Total administered dose of ibandronate determines its effects on bone mass and architecture in ovariectomized aged rats.
OBJECTIVE
Ibandronate is a highly potent nitrogen-containing bisphosphonate that can prevent bone loss in various animal models as well as in clinical trials. We evaluated the effects of different doses and treatment schedules in ovariectomized aged rats, a model of human osteoporosis.


METHODS
Eight-month-old female Wistar rats were ovariectomized or sham operated (n = 15/group). Doses of 0.1 to 30 microg/kg/day ibandronate were administered subcutaneously over a period of 20 weeks with or without a 5 times higher single loading dose starting one day postsurgery. In a subsequent experiment, the optimal preventive dose, which is the lowest dose that prevented bone loss completely, or a suboptimal preventive dose were administered over the same period, either daily or by 3 cyclical intermittent regimens (on/off weeks = 1/2, 1/4, and 1/6), resulting in the same cumulative total dose.


RESULTS
Ovariectomy induced significant bone loss in the following primary endpoints: femoral radiographic density, dry weight/tissue volume, and calcium content/tissue volume. Histomorphometry in the tibia resulted in reduced trabecular bone mass, thickness, and number, and increased separation. The optimal dose was 1.0 microg/kg/day, while 0.1 microg/kg/day was suboptimal. Higher doses resulted in a plateau. The loading dose had no effect on the results. Cyclical intermittent administration dose-dependently prevented bone loss, providing equivalent results per total dose, irrespective of the administration schedule.


CONCLUSIONS
There were no differences between the various regimens, suggesting that it is the total dose of ibandronate rather than the treatment schedule that is important for efficacy, at least within the tested dosing intervals.
Bauss
Frieder
F
Pharma Research, Bone Metabolism, Roche Diagnostics GmbH, Mannheim, Germany. frieder.bauss@roche.com
Wagner
Martina
M
Hothorn
Ludwig H
LH
D000375:Aging / Q000473:pathology*; D000818:Animals; D015519:Bone Density / Q000187:drug effects*; D004164:Diphosphonates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005269:Femur / Q000473:pathology; D000077557:Ibandronic Acid; D010024:Osteoporosis / Q000473:pathology / Q000517:prevention & control*; D010052:Ovariectomy; D051381:Rats; D017208:Rats, Wistar; D013977:Tibia / Q000473:pathology
D004164:Diphosphonates; D000077557:Ibandronic Acid