Ibandronate in osteoporosis: preclinical data and rationale for intermittent dosing

Ibandronate is a highly potent, nitrogen-containing bisphosphonate. Unlike most other bisphosphonates, it is under clinical development for both oral and intravenous (i.v.) administration. Ibandronate can be used in convenient intermittent regimens that may optimize therapeutic outcome with enhanced compliance by patients. The preclinical pharmacokinetics (PK) and pharmacology of ibandronate have been extensively explored in a large preclinical development program involving various recommended animal models of human osteoporosis. These experimental studies of ibandronate indicate that the preclinical pharmacology and PK profile of ibandronate are broadly similar to those of other nitrogen-containing bisphosphonates. The efficacy of intermittent administration of subcutaneous (s.c.) and i.v. ibandronate has been demonstrated in four animal models (rat, dog, minipig, and monkey). Thus in rats, dogs, and monkeys with estrogen depletion, and in minipigs with glucocorticoid-induced bone loss, ibandronate administered s.c. or i.v. with extended intervals between doses reduces bone turnover, increases bone mineral density, and maintains bone quality in a dose-dependent manner. Furthermore, studies in rats and dogs comparing continuous and intermittent treatment schedules indicate similar efficacy when the same cumulative dose is applied over the duration of the study. These studies with ibandronate illustrate the concept that the total cumulative dose of bisphosphonate administered determines the response, independent of whether the dose is given daily or less frequently in a given time period. The efficacy of intermittent regimens has also been verified in models of secondary osteoporosis due to secondary hyperparathyroidism or immobilization (both in rats), or due to glucocorticoids in minipigs. Important factors for determining efficacy and the magnitude of response are the doses given, the length of the interval between doses, and the underlying bone turnover rate. The mechanisms underlying the remarkable efficacy of intermittent bisphosphonate dosing are not fully understood and further research is needed. Importantly, ibandronate is the only bisphosphonate so far proven to reduce the risk of vertebral fractures significantly with a between-dose interval >2 months, in a prospective clinical trial. Collectively, the preclinical studies on ibandronate have provided a sound basis for the design of the convenient regimens currently being examined in clinical trials.