Adjuvant Bisphosphonates in Early Breast Cancer: Practice-Changing Findings?

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Adjuvant use of bisphosphonates reduced the risk of bone recurrence by 34% and the risk of breast cancer death by 17% in postmenopausal women with early breast cancer in a large meta-analysis conducted by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). The potentially practice-changing findings were presented at the 2013 San Antonio Breast Cancer Symposium by lead author Robert Coleman, MD, of University of Sheffield, United Kingdom.1

Adjuvant bisphosphonates achieved reductions in bone recurrence and breast cancer deaths in postmenopausal women regardless of estrogen receptor status, nodal status, and whether or not they received chemotherapy. However, no effects on disease outcome were observed in premenopausal women.

“In addition to the 3.1% absolute reduction in breast cancer-related mortality, adjuvant bisphosphonates led to an absolute reduction of 2.3% in all-cause mortality at 10 years,” Dr. Coleman stated.

EBCTCG Meta-analysis

The EBCTCG’s meta-analysis was prompted by evidence from previous trials suggesting that bisphosphonates reduce distant metastases, predominantly in bone. This effect is largely confined to postmenopausal women.

“Bisphosphonates interrupt the vicious cycle of bone destruction.” Dr. Coleman said. “They are thought to improve disease outcomes in women with low levels of reproductive hormones, such as those in naturally induced or treatment-induced menopause at start of treatment, and they have possible adverse effects on nonbone recurrence in premenopausal women.”

The meta-analysis was based on individual patient data from 36 randomized controlled trials comparing adjuvant use of a bisphosphonate vs no bisphosphonate or placebo; a total of 22,982 women were enrolled in these trials. Seven of the trials compared clodronate vs no bisphosphonate or placebo (n = 5,174) and 29 looked at aminobisphosphonates (n = 17,808). Two-thirds of women on aminobisphosphonates were taking zoledronic acid, about one-quarter received ibandronate, and 11% were on other aminobisphosphonates.

Primary Endpoints

Primary outcomes were time to any recurrence, time to first distant recurrence, and breast cancer mortality. Among all women, no significant difference was observed in the 10-year rate of all breast cancer recurrences or distant recurrences, including recurrence in bone. The recurrence rate was 25.4% in those who took bisphosphonates vs 26.5% in the nonbisphosphonate group; distant recurrence rates were 20.9% and 22.3%, respectively.

Bone recurrence rate was 6.9% and 8.4%, respectively, and the nonbone recurrence rate was 15% in both study arms. The overall rates of local recurrence and contralateral breast cancer were quite similar in both arms at 10 years.

However, among 11,036 postmenopausal women (including women aged more than 55 years if menopausal status was unknown), bisphosphonates achieved a highly significant difference in distant recurrence (18.4% in women on bisphosponates vs 21.9% on no bisphosphonates, P = .0003) and in bone recurrence (5.9% and 8.8%, respectively, P < .00001) vs no bisphosphonates. No significant effect of bisphosphonates was observed on nonbone recurrence.

Additional Data

Among all participants, the 10-year rates of breast cancer mortality and non–breast cancer mortality did not differ significantly.

In postmenopausal women, the 10-year rate of breast cancer mortality was 15.2% for those treated with bisphosphonates vs 18.3% for no bisphosphonates (P = .004), and the 10-year rate of all-cause mortality was 21.5% vs 23.8%, respectively (P = .007).

“Similar effects were seen on bone recurrence irrespective of type of bisphosphonate,” Dr. Coleman noted. ■

Disclosure: Dr. Coleman has given expert testimony for Novartis, and has received honoraria from Amgen.


1. Coleman R, Gnant M, Paterson A, et al: Effects of bisphosphonate treatment on recurrence and cause-specific mortality in women with early breast cancer: A meta-analysis of individual patient data from randomized trials. 2013 San Antonio Breast Cancer Symposium. Abstract S4-07. Presented December 12, 2013.

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