Fracture risk with high-dose thyroxine

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The Therapeutic Goods Administration has published a safety update, and the Product Information has been updated, warning about the increased risk of osteoporotic fractures in patients taking excessive thyroxine doses. When treating with thyroxine, monitor serum TSH regularly and adjust thyroxine doses accordingly. Extra caution is needed when treating older people with thyroid problems because of the physiological changes associated with ageing. Older women are more likely to require thyroxine because of the increased prevalence of hypothyroidism and their fracture risk is compounded by other factors such as decreased bone mineral density. In those needing thyroxine, dose requirements generally decrease with age.

New Product Information and Therapeutic Goods Administration (TGA) safety update for thyroxine dosing

In Australia the prevalence of recognised hypothyroidism is 10% with a potentially higher number of people with unrecognised disease.[1] Older women are more likely to require thyroxine because of an increased prevalence of hypothyroidism in this group.1–3 The TGA recently published a safety update on the risk of osteoporotic fracture in patients taking higher-than-needed thyroxine doses.4 This followed recent studies reporting an association between high thyroxine dose and the risk of fracture in men and women aged 60 years and over.5,6 (See below High-dose thyroxine therapy is associated with increased risk of fracture.) New information about the effect of thyroxine on bone mineral density (BMD) is now included in the latest Product Information with a recommendation that patients be given the minimum dose of thyroxine necessary to achieve the desired clinical and biochemical response.7,8

High-dose thyroxine therapy is associated with increased risk of fracture

Recent studies (one cohort and one nested case–control) examining fracture incidence in patients taking long-term thyroxine treatment found fracture risk was associated with high or excessive thyroxine dose.5,6 The cohort study found a 2-fold higher risk of hospitalisation or death due to osteoporotic fracture in patients aged 18 years or older with suppressed TSH (TSH ≤0.03 mU/L) compared with normal (0.4–4.0 mU/L).5 The case–control study showed a 3.5-fold higher risk of fracture in thyroxine replacement patients aged 70 years or older with a cumulative dose greater than 93 micrograms per day compared with patients on a low cumulative dose (<44 micrograms).6 Within doses commonly used in practice, medium cumulative doses (44–93 micrograms), were also associated with a 2.6-fold higher risk of fracture.6 A 3.4-fold higher risk of hip fracture was also seen with cumulative doses greater than 93 micrograms per day of thyroxine.6

Thyroxine treatment needs decrease in older people

Most older people will require a lower dose of thyroxine as age-associated physiological changes, such as a reduction in lean body mass, reduce their thyroxine replacement needs.9 Ageing is also associated with a reduction in thyroid function such that thyroid hormone production10, secretion by the pituitary11 and degradation decrease12, often resulting in unchanged serum total and free thyroxine concentrations.13

Thyroxine treatment may be associated with a higher risk of fracture in women than in men. This may be related to differences in body size and pharmacokinetics between men and women5,14,15 as well as the association between long-term thyroxine therapy and increased bone resorption resulting in decreased BMD in post-menopausal women overtreated with thyroxine.16 Thus, when considering risk factors for fracture, the measurement of BMD offers some predictive value, especially in women with other risk factors.16

Excess thyroid hormone can also increase the risk of arrhythmias17, muscle weakness18 and falls.16 Thus increasing the risk of fractures independent of BMD.

Thyroid function testing in older people can be problematic

Consider confounding factors when interpreting thyroid function tests in older people. Malnutrition and chronic illness may cause abnormal thyroid function test results.[19]

Older people often use medications which can affect the thyroid and cause:

  • hypothyroidism or hyperthyroidism resulting from iodine excess, exacerbating thyroid dysfunction (e.g. amiodarone, kelp tablets)
  • altered serum free thyroxine (e.g. phenytoin, carbamazepine, frusemide, heparin, aspirin, some NSAIDs)
  • low TSH levels (e.g. glucocorticoids, dopamine).13,20

Practice points for managing thyroxine dose

Changes to the Product Information indicate a reduction in the starting dose, and upper limit of thyroxine maintenance dose.7,8 Some guidelines may not be consistent with these changes.20–22

  • Start thyroxine therapy at a low dose to reduce the risk of fracture (and cardiac events).5,7,8,20
  • Whenever possible, whole tablets should be taken.7,8
Thyroxine dosing
People over 60 years of age and adults with ischaemic heart disease
Adults under 60 years of age

Start with 25–50 micrograms of thyroxine daily.7,8

Increase the daily dose by 25 micrograms as required at no less than 4-weekly intervals20 to 100–125A micrograms daily.7,8

Start with 25–50 micrograms of thyroxine daily.7,8 In the absence of ischaemic heart disease, therapy can be started at 50–100 micrograms daily.7,8

Increase the daily dose by 25–50 micrograms as required at not less than 4-weekly intervals20 to 100–150A micrograms daily.7,8

