Use of oral bisphosphonate drugs is associated with an increased risk of esophageal cancer, according to reports in the United States, Europe, and Japan.
Multiple agents in the class are associated with the esophageal cancer warning, which was raised by an epidemiologist at the Food and Drug Administration in a letter to the New England Journal of Medicine.
Between October 1995, when alendronate (Fosamax) was first approved by the FDA, and May 2008, the agency has received reports of 23 patients taking the drug diagnosed with esophageal cancer. This includes 21 cases where oral alendronate was the suspect drug and 2 where concomitant use of the agent was implicated, Diane K. Wysowski, Ph.D., wrote (N. Engl. J. Med. 2009;360:89–90).
Of the 23 patients, 18 (78%) were women and the median age was 74 years. The median time from alendronate use to diagnosis was 2.1 years (based on 16 patients).
One patient took alendronate despite having Barrett's esophagus, a precursor of esophageal adenocarcinoma, pointed out Dr. Wysowski, of FDA's Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research. She reported no relevant disclosures.
Merck, which manufactures alendronate, said in a statement that “the incidence of esophageal cancer in the general population increases with age and is reported to be more common in the older population. According to U.S. statistics from the National Cancer Institute, the annual incidence of esophageal cancer in the population aged 65 years or older is 22.3 per 100,000.”
The statement also noted that “data from Merck's clinical trials of Fosamax and from postmarketing reports do not suggest any association between alendronate and esophageal cancer. Fosamax has been studied in controlled clinical trials involving more than 17,000 patients, contributing as much as 10 years' data.”
The FDA's adverse event reporting database did not include any reports of esophageal cancer associated with other bisphosphonates. In contrast, reports for 31 patients in Europe and Japan included a diagnosis of this cancer following use of alendronate, risedronate (Actonel, Procter & Gamble), ibandronate (Boniva, Roche), and/or etidronate (Didronel, Procter & Gamble).
Twenty-two patients (71%) were women and the median age was 69 years. The median time from drug exposure to diagnosis was 1.3 years (based on 21 patients). Barrett's esophagus was diagnosed in three patients. The distal esophagus was affected in eight patients (with gastric involvement in four).
An association between esophagitis and oral bisphosphonates is suggested in studies (Radiology 1998;206:389–91; N. Engl. J. Med. 1996;335:1016–21), “usually when the drugs are not taken according to directions,” Dr. Wysowski wrote.
A second published report extends the link between use of bisphosphonates and jaw necrosis to the oral preparation of the agents, which had heretofore been thought to be without this risk. Although researchers previously demonstrated an elevated risk of osteonecrosis of the jaw (ONJ) with intravenous bisphosphonates (J. Oral Maxillofac. Surg. 2004;62:527–34), the current study is the first to show a similar elevated risk with long-term use of an oral agent. Parish P. Sedghizadeh, D.D.S., and his associates at the University of Southern California, Los Angeles, launched the study after evidence suggested the rate of ONJ secondary to alendronate treatment was higher at their institution than that reported by the manufacturer.
In 2006, Merck estimated incidence of this adverse outcome as 0.7 per 100,000 person-years of alendronate exposure, or 170 cases worldwide. An American Dental Association (ADA) expert panel cited this figure when stating that oral bisphosphonate use should not trigger modification of routine dental treatment (J. Am. Dent. Assoc. 2006;137:1144–50; J. Am. Dent. Assoc. 2008;139:1674–7).
Tooth extraction seems to be a significant trigger of jaw necrosis in patients on long-term bisphosphonates.
Dr. Sedghizadeh and his colleagues identified 208 patients with a history of alendronate in their electronic medical record system. This group included nine patients with active ONJ undergoing treatment at the University of Southern California clinics. The nine represented 1 in 23 of the patients taking alendronate, or about 4% of the study population.
“Most of the patients receiving alendronate at USC who developed ONJ did so after routine tooth extraction, suggesting that perhaps these patients should be identified as an at-risk population and preventive measures should be taken,” the authors wrote. The investigators had no relevant disclosures.
Merck released a written statement saying that the study “has material methodological flaws and scientific limitations, making it unreliable as a source for valid scientific conclusions regarding the prevalence of ONJ in patients taking alendronate.” The statement said that “In controlled clinical trials involving more than 17,000 patients … there have been no reports of ONJ.”