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Cited by 152Thyroid Disorders and TreatmentsBone health and osteoporosis researchPharmaceutical Practices and Patient Outcomes

Levothyroxine dose and risk of fractures in older adults: nested case-control study

Open access
Turner, M. R., Camacho, X., Fischer, H. D., Austin, P. C., Anderson, G. M., Rochon, P. A., Lipscombe, L. L.·2011·BMJ
DOI 10.1136/bmj.d2238PMC PMC3084377
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Abstract

OBJECTIVE: To quantify the effect of levothyroxine dose on risk of fractures in older adults. DESIGN: Nested case-control study. SETTING: Population based health databases, Ontario, Canada. PARTICIPANTS: Adults aged 70 or more prescribed levothyroxine between 1 April 2002 and 31 March 2007 and followed for fractures until 31 March 2008. Cases were cohort members admitted to hospital for any fracture, matched with up to five controls from within the cohort who had not yet had a fracture. MAIN OUTCOME MEASURE: Primary outcome was fracture (wrist or forearm, shoulder or upper arm, thoracic spine, lumbar spine and pelvis, hip or femur, or lower leg or ankle) in relation to levothyroxine use (current, recent past, remote). Risk among current users was compared between those prescribed high, medium, and low cumulative levothyroxine doses in the year before fracture. RESULTS: Of 213,511 prevalent levothyroxine users identified, 22,236 (10.4%) experienced a fracture over a mean 3.8 years of follow-up, 18,108 (88%) of whom were women. Compared with remote levothyroxine use, current use was associated with a significantly higher risk of fracture (adjusted odds ratio 1.88, 95% confidence interval 1.71 to 2.05), despite adjustment for numerous risk factors. Among current users, high and medium cumulative doses (>0.093 mg/day and 0.044-0.093 mg/day) were associated with a significantly increased risk of fracture compared with low cumulative doses (<0.044 mg/day): 3.45 (3.27 to 3.65) and 2.62 (2.50 to 2.76), respectively. CONCLUSION: Among adults aged 70 or more, current levothyroxine treatment was associated with a significantly increased risk of fracture, with a strong dose-response relation. Ongoing monitoring of levothyroxine dose is important to avoid overtreatment in this population.

AI snapshot

Written from the paper’s full text.

TL;DR

In older adults (≥70 years) prescribed levothyroxine in Ontario, current use was associated with a significantly higher risk of fracture than remote use, with a strong dose-response relation. Higher cumulative levothyroxine doses were associated with two- to threefold increased fracture risk compared with low doses.

Key findings

  • Among 213,511 levothyroxine users (mean age 82, mean follow-up 3.83 years), 22,236 (10.4%) sustained a fracture; 18,108 (88%) were women.
  • Current levothyroxine use was associated with higher risk of any fracture than remote use (adjusted odds ratio 1.88, 95% CI 1.71 to 2.05); recent past use was also associated with increased risk (1.33, 1.19 to 1.48). Current use was associated with hip fracture (adjusted OR 1.55, 1.35 to 1.78).
  • Among current users, medium cumulative dose (0.044-0.093 mg/day) and high cumulative dose (>0.093 mg/day) were associated with increased risk of any fracture versus low dose (<0.044 mg/day): adjusted OR 2.62 (2.50 to 2.76) and 3.45 (3.27 to 3.65), respectively. Hip fracture showed similar dose-related risks (2.54 and 3.39).
  • A dose increase in the previous year was associated with decreased fracture risk (0.90, 0.86 to 0.94), while a dose decrease was associated with increased risk (1.09, 1.04 to 1.15); any dose change was not significant after adjustment (0.98, 0.95 to 1.02).

Methods

  • Population-based retrospective cohort with nested case-control design using linked Ontario health databases; cohort included adults aged 70-105 with at least one levothyroxine prescription between 1 April 2002 and 31 March 2007, followed for fractures until 31 March 2008, excluding dialysis/palliative care, thyroid cancer, or previous hyperthyroidism.
  • Cases were cohort members with a first emergency department visit or hospital admission for fracture; up to five controls were matched on age (within one year), sex, and duration in cohort (±30 days). Conditional logistic regression estimated associations, adjusting for demographic, clinical, and health service confounders.
  • Levothyroxine exposure was classified as current, recent past, or remote. Current users were categorized by cumulative dose in the year before the index date: low (<0.044 mg/day), medium (0.044-0.093 mg/day), and high (>0.093 mg/day).

