Subclinical thyroid dysfunction and the risk for fractures: a systematic review and meta-analysis

Abstract

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.

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 (available at www.annals.org).

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.

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.