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).
It should be noted that 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 National Cancer Institute statistics in the U.S., 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 post-marketing reports do not suggest any association between alendronate and esophageal cancer.”
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. 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, “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 form of the agents. Although researchers previously demonstrated an elevated risk of osteonecrosis of the jaw (ONJ) with intravenous bisphosphonates, 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).
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.
“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.
In a written statement, Merck said the study “has material methodological flaws and scientific limitations” that prevent any conclusion from being drawn about alendronate. The statement said that “In controlled clinical trials involving more than 17,000 patients … there have been no reports of ONJ. This includes approximately … 800 patients taking alendronate for 8 to 10 years.”
In the current study, of the patients with a history of alendronate use, 66 (32%) had nonsurgical dental extraction. Four of these patients developed ONJ at the extraction site, and another five developed ONJ after denture-related mucosal ulceration. Of the 13,522 patients without a history of alendronate use in the database, 4,384 (32%) underwent dental extraction. “We observed no cases of ONJ among these patients,” the authors wrote (J. Am. Dent. Assoc. 2009;140:61–6).
Dr. Paul Jellinger, an endocrinologist in Hollywood, Fla., noted, “It has been reported that 225 million total prescriptions for bisphosphonates have been written since their introduction. Although these serious reports certainly deserve our attention and appropriate dosing precautions and patient selection is very important, the absolute risk for either of these events must be viewed as extremely low.”
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