Immediate Administration of Zoledronic Acid Reduces Aromatase Inhibitor–Associated Bone Loss in Postmenopausal Women With Early Breast Cancer: 12-Month Analysis of the E-ZO-FAST Trial

Abstract

Aromatase inhibitors (AIs), an increasingly common adjuvant treatment option for postmenopausal women with hormone receptor-positive early breast cancer, are associated with bone loss that can impair patient quality of life. This study (E-ZO-FAST; Clinical Trials Identifier: NCT00171314) demonstrates that initiation of zoledronic acid therapy concurrent with adjuvant AI treatment improved skeletal health compared with zoledronic acid therapy initiated after deterioration of bone health. Background: Letrozole is a proven and effective adjuvant therapy in postmenopausal women with hormone receptor-positive (HR ϩ ) early breast cancer (EBC). As with other aromatase inhibitors (AIs), long-term letrozole administration is associated with decreased bone mineral density (BMD) and increased fracture risk. This study compared potential bone-protecting effects of immediate vs. delayed administration of zoledronic acid (ZOL) in patients with EBC receiving adjuvant letrozole. Patients and Methods: Patients with HR ϩ EBC in whom adjuvant letrozole treatment was initiated (2.5 mg/day for 5 years) were randomized to immediate ZOL treatment (immediate ZOL) or delayed ZOL treatment (delayed ZOL) (both at 4 mg every 6 months). Patients in the delayed ZOL group received ZOL only for a BMD T-score that decreased to Ͻ -2.0 (lumbar spine [LS] or total hip [TH]) or for fracture. The primary endpoint was percentage change in the LS BMD at month 12. Patients were stratified by established or recent postmenopausal status, baseline T-scores, and adjuvant chemotherapy history. Results: At 12 months, the LS BMD increased in the immediate ZOL group (ϩ2.72%) but decreased in the delayed ZOL group (-2.71%); the absolute difference between groups was significant (5.43%; P Ͻ .0001). Across all subgroups, patients receiving immediate ZOL had significantly increased LS and TH BMD vs. those who received delayed ZOL (P Ͻ .0001). Differences in fracture incidence or disease recurrence could not be ascertained because of early data cutoff and low incidence of events. Adverse events were generally mild, transient, and consistent with the known safety profiles of both agents. Conclusion: Immediate ZOL administration effectively prevented BMD loss and increased BMD in postmenopausal women with HR ϩ EBC receiving adjuvant letrozole, regardless of BMD status at baseline.

Bone Homeostasis and Breast Cancer: Implications for Complex Therapy and the Maintenance of Bone Integrity

“…In the Z-FAST study, 602 postmenopausal patients receiving adjuvant letrozole therapy were randomized to upfront vs. delayed zoledronate therapy (in the delayed group therapy was started if the BMD decreased to −2.0) [36]. In the companion studies ZO-FAST and E-ZO-FAST, similar results were found, despite the fact that the 3 studies included patients from different geographical areas [37,38]. In the ABCSG-12 trial, the BMD was studied in premenopausal women treated with goserelin and either tamoxifen or anastrozole, with or without zoledronate.…”

Zoledronic acid for treatment of osteopenia and osteoporosis in women with primary breast cancer undergoing adjuvant aromatase inhibitor therapy: a 5-year follow-up

“…These trials evaluated whether upfront ZA administration for patients starting AI therapy would lead to BMD preservation and reduced fracture incidence, compared with delayed ZA administration (i.e., after T-score fell below −2.0 or fracture was sustained). An improvement in BMD was observed in patients receiving early ZA, though reduction in fracture risk was not seen in the studies assessing this endpoint [11][12][13]. The absence of fracture risk reduction has made routine early administration of ZA a controversial practice.…”

“…Further, ZA has been shown to directly inhibit breast cancer cell invasion in a dose-dependent manner, making it a natural choice in postmenopausal women with a history of breast cancer who are at risk for ongoing bone loss. A North Central Cancer Treatment Group (N03CC) trial and the Zometa-Femara Adjuvant Synergy sister trials (Z-FAST, ZO-FAST, and E-ZO-FAST) were designed to investigate whether ZA would be effective for prevention of bone loss and fractures in postmenopausal women without osteopenia or osteoporosis (i.e., T-score ≥−2.0) [11][12][13][14]. These trials evaluated whether upfront ZA administration for patients starting AI therapy would lead to BMD preservation and reduced fracture incidence, compared with delayed ZA administration (i.e., after T-score fell below −2.0 or fracture was sustained).…”

“…Zoledronic acid (ZA) is a potent intravenously administered bisphosphonate that has been used to promote skeletal stability in patients at particularly high risk for fracture, including those with cancer metastatic to the bone and multiple myeloma. ZA is also known to preserve BMD in postmenopausal women with T-scores better than −2.0 who are undergoing adjuvant AI therapy [11][12][13][14].…”

Cost–Utility of Adjuvant Zoledronic Acid in Patients with Breast Cancer and Low Estrogen Levels

“…Many of the completed trials investigated adjuvant bisphosphonate therapy for its effect on bone health [7][8][9][10][11][12] . Those trials often compared early with delayed bisphosphonate therapy rather than adjuvant za with no bisphosphonate, or considered primary endpoints that were unrelated to breast cancer outcomes.…”