Limitations

  • The paper states that laboratory and radiological data, including serum thyroid stimulating hormone levels and radiology reports, were unavailable; indication for levothyroxine could not be verified; and body mass index, family history, smoking, caffeine or alcohol use, and non-prescription calcium or vitamin D use were not measured.
  • The paper notes potential misclassification and selection bias, and that using fractures requiring emergency department visits or hospital admission may have missed minor or asymptomatic fractures such as vertebral fractures.
  • Evident from the text: the observational design cannot establish causality, and residual confounding remains possible despite adjustment; dose was estimated from prescription dispensing records rather than directly measured thyroid function or actual intake.

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

Integrity signals

Registry

Crossref · 10.1136/bmj.d2238

Cites

74 of 74 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

9 of 65 cited sources checked · 3 supported · 0 flagged · accuracy not yet measured

  • Interpretationcitation

    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”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [14] Somwaru LL, Arnold AM, Joshi N, Fried LP, Cappola AR. High frequency of and factors associated with thyroid hormone over-replacement and under-replacement in men and women aged 65 and over. J Clin Endocrinol Metab 2009; 94: 1342-5. 19126628 PMC2682480 source

      The Discussion (page not specified) suggests that women’s lower weight accounts for their greater representation in the low-TSH group. Clinical implications (page not specified) notes potential skeletal effects of excess thyroid hormone. The paper does not establish a greater fracture risk in women than men or attribute such a difference to sex-specific pharmacokinetics. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [28] Flynn RW, Bonellie SR, Jung RT, MacDonald TM, Morris AD, Leese GP. Serum thyroid-stimulating hormone concentration and morbidity from cardiovascular disease and fractures in patients on long-term thyroxine therapy. J Clin Endocrinol Metab 2010; 95: 186-93. 19906785 source
    • cites [61] Okosieme OE, Belludi G, Spittle K, Kadiyala R, Richards J. Adequacy of thyroid hormone replacement in a general population. QJM 2010; published online 24 November. 21109503 source
  • Premisecitation

    Older adults are more vulnerable to excessive levothyroxine replacement.

    “Our study specifically focused on older adults, who have a higher baseline risk of fracture15 26 56 and are more vulnerable to excessive levothyroxine replacement.11 12 13 14”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [11] Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med 2000; 160: 526-34. 10695693 source
    • cites [12] Stall GM, Harris S, Sokoll LJ, Dawson-Hughes B. Accelerated bone loss in hypothyroid patients overtreated with L-thyroxine. Ann Intern Med 1990; 113: 265-9. 2375563 source
    • cites [13] Lee JS, Buzkova P, Fink HA, Vu J, Carbone L, Chen Z, et al. Subclinical thyroid dysfunction and incident hip fracture in older adults. Arch Intern Med 2010; 170: 1876-83. 21098345 PMC4122328 source

      The COMMENT section (page unavailable in our copy) reports increased hip-fracture risk in older men with subclinical thyroid dysfunction and says the risk did not clearly depend on whether the dysfunction was endogenous or exogenous. This supports concern about excess thyroid hormone in older men, but the paper does not specifically establish that older adults are more vulnerable than younger adults to excessive levothyroxine replacement; it found no clear fracture association in older women. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
  • Premisecitation

    Older adults have a higher baseline risk of fracture.

