Cases of esophageal cancer in patients who had been taking oral bisphosphonate drugs for osteoporosis have been reported by an official from the Food and Drug Administration (FDA) in the January 1 issue of the New England Journal of Medicine.
"We are not able to determine if oral bisphosphonates cause or contribute to esophageal cancer without a study that collects information on known risk factors for esophageal cancer while also taking into account the oral bisphosphonate use," the author, Diane Wysowski, PhD, epidemiologist in the Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, FDA, commented to Medscape Oncology. She suggested that additional studies of this issue should be carried out.
Twenty-three cases (of which 8 were fatal) have been reported in the United States, all of them in association with alendronate (Fosamax, Merck), which was cited as the suspect drug in 21 cases and as a concomitant drug in 2 cases. These reports were received by the FDA in the 12-year period between October 1995 (when alendronate was launched in the United States) and mid-May 2008. No reports were received about esophageal cancer and any of the other oral bisphosphonate products.
A further 31 cases (6 fatal) have reported in Europe and Japan, with alendronate as the suspected drug in 21 cases. Of the remainder, 6 cases were associated with risedronate (Actonel, Procter & Gamble/Sanofi-Aventis), ibandronate (Boniva, Roche/GlaxoSmithKline), etidronate (Didronel, Procter & Gamble), or a combination of these, and 4 cases cited bisphosphonates as concomitant drugs.
The median time from drug exposure to diagnosis was 2.1 years for patients from the United States and 1.3 years for the patients from Europe and Japan. "We do not know when the cells in these esophageal cancer cases were transformed from being normal to being cancerous," Dr. Wysowski told Medscape Oncology. "If the drugs play a role in carcinogenesis, the time frames from drug exposure to diagnosis seem more consistent with the drugs acting as tumor promoters, as opposed to tumor initiators. However, whether this is the case is not known."
"It is possible that the oral bisphosphonate drugs that are known to have esophageal effects could have cause increased surveillance for cancer; however, this seems unlikely," Dr. Wysowski said. "For cases where information was available, patients developed esophageal symptoms and were diagnosed with esophageal cancer shortly thereafter. There was no mention in the reports of periodic monitoring or any special surveillance procedures."
"Also, it is possible that the bisphosphonate drugs may have played a role in detecting a cancer that was pre-existing," she added. "This cannot be ruled out using the reports submitted to the FDA."
In the letter by Dr. Wysowski, she notes that 4 of the patients had Barrett's esophagus, which is a precursor of esophageal adenocarcinoma. "Physicians should avoid prescribing oral bisphosphonates to patients with Barrett's esophagus," she writes.
Dr. Wysowski also points out that esophagitis has been associated with oral bisphosphonates, usually when the drugs are not taken according to directions. "Crystalline material similar to ground alendronate tablets has been found in patients with erosive esophagitis, and persistent mucosal abnormalities have been noted in some of these patients, suggesting a potential for carcinogenic effects," she writes.
Merck said in a statement that data from its clinical trials and postmarketing reports do not suggest any association between alendronate and esophageal cancer. The company pointed out that alendronate has been marketed for 13 years, during which time more than 150 million prescriptions have been written in the United States alone. Merck also noted that its clinical database includes more than 17,000 patients, of whom about 3000 osteoporosis patients took alendronate for 3 to 5 years and about 800 patients took alendronate for 8 to 10 years.
Dr. Wysowski said that "the benefits of prescribing a drug should always be considered along with its risks. The oral bisphosphonates are used primarily for the treatment of osteoporosis in postmenopausal women to prevent fractures, and the drugs' benefits are well known."
Source: N Engl J Med. 2009;1360:89-90.