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Cited by 98Thyroid Disorders and TreatmentsBone health and osteoporosis researchThyroid and Parathyroid Surgery

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

Open access
Abrahamsen, Bo, Jørgensen, Henrik L., Laulund, Anne Sofie, Nybo, Mads, Bauer, Doug C., Brix, Thomas H., Hegedüs, Laszlo·2015·Journal of Bone and Mineral Research
DOI 10.1002/jbmr.2416
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Abstract

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 = 8414) or normal TSH (n = 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 age-stratified 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. © 2015 American Society for Bone and Mineral Research.

AI snapshot

Written from the paper’s full text.

TL;DR

Among adults presenting with elevated TSH, baseline hypothyroidism was not associated with increased fracture risk, but cumulative time with low TSH—suggesting excessive thyroxine replacement—predicted higher hip and major osteoporotic fracture risk. The excess risk appeared driven by hyperthyroid time, especially in postmenopausal women, while hypothyroid time predicted fracture risk in younger men.

Key findings

  • Elevated baseline TSH was not associated with increased risk of hip fracture (HR 0.90; 95% CI, 0.80–1.02) or major osteoporotic fracture (HR 0.97; 95% CI, 0.90–1.05), and subsequent thyroxine prescription was not a predictor of increased fracture risk.
  • Each additional 6-month period with low TSH was associated with increased risk of hip fracture (HR 1.09; 95% CI, 1.04–1.15) and major osteoporotic fracture (HR 1.10; 95% CI, 1.06–1.14); this equated to doubling of hip fracture risk per 4 years of low TSH and doubling of major osteoporotic fracture risk per 3.6 years.
  • In gender- and age-stratified analyses, hyperthyroid time predicted major osteoporotic fracture risk in postmenopausal women, whereas hypothyroid time predicted increased fracture risk in men below age 75 years; in men alone, hypothyroid time was associated with major osteoporotic fractures (HR 1.08; 95% CI, 1.02–1.14).
  • Stratification by severity at presentation did not change findings: subclinical hypothyroidism had HR 0.96 (95% CI, 0.88–1.05) and overt hypothyroidism HR 0.98 (95% CI, 0.74–1.29) for major osteoporotic fractures.

Methods

  • Register-based open cohort in Funen, Denmark, including all adults aged 18 years or above with a new TSH measurement between January 1996 and December 2010; elevated TSH >4.0 mIU/L (n = 8414) versus normal TSH comparator (n = 222,138), with mean follow-up 7.2 years in the elevated-TSH group and 7.5 years in the normal-TSH group, totaling 1.7 million patient-years.
  • Fracture outcomes were hip and major osteoporotic fractures (hip, humerus, forearm, spine) identified from the National Hospital Discharge Register; Cox proportional hazards models included time-dependent covariates for initiation of thyroxine replacement and cumulative number of 6-month periods with high versus low TSH after index date.
  • Analyses adjusted for age, sex, prior major osteoporotic fracture, prednisolone use, osteoporosis drug use, and multiple comorbidities including heart failure, diabetes, renal disease, liver disease, malignancy, HIV/AIDS, and Charlson index.

Limitations

  • The paper states it is observational; lacked GP diagnosis codes for milder disease treated before the National Prescription Database began in 1995; vertebral fractures are regularly missed; and databases lacked height, weight, or lifestyle habits, so BMD, low body weight, muscle weakness, or falls could not be assessed.
  • The paper states laboratory data were reported to treating physicians in real time rather than batch-processed, and all 6-month intervals without TSH measurement were assumed most likely euthyroid; this assumption could not be tested.
  • The paper notes liothyronine or combination therapy could not be analyzed because only 18 persons received it, and testosterone levels were not routinely measured, limiting mechanistic interpretation; the age- and gender-stratified findings were post hoc and the younger-men association could be a chance finding.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1002/jbmr.2416

Cites

43 of 43 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 35 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Subsequent thyroxine prescription did not predict an increased risk of fractures.

