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Breast Cancer

Integrated Analysis of Zoledronic Acid for Prevention of Aromatase Inhibitor–Associated Bone Loss in Postmenopausal Women with Early Breast Cancer Receiving Adjuvant Letrozole

^aMagee-Womens Hospital, Pittsburgh, Pennsylvania, USA; ^bUniversity Hospital of South Manchester NHS Foundation Trust, Academic Department of Surgery, Education and Research Center, Wythenshawe, Manchester, United Kingdom; ^cAcademic Unit of Clinical Oncology, Weston Park Hospital, Sheffield, United Kingdom; ^dSouth Carolina Oncology Associates, Columbia, South Carolina, USA; ^eEast Valley Hematology & Oncology Medical Group, Burbank, California, USA; ^fPhilipps-Universität Marburg, University Hospital of Giessen and Marburg, GmbH, Marburg, Department of Gynecology, Marburg, Germany; ^gNovartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA; ^hMayo Clinic Jacksonville, Jacksonville, Florida, USA

Key Words. Breast neoplasm • Zoledronic acid • Aromatase inhibitor • Osteoporosis

Correspondence: Adam Brufsky, M.D., Ph.D., Magee-Womens Hospital, Suite 4628, 300 Halket Street, Pittsburgh, Pennsylvania 15123, USA. Telephone: 412-641-6500; Fax: 412-641-2296; e-mail: brufskyam{at}upmc.edu

Received October 26, 2007; accepted for publication April 8, 2008.

Disclosure: Study drugs (zoledronic acid and letrozole) were provided by Novartis Pharmaceuticals Corporation. A.B. has acted as a consultant for and has a financial interest in Novartis. N.B. has acted as a consultant for Novartis, AstraZeneca, and Pfizer. R.C. has acted as a consultant for, has a financial interest in, and has received research support from Novartis. S.E. owns stock in Novartis. No other potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.

Background. The interim (12-month) results of two similarly designed, ongoing studies (the Zometa®-Femara® Adjuvant Synergy Trials [Z-FAST and ZO-FAST]) suggest that zoledronic acid (4 mg intravenously every 6 months) when initiated with adjuvant letrozole increases bone mineral density (BMD) of the lumbar spine (LS) in postmenopausal women with early-stage breast cancer compared with patients who receive zoledronic acid only when bone loss became clinically significant or a fragility fracture occurred.

Methods. An integrated analysis was performed to maximize the value of the large pool of data from the two studies in answering clinically relevant questions. The primary objective was to compare the change in LS BMD at month 12. Secondary objectives included comparing (a) the change in total hip (TH) BMD, (b) changes in bone turnover marker concentrations, (c) time to disease recurrence, and (d) safety at month 12.

Findings. The integrated analysis included 1,667 patients. At month 12, LS BMD was 5.2% higher in the upfront group than in the delayed group; TH BMD was 3.5% higher. N-telopeptide and bone-specific alkaline phosphatase concentrations decreased by 21.3% and 12.8% in the upfront group and increased by 21.7% and 24.9% in the delayed group, respectively (p < .0001 for intergroup comparisons). Fewer patients receiving upfront zoledronic acid experienced disease recurrence than patients in the delayed group—seven patients (0.84%) versus 17 patients (1.9%) (p = .0401). Fracture rates were similar. No confirmed osteonecrosis of the jaw was reported.

Conclusions. The results of this analysis strengthen the statistical validity of the preliminary results of the Z-FAST and ZO-FAST studies, showing that upfront zoledronic acid prevents aromatase inhibitor–associated bone loss more effectively than delayed-start zoledronic acid in postmenopausal women with early-stage breast cancer receiving letrozole. Additionally, disease recurrence appears to be lower with upfront zoledronic acid, but further follow-up is needed to confirm these interim results.

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