The relationship between thyrotoxicosis and osteoporotic fractures remains controversial, particularly in men. Register-based cohort study including all patients with a serum thyrotropin (TSH) measurement in the region of Funen 1996-2010. All TSH determinations were done in the same lab, which served all hospitals and General Practice (GP) practices in the region. Persons with raised TSH or a history of thyroid/pituitary disease or use of thyroid medications were excluded. The study population consisted of 222,138 (96%) persons with normal and 9217 (4%) with low TSH (<0.3 mIU/L). A single low TSH at baseline was associated with increased risk of hip fractures (adj HR 1.16, 95% CI 1.07-1.26, p < 0.001) but not major osteoporotic fractures (MOF, adj HR 1.06, 95% CI 0.99-1.12, p ¼ 0.058) over a median follow-up of 7.5 years. When men were analyzed separately, results did not reach statistical significance. We found a significant association between duration of thyrotoxicosis and fracture. For each 6 months in which the mean TSH value was decreased (<0.3 mIU/L), hip fracture risk increased by a factor 1.07 (adj HR, 95% CI 1.04-1.10, p < 0.001) and MOF by 1.05 (adj HR, 95% CI 1.03-1.07, p < 0.001). Overt thyrotoxicosis was associated with an increased risk of hip fractures but not MOF. In euthyroid patients, the risk of fractures increased significantly with each SD unit of TSH decrease: Hip fracture (HR 1.45, 95% CI 1.22-1.71, p < 0.001) and MOF (HR 1.32, 95% CI 1.19-1.46, p < 0.001). In a population-based cohort, a single, first measurement of decreased TSH in patients without known thyroid disease was associated with an increased long-term risk of hip fracture, which remained significant in women but not in men after adjusting for confounders. Moreover, the risk of both hip fracture and MOF increased exponentially by the length of time during which TSH had remained low.

The long-term relationship between hypothyroidism and fracture risk is challenging to dissect because of the modifying influence of subsequent thyroxine replacement with the potential for excessive replacement doses. We studied changes in serum thyrotropin concentration (TSH) over time and association with fracture risk in real-world patients presenting with elevated TSH. All TSH determinations were done in the same laboratory, which served all hospitals and general practices. The study population consisted of all adults with a first measurement of TSH >4.0 mIU/L (n ¼ 8414) or normal TSH (n ¼ 222,138; comparator). We used a Cox proportional hazards analysis incorporating additional time-dependent covariates to represent initiation of thyroxine replacement and cumulative number of periods with high versus low TSH after index date with a mean follow-up of 7.2 years. Elevated baseline TSH was not associated with an increased risk of hip fracture (HR 0.90; 95% CI, 0.80 to 1.02) or major osteoporotic fractures (HR 0.97; 95% CI, 0.90 to 1.05), nor was subsequent thyroxine prescription predictive of increased risk of fractures. The number of subsequent 6-month periods with low TSH-suggesting excessive thyroxine dosing-was significantly associated with increased risk of both hip fracture (HR 1.09; 95% CI, 1.04 to 1.15) and major osteoporotic fracture (HR 1.10; 95% CI, 1.06 to 1.14). When gender-and agestratified analyses for major osteoporotic fractures were undertaken, hyperthyroid time was identified as a predictor of fracture risk in postmenopausal women whereas hypothyroid time predicted increased fracture risk in men below age 75 years. In conclusion, among patients who present with an elevated TSH, the long-term risk of hip and other osteoporotic fractures is strongly related to the cumulative duration of periods with low TSH-likely from excessive replacement. An independent effect of elevated TSH could only be observed in young and middle-aged men, suggesting gender-discrepant consequences on risk.

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Introduction and AimThe association between thyroid dysfunction and mortality is controversial. Moreover, the impact of duration of thyroid dysfunction is unclarified. Our aim was to investigate the correlation between biochemically assessed thyroid function as well as dysfunction duration and mortality.MethodsRegister-based follow-up study of 239,768 individuals with a serum TSH measurement from hospitals and/or general practice in Funen, Denmark. Measurements were performed at a single laboratory from January 1st 1995 to January 1st 2011. Cox regression was used for mortality analyses and Charlson Comorbidity Index (CCI) was used as comorbidity score.ResultsHazard ratios (HR) with 95% confidence intervals (CI) for mortality with decreased (<0.3 mIU/L) or elevated (>4.0 mIU/L) levels of TSH were 2.22; 2.14–2.30; P<0.0001 and 1.28; 1.22–1.35; P<0.0001, respectively. Adjusting for age, gender, CCI and diagnostic setting attenuated the risk estimates (HR 1.23; 95% CI: 1.19–1.28; P<0.0001, mean follow-up time 7.7 years, and HR 1.07; 95% CI: 1.02–1.13; P = 0.004, mean follow-up time 7.2 years) for decreased and elevated values of TSH, respectively. Mortality risk increased by a factor 1.09; 95% CI: 1.08–1.10; P<0.0001 or by a factor 1.03; 95% CI: 1.02–1.04; P<0.0001 for each six months a patient suffered from decreased or elevated TSH, respectively. Subdividing according to degree of thyroid dysfunction, overt hyperthyroidism (HRovert 1.12; 95% CI: 1.06–1.19; P<0.0001), subclinical hyperthyroidism (HRsubclinical 1.09; 95% CI: 1.02–1.17; P = 0.02) and overt hypothyroidism (HRovert 1.57; 95% CI: 1.34–1.83; P<0.0001), but not subclinical hypothyroidism (HRsubclinical 1.03; 95% CI: 0.97–1.09; P = 0.4) were associated with increased mortality.Conclusions and RelevanceIn a large-scale, population-based cohort with long-term follow-up (median 7.4 years), overt and subclinical hyperthyroidism and overt but not subclinical hypothyroidism were associated with increased mortality. Excess mortality with increasing duration of decreased or elevated serum TSH suggests the importance of timely intervention in individuals with thyroid dysfunction.

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