The FDA ( Food and Drug Administration ) is continuing to review data from published studies to evaluate whether use of oral bisphosphonate drugs is associated with an increased risk of cancer of the esophagus. There have been conflicting findings from studies evaluating this risk.

At this time, FDA believes that the benefits of oral bisphosphonate drugs in reducing the risk of serious fractures in people with osteoporosis continue to outweigh their potential risks.

The largest studies that FDA has reviewed, thus far, are two epidemiologic studies using one patient database ( the U.K. General Practice Research Database or GPRD ). One study found no increase in the risk of esophageal cancer. The second study found a doubling of the risk of esophageal cancer among patients who had 10 or more prescriptions of the drugs, or who had taken the drugs over 3 years.
Other external researchers investigating this issue, using different patient databases, have reported no increase in risk, or a reduced risk.

Oral bisphosphonate drugs include: Fosamax ( Alendronate ), Actonel ( Risedronate ), Boniva ( Ibandronate ), Atelvia ( Risedronate delayed release ), Didronel ( Etidronate ), and Skelid ( Tiludronate ).
Bisphosphonates may cause irritation of the esophagus. Irritation of the esophagus can lead to esophagitis or esophageal ulcers, which may bleed. The risk of these esophageal events is low when oral bisphosphonates are prescribed appropriately and the specific directions for use are followed by patients.

Data summary

In January 2009, a case series was published describing reports submitted to the FDA of esophageal cancer in patients prescribed oral bisphosphonates. Since then, several epidemiological studies looking at the association between oral bisphosphonates and esophageal cancer have been published, with discrepant findings. The two largest published studies used data from the U.K.'s General Practice Research Database.

One study compared the rate of esophageal cancer in patients taking an oral bisphosphonate to patients not taking an oral bisphosphonate. This study found no increase in the risk of esophageal cancer. Using the same database, a second study found a doubling of the risk of esophageal cancer among patients who had 10 or more prescriptions of oral bisphosphonates, or who had taken the drugs over 3 years.

Other investigators are researching this issue. In a large cohort of Danish patients with fractures, investigators found that bisphosphonate users ( who had taken them for a median of 1.5 years ) had a significantly reduced risk for esophageal cancer compared to patients with fractures who had not taken any bisphosphonate. Longer term follow-up of Alendronate ( Fosamax ) users and non-Alendronate users showed that Alendronate users had a higher frequency of endoscopic examination of the esophagus, no greater incidence of esophageal cancer, and no increase in esophageal cancer deaths.

Differences in methodologies in these studies may account for the discrepant findings. Also, since these studies are observational rather than randomized, they are subject to bias and confounding. For example, it is possible that the gastrointestinal side effects of bisphosphonates increase a patient's likelihood of undergoing an endoscopy, which could lead to earlier detection of a cancer or drug discontinuation. At this time, there is not enough information to make definitive conclusions about a possible association. FDA's safety review is ongoing. Additional studies conducted in different databases may be warranted.

Source: FDA, 2011

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