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FRIEDER BAUSS, MARTINA WAGNER, and LUDWIG H. HOTHORN

ABSTRACT.

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 µg/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 µg/kg/day, while 0.1 µg/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.

Conclusion. 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. (J Rheumatol 2002;29:990-8)

Key Indexing Terms:

BONE MINERAL DENSITY
BONE ARCHITECTURE
IBANDRONATE
INTERMITTENT TREATMENT
RATS

From Pharma Research, Bone Metabolism, Roche Diagnostics GmbH, Mannheim; Institute of Pharmacology and Toxicology, Heidelberg University, Mannheim; and Unit of Bioinformatics, Hannover University, Hannover, Germany.

F. Bauss, PhD, Roche Diagnostics GmbH Mannheim and Institute of Pharmacology and Toxicology, Heidelberg University; M. Wagner, Roche Diagnostics GmbH; L.H. Hothorn, PhD, Unit of Bioinformatics, Hannover University.

Address reprint requests to Dr. F. Bauss, Roche Diagnostics GmbH, Pharma Research, Bone Metabolism, c/o F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, Pharma Research, Grenzacherstrasse, Bldg. 70/139, CH-4070 Basel, Switzerland. E-mail: frieder.bauss@roche.com

Submitted March 19, 2001; revision accepted November 6, 2001.