    “nor was subsequent thyroxine prescription predictive of increased risk of fractures.”
    • Also stated in: § Fracture risk · plain
      “nor was subsequent thyroxine prescription a predictor of increased risk of fractures (Table 3).”
    Quote in the paperSubstantial claim
  • Findingown data

    After controlling for hyperthyroid and hypothyroid time, LT4 prescription itself was associated with a small decrease in major osteoporotic fracture risk (HR 0.85; 95% CI 0.75 to 0.96).

    “hypothyroid time, LT4 prescription per se was associated with a small decrease in the risk of major osteoporotic fractures (HR 0.85; 95% CI, 0.75 to 0.96)”
    Quote in the paperSubstantial claim
  • Findingown data

    In women of all ages, the effect of hypothyroid time on fracture risk was close to unity.

    “By contrast, the effect of hypothyroid time was close to unity in women of all ages in the study (Fig. 2)”
    Quote in the paperSubstantial claim
  • Findingown data

    In the same post hoc analysis, hyperthyroid time was associated with increased fracture risk in the 50 to 75 year age group.

    “whereas hyperthyroid time was also associated with increased fracture risk for the group aged between 50 and 75 years.”
    Quote in the paperSubstantial claim
  • Findingown data

    In women, the analysis found no independent clinically significant effect of hypothyroidism itself on fracture risk.

    “In the present analysis we did not identify any independent clinically significant effects of hypothyroidism itself on fracture risk in women”
    Quote in the paperSubstantial claim
  • May combine two claims. 16
  • Classified as probably not a substantial claim. 29

  • May combine two claims.

    Findingown data

    In women below age 50 years, hyperthyroid time had the same effect size on fracture risk but the association was not statistically significant (HR 1.09; 95% CI 0.97 to 1.22).

    “with the same effect size in women below age 50 years, but here the association was not statistically significant (HR 1.09; 95% CI, 0.97 to 1.22).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In postmenopausal women, fracture risk was associated only with hyperthyroid time, not with hypothyroid time.

    “In postmenopausal women, we observed a fracture risk association only with hyperthyroid time, not with hypothyroid time.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: All 6-month intervals without TSH measurement were treated as intervals in which the patient was most likely euthyroid.
    • The authors state this as an assumption: The assumption that unmeasured TSH intervals were euthyroid is unlikely to inflate the risk estimates.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    The study confirmed a higher prevalence of comorbid conditions in patients with hypothyroidism, as found in other studies.

    “We confirmed the higher prevalence of comorbid conditions in patients with hypothyroidism as found in other studies (3)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Thvilum, 2013, Type and extent of somatic morbidity before and after the diagnosis of hypothyroidism. A nationwide register study, PLoS One source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The findings were broadly similar to the MrOS cohort, where fracture risk related to each SD decrease in baseline TSH rather than sequential TSH.

    “and also broadly similar to the findings in the MrOS (28) cohort, in which fracture risk was related to each SD decrease in TSH at baseline rather than based on sequential TSH assessments.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Waring, 2013, Osteoporotic Fractures in Men (MrOS) Study. A prospective study of thyroid function, bone loss, and fractures in older men: the MrOS study, J Bone Miner Res source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    An independent effect of elevated TSH on fracture risk was observed only in young and middle-aged men, suggesting gender-discrepant consequences.

    “An independent effect of elevated TSH could only be observed in young and middle-aged men, suggesting gender-discrepant consequences on risk.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Flynn, 2010, Serum thyroid-stimulating hormone concentration and morbidity from cardiovascular disease and fractures in patients on long-term thyroxine therapy, J Clin Endocrinol Metab source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    No excess fracture risk was found in men and women with subclinical hypothyroidism in the US Cardiovascular Health Study.

    “though no excess risk was found in men and women with subclinical hypothyroidism in the recent report from the U.S. Cardiovascular Health Study.(20)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Garin, 2014, Subclinical thyroid dysfunction and hip fracture and bone mineral density in older adults: the Cardiovascular Health Study, J Clin Endocrinol Metab

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    A prospective US study confirmed increased hip fracture risk in male but not female patients.

    “which was since confirmed in a prospective study in the United States, which also found increased hip fracture risk in the male but not the female patients.(18)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Lee, 2010, Subclinical thyroid dysfunction and incident hip fracture in older adults, Arch Intern Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Most studies have found hyperthyroidism in the elderly to be accompanied by increased osteoporotic fracture risk.