    “Our study specifically focused on older adults, who have a higher baseline risk of fracture15 26 56 and are more vulnerable to excessive levothyroxine replacement.11 12 13 14”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [15] Cummings SR, Nevitt MC, Browner WS, Stone K, Fox KM, Ensrud KE, et al. Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. N Engl J Med 1995; 332: 767-73. 7862179 source

      Table 2 reports that hip-fracture risk increased with age among white women aged 65 or older (relative risk 1.5 per five years). The Discussion says the findings may not generalize to men or younger women. Thus the paper supports an age-related increase in hip-fracture risk in the studied population, but not the broader claim about all older adults or fractures generally. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [26] Wejda B, Hintze G, Katschinski B, Olbricht T, Benker G. Hip fractures and the thyroid: a case-control study. J Intern Med 1995; 237: 241-7. 7891045 source
    • cites [56] Riggs BL, Wahner HW, Seeman E, Offord KP, Dunn WL, Mazess RB, et al. Changes in bone mineral density of the proximal femur and spine with aging. Differences between the postmenopausal and senile osteoporosis syndromes. J Clin Invest 1982; 70: 716-23. 7119111 PMC370279 source
  • Findingown data

    Current levothyroxine use, compared with remote use, is associated with a higher risk of any fracture in both men and women.

    “Compared with remote use of levothyroxine, current use was associated with a higher risk of any fracture in both sexes and with a higher risk of hip fracture in women.”
    • Also stated in: § Discussion · plain
      “Our population based study found a significant association between current levothyroxine use and increased risk of fracture among older people (>70 years).”
    Quote in the paperSubstantial claim
  • Findingown data

    The interaction between sex and levothyroxine use was significant.

    “In addition, interactions between sex and levothyroxine use and dose were significant (table 5).”
    Quote in the paperSubstantial claim
  • May combine two claims. 22
  • Classified as probably not a substantial claim. 17
  • The quote only partly states this claim. 1

  • May combine two claims.

    Premisecitation

    An excess of thyroid hormone can increase the risk of arrhythmias and falls.

    “and increase the risk of arrhythmias24 25 and falls,15”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites 24 25

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [15] Cummings SR, Nevitt MC, Browner WS, Stone K, Fox KM, Ensrud KE, et al. Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. N Engl J Med 1995; 332: 767-73. 7862179 source

      Citation 15 is attached to falls, not arrhythmias. The Results and Discussion (p. 767) associate previous hyperthyroidism with hip fracture and suggest possible neuromuscular impairment, but they do not report whether excess thyroid hormone increases the risk of falling. Searches for hyperthyroidism and falls found no passage establishing that outcome. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Excess thyroid hormone can increase the risk of arrhythmias and muscle weakness in older people, which can contribute to a greater risk of falls.

    “Excess thyroid hormone can also increase the risk of arrhythmias24 25 and muscle weakness23 in older people, which can contribute to a greater risk of falls.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [24] Sawin CT, Geller A, Wolf PA, Belanger AJ, Baker E, Bacharach P, et al. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med 1994; 331: 1249-52. 7935681 source
    • cites [25] Auer J, Scheibner P, Mische T, Langsteger W, Eber O, Eber B. Subclinical hyperthyroidism as a risk factor for atrial fibrillation. Am Heart J 2001; 142: 838-42. 11685172 source
    • cites [23] Brennan MD, Powell C, Kaufman KR, Sun PC, Bahn RS, Nair KS. The impact of overt and subclinical hyperthyroidism on skeletal muscle. Thyroid 2006; 16: 375-80. 16646684 source

  • May combine two claims.

    Premisecitation

    Studies largely in younger people and postmenopausal women have not found a relation between any fracture or hip fractures and levothyroxine use.

    “Studies largely in younger people30 and postmenopausal women15 26 have not found a relation between any fracture or hip fractures and levothyroxine use.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [30] Vestergaard P, Rejnmark L, Mosekilde L. Influence of hyper- and hypothyroidism, and the effects of treatment with antithyroid drugs and levothyroxine on fracture risk. Calcif Tissue Int 2005; 77: 139-44. 16151671 source
    • cites [15] Cummings SR, Nevitt MC, Browner WS, Stone K, Fox KM, Ensrud KE, et al. Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. N Engl J Med 1995; 332: 767-73. 7862179 source

      In “Factors Not Significant after Multivariate Adjustment” (p. 767), the paper reports that current thyroid-hormone therapy was no longer significantly associated with hip-fracture risk after adjustment for a history of hyperthyroidism. This supports the claim for hip fractures in older white women, but the paper does not identify the therapy specifically as levothyroxine or address fractures of any type as an outcome. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [26] Wejda B, Hintze G, Katschinski B, Olbricht T, Benker G. Hip fractures and the thyroid: a case-control study. J Intern Med 1995; 237: 241-7. 7891045 source

  • May combine two claims.