[A] While a daily dose of 200 micrograms is no longer recommended[7,8], a tablet in this dose is available for patients requiring varied daily doses (based on a total weekly dose).[22]


  • Individualise the dose based on clinical response and thyroid function tests7,8
TSH levels for maintenance
People over 60 years of age and adults with ischaemic heart disease Adults under 60 years of age
Aim for a TSH concentration less than 5 mU/L.20 Adjust dose in older people primarily in accordance with clinical response within the first three months.20
Aim for TSH concentrations of 0.5–2 mU/L.20
Testing frequency
  • Schedule testing at least 4–6 weeks after changing dose to allow TSH to stabilise.22
  • Repeat testing every 6 weeks until the dose is stabilised. Increase this interval if the patient is approaching euthryroidism and is feeling well.22
  • Annual TSH measurement is adequate once the dose is stabilised.22
  • Older asymptomatic people with suspected autoimmune hypothyroidism (raised TSH and normal free thyroxine) require regular monitoring, approximately every 6 months.23

Information for patients

Thyroxine treatment is usually required lifelong, so patients need to be well informed about their condition in order to achieve optimal use of therapy and protect against avoidable adverse events such as fracture.

Patients may find information about their thyroid disorder from these reliable sources:

  1. Empson M, Flood V, Ma G, et al. Prevalence of thyroid disease in an older Australian population. Int Med J 2007;37:448–55. [Pubmed]
  2. Canaris GJ, Manowitz NR, Mayor G, et al. The Colorado thyroid disease prevalence study. Arch Int Med 2000;160:526–34. [Pubmed]
  3. O'Leary PC, Feddema PH, Michelangeli VP, et al. Investigations of thyroid hormones and antibodies based on a community health survey: the Busselton thyroid study. Clin Endocrinol 2006;64:97–104. [Pubmed]
  4. Australian Government Department of Health and Ageing Therapeutic Goods Administration. Medicines Safety Update Volume 4 Number 1. February 2013. (accessed 11 February 2013).
  5. Flynn RW, Bonellie SR, Jung RT, et al. 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. [Pubmed]
  6. Turner MR, Camacho X, Fischer HD, et al. Levothyroxine dose and risk of fractures in older adults: nested case-control study. BMJ 2011;342:d2238. [Pubmed]
  7. Aspen Pharma Pty Ltd. Product Information Oroxine. September 2012. 2012. (accessed 11 February 2013).
  8. Aspen Pharma Pty Ltd. Product Information Eutroxsig. September 2012. 2012. (accessed 11 February 2013).
  9. Topliss DJ, Eastman CJ. 5: Diagnosis and management of hyperthyroidism and hypothyroidism. Med J Aust 2004;180:186–93. [Pubmed]
  10. Rosenbaum RL, Barzel US. Levothyroxine replacement dose for primary hypothyroidism decreases with age. Annals Int Med 1982;96:53–5. [Pubmed]
  11. van Coevorden A, Laurent E, Decoster C, et al. Decreased basal and stimulated thyrotropin secretion in healthy elderly men. J Clin Endocrinol Metab 1989;69:177–85. [Pubmed]
  12. Gregerman RI, Gaffney GW, Shock NW, et al. Thyroxine turnover in euthyroid man with special reference to changes with age. J Clin Invest 1962;41:2065–74. [Pubmed]
  13. Peeters RP. Thyroid hormones and aging. Hormones (Athens) 2008;7:28–35. [Pubmed]
  14. Somwaru LL, Arnold AM, Joshi N, et al. 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. [Pubmed]
  15. Okosieme OE, Belludi G, Spittle K, et al. Adequacy of thyroid hormone replacement in a general population. QJM 2011;104:395–401. [Pubmed]
  16. Cummings SR, Nevitt MC, Browner WS, et al. Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. N Engl J Med 1995;332:767–73. [Pubmed]
  17. Sawin CT, Geller A, Wolf PA, et al. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med 1994;331:1249–52. [Pubmed]
  18. Brennan MD, Powell C, Kaufman KR, et al. The impact of overt and subclinical hyperthyroidism on skeletal muscle. Thyroid 2006;16:375–80. [Pubmed]
  19. van den Beld AW, Visser TJ, Feelders RA, et al. Thyroid hormone concentrations, disease, physical function, and mortality in elderly men. J Clin Endocrinol Metab 2005;90:6403–9. [Pubmed]
  20. Therapeutic guidelines. Endocrinology. version 4 ed. Melbourne: Therapeutic Guidelines Ltd, 2009.
  21. Australian medicines handbook. Adelaide: Australian Medicines Handbook Ltd, 2012.
  22. Davoren P. Modern management of thyroid replacement therapy. Aust Prescr 2008;31:159–61.
  23. Mortimer RH. Thyroid function tests. Aust Prescr 2011;34:12–5.