BIPHOSPHONATES FOR OSTEOPOROSIS REDUCE RISK FOR BREAST CANCER BY 30%

July 20, 2010 — Two retrospective studies suggesting that postmenopausal women who take oral bisphosphonates for osteoporosis have a reduced risk for breast cancer were published online June 21 in the Journal of Clinical Oncology.

Both studies were presented at the San Antonio Breast Cancer Symposium last year, as reported by Medscape Medical News at the time.

A third similar study was published earlier this year in the British Journal of Cancer.

Interestingly, all 3 studies show that bisphosphonate use reduces the relative risk for breast cancer by approximately 30%, writes Michael Gnant, MD, from the Medical University of Vienna, Austria, in an accompanying editorial.

However, because these were all retrospective studies, with confounders that might not have been controlled, these findings should "be viewed as hypothesis generating and not practice changing at this time," he writes.

"At this point, it would be premature to recommend the use of oral bisphosphonates to prevent breast cancer in all postmenopausal women," Dr. Gnant says.

"However, it is not unreasonable to consider the potential anticancer benefits of bisphosphonate therapy, in addition to its bone-protecting effects, when evaluating treatment options in women with postmenopausal osteoporosis, especially considering that bisphosphonates are well tolerated in this population," he concludes.

Data from the WHI Study

The largest of the studies, by Rowan Chlebowski, MD, PhD, from the University of California, Los Angeles, and colleagues, evaluated data from the Women's Health Initiative (WHI). Of the 154,768 participants, 2,816 postmenopausal women were taking oral bisphosphonates when they entered the study (90% were taking alendronate, 10% etidronate).

In carrying out their analysis, the researchers controlled for bone mineral density (BMD); low BMD is an indication for bisphosphonate use and is associated with a lower incidence of breast cancer.

After a mean of 7.8 years of follow-up, there was a significant reduction in the incidence of invasive breast cancer in women who had taken oral bisphosphonates (32% reduction; P < .01), and in the incidence of estrogen-receptor (ER)-positive invasive cancers (30% reduction; P = .02). A similar but nonsignificant trend was seen in ER-negative breast cancer.

"The findings are consistent with a direct effect of bisphosphonates on slowing or inhibiting growth of preclinical but already established breast cancers," Dr. Chlebowski and colleagues write.

However, there was a significant increase in the incidence of ductal carcinoma in situ (DCIS) in women taking oral bisphosphonates.

"The clinical significance of this finding is uncertain, as much DCIS either does not develop into invasive breast cancer or does so with such delay to question clinical relevance," the researchers note.

"In any event, if bisphosphonates prevent in situ cancers from progressing to an invasive stage or influence only invasive cancer, a relative increase in in situ cancers could occur," they speculate. They add that a similar observation came out of the Study of Tamoxifen and Raloxifene (STAR) in breast cancer prevention; although there was a significant decrease in invasive breast cancer with both drugs, there was a strong trend toward an increase in in situ cancers with raloxifene.

"As oral bisphosphonates are in widespread and increasing use in clinical practice, these findings have public health implications," Dr. Chlebowski and colleagues conclude.

Similar Findings From 2 Other Studies

The second study comes from Gad Rennert MD, PhD, from the Clalit Health Services National Cancer Control Center in Haifa, Israel, and colleagues.

They analyzed the pharmacy records of 4039 postmenopausal women, 1832 of whom were diagnosed with breast cancer; the remainder acted as control subjects. They found that 10.5% of patients and 14.8% of control subjects had used oral bisphosphonates, most commonly alendronate.

Dr. Rennert and colleagues calculated that taking bisphosphonates for a year or more reduced the risk for breast cancer by 28%.

In addition, the tumors detected in bisphosphonate users were different from those in nonusers; they had better prognostic markers, and there were significantly more ER-positive tumors and significantly fewer poorly differentiated tumors.

"The data support a possible significant protective effect of the use of bisphosphonates against breast cancer development," Dr. Rennert and colleagues conclude.

The study did not control for low BMD, which is known to be associated with a lower risk for breast cancer. But the finding that bisphosphonates need to be taken for a year before a preventive effect on breast cancer is seen "supports the notion that the effect seen is a reflection of the drug itself, and not the underlying condition of low bone density or osteoporosis," they note.

The third study, published earlier this year in the British Journal of Cancer (2010;102:799-802), comes from Polly Newcomb, PhD, MPH, and colleagues from the University of Wisconsin in Madison. They analyzed data for 2936 women with breast cancer and 2975 control subjects, and found a 33% reduction in the risk for breast cancer among current bisphosphonate users.

"Although this is a smaller study, this represents an additional independent report of the correlation between bisphosphonate use and decreased cancer risk," Dr. Gnant notes in his editorial.

"These significant correlations are profound and intriguing," he points out. "They suggest that bisphosphonate-induced changes to the microenvironment surrounding potential cancer cells can be exploited in preventing breast cancer."

Effect Also Seen in Breast Cancer Patients

Dr. Gnant points out that the potential anticancer effects of bisphosphonates have also been reported in several studies of women who already have breast cancer, including one by his team. In that study, the Austrian Breast and Colorectal Cancer Study Group trial (n = 1803), and in ZO-FAST (Zometa-Femara Adjuvant Synergy Trial; n = 1065), the intravenous bisphosphonate zolendronic acid reduced cancer recurrence in bone and nonbone sites, including contralateral breast cancer, he notes.

There were also 2 previous studies of the oral bisphosphonate clodronate in women with breast cancer (total n = 1371) that showed a delay in the development of bone metastases and an improvement in disease-free and overall survival.

In addition, laboratory studies suggest that bisphosphonates have both direct and indirect anticancer effects, including effects on cancer cell apoptosis, inhibition of cancer cell adhesion and extravasation, inhibition of angiogenesis, and activation of immune cells with anticancer activity.

It is possible that these are a class effect of the bisphosphonates, Dr. Gnant writes.

All of these researchers and the editorialist urge further study in this field, because, as Dr. Gnant writes, "the potential implications would be far-reaching."

Dr. Gnant reports acting as a consultant/advisor, and/or receiving honoraria and/or research funding from AstraZeneca, Novartis, Pfizer, Roche, and Sanofi-Aventis. Dr. Chlebowski reports acting as a consultant/advisor for AstraZeneca, Novartis, Pfizer, Amgen, and Eli Lilly, and receiving honoraria from AstraZeneca, Novartis, and Amgen. Several coauthors report links with Novartis and Merck, and one coauthor holds stock in Merck. Dr. Rennert, Dr. Newcomb, and their colleagues have disclosed no relevant financial relationships.

J Clin Oncol. Published online June 21, 2010. Abstract, Abstract, Abstract