Too Much Levothyroxine Increases the Risk of Fractures in Older Adults

A recent British Medical Journal (BMJ) study suggests that many older patients with hypothyroidism are being prescribed doses of levothyroxine that are too high, resulting in overtreatment and increasing their risk of fractures.

The study, published online April 28, 2011, demonstrated that older adults taking the thyroid hormone replacement drug levothyroxine had an increased risk of bone fractures and that this risk increased as the dose of levothyroxine increased.

The findings of this study have important public health implications, because more than 20 percent of older people have hypothyroidism and are taking long-term levothyroxine replacement therapy. In fact, levothyroxine is one of the most commonly used drugs in the U.S. In 2010, approximately 95 million prescriptions for either generic or brand-name levothyroxine were filled in the U.S.

BMJ study overview

Dr. Marci Turner and her co-authors used patients’ hospital medical records to assess the risk of having a fracture based on the cumulative dose of levothyroxine prescribed to them during the year preceding a fracture and on the timing, before having a fracture, of exposure to levothyroxine.

The researchers analyzed records for all 70- to 105-year-old residents of Ontario, Canada, with at least one prescription for levothyroxine during the five-year period from April 2002 to March 2007. Of those prescribed levothyroxine (213,511), the researchers then identified all patients who had a bone fracture after being prescribed levothyroxine and obtained pertinent medical information regarding risk factors for fractures.

They excluded from their analysis those patients who had a predisposition to fractures due to cancer involving the bones, multiple myeloma, seizures or other diseases.

The team labeled patients who had a fracture (22,236 patients, 10.4 percent of all those using levothyroxine) “index cases.” Of those patients who had a fracture, more than 80 percent were women (as will be discussed later, most people using levothyroxine are women). Each index case was matched with five control subjects who had been prescribed levothyroxine but had not suffered a fracture as of the date of fracture for the index case.

Effect of higher doses of levothyroxine on fracture risk

The researchers assessed how the average daily dose affected the risk for fracture by reviewing the total cumulative dose of levothyroxine in current users during the year prior to a fracture. For this part of the study, the patients were divided into low-dose (less than 44 micrograms [µg] per day), medium-dose (between 44 and 93 µg per day) and high-dose (greater than 93 µg per day) groups. In comparison to the low-dose group, medium-dose patients were 2.5 to 2.8 times more likely to have a fracture, and the high-dose group was 3.3 to 3.7 times more likely. Similarly, for those with hip fractures only, the medium-dose group’s risk was 2.3 to 2.8 times higher, and the high-dose group’s risk was 3.1 to 3.7 times higher than the low-dose group. The authors concluded that “dosages commonly used in clinical practice, especially over 93 µg per day, may be excessive for this [elderly] population.”

Effect of timing of levothyroxine use on fracture risk

The researchers also assessed how the timing of levothyroxine use affected the risk of fracture. For this part of the analysis, the researchers categorized the patients into three groups based on the timing of their exposure to levothyroxine prior to the fracture date of the index case: current users, recent past users, and remote users. Current users were those patients whose prescription for levothyroxine overlapped with the index patient’s date of the fracture. Recent past and remote users were those patients whose most recent prescription ended 15 to 180 days prior to the index-case fracture and more than 180 days prior to the index-case fracture, respectively.

After adjusting for various known risk factors for fractures, the researchers found that the risk of having a fracture in current users of levothyroxine was 1.7 to 2.1 times higher than in those patients who were remote users of the drug. Recent past users were 1.2 to 1.5 times more likely to have a fracture than remote users. When looking at patients with hip fracture, current users were 1.4 to 1.8 times more likely to have such fractures than remote users.

These latter findings concerning the timing of levothyroxine use help to establish the causal relationship between the use of levothyroxine and the subsequent fractures.

In current users, the risk of fracture was greater in women than in men.

What is hypothyroidism?

The thyroid gland, located in the front of the neck, normally produces two types of thyroid hormone, thyroxine (also known as T4) and triiodothyronine (also known as T3). These hormones play a key role in regulating body metabolism. Hypothyroidism is a condition where a patient’s thyroid gland fails to secrete enough of these thyroid hormones into the bloodstream.

Hypothyroidism has many causes, the most common in the U.S. being an autoimmune disease called Hashimoto’s thyroiditis. This disease occurs when a person’s immune system produces antibodies and white blood cells that attack and destroy the thyroid gland.

Hypothyroidism becomes more common with age. It is five to six times more likely in women than in men. Approximately 10 percent of women over age 55 have asymptomatic hypothyroidism.

Symptoms of hypothyroidism can include fatigue, weakness, muscle aches, cold intolerance, shortness of breath with exertion, weight gain, constipation, irregular menstrual cycles and cognition problems. During a physical exam, patients may have a low pulse, elevated diastolic blood pressure, an enlarged thyroid gland and swelling around the eyes. However, most patients — particularly those with early, mild forms of the disorder — do not have symptoms or physical exam abnormalities.

Most cases of hypothyroidism are diagnosed by a screening blood test that measures thyroid-stimulating hormone (TSH). TSH, which is produced by the pituitary gland, stimulates the thyroid gland to make and secrete more thyroid hormone.

When thyroid hormone levels decrease, the pituitary gland compensates by releasing more TSH. Thus, patients with hypothyroidism typically have an abnormally high TSH level.

Hypothyroidism treatment and the BMJ study results

Treatment for hypothyroidism includes the thyroid hormone drug levothyroxine, which is taken once daily as an oral pill for the rest of the patient’s life. Levothyroxine is available in many doses in generic form and under several different brand names (see “Available brand names for levothyroxine” box). A patient initially starts on a low dose, and after several weeks, the patient’s TSH level is checked. If the TSH level has decreased to the normal range, the patient is continued on the initial low dose of levothyroxine. If the TSH is still high, the dose of levothyroxine is gradually increased until the TSH level has decreased to the normal range.

The authors of the BMJ study concluded that “levothyroxine treatment is associated with a higher risk of fractures in a dose-response manner in older adults, and that dosages commonly used in clinical practice, especially over [93 µg] a day, may be excessive for this population.”

As people age, several changes in thyroid hormone physiology occur. In particular, the rate at which thyroid hormone is metabolized and removed from the body decreases. Furthermore, with increasing age, the level of TSH considered to be normal, which is supposed to be monitored to guide treatment, appears to increase. Therefore, as most people with hypothyroidism age, the amount of levothyroxine needed to maintain a normal thyroid hormone level decreases. In other words, older people generally need to take less levothyroxine to avoid being hypothyroid.

Unfortunately, many patients with hypothyroidism do not have their dose of levothyroxine appropriately adjusted downward as they grow older, because either their TSH is not being monitored or health care providers are not aware that the normal range for TSH may increase with age. Failure to lower the drug dose may lead to hyperthyroidism (too much thyroid hormone), secondary to levothyroxine overdose. Prior studies have shown that hyperthyroidism is a risk factor for osteoporosis and fractures.

What You Can Do

If you take levothyroxine for hypothyroidism, you should make sure your health care provider checks your TSH level periodically, usually on an annual basis. You should discuss your TSH results with your health care provider and ask whether your levothyroxine dose needs to be adjusted. This is especially true if you are elderly and are taking more than 93 µg per day, but may also be needed if you are taking lower doses. Anytime your levothyroxine dose is adjusted, your health care provider should order a repeat TSH-level test four to six weeks after the dose change to make sure the new dose is appropriate.

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