Subclinical Hyperthyroidism Caused by Leveothyroxine Use Can Increase Fracture Risk

the word hyperthyroidism on a tablet with medication in the backgroundIt’s thought that clinical hyperthyroidism can increase the risk of fractures—especially in elderly and postmenopausal populations.  Researchers from Canada wanted to see if subclinical hyperthyroidism (thyroid stimulating hormone [TSH] suppressed below the reference range and a free thyroxine level with the normal range)  caused by excessive thyroxine therapy would also cause an increased risk of fractures.

An article was published in April 2011 in the British Medical Journal that reported the results of the researchers’ population-based, retrospective cohort study with a nested case-control design.  The article was called “Levothyroxine dose and risk of fractures in older adults: nested case-control study.”  The September 2011 issue of Clinical Thyroidology had a review and commentary on the study.

For the study, the researchers used population-based health databases for Ontario, Canada.  The participants were adults 70-years-old or older who were prescribed levothyroxine between April 1, 2002, and March 31, 2007; they were followed for fractures until March 31, 2008.  There were 213,511 people in the cohort.

Cases were cohort members who were admitted to the hospital for any fracture, and they were matched with up to 5 controls from the cohort who hadn’t yet experienced a fracture.

The primary outcome was a 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 current, recent past, or remote levothyroxine use.  Among current users, the risk was compared between those prescribed high, medium, and low cumulative levothyroxine doses in the year leading up to the fracture.

In the study, 22,236 people (10.4%) had a fracture over a mean 3.8 years of follow-up. Of those people with fractures, 18,108 of them (88%) were women.

When comparing remote levothyroxine use to current use, researchers noted that current use was associated with a significantly higher risk of fracture (adjusted odds ratio [OR] 1.88, 95% confidence interval; 1.71 to 2.05).  This higher risk existed despite adjusting for numerous risk factors.

For current users, high cumulative doses (>0.093 mg/day; OR 3.45) and medium cumulative doses (0.044-0.093 mg/day; OR 2.62) were associated with a significantly increased risk of fracture when compared to low cumulative doses (<0.044 mg/day).

The study concluded that in adults aged 70 or older, current levothyroxine treatment is associated with a significant increase of fracture, and there is a strong dose-response relation. In this population, then, it’s essential to have ongoing monitoring in order to avoid overtreatment.

In her commentary on this study in Clinical Thyroidology, Stephanie L. Lee, MD, PhD notes, “[This] study raises the speculation that the TSH target for older adults needs to be modified and lowered, as National Health and Nutrition Examination Survey studies suggest that 70% of older patients with TSH >4.5 mIU/L were within their age-specific reference range.  Perhaps overreplacement with levothyroxine to achieve a TSH in a hypothyroid elderly patient with the reference range—that is, 0.4 to 4.5 mIU/L—may result in a relative thyroid hormone excess and abnormal bone metabolism.”1

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