Low Serum Thyrotropin Level and Duration of Suppression as a Predictor of Major Osteoporotic Fractures—The OPENTHYRO Register Cohort
Abstract
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 = 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. © 2014 American Society for Bone and Mineral Research
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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.
“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] .”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [30]
In a population-based cohort study, a single first measurement of decreased TSH was associated with an increased long-term risk of hip fractures in older women.
“In a population-based cohort study, a single first measurement of decreased TSH was associated with an increased long-term risk of hip fractures in older women [30] .”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [30]
Differences in the degree of TSH suppression, causes of subclinical hyperthyroidism, patient age, and duration of TSH suppression may influence the adverse consequences of endogenous subclinical hyperthyroidism.
“Differences in the degree of TSH suppression, causes of SHyper, patient age and duration of TSH suppression may influence the adverse consequences of Endo SHyper [3,5,30] .”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [30]
The effects of SHyper are likely influenced by the duration of the disease and associated risk factors for bone loss.
“In fact, the effects of SHyper are likely influenced by the duration of the disease and associated risk factors for bone loss [30] .”
From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [30]
Within the normal TSH reference range, TSH generally shows an inverse relationship with fracture risk, so low-normal TSH is associated with modestly increased fracture risk and decreased BMD.
“Variation in thyrotropin (TSH) levels within the normal reference range generally shows an inverse relationship with fracture risk so that low-normal TSH values are associated with modest increases in the risk of fractures.(13)(14)(15) and with decreases in BMD.(13,16)”
The low-TSH effect on fracture risk in this cohort was very similar to that previously found in spontaneous hyperthyroidism using the same method.
“The impact of low TSH in this setting was very similar to that previously found by our group in patients with spontaneous hyperthyroidism using the same methodology (14)”
Risk increased with duration of SH, such that after a median follow-up of 7.5 years, 13.5% of subjects with a low TSH level had experienced at least one major osteoporotic fracture, compared to 6.9% of subjects with a normal TSH level.
“Risk increased with duration of SH, such that after a median follow-up of 7.5 years, 13.5% of subjects with a low TSH level had experienced at least one major osteoporotic fracture, compared to 6.9% of subjects with a normal TSH level (407).”
From 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis (2016) · cites this paper as [407]
The most recent and by far the largest individual study to date (231,355 subjects) reported a hazard rate for all major osteoporotic fractures combined (hip, humerus, forearm, spine) of 1.13 [confidence intervals 1.014-1.26].
“The most recent and by far the largest individual study to date (231,355 subjects) reported a hazard rate for all major osteoporotic fractures combined (hip, humerus, forearm, spine) of 1.13 [confidence intervals 1.014-1.26].”
From 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis (2016) · cites this paper as [407]
A number of population-based studies have reported that certain groups of subjects with SH have increased fracture rates, including all adults, postmenopausal women, men, or subjects who progress to overt hyperthyroidism over time.
“A number of population-based studies have reported that certain groups of subjects with SH have increased fracture rates, including all adults (407), postmenopausal women (408), men (409), or subjects who progress to overt hyperthyroidism over time (391).”
From 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis (2016) · cites this paper as [407]
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- Authors
- Abrahamsen, B., Jørgensen, H. L., Laulund, A. S., Nybo, M., Brix, T. H., & Hegedüs, L.
- Affiliations
- University of Southern Denmark (DK)
- Bispebjerg Hospital (DK)
- Odense University Hospital (DK)
- Department of Endocrinology and MetabolismOdense University HospitalOdenseDenmark
- Corresponding author
- Abrahamsen, Bo
- Venue
- Journal of Bone and Mineral Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-04-09
- Volume
- 29
- Issue
- 9
- Pages
- 2040-2050
- ISSN
- 0884-0431 (ISSN-L)
- 1523-4681
- OpenAlex
- W1712440049
- Cited by
- 112
- References
- 41
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 7 · 2023: 6 · 2022: 14 · 2021: 11 · 2020: 10 · 2019: 14 · 2018: 13 · 2017: 10 · 2016: 8 · 2015: 10 · 2014: 3
- FWCI
- 10.70
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Journal of Bone and Mineral Research (publishedVersion)
- PubMed (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion)
- Funders
- Amgen
- Eli Lilly and Company
- Topics
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Keywords
- TSH suppression, thyrotoxicosis, osteoporotic fractures, hip fracture, major osteoporotic fracture, overt hypothyroidism, fracture risk prediction, Funen, thyroid function tests, euthyroid patients, pituitary disorders, thyroid medication
- MeSH terms
- Adolescent, Adult, Aged, Denmark, Dose-Response Relationship, Drug, Female, Hospitals, Humans, Male, Middle Aged, Reference Values, Registries, Thyrotoxicosis, Thyrotropin, Cohort Studies, Incidence, Proportional Hazards Models, Survival Analysis, Young Adult, General Practice, Osteoporotic Fractures
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