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Meta-Analysis Finds Benefits of Adjuvant Bisphosphonates for Postmenopausal Breast Cancer


Bisphosphonates can reduce the rate of breast cancer recurrence in bone, according to a meta-analysis of randomized trials of bisphosphonates as adjuvant therapy for women with early-stage breast cancer. Additional analyses showed that adjuvant bisphosphonates can also improve survival among women who are postmenopausal when the treatment begins.


The Lancet, July 23, 2015 (see the journal article).


Bisphosphonates are a class of drugs that are used to treat abnormally high blood calcium (hypercalcemia) and bone pain caused by some types of cancer. In breast cancer, bisphosphonates are used primarily to reduce bone loss (osteoporosis) and the risk of fracture among postmenopausal women with estrogen receptor-positive disease who receive aromatase inhibitors.

Because of their effects on bone, bisphosphonates have been studied for a potential role in reducing the risk of breast cancer recurrence in bone. Cancer cells released into the bloodstream by breast tumors may spread to bone and remain dormant there for extended periods. At some point, in a process that is not well understood, these cells may begin to divide and form small metastases. If bisphosphonates could protect against bone metastases, then these drugs might also improve survival. 

Clinical trials of bisphosphonates as adjuvant therapy for women with breast cancer have produced mixed results. Some, but not all, of these studies have suggested that the use of bisphosphonates can reduce rates of recurrence and death in certain women with breast cancer.

For example, a 2009 study found that adding the bisphosphonate zoledronic acid (Zometa®) to adjuvant hormone therapy improved clinical outcomes for premenopausal women with early-stage breast cancer. (Long-term results of this trial published in 2011 showed persistent benefits.) However, results published in 2011 from the AZURE trial showed that adding zoledronic acid to standard adjuvant therapy did not extend disease-free survival for women with stage II or III breast cancer.

The Study

To better understand the potential role of adjuvant bisphosphonate treatment for women with early-stage breast cancer, the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) conducted a meta-analysis of individual patient data for 18,766 participants in 26 randomized trials. These trials compared adjuvant bisphosphonate use for 2 to 5 years with no bisphosphonate use.

The primary endpoints of the study were any recurrence of breast cancer (which included breast cancer in either breast or at a distant site); a distant recurrence of breast cancer, that is, at a site other than in either breast; and death from breast cancer. Secondary outcomes included death without a recurrence of breast cancer; recurrence of the cancer in bone; recurrence in tissues other than bone or either breast; a new primary cancer in the other (contralateral) breast; and any bone fractures.

To determine whether any benefits of adjuvant bisphosphonate use were limited to certain subsets of women, the data were analyzed in groups according to several factors, including the women’s menopausal status, the class of bisphosphonate, the duration of treatment, tumor size, whether the cancer had spread to the lymph nodes, and whether the cancer was estrogen-receptor positive.

The study was funded by Cancer Research UK and the Medical Research Council.


Overall, the addition of adjuvant bisphosphonates was associated with a significant reduction in 10-year risk of bone recurrence (7.8 percent versus 9.0 percent). Although the authors observed reductions at 10 years for distant recurrence (20.4 percent versus 21.8 percent), and breast cancer mortality (16.6 percent versus 18.4 percent), these differences were of only borderline statistical significance.

When the study authors looked at the findings according to the trial participants’ menopausal status, they found that treatment with adjuvant bisphosphonates had no effect on any of the outcomes for premenopausal women. However, among the 11,767 postmenopausal women included in the analysis, the use of bisphosphonates was associated with statistically significant reductions in distant recurrence, in bone recurrence, and in death from breast cancer.

For example, during the first decade after diagnosis, 6.6 percent of postmenopausal women who used a bisphosphonate experienced a recurrence in bone, versus 8.8 percent of women who did not use the drug. During the same period, 14.7 percent of postmenopausal women who used a bisphosphonate died from breast cancer, versus 18.0 percent of women who did not use the drug.

The reductions in bone recurrence and the survival benefit for postmenopausal women did not depend on the class of bisphosphonate used, the duration of treatment, the size of the breast tumor, or whether the cancer had spread to the lymph nodes or was estrogen-receptor positive.

Among all participants, 3,453 women had a recurrence of cancer, and 2,106 women subsequently died of the disease. The risk of a recurrence of cancer and of dying of the disease did not differ between women who received bisphosphonates and those who did not.

Among the 501 women who died from causes other than breast cancer, the risk of death also did not differ between women who received bisphosphonates and those who did not.

Bisphosphonate use did not reduce the incidence of a new breast cancer developing in the contralateral breast. Bone fractures were reduced among women who received bisphosphonates compared with those who did not. Overall, the 5-year risk of fractures was 5.1 percent in women who were assigned to bisphosphonates and 6.3 percent in women who did not use them.  


Information about the occurrence of bone fractures was available for only 71 percent of the women included in the analysis (13,341 participants).

Additional studies are needed to help researchers determine whether different bisphosphonate regimens have different effects. “Much more reliable comparisons of different bisphosphonate regimens will emerge from ongoing trials that compare them directly,” the study authors wrote. The SWOG0307 trial, for example, is comparing three types of bisphosphonates in treating women who have undergone surgery for stage I, stage II, or stage III breast cancer. Reporting their initial results in abstract form, trial investigators said they found no differences in efficacy by type of bisphosphonate but there were differences in toxicities.

More research is also needed to help clarify the relationship between menopausal status and the response to bisphosphonates. “The complex interactions between reproductive hormones, tumor biology, bone cell function, and bone marrow stem cells could well change” as women progress from premenopause to postmenopause, the authors noted.


Jo Anne Zujewski, M.D., of NCI’s Cancer Therapy Evaluation Program (CTEP), who was not involved in the meta-analysis, noted that bisphosphonates have bone-protective effects and are generally well tolerated by patients.

“This study provides better evidence for prescribing bisphosphonates for women at an increased risk of a recurrence of breast cancer,” Dr. Zujewski commented. Physicians should consider the new results when making treatment decisions and in their discussions with patients about the risks and benefits of using bisphosphonates, she added.

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