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

Purpose: Despite evidence that clodronate inhibits tumor-induced osteo lysis, no studies have directly assessed the optimal dose for long-ter m treatment. The aim of this double-blind, placebo-controlled study wa s to determine the safety and efficacy of different doses of clodronat e in affected patients. Patients and Methods: Eighty-four patients wit h tumor-induced osteolysis were randomized to receive treatment with p lacebo, or 400 mg, 1,600 mg, or 3,200 mg af clodronate, daily for 4 we eks. Patients were reviewed weekly during treatment. Fasting urinary c alcium excretion was the primary variable used to assess response. Vis ual analog pain scores and adverse events were documented. Results: In the clodronate-treated groups, there was a dose-dependent reduction i n fasting calcium excretion with a highly significant difference betwe en placebo and 1,600 mg clodronate (P = .0002) and placebo and 3,200 m g clodronate (P = .0001), but no significant difference between 1,600 mg and 3,200 mg clodronate. There was no discernible change in pain sc ores or analgesic requirements. Bone-derived isoenzyme alkaline phosph atase values increased in all groups, with a significant difference be tween baseline and final values in the 1,600-mg and 3,200-mg groups (P < .01 and P = .03, respectively). Adverse events were distributed eve nly across the four treatment groups. Compliance was greeter than 99% in all treatment groups. Conclusion: Oral clodronate at a dose of 1,60 0 mg or 3,200 mg will inhibit bone resorption. Since there was no sign ificant difference between these two doses in terms af efficacy at 4 w eeks, 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) 199 5 by American Society of Clinical Oncology.