A phase I dose-ranging trial of monthly infusions of zoledronic acid for the treatment of osteolytic bone metastases

James R. Berenson, Robert A. Vescio, Lee S. Rosen, Joseph M. Vonteichert, Margie Woo, Regina Swift, Allison Savage, James R. Berenson, Robert A. Vescio, Lee S. Rosen, Joseph M. Vonteichert, Margie Woo, Regina Swift, Allison Savage, Elise Givant, Mieke Hupkes, Harold Harvey, Allan Lipton

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Abstract

Bisphosphonates are potent inhibitors of bone resorption and provide a therapeutic benefit for patients with bone metastases. Zoledronic acid is a highly potent, nitrogen-containing bisphosphonate. In the present trial, we assessed the safety and tolerability of increasing doses of zoledronic acid and its effects on urinary markers of bone resorption in cancer patients with bone metastases. Fifty-nine cancer patients with bone metastases were enrolled sequentially into one of 8 treatment groups in the core protocol. Each patient received a 5-min i.v. infusion of 0.1, 0.2, 0.4, 0.8, 1.5, 2, 4, or 8 mg zoledronic acid monthly for 3 months. Patients were monitored for clinical findings, adverse events, electrocardiograms, markers of bone resorption, as well as routine hematology, blood chemistries, and urinalysis. Thirty patients who demonstrated a radiographic response to treatment or stable disease in the core protocol were enrolled in a humanitarian extension protocol and continued to receive monthly infusions. Zoledronic acid was well tolerated at all dose levels. Adverse events reported by >10% of patients included skeletal pain, nausea, fatigue, upper respiratory tract infection, constipation, headache, diarrhea, and fever. Three patients in the core protocol and one patient in the extension protocol experienced grade 3 skeletal pain, "flulike" symptoms, or hypophosphatemia, which were possibly related to treatment; all recovered completely. Adverse events were reported with similar frequency across all of the dosage groups. Zoledronic acid resulted in sustained, dose-dependent decreases in urinary markers of bone resorption. Zoledronic acid was safe and well tolerated and demonstrated potent inhibition of bone resorption.

Original languageEnglish (US)
Pages (from-to)478-485
Number of pages8
JournalClinical Cancer Research
Volume7
Issue number3
StatePublished - Jan 1 2001

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Berenson, J. R., Vescio, R. A., Rosen, L. S., Vonteichert, J. M., Woo, M., Swift, R., Savage, A., Berenson, J. R., Vescio, R. A., Rosen, L. S., Vonteichert, J. M., Woo, M., Swift, R., Savage, A., Givant, E., Hupkes, M., Harvey, H., & Lipton, A. (2001). A phase I dose-ranging trial of monthly infusions of zoledronic acid for the treatment of osteolytic bone metastases. Clinical Cancer Research, 7(3), 478-485.