The Excess Risk of Major Osteoporotic Fractures in Hypothyroidism Is Driven by Cumulative Hyperthyroid as Opposed to Hypothyroid Time: An Observational Register-Based Time-Resolved Cohort Analysis

Abrahamsen, Bo; Jørgensen, Henrik L.; Laulund, Anne Sofie; Nybo, Mads; Bauer, Doug C.; Brix, Thomas Heiberg; Hegedűs, László

doi:10.1002/jbmr.2416

Cited by 88 publications

(55 citation statements)

References 46 publications

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“…These findings were in accordance with recent studies in which thyroid autoantibodies and autoimmune thyroiditis were more prevalent in patients with PCOS compared to controls . Prolonged periods of thyroid‐stimulating hormone (TSH) suppression, whether from overzealous thyroxine replacement therapy or from thyrotoxicosis (in this age group generally Graves' disease rather than toxic nodular goiter) are known to substantially increase the risk of fractures in adulthood . However, though increased relative to the background population, thyroid disorders were still relatively infrequent and adjusting for a history of thyroid disease did not affect our findings.…”

Section: Discussionsupporting

confidence: 92%

Fracture Risk Is Decreased in Women With Polycystic Ovary Syndrome: A Register-Based and Population-Based Cohort Study

Rubin

Glintborg

Nybo

et al. 2015

Journal of Bone and Mineral Research

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Hyperandrogenism, obesity, and hyperinsulinemia may protect against osteoporosis, whereas amenorrhea, increased cortisol, and low growth hormone may be associated with higher fracture risk in polycystic ovary syndrome (PCOS). The objective of this study was to investigate fracture risk in PCOS. In the PCOS Denmark study, women with PCOS and/or hirsutism were identified in the Danish National Patient Register (1995)(1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012). Each patient was assigned three age-matched controls on the index date of PCOS diagnosis. Individuals with a previous endocrine diagnosis were excluded. Within PCOS Denmark, we embedded a wellcharacterized subcohort of patients, PCOS OUH, diagnosed with PCOS at Odense University Hospital (n ¼ 1217). We identified incident fractures by International Classification of Diseases, 10th Revision (ICD-10) codes and used conditional Cox regression analyses to compare fracture risk. In the PCOS Denmark study, there were 19,199 women with PCOS and 57,483 controls were included, mean age 30.6 years (range, 12-60 years). Fracture rates were decreased in PCOS Denmark (10.3/1000 patient years) versus controls (13.6/1000 patient years). The adjusted ORs were 0.76 (95% CI, 0.71 to 0.80) for all fractures, 0.82 (95% CI, 0.74 to 0.92) for major osteoporotic fractures, and 0.57 (95% CI, 0.47 to 0.70) for fractures of head and face. The risk reduction was more pronounced below the age of 30 years at diagnosis. Women with PCOS had significant more hospital contacts due to strains and sprains. In the PCOS OUH subcohort, the risk reduction of fractures did not differ between PCOS women with elevated versus normal testosterone levels and the risk reduction was nominally smaller in overweight versus normal weight PCOS women. Women with PCOS had reduced risk of fractures, in particular of the appendicular skeleton. The risk reduction was greater in women with younger age at diagnosis suggesting that the skeletal effects of PCOS may be greater in women who have not yet reached peak bone mass. Reduced participation in sports activities was probably not the reason for the reduced risk of fractures.

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Section: Discussionsupporting

confidence: 92%

Fracture Risk Is Decreased in Women With Polycystic Ovary Syndrome: A Register-Based and Population-Based Cohort Study

Rubin

Glintborg

Nybo

et al. 2015

Journal of Bone and Mineral Research

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“…Although theories for how TSH suppression may lead to bone loss include a possible direct effect on bone formation and bone resorption mediated by the TSH receptor on osteoblast and osteoclast precursors , it has previously not been clear if risks of TSH suppression pertained equally to men as to women. Additionally, data on how the severity and duration of low TSH affects bone health are conflicting . It is unknown whether findings from studies on endogenous hyperthyroidism should be extrapolated to exogenous hyperthyroidism, and the duration of persistently low TSH necessary to affect the skeleton remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Risk of Osteoporosis and Fractures in Patients with Thyroid Cancer: A Case-Control Study in U.S. Veterans

