Cancer treatment dosing regimens of zoledronic acid result in near-complete suppression of mandible intracortical bone remodeling in beagle dogs

Matthew Allen, Daniel J. Kubek, David Burr

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56 Citations (Scopus)

Abstract

Bisphosphonate doses used in cancer treatment are substantially higher than those used for osteoporosis. Little is known about the effects of these high doses on tissue-level remodeling suppression. The aim of this study was to assess the effects of cancer dosing regimens of zoledronic acid on tissue-level bone remodeling at different skeletal sites. Skeletally mature female beagle dogs were treated with monthly intravenous infusions of vehicle (VEH, saline) or zoledronic acid (ZOL, 0.067 mg/kg); an additional group of animals was treated daily with oral alendronate (ALN, 0.2 mg/kg/day). Doses of ZOL and ALN were, on a milligram per kilogram basis, consistent with those used for cancer and osteoporosis, respectively. Following either 3 or 6 months of treatment, animals were euthanized, and mandible, rib, and tibia were processed for dynamic bone histology. There was no evidence of oral lesions or bone matrix necrosis in the mandibles of any animals. After 3 months, the rate of intracortical bone remodeling in the mandible was significantly suppressed with ZOL (-95%) compared with VEH; by 6 months, ZOL had produced nearly complete suppression (-99%) compared with VEH. ZOL also significantly suppressed remodeling in the rib cortex at both 3 (-83%) and 6 (-85%) months compared with VEH; tibia cortex bone formation rate was nonsignificantly lower with ZOL treatment (-68% to -75%). Remodeling suppression in ZOL-treated animals was significantly greater than in ALN-treated animals at both the mandible and the rib; ALN and VEH were not different for any of the assessed parameters at any of the sites. Compared across skeletal sites, the absolute level of remodeling suppression with ZOL treatment was significantly greater at sites with higher remodeling, whereas the percent reduction was similar among the sites. These results document nearly complete intracortical remodeling suppression resulting from monthly intravenous zoledronic acid dosing, with changes being most dramatic at the mandible.

Original languageEnglish
Pages (from-to)98-105
Number of pages8
JournalJournal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
Volume25
Issue number1
DOIs
StatePublished - Jan 2010

Fingerprint

zoledronic acid
Bone Remodeling
Mandible
Dogs
Ribs
Neoplasms
Tibia
Osteoporosis
Therapeutics
Alendronate
Bone Matrix
Osteonecrosis
Diphosphonates
Intravenous Infusions
Osteogenesis
Histology
Bone and Bones

Keywords

  • Bisphosphonates
  • Cancer treatment
  • Jaw
  • Osteonecrosis
  • Remodeling suppression

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

@article{0a9a37e9f507454ebdba5007cf7072fd,
title = "Cancer treatment dosing regimens of zoledronic acid result in near-complete suppression of mandible intracortical bone remodeling in beagle dogs",
abstract = "Bisphosphonate doses used in cancer treatment are substantially higher than those used for osteoporosis. Little is known about the effects of these high doses on tissue-level remodeling suppression. The aim of this study was to assess the effects of cancer dosing regimens of zoledronic acid on tissue-level bone remodeling at different skeletal sites. Skeletally mature female beagle dogs were treated with monthly intravenous infusions of vehicle (VEH, saline) or zoledronic acid (ZOL, 0.067 mg/kg); an additional group of animals was treated daily with oral alendronate (ALN, 0.2 mg/kg/day). Doses of ZOL and ALN were, on a milligram per kilogram basis, consistent with those used for cancer and osteoporosis, respectively. Following either 3 or 6 months of treatment, animals were euthanized, and mandible, rib, and tibia were processed for dynamic bone histology. There was no evidence of oral lesions or bone matrix necrosis in the mandibles of any animals. After 3 months, the rate of intracortical bone remodeling in the mandible was significantly suppressed with ZOL (-95{\%}) compared with VEH; by 6 months, ZOL had produced nearly complete suppression (-99{\%}) compared with VEH. ZOL also significantly suppressed remodeling in the rib cortex at both 3 (-83{\%}) and 6 (-85{\%}) months compared with VEH; tibia cortex bone formation rate was nonsignificantly lower with ZOL treatment (-68{\%} to -75{\%}). Remodeling suppression in ZOL-treated animals was significantly greater than in ALN-treated animals at both the mandible and the rib; ALN and VEH were not different for any of the assessed parameters at any of the sites. Compared across skeletal sites, the absolute level of remodeling suppression with ZOL treatment was significantly greater at sites with higher remodeling, whereas the percent reduction was similar among the sites. These results document nearly complete intracortical remodeling suppression resulting from monthly intravenous zoledronic acid dosing, with changes being most dramatic at the mandible.",
keywords = "Bisphosphonates, Cancer treatment, Jaw, Osteonecrosis, Remodeling suppression",
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AU - Allen, Matthew

