Adults aged ≥70 years treated with levothyroxine have a significantly increased risk of fractures, with a strong dose-response relationship, a Canadian research group has found.
Thyroid hormone metabolism slows with aging, and individuals with hypothyroidism who rely on replacement therapy with levothyroxine are at risk of overtreatment and so-called 'iatrogenic hyperthyroidism'. Although excess levels of thyroid hormone are known to be associated with an increased risk of fracture, previous studies have been inconsistent regarding the relationship between levothyroxine replacement and fracture risk, particularly in the elderly.
Turner et al. sought to explore the association between levothyroxine replacement and fractures in a high-risk population—adults ≥70 years of age who were prescribed levothyroxine between 1 April 2002 and 31 March 2007 and in whom the occurrence of fractures was monitored until 31 March 2008—and to determine whether a specific dose of levothyroxine might be particularly linked with fractures in these individuals.
“We analyzed the cohort using a nested case–control design, as it allows for consideration of the time-dependent nature of drug use, and it provides estimates that would be similar to a time-to-event analysis but with more computational efficiency,” explains senior investigator Lorraine L. Lipscombe from the Women's College Research Institute in Toronto. Cases were defined as any individual with at least one fracture during follow-up, and the date of fracture-related admission to hospital was defined as the index date. Up to five controls were matched to each case. Each control received the same index date as their respective case. On the basis of the timing of their latest levothyroxine prescription, all cohort members were defined as current users, recent past users (drug discontinued 15–180 days before the index date) or remote users (drug discontinued >180 days before the index date).
The study cohort consisted of 213,511 adults treated with levothyroxine who were aged 82 years on average and who were followed up for a mean of 3.83 years. In total, 10.4% of individuals (88% women) sustained at least one fracture, and 27.2% died during follow-up.
The researchers determined that the risk of fracture—any fracture and hip fracture—was increased in patients who were current or recent past users of levothyroxine at the time of a first fracture, compared with remote users. “There was also a strong dose-response between current levothyroxine use and risk of fracture in both sexes, despite adjustment for multiple fracture risk factors,” adds Lipscombe. “Older men and women using more than 0.093 mg of levothyroxine per day were particularly at risk, with a more than threefold increase in fractures.” Medium cumulative doses (0.044–0.093 mg per day) were also associated with a significantly higher risk of any fracture compared with low cumulative doses (<0.044 mg per day).
In the future, Lipscombe and colleagues hope to further unravel the relationship between levothyroxine and fractures, specifically with respect to the effect of duration of levothyroxine therapy on fracture risk. “Also, our health databases will include laboratory data such as TSH levels, which will facilitate the ability to assess how the higher levothyroxine doses implicated in fractures relate to TSH values in these patients,” comments Lipscombe. This added information could help determine whether and to what extent previous findings are due to 'suppression' of TSH levels by high levothyroxine doses. Another possibility is that TSH levels are found to be within the accepted 'normal range', which might subsequently prompt an adjustment of current TSH treatment targets for elderly patient groups.
In conclusion, the findings by Turner et al. suggest that dosages of levothyroxine commonly used in clinical practice are associated with an increased risk of fractures in adults aged ≥70 years. To avoid overtreatment in this population, the investigators recommend regular monitoring of levothyroxine doses throughout life, as well as an annual blood test to measure TSH levels.
ORIGINAL RESEARCH PAPER
Turner, M. R. Levothyroxine dose and risk of fractures in older adults: nested case–control study. BMJ 342, d2238 (2011)
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Koch, L. Levothyroxine in the elderly—finding the breaking point. Nat Rev Endocrinol 7, 435 (2011). https://doi.org/10.1038/nrendo.2011.99
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