    Study design and conductcitation

    The study minimised the potential for misclassification by using hospital based fractures as the outcome and by considering cumulative levothyroxine dosage over the previous year rather than a single prescription to estimate drug use.

    “We minimised the potential for misclassification by using hospital based fractures as our outcome and by considering cumulative levothyroxine dosage over the previous year rather than a single prescription to estimate drug use.66”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [66] Kopec JA, Esdaile JM. Bias in case-control studies. A review. J Epidemiol Community Health 1990; 44: 179-86. 2273353 PMC1060638 source

      The review’s “Secondary Base” section says that verifying diagnoses with auxiliary sources, including hospital records, can reduce outcome misclassification. Its “Measurement of Exposure” section favors improved measurement quality, but does not address fractures, levothyroxine, or whether cumulative dosage over a year is more accurate than a single prescription. Page numbers were not supplied for these passages. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

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

    Premisecitation

    The nested case-control design is commonly used in pharmacosurveillance research and provides estimates of effects that are consistent with those obtained from time to event analysis.

    “The nested case-control design is commonly used in pharmacosurveillance research and provides estimates of effects that are consistent with those obtained from time to event analysis.67 68 69 70”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [67] Ernster VL. Nested case-control studies. Prev Med 1994; 23: 587-90. 7845919 source
    • cites [68] Essebag V, Genest J Jr, Suissa S, Pilote L. The nested case-control study in cardiology. Am Heart J 2003; 146: 581-90. 14564310 source
    • cites [69] Essebag V, Platt RW, Abrahamowicz M, Pilote L. Comparison of nested case-control and survival analysis methodologies for analysis of time-dependent exposure. BMC Med Res Methodol 2005; 5: 5. 15670334 PMC548149 source

  • May combine two claims.

    Findingown data

    A dose-related association was observed for hip fractures and any fracture in both men and women.

    “A dose related association was observed for hip fractures as well as for any fracture in both men and women (table 5).”
    • Also stated in: § Conclusion · boosted
      “Our study shows that levothyroxine treatment is associated with a higher risk of fractures in a dose-response manner in older adults”
    Quote in the paperSubstantial claim

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

    Findingown data

    Nearly 8% of the study participants had discontinued levothyroxine.

    “This might potentially explain the larger than expected proportion of people (nearly 8%) who had discontinued levothyroxine, given that it is generally continued lifelong when prescribed for hypothyroidism.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Older women and older people in general are more vulnerable to adverse events related to overtreatment.

    “This problem has not been dealt with adequately in older women, and older people in general, who are at higher risk of fractures,15 26 31 more likely to be treated with levothyroxine,11 32 and more vulnerable to adverse events related to overtreatment.14 33 34 35 36”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites 14 33 34 35 36

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Premisecitation

    Over 20% of older people receive levothyroxine replacement long term.

    “over 20% of older people receive levothyroxine replacement long term.2”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Canadian Institute for Health Information. Drug use among seniors on public drug programs in Canada, 2002 to 2008. CIHI, 2010.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    As levothyroxine requirements decrease with age, iatrogenic hyperthyroidism is more common in older people.

    “As levothyroxine requirements decrease with age, iatrogenic hyperthyroidism is more common in older people.3 5”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] Mooradian AD. Normal age-related changes in thyroid hormone economy. Clin Geriatr Med 1995; 11: 159-69. 7606687 source
    • cites [5] Sawin CT, Geller A, Hershman JM, Castelli W, Bacharach P. The aging thyroid. The use of thyroid hormone in older persons. JAMA 1989; 261: 2653-5. 2709545 source

  • The quote only partly states this claim.

    Interpretationown data

    There is a dose-response relation between levothyroxine dose and risk of any fracture among current users.

