Effective inhibition of aromatase inhibitor‐associated bone loss by zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole

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. Cancer 2008. © 2008 American Cancer Society. Aromatase inhibitors may be associated with bone loss and higher incidence of fracture; this 5‐year study was designed to evaluate the effectiveness of immediate versus delayed bone protection therapy with zoledronic acid. After 1 year, results from the ZO‐FAST trial indicated that immediate 4 mg zoledronic acid therapy administered on a 6‐month schedule prevented bone loss in postmenopausal women who were receiving adjuvant letrozole for early stage breast cancer.