Double-blind, randomised, placebo-controlled, dose-finding study of oral ibandronate in patients with metastatic bone disease

Background. Bisphosphonates are an important component of the treatment of metastatic bone disease but more potent, oral formulations are required to improve the effectiveness and convenience of treatment. An oral formulation of the new bisphosphonate, ibandronate (BM 21.0955) has recently been developed. Patients and methods: One hundred ten patients with bone metastases (77 breast, 16, prostate, 3 myeloma, 14 others) were recruited from a single institution to this double blind placebo-controlled evaluation of four oral dose levels (5, 10, 20 and 50 mg) of ibandronate. No changes in systemic anti-cancer treatment were allowed in the month before commencing treatment or during the study period. After an initial four-week tolerability phase, patients could continue on treatment for a further three months without unblinding; patients initially allocated to placebo received ibandronate 50 mg. The primary endpoint was urinary calcium excretion (UCCR). Bone resorption was also assessed by measurement of pyridinoline (Pyr), deoxypyridinoline (Dpd), and the N-terminal (NTX) and C-terminal (Crosslaps) portions of the collagen crosslinking molecules. Results. Two patients did not receive any trial medication thus, 108 patients were evaluable for safety. Ninety-two patients were evaluable for efficacy. A dose dependent reduction was observed in both UCCR and collagen crosslink excretion. At the 50 mg dose level, the percentage reductions from baseline in UCCR, Pyr, Dpd, Crosslaps and NTX were 71%, 28%, 39% 80% and 74% respectively. One or more gastrointestinal (GI) adverse events occurring in the first month of treatment were reported by six (30%), seven (33%), nine (39%), nine (41%) and eleven (50%) patients at the placebo, 5, 10, 20 and 50 mg dose levels respectively. One patient (20 mg dose) developed radiographically confirmed oesophageal ulceration. GI tolerability may have been adversely affected by concommitant administration of non-steroidal antiinflammatory agents. Nine (8%) patients stopped treatment within the first month due to GI intolerability but these patients were evenly distributed across the five treatment groups. There was no difference in non-GI adverse events between groups. Conclusions: Oral ibandronate has potent effects on the rate of bone resorption at doses which are generally well tolerated. Further development is appropriate to evaluate the effects of long-term administration in the prevention of metastatic bone disease and the management of established skeletal metastases.