    “Among adults aged 70 or more, current levothyroxine treatment was associated with a significantly increased risk of fracture, with a strong dose-response relation.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    An increase in levothyroxine dose may reflect previous hypothyroidism, which may have been protective for bone and reduce the risk of fractures.

    “and an increase in dose may reflect previous hypothyroidism, which may have been protective for bone and reduce the risk of fractures.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Older women and older people in general are at higher risk of fractures.

    “This problem has not been dealt with adequately in older women, and older people in general, who are at higher risk of fractures,15 26 31 more likely to be treated with levothyroxine,11 32 and more vulnerable to adverse events related to overtreatment.14 33 34 35 36”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites 15 26 31

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Interpretationreasoning

    A recent decrease in levothyroxine dose may reflect previous hyperthyroidism, which may predispose to fractures.

    “A recent decrease in dose may reflect previous hyperthyroidism, which may predispose to fractures”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Iatrogenic hyperthyroidism can decrease bone quality and bone mineral density, leading to a higher risk of fracture.

    “which can decrease bone quality22 and bone mineral density,60 leading to a higher risk of fracture.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [22] Gomez Acotto C, Schott AM, Hans D, Niepomniszcze H, Mautalen CA, Meunier PJ. Hyperthyroidism influences ultrasound bone measurement on the os calcis. Osteoporos Int 1998; 8: 455-9. 9850354 source
    • cites [60] Eriksen EF, Mosekilde L, Melsen F. Trabecular bone remodeling and bone balance in hyperthyroidism. Bone 1985; 6: 421-8. 4096878 source

  • May combine two claims.

    Premisecitation

    Older women and older people in general are more likely to be treated with levothyroxine.

    “This problem has not been dealt with adequately in older women, and older people in general, who are at higher risk of fractures,15 26 31 more likely to be treated with levothyroxine,11 32 and more vulnerable to adverse events related to overtreatment.14 33 34 35 36”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites 11 32

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Controls were matched to cases on age (within one year), sex, and duration in cohort (follow-up 30 days either way).

    “We matched controls to cases on age (within one year), sex, and duration in cohort (follow-up 30 days either way).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The study used conditional logistic regression to estimate associations between levothyroxine use and fracture outcomes, controlling for potential confounders including neighbourhood income, Charlson comorbidity index, history of health service use, previous fractures, risk factors for fracture, comorbid conditions, and use of other prescription drugs.

    “We used conditional logistic regression to estimate associations between levothyroxine use and fracture outcomes in the matched cases and controls, controlling for potential confounders such as fifth of neighbourhood income (from 1 to 5 for the lowest to highest income fifth), Charlson comorbidity index, and history of health service use at the index date.”
    • Also stated in: § Statistical analysis · plain
      “This logistic regression also controlled for other confounders, including previous fractures, risk factors for fracture, and comorbid conditions in the five years before the index date, and the use of other prescription drugs in the year before the index date.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    For many people, levothyroxine dosage is not adjusted as they age because monitoring for thyroid dysfunction may not be carried out or indicated dose adjustments identified by monitoring may not be implemented.

    “Despite this, studies show that for many people levothyroxine dosage is not adjusted as they age because either monitoring for thyroid dysfunction may be not be carried out or indicated dose adjustments identified by monitoring may not be implemented.9 10 11 12 13 14”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [9] Mandel SJ, Brent GA, Larsen PR. Levothyroxine therapy in patients with thyroid disease. Ann Intern Med 1993; 119: 492-502. 8357116 source
    • cites [10] De Whalley P. Do abnormal thyroid stimulating hormone level values result in treatment changes? A study of patients on thyroxine in one general practice. Br J Gen Pract 1995; 45: 93-5. 7702890 PMC1239143
    • cites [11] Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med 2000; 160: 526-34. 10695693 source

  • May combine two claims.

    Premisecitation

    With normal ageing, thyroid hormone production, secretion, and degradation decreases.

    “With normal ageing, thyroid hormone production, secretion, and degradation decreases,3 4 5”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites 3 4 5

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Study design and conductcitation

    The discharge abstract database has been validated against hospital medical records for accuracy of procedures, diagnoses for primary admission, and major complications, and has been used extensively for data on fractures.

