Serum Thyroid-Stimulating Hormone Concentration and Morbidity from Cardiovascular Disease and Fractures in Patients on Long-Term Thyroxine Therapy
Abstract
CONTEXT: For patients on T(4) replacement, the dose is guided by serum TSH concentrations, but some patients request higher doses due to adverse symptoms. OBJECTIVE: The aim of the study was to determine the safety of patients having a low but not suppressed serum TSH when receiving long-term T(4) replacement. DESIGN: We conducted an observational cohort study, using data linkage from regional datasets between 1993 and 2001. SETTING: A population-based study of all patients in Tayside, Scotland, was performed. PATIENTS: All patients taking T(4) replacement therapy (n = 17,684) were included. MAIN OUTCOME MEASURES: Fatal and nonfatal endpoints were considered for cardiovascular disease, dysrhythmias, and fractures. Patients were categorized as having a suppressed TSH ( 4.0 mU/liter). RESULTS: Cardiovascular disease, dysrhythmias, and fractures were increased in patients with a high TSH: adjusted hazards ratio, 1.95 (1.73-2.21), 1.80 (1.33-2.44), and 1.83 (1.41-2.37), respectively; and patients with a suppressed TSH: 1.37 (1.17-1.60), 1.6 (1.10-2.33), and 2.02 (1.55-2.62), respectively, when compared to patients with a TSH in the laboratory reference range. Patients with a low TSH did not have an increased risk of any of these outcomes [hazards ratio: 1.1 (0.99-1.123), 1.13 (0.88-1.47), and 1.13 (0.92-1.39), respectively]. CONCLUSIONS: Patients with a high or suppressed TSH had an increased risk of cardiovascular disease, dysrhythmias, and fractures, but patients with a low but unsuppressed TSH did not. It may be safe for patients treated with T(4) to have a low but not suppressed serum TSH concentration.
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Musculoskeletal effects including reduced bone mineral density and fracture risk occur via accelerated bone turnover, particularly in postmenopausal women and older adults.
“Musculoskeletal effects, including reduced bone mineral density and fracture risk, occur via accelerated bone turnover, particularly in postmenopausal women and older adults.”
From Risk of cardiac, neuropsychiatric and musculoskeletal adverse events with levothyroxine: Systematic review (2026) · cites this paper as [9]
Nine studies over nearly 30 years across five different countries show that only 50%-70% of patients prescribed levothyroxine maintain serum TSH within reference range.
“nine studies over nearly 30 years across five different countries show that only 50% -70% of patients prescribed levothyroxine maintain serum TSH within reference range. 20,30 -34”
From Use of liothyronine (T3) in hypothyroidism: Joint British Thyroid Association/Society for endocrinology consensus statement (2023) · cites this paper as [31]
Overtreatment in older individuals increases the risk of atrial fibrillation and osteoporosis, complications that are very common in this age group.
“Furthermore, overtreatment in older individuals increases the risk of atrial fibrillation and osteoporosis, complications that are very common in this age group.150”
From Hypothyroidism (2024) · cites this paper as [150]
Levothyroxine has a narrow therapeutic index, and both under-treatment (TSH above reference range) and over-treatment (TSH below reference range) are common, with cross-sectional studies consistently showing that 30%-50% of patients on levothyroxine have TSH values outside of the laboratory reference range.
“Levothyroxine has a narrow therapeutic index, however, and both under -treatment (TSH above the reference range) and over -treatment (TSH below the reference range) are common, with cross -sectional studies consistently showing that 30% -50% of patients on levothyroxine have TSH values outside of the laboratory reference range. 20,30 -34,65”
From Use of liothyronine (T3) in hypothyroidism: Joint British Thyroid Association/Society for endocrinology consensus statement (2023) · cites this paper as [31]
Long-term over-treatment is associated with well-established risks of cardiac arrhythmia, stroke and osteoporosis, while under-treatment may be associated with impaired well-being, dyslipidaemia and cardiovascular disease.
“Long -term over -treatment is associated with well -established risks of cardiac arrhythmia, stroke and osteoporosis, while under -treatment may be associated with impaired well -being, dyslipidaemia and cardiovascular disease. 31,68”
From Use of liothyronine (T3) in hypothyroidism: Joint British Thyroid Association/Society for endocrinology consensus statement (2023) · cites this paper as [31]
Serum thyrotropin levels below or above the reference range while taking levothyroxine have been associated with increased risk of adverse cardiovascular events.
