Effects of treatment with ibandronate on bone mass, architecture, biomechanical properties, and bone concentration of ibandronate in ovariectomized aged rats.
OBJECTIVE
To investigate the effects of treatment with ibandronate, a highly potent nitrogen-containing bisphosphonate, on bone loss, bone quality, biomechanical properties, and bone concentrations in aged ovariectomized rats.


METHODS
Eight-month-old female Wistar rats were ovariectomized (Ovx) or sham-operated. Treatment was started 10 weeks following Ovx with subcutaneous ibandronate in doses of 0.2, 1.0, 5.0, or 25 micro g/kg/day for 12 mo. Additional groups received 25 or 125 micro g/kg intermittently every 25 days, resulting in the same total dose as compared to 1.0 or 5.0 micro g/kg/day, respectively. Bone analyses by x-ray densitometry, peripheral quantitative computed tomography (pQCT), dual energy x-ray absorptiometry (DEXA), histomorphometry, 3-point bending, and compression tests were performed in femora, tibiae, and lumbar vertebrae in separate groups at the beginning and the end of treatment. Ibandronate concentration in tibiae and vertebrae was determined by gas chromatography mass spectroscopy at the end of the study.


RESULTS
Ovariectomy resulted in a significant reduction in bone mass (p <or= 0.0001) and strength (p < 0.05) by 10 weeks after surgery in long bones, while only a trend was present in vertebrae. When compared to age matched Ovx controls, ibandronate resulted in a dose dependent increase in bone mineral density (BMD), trabecular bone volume and trabecular number, load to failure (Fmax), and yield load in long bones and vertebrae. The lowest significant dose, which was different from Ovx controls, ranged between 0.2 and 1.0 micro g/kg/day, with higher doses not differing from sham controls. Increased trabecular separation (p <or= 0.0001) was fully prevented by all doses. Vertebral BMD (pQCT and DEXA) positively correlated with Fmax by r = 0.88 (p <or= 0.0001) both; correlation of femoral Fmax versus cortical BMD was r = 0.61 (p <or= 0.0001).


CONCLUSIONS
Bone concentrations of ibandronate were linear with the dose, suggesting linear kinetics in the applied dose range. In general, the same total cumulative ibandronate dose given provided equivalent results, independent of the administration schedule.
Bauss
Frieder
F
Pharma Research, Bone Metabolism, Roche Diagnostics GmbH, Penzberg, Germany. frieder.bauss@roche.com
Lalla
Sigrid
S
Endele
Richard
R
Hothorn
Ludwig A
LA
D015502:Absorptiometry, Photon; D000375:Aging; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001862:Bone Resorption / Q000139:chemically induced*; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004164:Diphosphonates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects; D000077557:Ibandronic Acid; D007279:Injections, Subcutaneous; D008159:Lumbar Vertebrae / Q000187:drug effects / Q000473:pathology; D010052:Ovariectomy; D051381:Rats; D017208:Rats, Wistar; D013977:Tibia / Q000187:drug effects / Q000473:pathology; D013997:Time Factors
D004164:Diphosphonates; D000077557:Ibandronic Acid