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Original Investigation |

Effect of Bisphosphonate Use on Risk of Postmenopausal Breast Cancer:  Results From the Randomized Clinical Trials of Alendronate and Zoledronic Acid

Trisha F. Hue, PhD, MPH1; Steven R. Cummings, MD1,2; Jane A. Cauley, DrPH3; Douglas C. Bauer, MD1; Kristine E. Ensrud, MD4; Elizabeth Barrett-Connor, MD5; Dennis M. Black, PhD1
[+] Author Affiliations
1San Francisco Coordinating Center, Department of Epidemiology and Biostatistics, University of California, San Francisco
2California Pacific Medical Center Research Institute, San Francisco
3Center for Aging and Population Health, Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania
4Department of Medicine, University of Minnesota, Minneapolis
5Division of Epidemiology, Department of Family and Preventive Medicine, University of California, San Diego
JAMA Intern Med. 2014;174(10):1550-1557. doi:10.1001/jamainternmed.2014.3634.
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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).

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Figures

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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.

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Figure 2.
Cumulative Incidence of Breast Cancer in the Fracture Intervention Trial (FIT)
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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.

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Figure 4.
Cumulative Incidence of Breast Cancer in Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly–Pivotal Fracture Trial (HORIZON-PFT)
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