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Long-term protective effects of zoledronic acid on cancellous and cortical bone in the ovariectomized rat.

Gasser, Juerg Andreas and Ingold, Peter and Venturiere, Andrea and Shen, Victor and Green, Jonathan (2008) Long-term protective effects of zoledronic acid on cancellous and cortical bone in the ovariectomized rat. Journal of Bone and Mineral Research : the official journal of the American Society for Bone and Mineral Research, 23 (4). pp. 544-551. ISSN 1523-4681

Abstract

Current bisphosphonate therapies effectively prevent bone loss in postmenopausal women. We studied the effect of a single intravenous dose of ZOL in ovariectomized rats. Protection from bone loss was dose dependent, lasting for up to 32 weeks, supporting the rationale for an annual intravenous dosing regimen of ZOL for treatment of postmenopausal osteoporosis. INTRODUCTION: Once-yearly dosing with zoledronic acid (ZOL) 5 mg can increase BMD and reduce fracture rate in postmenopausal women with low BMD. The primary objective of this study was to determine the duration of bone protective effects of a single dose of ZOL in ovariectomized rats, an animal model of postmenopausal osteopenia. Secondary objectives were to determine the effects on bone turnover and mechanical properties. MATERIALS AND METHODS: Female Wistar rats (10 per group) received single intravenous doses of ZOL 0.8, 4, 20, 100, or 500 microg/kg, alendronate 200 microg/kg, or isotonic saline 4 days before bilateral ovariectomy. Sham-operated controls were pretreated with saline. Mass and density of cancellous and cortical bone (pQCT) were measured at 4-wk intervals for 32 wk. Bone architecture (microCT), bone formation dynamics (fluorochrome label-based histomorphometry), and biomechanical strength in compression testing were also assessed at 32 wk. RESULTS: Ovariectomy-associated BMD loss was significantly attenuated for 32 wk by ZOL >or=4 microg/kg for total BMD, ZOL >or=20 microg/kg for cortical BMD, and ZOL >or=4 microg/kg for cancellous BMD (p < 0.01 versus ovariectomized controls). Alendronate 200 microg/kg was of equivalent potency to ZOL 20 microg/kg. Ovariectomy-associated decreases in trabecular architectural parameters were dose-dependently attenuated by ZOL. Alendronate 200 microg/kg was equivalent to ZOL 20 microg/kg. The bone resorption marker TRACP5b indicated transient suppression of elevated osteoclast activity by ZOL relative to OVX-rats even at the lowest dose of 0.8 microg/kg, whereas at 100-500 microg/kg, the effect was significant relative to the OVX control for the entire duration of the study of 32 wk. Bone formation parameters were not significantly affected by ZOL 20 microg/kg but were significantly reduced by ZOL 100-500 microg/kg. Alendronate 200 microg/kg was equivalent to ZOL 100 microg/kg. ZOL produced dose-related improvements in bone strength parameters after ovariectomy. Alendronate 200 microg/kg was of similar potency to ZOL 20 microg/kg. CONCLUSIONS: The duration and magnitude of the bone-protecting effect of a single intravenous dose of ZOL in ovariectomized rats is dose dependent and lasts for up to 32 wk. Compared with alendronate, ZOL shows 10-fold higher potency in preventing bone loss. These data support the use of an annual intravenous ZOL dosing regimen for the treatment of osteoporosis.

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Date Deposited: 14 Dec 2009 13:51
Last Modified: 31 Jan 2013 01:04
URI: https://oak.novartis.com/id/eprint/894

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