Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases


Bone involvement in metastatic cancer is a common clini-cal problem. The US Food and Drug Administration ap-proved zoledronic acid, a third-generation aminobis-phosphonate, for the treatment of patients with multiple myeloma and bone metastases from solid tumors. Zoledronic acid administered intravenously every 3 to 4 weeks reduces pain and the incidence of skeletal-related events, including clinical fracture, spinal cord compression, radiation to bone, and surgery to bone by 25% to 40%.1-3

Bisphosphonates are generally well tolerated, but are as-sociated with toxic effects, including osteonecrosis of the jaw, nephrotoxicity, and hypocalcemia. The incidence of osteone-crosis of the jaw increases with cumulative drug exposure from 1.5% for patients treated for 4 months to 12 months to 7.7% for patients treated for 37 months to 48 months.4 Bisphospho-nates are nephrotoxic, manifesting as elevated serum creati-nine levels. Hypocalcemia is rarely clinically symptomatic.5

The optimal dosing interval for zoledronic acid has not been determined. The standard dosing interval of every 4 weeks was derived empirically rather than from comparative studies or compelling pharmacodynamic data. Several stud-ies have addressed the dosing interval. In the ZOOM6 and OPTIMIZE-27 trials, patients with breast cancer and skeletal me-tastases were pretreated with zoledronic acid every 4 weeks for 9 months to 15 months and then randomized to receive zole-dronic acid every 4 weeks or every 12 weeks for 12 months. Nei-ther study showed significant differences in efficacy or toxic-ity for the 2 dosing regimens.

The hypothesis of this study was that zoledronic acid ad-ministered every 12 weeks for 2 years would be noninferior to zoledronic acid administered at the standard interval of ev-ery 4 weeks for 2 years among patients with metastatic breast cancer, metastatic prostate cancer, or multiple myeloma.

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