meta-analyses provide evidence, based also on IPD data, for treating SHyper with undetectable TSH because of an excess risk of total mortality, CHD mortality, HF, incident AF and fractures among adults with grade 2 SHyper [71,75,108,109] .”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [109]
The cited source says what the claim attributes to it.
In the citing paper
“Although these meta-analyses do not show evidence that treatment is effective in improving the risks associated with untreated SHyper, they demonstrate that SHyper is a potentially life-threatening condition.”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [109]
In the citing paper
“A recent participant-level meta-analysis of 13 cohorts (70,298 participants, median follow-up of 12.1 years) con-cluded that SH subjects had significantly elevated hazard ratios of 1.36 for hip fractures (6 vs. 4.9 fractures per 1000 person-years) and 1.28 for any fractures (14.4 vs. 11.2fractures per 1000 person-years) (413).”
From 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis (2016) · cites this paper as [413]
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Self-citation
Metadata
- Authors
- Blum, M. R., Bauer, D. C., Collet, T.-H., Fink, H. A., Cappola, A. R., da Costa, B. R., Wirth, C. D., Peeters, R. P., Åsvold, B. O., den Elzen, W. P. J., Luben, R. N., Imaizumi, M., Bremner, A. P., Gogakos, A., Eastell, R., Kearney, P. M., Strotmeyer, E. S., Wallace, E. R., Hoff, M., Ceresini, G., Rivadeneira, F., Uitterlinden, A. G., Stott, D. J., Westendorp, R. G. J., Khaw, K.-T., Langhammer, A., Ferrucci, L., Gussekloo, J., Williams, G. R., Walsh, J. P., Jüni, P., Aujesky, D., & Rodondi, N.
- Affiliations
- University Hospital of Bern (CH)
- University of California, San Francisco (US)
- Centre Hospitalier Universitaire Vaudois (CH)
- University of Minnesota (US)
- University of Pennsylvania Health System (US)
- Department of Physical Therapy, Nicole Wertheim College of Nursing and Health Science, Florida International University, Miami
- Erasmus MC (NL)
- Norwegian University of Science and Technology (NO)
- Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands
- University of Cambridge (GB)
- Radiation Effects Research Foundation (JP)
- The University of Western Australia (AU)
- Imperial College London (GB)
- University of Sheffield (GB)
- University College Cork (IE)
- University of Pittsburgh (US)
- University of Washington (US)
- Ospedale di Parma (IT)
- University of Glasgow (GB)
- University of Copenhagen (DK)
- National Institutes of Health (US)
- Leiden University Medical Center (NL)
- University of Bern (CH)
- Corresponding author
- Rodondi, Nicolas
- ORCID
- Blum, Manuel R.
- Bauer, Douglas C.
- Collet, Tinh-Hai
- Fink, Howard A.
- Cappola, Anne R.
- Wirth, Christina D.
- Peeters, Robin P.
- Åsvold, Bjørn O.
- Luben, Robert N.
- Bremner, Alexandra P.
- Gogakos, Apostolos
- Eastell, Richard
- Kearney, Patricia M.
- Strotmeyer, Elsa S.
- Wallace, Erin R.
- Hoff, Mari
- Ceresini, Graziano
- Rivadeneira, Fernando
- Uitterlinden, André G.
- Stott, David J.
- Westendorp, Rudi G. J.
- Khaw, Kay-Tee
- Ferrucci, Luigi
- Gussekloo, Jacobijn
- Williams, Graham R.
- Walsh, John P.
- Jüni, Peter
- Aujesky, Drahomir
- Rodondi, Nicolas
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2015-05-26
- Volume
- 313
- Issue
- 20
- Pages
- 2055
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC4729304
- OpenAlex
- W1651572921
- Cited by
- 343
- References
- 71
- Citations by year
- 2026: 25 · 2025: 27 · 2024: 22 · 2023: 28 · 2022: 37 · 2021: 42 · 2020: 45 · 2019: 22 · 2018: 37 · 2017: 23 · 2016: 24 · 2015: 11
- FWCI
- 4.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion, other-oa)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Pure Amsterdam UMC (acceptedVersion, other-oa)
- PubMed Central (acceptedVersion)
- SERVAL (Université de Lausanne) (acceptedVersion, other-oa)
- IRIS (submittedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Bern Open Repository and Information System (University of Bern) (submittedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Open Access CRIS of the University of Bern
- Funders
- National Science Foundation
- American Heart Association
- Amgen
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- GlaxoSmithKline
- Alexion Pharmaceuticals
- Alere
- University of Pittsburgh
- Norges Teknisk-Naturvitenskapelige Universitet
- Radius Health
- Cancer Research UK
- National Institute for Health and Care Research (NF-SI-0512-10114, UL1TR000128, NF-SI-0513-10073)
- National Osteoporosis Society
- European Commission
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (320 030-150 025, 150025, 138267, 145870, 320030, 155318)
- ZonMw
- Fonterra Co-Operative Group
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (911-03-016)
- Schweizerische Herzstiftung
- International Osteoporosis Foundation
- National Institutes of Health (N01-AG-6-2103, n01hc085082-026, n01hc085081-021, n01hc085079-024, UL1TR000128, n01hc085083-027, n01hc085080-026, N01‐AG‐6‐2106, n01hc085086-022, HHSN268200800007C, N01-AG-6-2101, HHSN268201200036C, n01hc055222-001, N01HC85086, N01-HC-85082, N01HC85079, N01HC85080, N01HC85083, N01-HC-85081)
- Canadian Institutes of Health Research
- Medical Research Council (MR/K006312/1)
- Norwegian Institute of Public Health
- National Institute on Aging (N01‐AG‐6–2101, N01HC85081, N01HC85079, U01AG042145, N01-HC-85080, N01-HC-85082, U01AG042168, R01AG028050, N01HC55222, HHSN268200800007C, U01AG042143, U01AG027810, N01-HC-85083, U01AG042139, N01AG62106, U01AG042124, N01HC85083, N01HC85086, U01AG042140, N01‐HC‐85086, R01AG023629, N01-AG-62103, HHSN268201200036C)
- National Heart, Lung, and Blood Institute (N01-HC-85081, N01 HC085086, N01HC-85083, N01 HC085079, N01 HC085083, N01HC85082, N01 HC85086, HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01 HC085080, HHSN 268200800007C, N01HC85080, N01AG62101, N01 HC55222, N01AG62106, HHSN268201200036C, N01HC085082, U01HL080295, N01 HC055222, N01AG62103, N01 HC085081, N01-HC85079)
- National Institute of Nursing Research (N01-AG-6–2101, N01-AG-6-2103, N01-AG-6–2106, R01NR012459)
- National Institute of Neurological Disorders and Stroke (N01-AG-6-2106, N01-AG-6-2103, HHSN268200800007C, N01-HC-85080, N01-HC-85083, N01HC85082, N01-AG-6-2101, N01-HC-85081, N01-HC-85086, N01 HC-55222, N01HC85079, HHSN268201200036C)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (U01AR066160, K24AR051895)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Keywords
- subclinical thyroid dysfunction, subclinical hyperthyroidism, subclinical hypothyroidism, hip fracture, fracture risk, thyroid-stimulating hormone, spinal fractures, fracture risk factors, bone health, osteoporosis, vitamin D, calcium intake, physical activity, sex differences, age differences, individual patient data meta-analysis, prospective cohort
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Female, Hip Fractures, Humans, Hyperthyroidism, Hypothyroidism, Male, Middle Aged, Risk Factors, Thyrotropin, Spinal Fractures, Fractures, Bone, Young Adult
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