    “Although most studies have found hyperthyroidism in the elderly to be accompanied by increased risk of osteoporotic fractures, (10)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Nicholls, 2012, The skeletal consequences of thyrotoxicosis, J Endocrinol source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    An external quality control program assured comparability of TSH measurements for the entire period.

    “An external quality control program (Ringversuche, RfB, Bonn, Germany) also assured comparability for the entire period.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Fracture risk analyses were adjusted for age, sex, prior major osteoporotic fracture, prednisolone use, osteoporosis drug use, and multiple comorbidities.

    “Results adjusted for age, sex, prior major osteoporotic fracture, use of prednisolone, use of osteoporosis drugs, heart failure, peripheral vascular disease, dementia, pulmonary disease, collagen disorders, ulcer disease, diabetes, renal disease, liver disease, malignancy, HIV, and AIDS.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Method comparison in 120 patient samples showed comparable means and a regression coefficient of 0.991 between the two TSH assays.

    “method comparison was performed in 120 patient samples showing comparable means (range, 0.008 to 49 mIU/L) and a regression coefficient of 0.991.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A large UK GPRD study found increased proximal femur fracture risk in male but not female LT4 users.

    “Thus, a large study using data from the UK General Practice Research Database (GPRD) database found increased proximal femur fracture risk in male but not female LT4 users, (17)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Sheppard, 2002, Levothyroxine treatment and occurrence of fracture of the hip, Arch Intern Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The proportional hazards assumption was evaluated using Schoenfeld residuals and interaction terms with survival time.

    “The validity of the proportional hazards assumption was evaluated by inspection of Schoenfeld residuals while for proportional hazards models using multiple time-dependent covariates, we calculated interaction terms of the predictors as a function of survival time in the SAS (SAS Institute, Inc., Cary, NC, USA) “phreg” procedure and evaluated them using the “proportionality_test” feature.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    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)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [13] Murphy, 2010, Thyroid function within the upper normal range is associated with reduced bone mineral density and an increased risk of nonvertebral fractures in healthy euthyroid postmenopausal women, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [14] Abrahamsen, 2014, Low serum thyrotropin level and duration of suppression as a predictor of major osteoporotic fractures—the OPENTHYRO Register Cohort, J Bone Miner Res source

      Not checked in the free run.

    • cites [15] Taylor, 2013, Clinical review: a review of the clinical consequences of variation in thyroid function within the reference range, J Clin Endocrinol Metab source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A Canadian observational study reported significantly increased fracture risk in both elderly men and women treated with LT4.

    “A Canadian observational study reported a significantly increased risk of fractures in both elderly men and women when treated with LT4 (19)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Turner, 2011, Levothyroxine dose,risk of fractures in older adults: nested case-control study, BMJ source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Results were adjusted for individual comorbidities and Charlson index.

    “Results were adjusted both for individual comorbidities and for Charlson index.(26)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Quan, 2005, Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data, Med Care source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Thyroid hormones increase bone turnover and decrease bone mass, which is essentially reversible if trabecular thickness is sufficient to prevent lasting structural damage from trabecular perforations.

    “In the adult skeleton, thyroid hormones increase bone turnover and bring about a decrease in bone mass that is essentially reversible, as long as trabecular thickness is sufficient to prevent the increased bone remodeling from leading to lasting structural damage due to trabecular perforations.(7)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Mosekilde, 1990, Effects of thyroid hormones on bone and mineral metabolism, Endocrinol Metab Clin North Am source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All TSH measurements were performed in the same laboratory, which served all hospitals and general practices.

    “All TSH determinations were done in the same laboratory, which served all hospitals and general practices.”
    • Also stated in: § Study population · plain
      “All measurements were performed in the same laboratory, which served all hospitals and GP practices.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Men may be less susceptible to the skeletal effects of LT4 and more susceptible to effects of hypothyroidism itself.

    “By contrast, men may be less susceptible to the skeletal effects of LT4 and more susceptible to effects of hypothyroidism itself.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Previous studies show increased susceptibility of postmenopausal women to accelerated bone loss in hyperthyroid states due to estrogen deficiency.

