Long-term Risks of Bisphosphonates Probed

A growing body of evidence suggests that long-term use of apopular class of drugs for osteoporosis and other bone disorders may be associated with the development of rare complications in some patients.

Bisphosphonate drugs, which stop the resorption of bone, are widely prescribed to treat such conditions as osteoporosis, Paget disease, and certain conditions in cancer patients. However, emerging data show a possible connection between long-term bisphosphonate use and some rare but serious adverse events, such as low-energy femoral fractures (caused by falls from a standing height or less) and osteonecrosis of the jaw. Additionally, a scientist at the US Food and Drug Administration (FDA) recently noted reports of esophageal cancer in patients taking alendronate.

Such reports add to the list of adverse effects already linked to bisphosphonates. In January 2008, the FDA alerted physicians that some patients taking these drugs may experience severe musculoskeletal pain within days, months, or years of initiating bisphosphonate therapy. The pain may subside after discontinuation of the drugs. The incidence and risk factors for such pain are unknown.

There also have been recent reports of increased rates of serious atrial fibrillation in patients taking bisphosphonates (Black DM et al. N Engl J Med. 2007;356[18]:1809-1822 and Heckbert SR et al. Arch Intern Med. 2008; 168[8]:826-831). But an FDA analysis of data, including 19 687 patients taking bisphosphonates and 18 358 taking a placebo, found no clear association between use of these drugs and cardiac arrhythmia. One large trial of zoledronic acid reviewed by the FDA showed a significant increase in serious atrial fibrillation, and this drug's label notes the risk. Despite the conflicting data, the FDA in November stated that physicians should not alter their prescribing habits, and patients should not stop taking bisphosphonates.

While bisphosphonates reduce the rate of hip fractures, they appear to increase the risk of rare low-energy femoral fractures in some patients taking the drugs for long periods. Joseph M. Lane, MD, professor of orthopedics at the Hospital for Special Surgery and New York Presbyterian Hospital in New York City, and colleagues recently documented such a pattern through a retrospective case-control analysis of women presenting with femoral fractures between 2000 and 2007 (Lenart BA et al. Osteoporos Int. doi:10.1007/s00198-008-0805-x [published online ahead of print December 9, 2008]).

Lane and colleagues found that 15 of the 41 patients (37%) with subtrochanteric and femoral shaft fractures were taking alendronate vs 9 of 82 control patients (11%) with hip and femoral neck fractures. X-ray films also revealed a common pattern of fracture in 10 of the 15 bisphosphonate users, which was associated with a longer duration of use.

Although the study does not prove that the drugs caused these fractures, Lane described 2 hypotheses about how long-term use of bisphosphonates might lead to such events. One posits that because the drugs slow or stop normal bone remodeling over time, patients may accumulate bone-weakening microdamage. Alternatively, some recent data suggest the drugs may weaken collagen. Lane said further large-scale trials are needed to elucidate the role of bisphosphonates in low-energy femoral fractures.

In the meantime, researchers say there is reason for cautious use of bisphosphonates. Lane explained that the premarketing trials of these drugs lasted 3 to 5 years, but the drugs have half-lives of 10 years or more. As a result, clinicians are still learning about the best way to use them.

Lane advised physicians to check markers of bone metabolism in patients taking bisphosphonates and consider a drug holiday if bone remodeling appears to have stopped. He said he and his colleagues now discontinue bisphosphonate treatment in patients after 5 years; these patients are given calcium and vitamin D and are monitored for bone loss during that holiday. Bisphosphonate treatment is resumed in patients who experience bone loss, but at the lowest possible dose.

“Until we get more data from industry and the FDA, we are stepping back,” he said.

As early as 2006, dentists began documenting a rare condition in patients taking bisphosphonates, osteonecrosis of the jaw, predominantly those taking high-dose intravenous formulations for cancer-related problems. However, more recent data suggest that a subset of patients taking oral formulations of these drugs may be at greater risk than previously appreciated, according to an analysis of patients at the University of Southern California School of Dentistry in Los Angeles (Sedghizadeh PP et al. J Am Dent Assoc. 2009;140[1]:61-66).

Parish P. Sedghizadeh, DDS, assistant professor at the dental school, and his colleagues analyzed the electronic medical records of 208 dental patients who were also alendronate users and found that 9 of them (4%) had osteonecrosis of the jaw. All were long-term patients at the dental school, suggesting the elevated rate was not the result of referral bias. All the patients had dental trauma from either a tooth extraction or ill-fitting dentures, most had been taking the drugs for several years, and many shared comorbidities such as diabetes and cardiovascular problems. A recent review estimated that 5% of patients with osteonecrosis of the jaw were taking bisphosphonates for osteoporosis (Reid IR. Bone. 2009;44[1]:4-10).

Sedghizadeh said that larger multi-institution analyses are necessary to confirm the results, but noted that jaw osteonecrosis in patients taking these lower-dose formulations seems plausible. Because of the drugs' long half-life, patients taking the oral formulations for years may eventually reach the same dose equivalence as patients treated intravenously. The exact mechanism of osteonecrosis of the jaw in patients taking bisphosphonates is not known. More cases are likely to be seen in the future, Sedghizadeh said, as patients accumulate years of use.

However, this possible complication of bisphosphonate use may be preventable. Sedghizadeh reports that since he and his colleagues began taking precautions in patients taking these drugs, they have seen no new cases among these individuals, only among patients referred to them. Such precautions include consulting with physicians prior to patients starting bisphosphonates to determine whether dental procedures should be completed first and taking steps to reduce bacteria in the mouth of patients who must undergo procedures while taking these drugs.

Esophageal irritation has long been associated with use of oral bisphosphonates, and patients are advised to remain upright for at least 30 minutes after taking these drugs. Recent reports of esophageal cancer in patients taking bisphosphonates are raising concerns that such irritation might lead to more serious problems.

Between October 1995 and May 2008, the FDA has received 23 reports of esophageal cancer, including 8 deaths, in US patients taking alendronate, according to a letter from FDA scientist Diane K. Wysowski, PhD (Wysowski DK. N Engl J Med. 2009;360[1]:89-90). One case occurred in a patient who had been diagnosed with Barrett esophagus, a condition related to long-term reflux that places patients at higher risk of developing esophageal cancer, prior to taking the drug. Additionally, cases of esophageal cancer have been reported in 31 patients taking alendronate in Europe and Japan.

In the letter, Wysowski recommends that physicians avoid prescribing oral bisphosphonates to patients with Barrett esophagus. She also suggests further study of the cancer risk associated with these drugs.