“Serum thyrotropin levels below or above the reference range while taking levothyroxine have been associated with increased risk of adverse cardiovascular events. 72-75”
From Hypothyroidism: A Review (2025) · cites this paper as [72]
The larger risk of fracture in women than men may be related to differences in body size and pharmacokinetics between the sexes.
“This may be related to differences in body size and pharmacokinetics between the sexes.14 28 61”
From Levothyroxine dose and risk of fractures in older adults: nested case-control study (2011) · cites this paper as [28]
A population based cohort study of people aged over 18 years found an increased risk of fractures only in those taking excess levothyroxine replacement based on suppression of serum thyroid stimulating hormone levels.
“Recently a population based cohort study of people aged over 18 years found an increased risk of fractures only in those taking excess levothyroxine replacement based on suppression of serum thyroid stimulating hormone levels.28”
From Levothyroxine dose and risk of fractures in older adults: nested case-control study (2011) · cites this paper as [28]
Flynn and colleagues concluded that there was an increased risk of cardiovascular disease, dysrhythmias, and fractures in patients having high or suppressed TSH, but not in patients with low, but unsuppressed, TSH levels.
“The researchers concluded that there was an increased risk of cardiovascular disease, dysrhythmias, and fractures in patients having high or suppressed TSH, but not in patients with low, but unsuppressed, TSH levels”
From Diagnosis and management of treatment-refractory hypothyroidism: an expert consensus report (2017) · cites this paper as [97]
In an observational cohort study of 17,684 patients >18 years old on long-term levothyroxine therapy, a twofold increase in fracture risk was reported in patients having undetectable TSH levels (≤0.03 mU/L) compared to those with TSH levels in the normal range.
“In a recent observational cohort study that examined the risk of fracture in 17,684 patients >18 years old (mean age: 60.3 females, 61.8 males) on long-term levothyroxine therapy, a twofold increase in fracture risk was reported in patients having undetectable TSH levels (≤0.03 mU/L) compared to those with TSH levels in the normal range”
From Diagnosis and management of treatment-refractory hypothyroidism: an expert consensus report (2017) · cites this paper as [97]
Even intermittent oversuppression of TSH using levothyroxine can result in increased bone loss, cardiovascular, and other more serious medical conditions.
“Studies have demonstrated that even intermittent oversuppression of TSH using levothyroxine can result in increased bone loss, cardiovascular, and other more serious medical conditions [97, 99, 101].”
From Diagnosis and management of treatment-refractory hypothyroidism: an expert consensus report (2017) · cites this paper as [97]
An earlier study by Flynn et al included multiple TSH measures for each patient but used these to create a single weighted mean value that was used to assign patients to one of four categories (suppressed, low, normal, and high TSH); the method did not account for changes in TSH concentration or category during follow-up.
“An earlier study by Flynn et al included multiple TSH measures for each patient but used these to create a single weighted mean value that was used to assign patients to one of four categories (suppressed, low, normal, and high TSH)6; the method did not account for changes in TSH concentration or category during the follow-up period.”
The Scottish TEARS study found a more pronounced risk increase, with a doubling of osteoporotic fracture risk in the low-TSH population.
“Other studies such as the Scottish TEARS study (29) found a more pronounced risk increase with a doubling of the risk of osteoporotic fractures in the low-TSH population.”
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- Authors
- Flynn, R. W., Bonellie, S. R., Jung, R. T., MacDonald, T. M., Morris, A. D., & Leese, G. P.
- Affiliations
- University of Dundee (GB)
- Edinburgh Napier University (GB)
- Corresponding author
- Leese, Graham P.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2010-01
- Volume
- 95
- Issue
- 1
- Pages
- 186-193
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2169531519
- Cited by
- 415
- References
- 33
- Citations by year
- 2026: 17 · 2025: 25 · 2024: 28 · 2023: 30 · 2022: 32 · 2021: 37 · 2020: 26 · 2019: 36 · 2018: 29 · 2017: 23 · 2016: 24 · 2015: 16 · 2014: 30 · 2013: 18 · 2012: 18
- FWCI
- 10.68
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- Funders
- Chest Heart and Stroke Scotland
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Keywords
- thyroid-stimulating hormone, levothyroxine, thyroid hormone replacement, TSH suppression, cardiovascular disease, fracture, cardiac arrhythmias, hypothyroidism, drug safety
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Cardiovascular Diseases, Female, Humans, Hypothyroidism, Male, Middle Aged, Osmolar Concentration, Osteoporosis, Thyrotropin, Thyroxine, Time Factors, Comorbidity, Hormone Replacement Therapy, Fractures, Bone, Young Adult
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