    “This is in agreement with previous studies demonstrating the increased susceptibility of postmenopausal women to the accelerated bone loss in hyperthyroid states brought about by estrogen deficiency.(7,36,37)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [7] Mosekilde, 1990, Effects of thyroid hormones on bone and mineral metabolism, Endocrinol Metab Clin North Am source

      Not checked in the free run.

    • cites [36] Van Rijn, 2014, Low bone mineral density is related to high physiological levels of free thyroxine in peri-menopausal women, Eur J Endocrinol source

      Not checked in the free run.

    • cites [37] Stall, 1990, Accelerated bone loss in hypothyroid patients overtreated with L-thyroxine, Ann Intern Med source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Serial TSH measurements were available in the great majority of patients with initially abnormal values.

    “serial measurements of TSH were available in the great majority of patients with initially abnormal values.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Although increased mean wall thickness has been reported in hypothyroidism, there does not appear to be increased resorption depth with a corresponding reduction in mean wall thickness in isolated hyperthyroidism; however, biopsy studies have not been large.

    “thus although increased mean wall thickness has been reported in hypothyroidism there does not appear to be increased resorption depth with a corresponding reduction in mean wall thickness in isolated hyperthyroidism; however, biopsy studies have not been large.(43)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Kragstrup, 1981, Effects of thyroid hormone(s) on mean wall thickness of trabecular bone packets, Metab Bone Dis Relat Res source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The statistical analysis was controlled for individual comorbidities.

    “and controlled the statistical analysis for individual comorbidities.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductcitation

    Capture of fracture outcomes using national health databases is generally very good for hip fractures but vertebral fractures are regularly missed by healthcare providers.

    “Capture of fracture outcomes using national health databases is generally very good for hip fractures, (25,38) but vertebral fractures are regularly missed by healthcare providers.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [25] Hundrup, 2004, The validity of self-reported fractures among Danish female nurses: comparison with fractures registered in the Danish National Hospital Register, Scand J Public Health source

      Not checked in the free run.

    • cites [38] Vestergaard, 2011, Risk of femoral shaft and subtrochanteric fractures among users of bisphosphonates and raloxifene, Osteoporos Int source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    The health databases do not provide information on height, weight, or lifestyle habits, so the study cannot determine whether the added fracture risk is due entirely to loss of bone mass and structure or whether low body weight, muscle weakness, or falls explain part of the risk increase.

    “The health databases do not provide information on height, weight, or lifestyle habits-hence we are unable to determine whether the added fracture risk could be due entirely to loss of bone mass and structure or whether low body weight, muscle weakness, or falls could explain part of the risk increase.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    This hypogonadism could contribute to the increased fracture risk observed in younger and middle-aged men, an association absent in those over 75.

    “This could contribute to the observed increased fracture risk seen in younger and middle-aged men-an association that was absent in those >75 years old.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A small study of 22 young men with severe hypothyroidism found low serum testosterone but normal estradiol levels.

    “but a small study in 22 young men with severe hypothyroidism found low serum testosterone but normal estradiol levels.(32)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Kumar, 2007, Secretion of testicular steroids and gonadotrophins in hypothyroidism, Andrologia source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Estradiol levels may be more important for skeletal health in men than testosterone levels, based on evidence from aromatase-deficient men, disrupted estrogen signaling, and observational studies.

    “However, estradiol levels may be more important for skeletal health in men than testosterone levels, as evidenced both by pronounced osteoporosis in aromatase-deficient men and men with disrupted estrogen signaling, and by observational studies in the general population.(31)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Khosla, 2002, Clinical review 144: estrogen and the male skeleton, J Clin Endocrinol Metab source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Patients with hypothyroidism in the study were both diagnosed and treated in real time, which is a useful scenario for studying risks associated with hypothyroidism and its treatment.

    “Patients with hypothyroidism in our study were both diagnosed and treated in real time; this is a useful scenario for studying the risks associated with hypothyroidism and with treatment of hypothyroidism.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Laboratory data were reported to the treating physician in real time, unlike cohort studies where baseline samples are processed as a single batch at the end.

    “It is also important to recognize that laboratory data had been reported to the treating physician in real time, unlike cohort studies in which baseline samples are processed as a single batch at the end of the study.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Information about chronic diseases and drug history was retrieved to ensure patients were new cases examined on clinical suspicion of thyroid disease rather than follow-up of previously diagnosed patients.

