DOUBLE-BLIND, PLACEBO-CONTROLLED, DOSE-RESPONSE TRIAL OF ORAL CLODRONATE IN PATIENTS WITH BONE METASTASES

Purpose: Despite evidence that clodronate inhibits tumor-induced osteolysis, no studies have directly assessed the optimal dose for long-term treatment. The aim of this double-blind, placebo-controlled study was to determine the safety and efficacy of different doses of clodronate in affected patients. Patients and Methods: Eighty-four patients with tumor-induced osteolysis were randomized to receive treatment with placebo, or 400 mg, 1,600 mg, or 3,200 mg af clodronate, daily for 4 weeks. Patients were reviewed weekly during treatment. Fasting urinary calcium excretion was the primary variable used to assess response. Visual analog pain scores and adverse events were documented. Results: In the clodronate-treated groups, there was a dose-dependent reduction in fasting calcium excretion with a highly significant difference between placebo and 1,600 mg clodronate (P = .0002) and placebo and 3,200 mg clodronate (P = .0001), but no significant difference between 1,600 mg and 3,200 mg clodronate. There was no discernible change in pain scores or analgesic requirements. Bone-derived isoenzyme alkaline phosphatase values increased in all groups, with a significant difference between baseline and final values in the 1,600-mg and 3,200-mg groups (P < .01 and P = .03, respectively). Adverse events were distributed evenly across the four treatment groups. Compliance was greeter than 99% in all treatment groups. Conclusion: Oral clodronate at a dose of 1,600 mg or 3,200 mg will inhibit bone resorption. Since there was no significant difference between these two doses in terms af efficacy at 4 weeks, 1,600 mg/d con be recommended for long-term treatment. This dose is well tolerated and may promote bane repair, as judged by increases in bone alkaline phosphatase levels. J Clin Oncol 13:929-934. (C) 1995 by American Society of Clinical Oncology.