Benefits of bisphosphonates on breast cancer outcomes

From the Malone Group, Public Health Sciences Division

Bisphosphonates are the most commonly prescribed and most effective class of drugs for the treatment of osteoporosis. In the United States, it is estimated that as many as one in seven postmenopausal women have been prescribed a bisphosphonate to prevent bone loss. Additional potential beneficial effects of this class of drugs in cancer treatment gained attention after preclinical studies revealed that bisphosphonates may exhibit antitumor activity. Subsequent studies revealed beneficial impacts in treatment of bone metastases, the most common site of metastatic breast cancer. This has been followed by studies on the efficacy of bisphosphonates in preventing breast cancer recurrences. Breast cancer continues to be a major burden, with more than a quarter of a million women in the United States expected to be diagnosed this year. Thus, the dual benefits of bisphosphonates on bone loss and cancer-related events may have a significant impact on women’s health. In a recently published study in Cancer Epidemiology, Biomarkers & Prevention, Dr. Kathleen Malone and researchers in the Public Health Sciences Division at Fred Hutch report that in women with invasive breast cancer, the use of bisphosphonates for treatment of osteoporosis has significant beneficial effects on breast cancer outcomes.

Past studies on the association of bisphosphonate use and breast cancer-related outcomes have had somewhat mixed results and there remain questions about which patient subgroups benefit and for which outcomes. For example, pooled analyses of randomized controlled trials of bisphosphonates in breast cancer patients recently found beneficial effects on breast cancer outcomes in postmenopausal, but not premenopausal, women, and for bone but not for non-bone distant recurrences. In the new study, the authors aimed to examine whether premenopausal women might benefit from bisphosphonate use, and in addition to postmenopausal women, they also included pre- and perimenopausal women in the analyses. They also sought to determine whether bisphosphonate use is associated with beneficial effects on metastases outside of bone.

The authors utilized data from a population-based prognostic cohort study and included over 1,800 women diagnosed with invasive breast cancer between ages 45 to 79 in their analyses. The women were followed until a recurrence, a new primary breast cancer, a non-breast primary cancer, death, or the end of study follow-up. A major strength of this study is the extended follow-up time, with nearly 12 years for recurrences and 15 years for mortality in women without events, which allowed the researchers to assess potential long-term benefits of bisphosphonates that might not have been captured in previous studies of shorter duration. The authors classified women according to whether or not they had used bisphosphonates use post-diagnosis, and according to use details such as duration and recency. Women in this study were first diagnosed before bisphosphonates were introduced as a breast cancer therapy, and women who were prescribed bisphosphonates for the treatment of skeletal metastases were excluded from the analyses.

Graphical representation of hazard ratios.
Association of post-diagnosis bisphosphonate use with breast cancer events. Hazard ratios and 95% confidence intervals are shown for use of bisphosphonates for at least one year and breast cancer mortality (HR, 0.40; 95% CI, 0.23-0.69) and for any use of bisphosphonate following breast cancer diagnosis and any breast cancer event (recurrence or second primary breast cancer; HR, 0.65; 95% CI, 0.47-0.90). Image by Maggie Burhans

Any use of bisphosphonates post-diagnosis was found to be significantly associated with a 35% decreased risk for any second breast cancer event (see Figure). An even greater 50% reduction in risk for breast cancer recurrence or second primary breast cancer was observed in women who started bisphosphonate use within 3 years after breast cancer diagnosis. There was also a significant association of bisphosphonate use and breast cancer mortality, when used for at least one year, the risk of dying from breast cancer was reduced by 60% (see Figure).

A greater reduction in risk was observed in the non-postmenopausal group than in the postmenopausal group, although the reduction in risk was significant in both groups and the numbers of non-postmenopausal women were small. Although not statistically significant, there were suggestive large magnitude reductions in risk of both bone and non-bone first distant recurrences.

When considering the previous and current study results together, Malone indicated that, “we were struck by the fact that the magnitude of risk reductions seemed to be considerably greater in the observational studies.” While limitations inherent to an observational design could well be a contributing factor, an additional explanation that could in part reconcile these differences is that the benefits of this class of drugs may depend on a woman’s bone density status. As explained in more detail by Malone, “The randomized controlled trials treated breast cancer patients with bisphosphonates regardless of bone density status, and thus included many women with normal density.” This differs from the women included in the observational studies, “most of which (including our own) largely predated the introduction of bisphosphonates as adjuvant breast cancer therapy, and almost exclusively focus on populations given bisphosphonates for low bone density,” said Malone.

Moving forward, Malone indicated that follow-up studies on the association between bisphosphonates and breast cancer progression and mortality are needed. “Our study provides timely data on oral bisphosphonates used widely for the treatment of osteoporosis but which have received sparse attention in terms of potential therapeutic benefits for breast cancer. These medications warrant further investigation for their potential benefits in relation to outcomes after breast cancer,” said Malone. Questions that remain include understanding whether the potential benefits of this class of drugs are modified by bone density and whether there are potential benefits in premenopausal women. And finally, although it is hypothesized that low bone density may be an important factor, much remains unknown about possible predictors of bisphosphonate efficacy as a breast cancer therapy and even as to the exact mechanisms through which this class of drugs influences the course of breast cancer.

Also contributing to this research from the Fred Hutch were Mr. David Doody and Drs. Larissa Korde, Li Hsu, and Peggy Porter.

Korde LA, Doody DR, Hsu L, Porter PL, Malone KE. 2017. Bisphosphonate use and risk of recurrence, second primary breast cancer, and breast cancer mortality in a population-based cohort of breast cancer patients. Cancer Epidemiol Biomarkers Prev. doi: 10.1158/1055-9965.EPI-17-0556.

This research was supported by the National Cancer Institute.