    “We retrieved information about chronic diseases and drug history to ensure that patients represented new cases examined on the clinical suspicion of thyroid disease rather than follow-up of patients who had been diagnosed earlier.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Loss of gonadal steroids leads to increased activation frequency and osteoclastic hyperactivity with increased resorption depth and increased likelihood of trabecular perforations, ultimately creating irreversible bone loss.

    “Loss of gonadal steroids leads to an increase in activation frequency and osteoclastic hyperactivity with increased resorption depth with an increased likelihood of trabecular perforations, ultimately creating irreversible bone loss.(7,42)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7] Mosekilde, 1990, Effects of thyroid hormones on bone and mineral metabolism, Endocrinol Metab Clin North Am source

      Not checked in the free run.

    • cites [42] Shabestari, 2013 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The classical effect of thyroid hormone excess in adults is increased activation frequency leading to reversible bone loss.

    “The classical effect on thyroid hormone excess in adults is essentially one of increased activation frequency leading to a reversible bone loss”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Kragstrup, 1981, Effects of thyroid hormone(s) on mean wall thickness of trabecular bone packets, Metab Bone Dis Relat Res source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Testosterone levels are not routinely measured in men with hypothyroidism, so the study cannot directly elucidate a mechanism for possible sexual dimorphism in effect.

    “Testosterone levels are not routinely measured in men with hypothyroidism so we are unable to directly elucidate a mechanism underlying any possible sexual dimorphism in effect.”
    Quote in the paperNot a substantial claim
35 of 35

  • The paper relies on this without support.

    Low TSH in this cohort indicates excessive thyroxine dosing.

    “The number of subsequent 6-month periods with low TSH-suggesting excessive thyroxine dosing-was significantly associated with increased risk of both hip fracture”
    “the number of subsequent 6-month periods with low TSHsuggesting excessive thyroxine dosing-was significantly associated with increased risk of both hip fracture”

  • The paper relies on this without support.

    Cumulative sequential TSH assessments had not previously been used to investigate fracture risk in hypothyroidism.

    “This is the first time cumulative sequential TSH assessments have been used to investigate the risk of fractures in hypothyroidism.”

  • The paper relies on this without support.

    The OPENTHYRO cohort is representative of real-world patients with elevated TSH beyond the study setting.

    “We studied changes in serum thyrotropin concentration (TSH) over time and association with fracture risk in real-world patients presenting with elevated TSH.”
    “In the following, we studied changes in serum TSH levels over time and the association with fracture risk in real-world patients who presented with initially elevated TSH.”

  • The paper relies on this without support.

    The National Hospital Discharge Register accurately identifies major osteoporotic fractures, not only hip fractures.

    “Fracture outcomes in the form of major osteoporotic fractures (22) were collected from the NHDR.”
    “The register has been validated for hip fracture outcomes (25) and has been extensively used in fracture epidemiology.”

  • The paper relies on this without support.

    TSH is a reliable indicator of thyroid status in patients without pituitary disease.

    “patients with pituitary disorders were excluded from the study because TSH is not a reliable indicator of thyroid disorders in the presence of pituitary dysfunction.”

  • The authors state this as an assumption.

    All 6-month intervals without TSH measurement were treated as intervals in which the patient was most likely euthyroid.

    “We treated all 6-month time intervals where TSH had not been measured as a time interval in which the patient was most likely euthyroid”

  • The authors state this as an assumption.

    The assumption that unmeasured TSH intervals were euthyroid is unlikely to inflate the risk estimates.

    “it is not possible to test the accuracy of this assumption but it is unlikely to inflate the risk estimates.”

  • The paper relies on this without support.

    No studies have demonstrated an increased risk of falls in patients with hypothyroidism, treated or not.

    “To our knowledge, no studies have demonstrated an increased risk of falls in patients with hypothyroidism, treated or not.”
8 of 8

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In a subsequent study, the excess risk of major osteoporotic fractures in hyperthyroidism in postmenopausal women was associated with cumulative hyperthyroid time (excessive thyroxine dosing).

    “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] .”