    “Independent comparisons have validated the discharge abstract database against hospital medical records, determining accuracy of the database for procedures, diagnoses for primary admission, and major complications,38 39 40 41 and have been used extensively for data on fractures.42 43 44”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites 38 39 40 41

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites 42 43 44

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim.

    Premisenone given

    Before this study, the effect of levothyroxine dose on fracture outcomes was not known, particularly in the at risk population of older people (≥70 years).

    “Before this study the effect of levothyroxine dose on fracture outcomes was not known, particularly in the at risk population of older people (≥70 years)”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Cases and controls were matched on age, sex, and duration in the study cohort, and regression techniques were used to adjust for potential confounders.

    “Cases and controls were matched on age, sex, and duration in the study cohort, and we used regression techniques to adjust for potential confounders.”
    Quote in the paperSubstantial claim

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

    Premisereasoning

    Previous studies examining the association between levothyroxine replacement and fracture risk have yielded inconsistent conclusions and have not tackled the role of levothyroxine dose in this relation.

    “Previous studies examining the association between levothyroxine replacement and fracture risk have yielded inconsistent conclusions and have not tackled the role of levothyroxine dose in this relation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Secondary analyses of other studies have only found associations between levothyroxine replacement and hip fractures in men and forearm fractures in older adults within the first two years of treatment.

    “Secondary analyses of other studies have only found associations between levothyroxine replacement and hip fractures in men27 and forearm fractures in older adults within the first two years of treatment.29”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [27] Sheppard MC, Holder R, Franklyn JA. Levothyroxine treatment and occurrence of fracture of the hip. Arch Intern Med 2002; 162: 338-43. 11822927 source
    • cites [29] Vestergaard P, Weeke J, Hoeck HC, Nielsen HK, Rungby J, Rejnmark L, et al. Fractures in patients with primary idiopathic hypothyroidism. Thyroid 2000; 10: 335-40. 10807062 source

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

    Premisecitation

    Hip fractures carry the greatest morbidity and mortality for older adults.

    “Levothyroxine was also associated with an increase in hip fractures specifically, which carry the greatest morbidity and mortality for older adults.55”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Chrischilles EA, Butler CD, Davis CS, Wallace RB. A model of lifetime osteoporosis impact. Arch Intern Med 1991; 151: 2026-32. 1929691 source

  • May combine two claims.

    Interpretationown data

    The effect of failing to capture minor fractures on the results is possibly minimal, given that analysis using hip fractures alone yielded the same associations.

    “The effect of this on our results is possibly minimal, however, given that our analysis using the outcome of hip fractures alone, a highly specific fracture requiring regular admission to hospital, yielded the same associations.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Flynn RW, Bonellie SR, Jung RT, MacDonald TM, Morris AD, Leese GP. Serum thyroid-stimulating hormone concentration and morbidity from cardiovascular disease and fractures in patients on long-term thyroxine therapy. J Clin Endocrinol Metab 2010; 95: 186-93. 19906785 source

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Excess levothyroxine and subclinical hyperthyroidism are associated with lower bone density as well as other risk factors for falls and fractures.

    “Excess levothyroxine and subclinical hyperthyroidism are associated with lower bone density as well as other risk factors for falls and fractures”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The optimal levothyroxine dose for adults is 1.6-1.8 μg/kg/day.

    “While the optimal levothyroxine dose for adults is 1.6-1.8 µg/kg/day,1 9”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Roberts CG, Ladenson PW. Hypothyroidism. Lancet 2004; 363: 793-803. 15016491 source
    • cites [9] Mandel SJ, Brent GA, Larsen PR. Levothyroxine therapy in patients with thyroid disease. Ann Intern Med 1993; 119: 492-502. 8357116 source

  • Classified as probably not a substantial claim.

    Interpretationcitation

    It is possible that levothyroxine treatment may have deleterious effects on bone even in people who are biochemically euthyroid.

