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.

BACKGROUND: Letrozole is a proven and effective adjuvant therapy in postmenopausal women with hormone receptor-positive (HR(+)) 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(+) 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 < -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 (+2.72%) but decreased in the delayed ZOL group (-2.71%); the absolute difference between groups was significant (5.43%; P < .0001). Across all subgroups, patients receiving immediate ZOL had significantly increased LS and TH BMD vs. those who received delayed ZOL (P < .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(+) EBC receiving adjuvant letrozole, regardless of BMD status at baseline.

Integrated analysis of zoledronic acid for prevention of aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole.

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.

Effective inhibition of aromatase inhibitor-associated bone loss by zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: ZO-FAST Study results.

BACKGROUND: Letrozole is safe and effective in postmenopausal women with estrogen receptor-positive early breast cancer, but long-term aromatase inhibitor use may cause bone loss and increase fracture risk. This study evaluated an immediate or delayed strategy of bone protection therapy with zoledronic acid. METHODS: A total of 1065 patients who were receiving adjuvant letrozole were randomized to immediate-start or delayed-start zoledronic acid (4 mg intravenously biannually for 5 years). The delayed group received zoledronic acid if lumbar spine or total hip T-score decreased below -2.0 or when a nontraumatic fracture occurred. The primary endpoint was change in lumbar spine bone mineral density (BMD) at Month 12. Secondary endpoints included changes in total hip BMD, serum bone turnover markers, and safety at Month 12. RESULTS: Lumbar spine BMD increased from baseline in the immediate arm, while it decreased from baseline in delayed-arm patients. At Month 12, the differences between the groups in lumbar spine and total hip BMD were 5.7% (P < .0001; 95% confidence intervals [CI], 5.2% to 6.1%), and 3.6% (P < .0001; 95% CI, 3.3 to 4.0%), respectively. Both regimens were well tolerated with few serious adverse events. Bone pain was higher in the immediate group, as expected, because some patients experienced acute-phase reactions after zoledronic acid infusion. CONCLUSIONS: At 12 months, immediate zoledronic acid therapy prevented bone loss in postmenopausal women who were receiving adjuvant letrozole.