A second look at British registry data indicates that esophageal cancer may be more common after all in patients taking oral bisphosphonate drugs for long periods.

In a nested case-control analysis involving some 80,000 patients tracked for more than seven years on average, individuals diagnosed with esophageal cancer of were 1.93 times as likely (95% CI 1.37 to 2.70) to have received at least 10 prescriptions for oral bisphosphonates, compared with controls not having cancer, reported Jane Green, MD, DPhil, of the University of Oxford in England, and colleagues online in BMJ.

The likelihood of receiving at least one bisphosphonate prescription among esophageal cancer patients was 1.30 (95% CI 1.02 to 1.66) relative to controls, the researchers found.

The findings were especially remarkable because another research group conducting a case-control study of the same registry -- Great Britain's General Practice Research Database, containing records on some six million patients -- recently reported no increase in esophageal cancer rates in patients treated with bisphosphonates.

Green and colleagues explained the discrepancy by noting that mean observation time prior to diagnosis in the other analysis was substantially shorter, 4.5 versus 7.7 years.

Also, they noted, their study used five matched controls for each case, whereas the earlier study had equal numbers of cases and controls.

"Our study thus had the potential to include people with longer durations of bisphosphonate use and also had greater statistical power," Green and colleagues asserted.

An accompanying editorial by an FDA epidemiologist, Diane Wysowski, PhD, noted that links between bisphosphonates and esophageal cancer have been proposed for more than 15 years. (The editorial carried a disclaimer that it did not necessarily express the agency's official view.)

The FDA has collected a total of 68 case reports of esophageal cancer in patients taking bisphosphonates, half in the U.S. and the rest in Europe and Japan, but has not ordered label warnings. Prescribing information for oral bisphosphonates does include information on risks of other esophageal effects such as erosions and strictures, and dosing instructions are geared toward speeding the drugs through the esophagus.

The suggestion of a connection between these agents and esophageal cancer have prompted efforts at systematic research, including the new study.

Green and colleagues examined records of 2,954 patients with esophageal cancer, 2,018 patients with stomach cancer, and 10,641 with colon cancer, along with five controls for each of these cases matched for age, sex, observation time prior to diagnosis, and practice location.

About 3.1% of the esophageal cancer patients had received at least one bisphosphonate prescription before diagnosis, compared with 2.4% of the controls over a similar period (relative risk 1.30 after adjusting for smoking status, alcohol intake, and body mass index).

Rates of bisphosphonate use were similar in the stomach and colon cancer patients relative to controls, the researchers found.

In the esophageal cancer patients, the relationship with bisphosphonate use appeared to strengthen with the number of prescriptions and with the estimated duration of use.

Green and colleagues calculated a relative risk of 1.93 for receiving at least 10 prescriptions in cases versus controls, whereas esophageal cancer patients had virtually the same likelihood of receiving one to nine prescriptions as controls (RR 0.93, 95% CI 0.66 to 1.31).

Similarly, estimated duration of use (based on the distribution of prescriptions over time) of at least three years was linked to esophageal cancer with a relative risk of 2.24 (95% CI 1.47 to 3.42), but shorter duration was seen in about equal numbers of cases and controls.

These patterns were also not seen in the stomach or colorectal cancer patients.

"The association [in esophageal cancer patients] did not vary materially within subgroups defined by age, sex, smoking status, alcohol drinking, or body mass index; diagnosis of osteoporosis, previous fracture, or previous upper gastrointestinal disease; or prescription of nonsteroidal anti-inflammatory drugs, corticosteroids, or acid suppressant drugs," Green and colleagues added.

But the researchers stopped short of concluding that bisphosphonate treatment contributes to esophageal cancer, noting that they could not "rule out the possibility that the associations observed reflect other, unknown, factors that are linked to prolonged use of bisphosphonates and that also increase the risk of esophageal cancer."

Other limitations included the lack of data on the extent to which patients used drugs prescribed to them or on prescriptions received before entry into the database.

in the editorial, Wysowski didn't take a position on whether there is a causal link, noting that the evidence remains divided and weak. Even if there is such a connection, she wrote, "the incidence in the population would be expected to remain relatively low."

Still, she suggested that physicians consider the possibility of risk when prescribing the drugs and, when talking to patients, reiterate the importance of following the label directions for taking these drugs, which minimize the drugs' direct contact with the esophageal tract.

Wysowski also recommended that doctors urge patients to report difficulty swallowing or other gastrointestinal symptoms promptly.

Primary source: BMJ
Source reference:
Green J, et al "Oral bisphosphonates and risk of cancer of oesophagus, stomach, and colorectum: case-control analysis within a UK primary care cohort" BMJ 2010; DOI: link.

Additional source: BMJ
Source reference:
Wysowski D, "Oral bisphosphonates and oesophageal cancer" BMJ 2010; DOI: link.