A phase I, open label, dose ranging trial of intravenous bolus zoledronic acid, a novel bisphosphonate, in cancer patients with metastatic bone disease

BACKGROUND. Bone metastases typically are associated with osteolytic bone d estruction, resulting in bone pain. pathologic fractures, spinal cord compr ession, and hypercalcemia. Bisphosphonates are potent inhibitors of normal and pathologic bone resorption and represent a significant therapeutic impr ovement in the management of patients with lytic bone metastases. Zoledroni c acid is a new-generation, highly potent, nitrogen-containing bisphosphona te that to the authors knowledge is the most potent inhibitor of bone resor ption currently in clinical trials. The objectives of the current study wer e to assess the safety and tolerability of increasing doses of zoledronic a cid and to determine its activity with respect to reducing biochemical mark ers of bone resorption in cancer patients with bone metastases. METHODS. Forty-four cancer patients with bone metastases or primary bone le sions were enrolled sequentially into 1 of 5 fixed ascending-dose treatment groups. Each patient received a single intravenous bolus injection of 1, 2 , 4, 8, or 16 mg of zoledronic acid over 30-60 seconds. Patients were monit ored for 8 weeks for the evaluation of clinical findings, adverse events, v ital signs, electrocardiograms, markers of bone resorption, and urinary N-a cetyl-beta -D-glucosaminidase. RESULTS. Zoledronic acid was safe and well tolerated at all dose levels tes ted. Commonly reported adverse events included bone pain, fever, anorexia, constipation, and nausea, which were experienced by a similar proportion of patients in each treatment group. Seven patients reported serious adverse events, none of which appeared to be related to the study drug. Zoledronic acid effectively suppressed biochemical markers of bone resorption, includi ng the highly specific markers N-telopeptide and deoxypyridinoline, for up to 8 weeks in the 2-16-mg dose groups and for a shorter duration in the 1-m g group. CONCLUSIONS. In the current study, zoledronic acid was safe and well tolera ted and demonstrated potent inhibition of bone resorption. The authors beli eve it may improve the treatment of metastatic bone disease. Cancer 2001;91 :144-54. (C) 2001 American Cancer Society.