    From The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism (2015) · cites this paper as [107]

    The Fracture risk and Discussion sections report that cumulative hyperthyroid time was associated with major osteoporotic fracture risk in women aged 50 or older, and link low TSH to likely excessive thyroxine replacement. However, the Abstract defines the study population as patients presenting with elevated TSH; it did not study women presenting with hyperthyroidism, as the claim suggests. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Hypothyroidism is linked to increased risk of osteoporosis and fracture.

    “Previous studies have indicated that hypothyroidism can be accompanied by decrease of bone mineral density (BMD), osteoporosis, even fracture [7–9].”

    From Effects of levothyroxine therapy on bone and mineral metabolism in hypothyroidism: a systematic review and meta-analysis (2025) · cites this paper as [9]

    The Fracture risk section reports increased major osteoporotic fracture risk with hypothyroid time in men under 75, supporting a qualified fracture association. But the Introduction says fracture risk in hypothyroidism is uncertain, and the Discussion attributes much of the excess risk to periods of thyroid-hormone excess during replacement treatment. The paper does not establish that hypothyroidism itself causes decreased BMD or osteoporosis; its discussion of decreased BMD concerns low-normal TSH, not hypothyroidism. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The effects of long-term LT4 treatment on bone loss may be attributed to the cumulative impact of hyperthyroidism and the control level of TSH during treatment, rather than the thyroid hormone itself.

    “These effects may be attributed to the cumulative impact of hyperthyroidism and the control level of TSH during treatment, rather than the thyroid hormone itself [9].”

    From Effects of levothyroxine therapy on bone and mineral metabolism in hypothyroidism: a systematic review and meta-analysis (2025) · cites this paper as [9]

    The Discussion (page unavailable) links long-term fracture risk in women to the cumulative duration of low TSH, likely from excessive thyroid-hormone replacement. The paper studies fractures, not bone loss, and does not establish that thyroid hormone itself has no effect on bone; the Introduction says thyroid hormones can decrease bone mass. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Osteoporosis-medication percentages are reversed in the text

    Minor

    The prose gives 0.7% for the elevated-TSH group and 0.6% for the normal-TSH group, but Table 1 gives 0.6% and 0.7%, respectively.

  • Liver-disease percentage does not round to the table value

    Minor

    Among 8,413 people with elevated TSH, 259 is 3.08%, which rounds to 3.1% at the table's precision, not 3.0%.

    Reported 3 · recomputed 3.078569

2 of 2

Cites

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Related

Authors
Abrahamsen, B., Jørgensen, H. L., Laulund, A. S., Nybo, M., Bauer, D. C., Brix, T. H., & Hegedüs, L.
Affiliations
  • University of Southern Denmark (DK)
  • Bispebjerg Hospital (DK)
  • Odense University Hospital (DK)
  • University of California, San Francisco (US)
  • Department of Endocrinology and MetabolismOdense University HospitalOdenseDenmark
Corresponding author
Abrahamsen, Bo
ORCID
Venue
Journal of Bone and Mineral Research
Publisher
Oxford University Press (OUP)
Published
2014-11-27
Volume
30
Issue
5
Pages
898-905
ISSN
  • 0884-0431 (ISSN-L)
  • 1523-4681
DOI
10.1002/jbmr.2416
OpenAlex
W1553676168
Semantic Scholar
5797337fe0d8ae777b0ae90a62723f7bb1b9a2b5
Cited by
98
References
43
Citations by year
2026: 3 · 2025: 7 · 2024: 15 · 2023: 9 · 2022: 12 · 2021: 7 · 2020: 11 · 2019: 8 · 2018: 9 · 2017: 8 · 2016: 5 · 2015: 4
FWCI
4.56
Type
journal article
Language
en
Open access
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)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
  • Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
Keywords
hypothyroidism, hyperthyroidism, osteoporotic fractures, hip fracture, serum thyrotropin, thyroxine replacement, fracture risk, sex differences, postmenopausal women
MeSH terms
Adolescent, Adult, Aged, Demography, Female, Humans, Hyperthyroidism, Hypothyroidism, Male, Middle Aged, Registries, Risk Factors, Thyrotropin, Cohort Studies, Incidence, Young Adult, Osteoporotic Fractures

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-08.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-08.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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