Effect of bisphosphonate use on risk of postmenopausal breast cancer: results from the randomized clinical trials of alendronate and zoledronic acid

Abstract

Importance: Studies have shown that bisphosphonates may have antitumor and antimetastatic properties. Recently, observational studies have suggested a possible protective effect of bisphosphonates on breast cancer, but the effect of bisphosphonate use on risk of breast cancer has not been tested in randomized trials.

Objective: To assess the relationship of postmenopausal breast cancer incidence and bisphosphonate use using data from 2 randomized (1:1), double-blind, placebo-controlled trials.

Design, setting, and participants: The Fracture Intervention Trial (FIT) randomly assigned 6459 women aged 55 to 81 years to alendronate or placebo for a mean follow-up of 3.8 years. The Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT) randomly assigned 7765 women aged 65 to 89 years to annual intravenous zoledronic acid or placebo for a mean follow-up of 2.8 years. Data were collected at clinical centers in the United States (FIT and HORIZON-PFT) and in Asia and the Pacific, Europe, North America, and South America (HORIZON-PFT). Women, in either study, with recurrent breast cancer or who reported a history of breast cancer were excluded from analyses. In each trial, a blinded review was conducted of each cancer adverse event report to verify incident invasive breast cancer cases. The primary analysis compared events in the active vs placebo group using a log-rank test.

Intervention: Alendronate vs placebo (FIT) or zoledronic acid vs placebo (HORIZON-PFT).

Main outcomes and measures: Hazard ratio for incident breast cancer in the bisphosphonate treatment group compared to the placebo group.

Results: There was no significant difference in the rate of breast cancer in FIT: 1.5% (n = 46) in the placebo group and 1.8% (n = 57) in the alendronate group (hazard ratio [HR], 1.24 [95% CI, 0.84-1.83]). In HORIZON-PFT, there was also no significant difference: 0.8% (n = 29) in the placebo group and 0.9% (n = 33) in the zoledronic acid group (HR, 1.15 [95% CI, 0.70-1.89]). There was also no significant difference when the data from FIT and HORIZON-PFT were pooled (HR, 1.20 [95% CI, 0.89-1.63]).

Conclusions and relevance: These 2 randomized clinical trials do not support the findings from observational research. Contrary to the results from observational studies, we found that 3 to 4 years of bisphosphonate treatment did not decrease the risk of invasive postmenopausal breast cancer.

Trial registration: clinicaltrials.gov Identifier: NCT00049829 (HORIZON-PFT).

Figure 1

Fracture Intervention Trial (FIT) Participant Flow Diagram ^aAdherence was measured using pill counts at each study visit and the participant’s self-reported therapy record. High study treatment adherence was defined as greater than 70% (of expected) study treatment use on the basis of pill counts and 75% or greater use of nonstudy concomitant medications on the basis of therapy.

Figure 2

Cumulative Incidence of Breast Cancer in the Fracture Intervention Trial (FIT)

Figure 3. Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly–Pivotal Fracture Trial (HORIZON-PFT) Participant Flow Diagram

^aParticipants were randomized to either an annual intravenous administration of zoledronic acid 5 mg or placebo for 3 years (received at baseline, month 12, and month 24). High adherence was defined as receipt of all 3 treatment (zoledronic acid or placebo) doses. Low adherence was defined as receipt of 1 or 2 treatment doses.

Figure 4

Cumulative Incidence of Breast Cancer in Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly–Pivotal Fracture Trial (HORIZON-PFT)