Subclinical Thyroid Dysfunction and the Risk for Fractures: A Systematic Review and Meta-analysis
Open accessAbstract
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.
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In grade 1 SHyper, the HR for non-spine fractures was 1.15 (95% CI 0.75-1.77).
“The HR was 1.46 (95% CI: 0.62-3.45)for hip fractures and 1.15 (95% CI: 0.75-1.77)for non-spine fractures in grade 1 SHyper and, respectively, 2.03 (95% CI: 0.27-15.00)and 1.97 (95% CI: 0.36-10.74)for grade 2 SHyper [108] .”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [108]
The Results section on subclinical hyperthyroidism and nonspine fractures reports an elevated, statistically nonsignificant risk, with a pooled HR of 1.20 (CI, 0.83 to 1.72) for the higher-quality studies. Our copy does not give the claimed grade 1 estimate of 1.15 (95% CI, 0.75–1.77), so it supports the general association but not that specific figure or grade. (LLM, conf=0.78)
Experimental — accuracy not yet measuredThe pooled results of a meta-analysis of seven prospective cohort studies indicate that SHyper was associated with an increased risk for hip fractures and non-spine fractures.
“The pooled results indicate that SHyper was associated with an increased risk for hip fractures and non-spine fractures [108] .”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [108]
The Results sections on hip and nonspine fractures report elevated pooled risk estimates for subclinical hyperthyroidism, and the Study Characteristics section identifies seven included cohorts. However, the confidence intervals for both fracture outcomes include no increased risk; the nonspine Results section explicitly says the increase was not statistically significant. The sentence presents the association more definitively than the pooled results warrant. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn grade 1 SHyper, the HR for hip fractures was 1.46 (95% CI 0.62-3.45).
“The HR was 1.46 (95% CI: 0.62-3.45)for hip fractures and 1.15 (95% CI: 0.75-1.77)for non-spine fractures in grade 1 SHyper and, respectively, 2.03 (95% CI: 0.27-15.00)and 1.97 (95% CI: 0.36-10.74)for grade 2 SHyper [108] .”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [108]
The Results section (Subclinical Hyperthyroidism and Hip Fractures; page unavailable) reports the exact HR and CI for studies using a TSH cutoff below 0.45 mIU/L. It does not identify that pooled estimate as specific to grade 1 SHyper; the Methods define subclinical hyperthyroidism as TSH below 0.45 mIU/L, which can also include lower TSH levels. (LLM, conf=0.86)
Experimental — accuracy not yet measuredData from 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.
“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 [108]
The Results sections on hip and nonspine fractures report higher estimated risks with subclinical hyperthyroidism, but neither pooled estimate is statistically significant. The hip-fracture estimate is higher in studies using a TSH cutoff of 0.1 mIU/L or less, with a very wide confidence interval; our copy does not establish a greater risk for grade 2 subclinical hyperthyroidism across both fracture types. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThese meta-analyses do not show evidence that treatment is effective in improving the risks associated with untreated SHyper.
“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 [108]
The Discussion (page unavailable) says no studies showed that treating subclinical hyperthyroidism reduced fracture risk, and calls for trials to assess treatment efficacy. This supports the claim for fracture risk, but the paper does not establish a lack of treatment evidence for the broader range of risks implied by the citing sentence; it also describes interventional evidence concerning bone mineral density. (LLM, conf=0.84)
Experimental — accuracy not yet measured
These meta-analyses demonstrate that SHyper is a potentially life-threatening condition.
“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 [108]
The Results report a possible increase in hip-fracture risk with subclinical hyperthyroidism, and the Discussion says no study showed that treatment reduced fracture risk. But the pooled fracture estimates are uncertain, and this meta-analysis does not establish that the condition is life-threatening or assess whether treatment improves all risks associated with it. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThree 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.
“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 [108]
The Results (Subclinical Hyperthyroidism and Hip Fractures; page unavailable) report an elevated hip-fracture estimate for TSH ≤0.1 mIU/L, but its wide confidence interval includes no increase. The Discussion (page unavailable) describes the fracture risk as possible, says this meta-analysis used observational rather than individual-participant data, and notes that no study showed treatment reduced fracture risk. This source therefore contributes limited evidence on fractures, not evidence for treatment based on all the listed outcomes. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn grade 2 SHyper, the HR for hip fractures was 2.03 (95% CI 0.27-15.00).
