Bisphosphonate Use May Be Linked to Reduced Risk of Colorectal Cancer

Bisphosphonates may hold promise for chemoprevention of colorectal cancer, based on a case-control study conducted in Israel, but randomized trials will be needed to confirm the results.

Among the 1,866 postmenopausal women studied, the use of a bisphosphonate for more than 1 year was associated with a 59% reduction in the risk of colorectal cancer, according to data reported at the meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

“It’s an association study. … One needs to be careful,” lead investigator Dr. Gad Rennert acknowledged in an interview. “It will call for randomized trials now to see that it really is true.”

The vast majority of women were taking alendronate, an oral bisphosphonate sold in the United States under the brand name Fosamax but also available generically. The apparent anticancer benefit became significant after 1 year of use and did not increase by much with longer duration.

“If it is shown to be true, then we are talking about a simple, cheap drug for short use,” commented Dr. Rennert, who is director of the National Israeli Cancer Control Center and a professor at Technion–Israel Institute of Technology in Haifa. “This is perfect … if it is supported by other studies.”

Last year, his research team found that bisphosphonate use was associated with a reduced risk of breast cancer, a finding that has since been verified by three other investigative groups. However, a concern with that association is the potential confounding by low estrogen levels, which would not only cause osteoporosis (and hence bisphosphonate use) but also reduce breast cancer risk.

The new study, therefore, looked at colorectal cancer, in which such confounding is unlikely. “This is a tumor that is not known to have strong hormonal influences, so estrogen deprivation is not necessarily known to be a protective situation for colorectal cancer,” he explained.

The study was conducted within the MECC (Molecular Epidemiology of Colorectal Cancer) study, which ascertained all incident cases of the disease diagnosed in northern Israel in 1998-2004 and matched those patients with unaffected individuals from the general population. Study participants were interviewed to collect information on their social, demographic, and medical characteristics.

The bisphosphonate analysis focused only on postmenopausal women: 933 who had experienced colorectal cancer and 933 who had not. They had mean ages of 71 and 72 years, respectively, according to results reported in a poster session.

Pharmacy records indicated that the women who had experienced colorectal cancer were less likely to have filled at least three bisphosphonate prescriptions (10% vs. 15%; P = .004) and to have used these agents for more than 1 year (6% vs. 11%; P less than .0001).

The analyses showed that compared with no bisphosphonate use, any use was associated with a significantly lower risk of colorectal cancer (odds ratio, 0.67).

When duration was considered, there was no benefit with less than 1 year of use. But there was significant benefit with at least 1 year of use (OR, 0.50) that was roughly the same with more than 2 years of use (OR, 0.51) and with more than 3 years of use (OR, 0.39).

This protection with relatively short use and its fairly stable magnitude thereafter bode well for using bisphosphonates for chemoprevention, according to Dr. Rennert.

“It’s important because if we ever want to use this drug for prevention, it actually means that we will be able to give it for a very short period only,” he explained. “So it’s not a drug that somebody will need to take for years or for a lifetime.”

In a multivariate model that took into account confounders (family history, sports activity, body mass index, vegetable intake, and use of aspirin, statins, postmenopausal hormones, vitamin D, and calcium), the use of bisphosphonates for more than 1 year was associated with a greater-than-one-half reduction in the risk of colorectal cancer (relative risk, 0.41; 95% confidence interval, 0.25-0.67).

Moreover, a similar risk reduction was seen for cancers of the right colon and cancers of the left colon individually. The risk of rectal cancer was also reduced, but not significantly so.

The investigators speculate that the anticancer benefit of bisphosphonates is related to their effects on the mevalonate metabolic pathway and inhibition of isoprenoid biosynthesis, which cancer cells require for growth-related processes.

Fosamax is currently approved by the U.S. Food and Drug Administration for the prevention of osteoporosis in postmenopausal women, for the treatment of osteoporosis in men and postmenopausal women, and for some other conditions compromising skeletal health.