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Upon completion of this activity, participants will be able to:

1. Report the antiproliferative actions of nitrogen-containing bisphosphonates.
2. Examine the association between bisphosphonate use and breast cancer.

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CME Released: 03/16/2010; Valid for credit through 03/16/2011

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March 16, 2010 — A third study, and the first to be published, has found a reduction in the risk for breast cancer among postmenopausal women taking bisphosphonates for the treatment of osteoporosis.

The new finding, reported in the March 2 issue of the British Journal of Cancer,comes from a case–control analysis of more than 6000 women in Wisconsin, half of whom were diagnosed with invasive breast cancer. It found that the use of bisphosphonates was associated with a 30% reduction in the risk for breast cancer.

"This large study provides new evidence that the use of bisphosphonates is associated with a potentially important reduction in breast cancer risk," lead author Polly Newcomb, PhD, MPH, head of the Cancer Prevention Program at the Fred Hutchinson Cancer Research Center in Seattle, Washington, said in a statement.

This reduction in breast cancer risk is similar to that already reported in 2 other studies, both of which were presented in December 2009 at the San Antonio Breast Cancer Symposium. One was an analysis of more than 150,000 postmenopausal women participating in several Women's Health Initiative studies, which found that bisphosphonate use reduced the risk for invasive breast cancer by 32%. The other involved an analysis of 4575 postmenopausal women in Israel, which found a 34% reduction.

At the time, the fact that a similar finding came out of 2 geographically different populations was described as "encouraging," by Theresa Guise, MD, professor of medicine and oncology at the Indiana University School of Medicine in Indianapolis, who was not involved in either study. However, she cautioned that "this needs to be confirmed by controlled clinical trials."

There was some discussion at that meeting about possible confounding factors. For example, women who were taking bisphosphonates for osteoporosis would have low bone-mineral density, and this in itself would indicate lower estrogen levels, which would influence the risk for breast cancer.

Accounting for Confounding Factors

In the latest study, Dr. Newcomb and colleagues emphasized that they were able to account for important confounders, such as body mass index and postmenopausal hormone use.

In addition, they analyzed the reasons for which bisphosphonates were prescribed, such as fractures, height loss, and physician-diagnosed osteoporosis. There was a suggestion that the use of bisphosphonates was associated with a reduced risk for breast cancer only among women reporting symptoms of bone loss, but this was not statistically significant.

"This association was not attributed to the primary indication for use, bone density loss, or fractures, which we and others have previously shown as a risk factor for breast cancer," the authors write.

These findings may reflect real benefits due to antitumor mechanisms.

The researchers therefore conclude that "these findings may reflect real benefits due to antitumor mechanisms" of bisphosphonates.

However, the association with a reduction in the risk for breast cancer was seen only among women who were not obese; they were not seen among obese women. This suggests that the inhibitory action of these drugs is related to some threshold effect of hormonal or other growth factors, which are known to be important etiological exposures in breast cancer, the researchers write in their paper.

"Obese women may have elevated estrogen levels, so underlying hormones may influence the ability of bisphosphonates to reduce breast cancer risk," Dr. Newcomb added in a statement.

How bisphosphonates could prevent breast cancer is not known, but these drugs have several actions that might be relevant; they have been shown to cause tumor apoptosis, inhibit angiogenesis, and prevent tumor-cell adhesions. "These drugs may affect cell function and be important in cell growth and death — specifically the death of tumors or even premalignant disease," Dr. Newcomb noted.

There has also been a large study reporting beneficial antitumor effects of bisphosphonates in women who already have breast cancer, which hints of this effect from another 2 studies. A recent editorial in the Journal of Clinical Oncology (2009;27:4043-4046) discussing these findings suggested that in the "seed and soil" hypothesis for cancer development, bisphosphonates might create an "unfavorable soil" in which the development of cancer cells is thwarted.

Dr. Newcomb and colleagues have disclosed no relevant financial relationships. Dr. Guise reports having served on advisory boards for Amgen, Lilly, Novartis, and Roche.

Br J Cancer. 2010;102:799-802. Abstract

Clinical Context

Study Highlights

• In this population-based case-control study, women aged 20 to 69 years, from Wisconsin's mandatory cancer registry, with a new diagnosis of invasive breast cancer from 2003 to 2006 were identified. Similarly aged community women were randomly selected as control subjects.
• The study included 2988 case patients with breast cancer and 3004 control subjects initially; however, 2936 patients and 2975 control subjects were used for analysis.
• Bisphosphonate use and potential confounders were assessed by interview.
• Current use of bisphosphonates was defined as use in the year before the reference year, and former users had taken bisphosphonates at any time before this period.
• Multivariable logistic regression models were used to estimate odds ratios and 95% confidence intervals and tests for linear trend across ordinal values of categoric variables.
• Women with breast cancer vs control subjects were more likely to have a family history of breast cancer, a college degree, to be older at first birth or nulliparous, to have gained more weight since age 18 years, and to use postmenopausal hormones.
• Results demonstrated that the odds ratio for breast cancer in current bisphosphonate users vs nonusers was 0.67 (95% confidence interval, 0.51 - 0.89).
• Increasing duration of use was associated with a greater reduction in risk (P for trend = .01).
• Risk reduction was observed in women who were not obese (P for interaction = .005).
• Limitations of this study included lack of adjustment for unmeasured or unknown confounding factors, inability to evaluate different types of bisphosphonate preparations that may have very different mechanisms of action, inability to evaluate breast cancer subgroups that may experience different responses to bisphosphonates, and prevalence of bisphosphonate use possibly lower than expected because the study population was limited to women younger than 70 years.

Clinical Implications

• Nitrogen-containing bisphosphonates affect cell function and survival duration by inhibiting the mevalonate pathway as well as inducing tumor apoptosis, inhibiting angiogenesis, and preventing tumor cell adhesion.
• Findings demonstrated that bisphosphonates are associated with a reduction in the risk for breast cancer.