    “It is also possible that levothyroxine treatment may have deleterious effects on bone even in people who are biochemically euthyroid.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Most recommend a reduced dose of 0.5 μg/kg/day in seniors (age >65 years).

    “older people often require much lower doses to achieve euthyroidism, and most recommend a reduced dose of 0.5 µg/kg/day in seniors (age >65 years).1 62”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Roberts CG, Ladenson PW. Hypothyroidism. Lancet 2004; 363: 793-803. 15016491 source
    • cites [62] Sawin CT, Herman T, Molitch ME, London MH, Kramer SM. Aging and the thyroid. Decreased requirement for thyroid hormone in older hypothyroid patients. Am J Med 1983; 75: 206-9. 6881172 source

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

    Study design and conductnone given

    Misclassification and selection bias are potential threats to validity in observational studies such as this one.

    “Misclassification and selection bias are also potential threats to validity in observational studies such as ours.”
    Quote in the paperNot a substantial claim
33 of 33

  • The paper relies on this without support.

    The effect of levothyroxine dose on risk of fracture has not been explored.

    “Similarly, the effect of levothyroxine dose on risk for fracture has not been explored.”
1 of 1

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?

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.

  • Women's percentage among fracture cases is incorrect

    Minor

    The abstract says 18,108 of 22,236 people with fractures were women, but that is 81.44%, not 88%.

    Reported 88 · recomputed 81.43551

  • Reported median cumulative daily dose conflicts with dose categories

    Minor

    The text calls 24.94 mg the median cumulative daily dose, yet categorises the middle of that distribution as 0.044-0.093 mg/day. A median of 24.94 mg/day cannot fall in that middle category; the 24.94 mg figure appears to use a different time basis.

  • Female current-user case counts differ between tables

    Minor

    Table 1 reports 18,108 female cases among current users, whereas table 5 reports 18,119 female cases for current versus remote use.

3 of 3

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. [41]Richards J, Brown A, Homan C. The data quality study of the Canadian discharge abstract database. Achieving data quality in a statistical agency: a methodological perspective. Proceedings of Statistics Canada Symposium. Statistics Canada, 2001.

Cited by

Sorted by citations

Related

Authors
Turner, M. R., Camacho, X., Fischer, H. D., Austin, P. C., Anderson, G. M., Rochon, P. A., & Lipscombe, L. L.
Affiliations
  • University of Toronto (CA)
  • Institute for Clinical Evaluative Sciences (CA)
  • Women’s College Hospital Research and Innovation Institute (CA)
Corresponding author
Lipscombe, L. L.
ORCID
Venue
BMJ
Publisher
BMJ
Published
2011-04-28
Volume
342
Issue
apr28 2
Pages
d2238-d2238
ISSN
  • 0007-1447 (ISSN-L)
  • 0959-8138
  • 1468-5833
DOI
10.1136/bmj.d2238
PMC
PMC3084377
OpenAlex
W2156140430
Semantic Scholar
3655d4fe62d7a2636431b4dfd05a0217ed9a1d28
Cited by
152
References
73
Citations by year
2026: 9 · 2025: 6 · 2024: 8 · 2023: 5 · 2022: 6 · 2021: 8 · 2020: 6 · 2019: 6 · 2018: 14 · 2017: 9 · 2016: 12 · 2015: 7 · 2014: 16 · 2013: 13 · 2012: 15
FWCI
13.16
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • BMJ (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc)
Funders
Canadian Institutes of Health Research (80075_1, 88591_1)
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 › Geriatrics and Gerontology › Pharmaceutical Practices and Patient Outcomes
Keywords
levothyroxine, fracture risk, older adults, dose-response relationship, hypothyroidism treatment, overtreatment, bone health, thyroid hormone replacement
MeSH terms
Aged, Aged, 80 and over, Dose-Response Relationship, Drug, Female, Follow-Up Studies, Humans, Hypothyroidism, Male, Risk Factors, Thyroxine, Case-Control Studies, Fractures, Bone

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 2026-10-27.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-27.

Cited sources are checked by gpt-6-sol.

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.

What counts as a claim ›How we measure confidence ›How we check this ›

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