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 deve loped. Patients and methods: One hundred ten patients with bone metastases (77 bre ast, 16, prostate, 3 myeloma, 14 others) were recruited from a single insti tution 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-c ancer treatment were allowed in the month before commencing treatment or du ring the study period. After an initial four-week tolerability phase, patie nts could continue on treatment for a further three months without unblindi ng; 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 coll agen crosslinking molecules. Results. Two patients did not receive any trial medication thus, 108 patien ts were evaluable for safety. Ninety-two patients were evaluable for effica cy. A dose dependent reduction was observed in both UCCR and collagen cross link excretion. At the 50 mg dose level, the percentage reductions from bas eline in UCCR, Pyr, Dpd, Crosslaps and NTX were 71%, 28%, 39% 80% and 74% r espectively. One or more gastrointestinal (GI) adverse events occurring in the first mon th 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 lev els respectively. One patient (20 mg dose) developed radiographically confi rmed oesophageal ulceration. GI tolerability may have been adversely affect ed by concommitant administration of non-steroidal antiinflammatory agents. Nine (8%) patients stopped treatment within the first month due to GI into lerability but these patients were evenly distributed across the five treat ment groups. There was no difference in non-GI adverse events between group s. Conclusions: Oral ibandronate has potent effects on the rate of bone resorp tion at doses which are generally well tolerated. Further development is ap propriate to evaluate the effects of long-term administration in the preven tion of metastatic bone disease and the management of established skeletal metastases.