“The HR was 1.46 (95% CI: 0.62-3.45)for hip fractures and 1.15 (95% CI: 0.75-1.77)for non-spine fractures in grade 1 SHyper and, respectively, 2.03 (95% CI: 0.27-15.00)and 1.97 (95% CI: 0.36-10.74)for grade 2 SHyper [108] .”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [108]
Only two studies reported data on grade 2 SHyper.
“However, only two studies reported data on grade 2 SHyper.”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [108]
For participants with Endo SHyper, the HR for non-spine fractures was 1.43 (95% CI 0.73-2.78).
“The HRs for participants with Endo SHyper were 2.16 (95% CI: 0.87-5.37)for hip fractures and 1.43 (95% CI: 0.73-2.78)for non-spine fractures [108] .”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [108]
For participants with Endo SHyper, the HR for hip fractures was 2.16 (95% CI 0.87-5.37).
“The HRs for participants with Endo SHyper were 2.16 (95% CI: 0.87-5.37)for hip fractures and 1.43 (95% CI: 0.73-2.78)for non-spine fractures [108] .”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [108]
No difference was found in women compared to men for fracture risk.
“No difference was found in women compared to men [108] .”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [108]
In grade 2 SHyper, the HR for non-spine fractures was 1.97 (95% CI 0.36-10.74).
“The HR was 1.46 (95% CI: 0.62-3.45)for hip fractures and 1.15 (95% CI: 0.75-1.77)for non-spine fractures in grade 1 SHyper and, respectively, 2.03 (95% CI: 0.27-15.00)and 1.97 (95% CI: 0.36-10.74)for grade 2 SHyper [108] .”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [108]
The Results section on nonspine fractures reports an overall pooled HR of 1.20 (CI, 0.83 to 1.72), but does not give an HR for grade 2 subclinical hyperthyroidism. The Results section on hip fractures gives the cited grade 2 figures for hip fractures, not nonspine fractures. Searches for 1.97, 0.36–10.74, and nonspine fractures at the suppressed-TSH cutoff did not locate the claimed estimate in our copy; page numbers were unavailable. (LLM, conf=0.72)
Experimental — accuracy not yet measured
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- Authors
- Wirth, C. D., Blum, M. R., da Costa, B. R., Baumgartner, C., Collet, T.-H., Medici, M., Peeters, R. P., Aujesky, D., Bauer, D. C., & Rodondi, N.
- Affiliations
- University of Bern (CH)
- 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.
- ORCID
- Venue
- Annals of Internal Medicine
- Publisher
- American College of Physicians
- Published
- 2014-08-05
- Volume
- 161
- Issue
- 3
- Pages
- 189-199
- ISSN
- 0003-4819 (ISSN-L)
- 1539-3704
- PMC
- PMC4403766
- OpenAlex
- W1985689567
- Cited by
- 85
- References
- 102
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 1 · 2023: 5 · 2022: 7 · 2021: 8 · 2020: 11 · 2019: 7 · 2018: 10 · 2017: 7 · 2016: 7 · 2015: 13 · 2014: 2
- FWCI
- 1.53
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annals of Internal Medicine (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- PubMed Central (acceptedVersion)
- Archive ouverte UNIGE (University of Geneva) (acceptedVersion, other-oa)
- IRIS (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Bern Open Repository and Information System (University of Bern) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion, other-oa)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- National Science Foundation
- U.S. Department of Veterans Affairs
- University of Pennsylvania
- University of Minnesota
- Norges Teknisk-Naturvitenskapelige Universitet
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (138267, 145870, 320030)
- Schweizerische Herzstiftung
- Perelman School of Medicine, University of Pennsylvania
- University of California, San Francisco
- Geriatric Research Education and Clinical Center
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (K24AR051895)
- NIH Clinical Center
- 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, thyroxine therapy, bone health, thyroid function
- MeSH terms
- Hip Fractures, Humans, Hyperthyroidism, Hypothyroidism, Thyroid Hormones, Fractures, Bone
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