et al. 2019

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Background Data on osteoporosis and fractures in patients with thyroid cancer, especially men, are conflicting. Our objective was to determine osteoporosis and fracture risk in U.S. veterans with thyroid cancer. Materials and Methods This is a case‐control study using the Veterans Health Administration Corporate Data Warehouse (2004–2013). Patients with thyroid cancer (n = 10,370) and controls (n = 10,370) were matched by age, sex, weight, and steroid use. Generalized linear mixed‐effects regression model was used to compare the two groups in terms of osteoporosis and fracture risk. Next, subgroup analysis of the patients with thyroid cancer using longitudinal thyroid‐stimulating hormone (TSH) was performed to determine its effect on risk of osteoporosis and fractures. Other covariates included patient age, sex, median household income, comorbidities, and steroid and androgen use. Results Compared with controls, osteoporosis, but not fractures, was more frequent in patients with thyroid cancer (7.3% vs. 5.3%; odds ratio [OR], 1.33; 95% confidence interval [CI], 1.18–1.49) when controlling for median household income, Charlson/Deyo comorbidity score, and androgen use. Subgroup analysis of patients with thyroid cancer demonstrated that lower TSH (OR, 0.93; 95% CI, 0.90–0.97), female sex (OR, 4.24; 95% CI, 3.53–5.10), older age (e.g., ≥85 years: OR, 17.18; 95% CI, 11.12–26.54 compared with <50 years), and androgen use (OR, 1.63; 95% CI, 1.18–2.23) were associated with osteoporosis. Serum TSH was not associated with fractures (OR, 1.01; 95% CI, 0.96–1.07). Conclusion Osteoporosis, but not fractures, was more common in U.S. veterans with thyroid cancer than controls. Multiple factors may be contributory, with low TSH playing a small role. Implications for Practice Data on osteoporosis and fragility fractures in patients with thyroid cancer, especially in men, are limited and conflicting. Because of excellent survival rates, the number of thyroid cancer survivors is growing and more individuals may experience long‐term effects from the cancer itself and its treatments, such as osteoporosis and fractures. The present study offers unique insight on the risk for osteoporosis and fractures in a largely male thyroid cancer cohort. Physicians who participate in the long‐term care of patients with thyroid cancer should take into consideration a variety of factors in addition to TSH level when considering risk for osteoporosis.

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“…This large-scale study demonstrated a clear correlation between level of TSH, duration of low TSH and risk of osteoporotic fractures in relation to age and sex [30]. In a subsequent study, the same authors demonstrated that the excess risk of major osteoporotic fractures in hyperthyroidism in postmenopausal women was associated with cumulative hyperthyroid time (excessive thyroxine dosing) [107]. …”

Section: Risks Associated With Persistent and Untreated Endo Subclinimentioning

confidence: 96%

The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism

Biondi¹,

Bartalena²,

Cooper³

et al. 2015

Eur Thyroid J

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Endogenous subclinical hyperthyroidism (SHyper) is caused by Graves' disease, autonomously functioning thyroid nodules and multinodular goitre. Its diagnosis is based on a persistently subnormal serum thyroid-stimulating hormone (TSH) level with free thyroid hormone levels within their respective reference intervals. In 2014 the European Thyroid Association Executive Committee, given the controversies regarding the treatment of Endo SHyper, formed a task force to develop clinical practice guidelines based on the principles of evidence-based medicine. The task force recognized that recent meta-analyses, including those based on large prospective cohort studies, indicate that SHyper is associated with increased risk of coronary heart disease mortality, incident atrial fibrillation, heart failure, fractures and excess mortality in patients with serum TSH levels <0.1 mIU/l (grade 2 SHyper). Therefore, despite the absence of randomized prospective trials, there is evidence that treatment is indicated in patients older than 65 years with grade 2 SHyper to potentially avoid these serious cardiovascular events, fractures and the risk of progression to overt hyperthyroidism. Treatment could be considered in patients older than 65 years with TSH levels 0.1-0.39 mIU/l (grade 1 SHyper) because of their increased risk of atrial fibrillation, and might also be reasonable in younger (<65 years) symptomatic patients with grade 2 SHyper because of the risk of progression, especially in the presence of symptoms and/or underlying risk factors or co-morbidity. Finally, the task force concluded that there are no data to support treating SHyper in younger asymptomatic patients with grade 1 SHyper. These patients should be followed without treatment due to the low risk of progression to overt hyperthyroidism and the weaker evidence for adverse health outcomes.

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The Excess Risk of Major Osteoporotic Fractures in Hypothyroidism Is Driven by Cumulative Hyperthyroid as Opposed to Hypothyroid Time: An Observational Register-Based Time-Resolved Cohort Analysis

Cited by 88 publications

References 46 publications

Fracture Risk Is Decreased in Women With Polycystic Ovary Syndrome: A Register-Based and Population-Based Cohort Study

Fracture Risk Is Decreased in Women With Polycystic Ovary Syndrome: A Register-Based and Population-Based Cohort Study

Risk of Osteoporosis and Fractures in Patients with Thyroid Cancer: A Case-Control Study in U.S. Veterans

The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism

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