BIPHOSPHONATES NOT LINKED TO ESOPHAGEAL CANCER

August 10, 2010 — Oral bisphosphonates are not significantly associated with esophageal or gastric cancer, according to a large cohort study from the United Kingdom published in the August 11 issue of the Journal of the American Medical Association.

The new study comes out about a year and a half after the US Food and Drug Administration (FDA) reported 23 cases of esophageal cancer between 1995 and 2008 in patients using alendronate and another 31 cases in patients using a variety of bisphosphonates in Europe and Japan.

These cases "possibly" indicate "risk of malignancy associated with bisphosphonate use," note the authors of the new study.

The authors took up the challenge of investigating the possible link between these cancers and oral bisphosphonates, the use of which has "dramatically" increased in recent years in the Western world.

The link was not proven in 2 recent smaller studies, say the authors, led by Chris Cardwell, PhD, from the Center for Public Health at Queen's University in Belfast, Northern Ireland.

The lack of a link to cancer stands in contrast to the proven link between the use of oral bisphosphonates and esophagitis.

"Oral bisphosphonates are known to cause serious esophagitis in some users," write Dr. Cardwell and his coauthors, who include Christian Abnet, PhD, from the Division of Cancer Epidemiology of the National Cancer Institute in Rockville, Maryland.

Esophagitis related to reflux is an "established risk factor for esophageal cancer through the Barrett pathway," they point out.

However, "it is not known whether bisphosphonate-related esophagitis can also increase cancer risk," they say.

The new study does not make a determination about bisphosphonate-related esophagitis; it only examines whether the use of these drugs increases cancer risk.

The study consisted of more than 80,000 patients, who were mostly women and had a mean age of 70 years, and found that the incidence of esophageal and gastric cancer combined was 0.7 per 1000 person-years of risk in both the bisphosphonate user and control (nonuser) cohorts.

Bisphosphonate users were defined as any patient receiving at least 1 prescription between 1996 and 2006.

Hazard ratios did not reveal any difference in the risk for the cancers between the user and nonuser cohorts.

Importantly, there also was no difference in risk for esophageal or gastric cancer with duration of bisphosphonate intake, say the authors.

The mean follow-up time was 4.5 and 4.4 years in the bisphosphonate and control cohorts, respectively.

"Our study, to my knowledge, has the longest duration of follow-up of any study so far into bisphosphonates and esophageal cancer," Dr. Cardwell told Medscape Medical News.

The study was funded by the Medical Research Council in the United Kingdom, which describes itself as an independent agency.

Addressing the Call

Diane Wysowski, PhD, from the FDA, published the first-ever report on cases of esophageal cancer in users of oral bisphosphonates in January 2009 (N Engl J Med. 2009;360:89-90).

A few months later, the journal published a series of letters responding to the report. In her response to those letters (N Engl J Med. 2009;360:1789-1792), Dr. Wysowski called for further study of the matter.

"Such studies should include a control group and be of sufficient size, with a sufficient duration of exposure and follow-up and with analyses of confounding variables," she writes.

When Medscape Medical News asked Dr. Cardwell whether he and his team had fully addressed Dr. Wysowski's requirements, he said: "I think our study adequately addresses these issues better than any study to date."

To explore any association between oral bisphosphonate use and esophageal and/or gastric cancer, Dr. Cardwell and colleagues used the UK General Practice Research Database, the "world's largest computerized database of anonymized longitudinal patient records."

Bisphosphonate users were matched with controls of the same age and sex.

The study authors looked at the bisphosphonate users in a number of ways, including by "any use" and by the type of bisphosphonate.

They also looked at users by the amount prescribed, which was converted into "defined daily dose" (DDD) figures. To investigate dose response, analyses were conducted for users by DDDs that were equivalent to 6-month, 1-year, 2-year, and 3-year supplies. In these analyses, the follow-up period started from the date that the user received the required number of prescriptions to achieve one of these supply periods.

Findings

Of the bisphosphonate users in the database during the study period, 41,826 had at least 6 months of follow-up and qualified, along with their matched controls, for the study analyses.

With regard to patients with "any bisphosphonate use" and their matched controls, there was no difference in combined esophageal and gastric cancer risk between the cohorts before (hazard ratio [HR], 1.00; 95% confidence interval [CI], 0.77 - 1.29) or after (0.96; 95% CI, 0.74 - 1.25) adjustment for potential confounders.

The included variables such as smoking, alcohol use, and body mass index.

The authors also did not find any evidence of an increase in cancer risk by duration of use of the drugs. The durations ranged from 6 months to 3 years and beyond.

For example, there was no difference in risk between the patients who used the drugs for about a year and their matched controls.

"After receipt of 365 bisphosphonate DDDs (equivalent to a 1-year supply), the risk of esophageal and gastric cancer combined (or esophageal cancer alone) was similar in the bisphosphonate and control cohorts (unadjusted HR, 0.94 [95% CI, 0.64 - 1.39] and 0.88 [95% CI, 0.55 - 1.43], respectively)," they write.

The authors also did some analyses to maximize follow-up periods. In one analysis, they only included patients whose date of first receipt of bisphosphonates was before the year 2000. This subset of 7082 patients had a mean follow-up of 6.8 years. Still, there was no evidence of an association between bisphosphonate use and cancer risk.

The type of bisphosphonate (nitrogen-containing bisphosphonates, alendronate, and non-nitrogen-containing bisphosphonates) also did not show any association with cancer risk. Dr. Cardwell said that alendronate was separated out because Dr. Wysowski's report mentions alendronate specifically.

The authors, mindful of the importance of reflux in this population, also looked at cancer risk among a subset of patients who had a history of gastroesophageal reflux disease. Again, there was no evidence of elevated risk among the users of bisphosphonates.

Too few patients had a history of Barrett's esophagus to examine the cancer rates in this subgroup, say the authors.

Previously, Dr. Wysowski advised that clinicians would be "prudent" to "advise against the use of these drugs in patients with Barrett's esophagus."

Dr. Cardwell neither endorsed nor refuted this recommendation. "I do not think that we have sufficient numbers of individuals with Barrett's esophagus in our cohort to comment directly on this issue."

The authors have disclosed no relevant financial relationships.

JAMA. 2010;304:657-663.