AU - Kubek, Daniel J.

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PY - 2010/1

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N2 - Bisphosphonate doses used in cancer treatment are substantially higher than those used for osteoporosis. Little is known about the effects of these high doses on tissue-level remodeling suppression. The aim of this study was to assess the effects of cancer dosing regimens of zoledronic acid on tissue-level bone remodeling at different skeletal sites. Skeletally mature female beagle dogs were treated with monthly intravenous infusions of vehicle (VEH, saline) or zoledronic acid (ZOL, 0.067 mg/kg); an additional group of animals was treated daily with oral alendronate (ALN, 0.2 mg/kg/day). Doses of ZOL and ALN were, on a milligram per kilogram basis, consistent with those used for cancer and osteoporosis, respectively. Following either 3 or 6 months of treatment, animals were euthanized, and mandible, rib, and tibia were processed for dynamic bone histology. There was no evidence of oral lesions or bone matrix necrosis in the mandibles of any animals. After 3 months, the rate of intracortical bone remodeling in the mandible was significantly suppressed with ZOL (-95%) compared with VEH; by 6 months, ZOL had produced nearly complete suppression (-99%) compared with VEH. ZOL also significantly suppressed remodeling in the rib cortex at both 3 (-83%) and 6 (-85%) months compared with VEH; tibia cortex bone formation rate was nonsignificantly lower with ZOL treatment (-68% to -75%). Remodeling suppression in ZOL-treated animals was significantly greater than in ALN-treated animals at both the mandible and the rib; ALN and VEH were not different for any of the assessed parameters at any of the sites. Compared across skeletal sites, the absolute level of remodeling suppression with ZOL treatment was significantly greater at sites with higher remodeling, whereas the percent reduction was similar among the sites. These results document nearly complete intracortical remodeling suppression resulting from monthly intravenous zoledronic acid dosing, with changes being most dramatic at the mandible.

AB - Bisphosphonate doses used in cancer treatment are substantially higher than those used for osteoporosis. Little is known about the effects of these high doses on tissue-level remodeling suppression. The aim of this study was to assess the effects of cancer dosing regimens of zoledronic acid on tissue-level bone remodeling at different skeletal sites. Skeletally mature female beagle dogs were treated with monthly intravenous infusions of vehicle (VEH, saline) or zoledronic acid (ZOL, 0.067 mg/kg); an additional group of animals was treated daily with oral alendronate (ALN, 0.2 mg/kg/day). Doses of ZOL and ALN were, on a milligram per kilogram basis, consistent with those used for cancer and osteoporosis, respectively. Following either 3 or 6 months of treatment, animals were euthanized, and mandible, rib, and tibia were processed for dynamic bone histology. There was no evidence of oral lesions or bone matrix necrosis in the mandibles of any animals. After 3 months, the rate of intracortical bone remodeling in the mandible was significantly suppressed with ZOL (-95%) compared with VEH; by 6 months, ZOL had produced nearly complete suppression (-99%) compared with VEH. ZOL also significantly suppressed remodeling in the rib cortex at both 3 (-83%) and 6 (-85%) months compared with VEH; tibia cortex bone formation rate was nonsignificantly lower with ZOL treatment (-68% to -75%). Remodeling suppression in ZOL-treated animals was significantly greater than in ALN-treated animals at both the mandible and the rib; ALN and VEH were not different for any of the assessed parameters at any of the sites. Compared across skeletal sites, the absolute level of remodeling suppression with ZOL treatment was significantly greater at sites with higher remodeling, whereas the percent reduction was similar among the sites. These results document nearly complete intracortical remodeling suppression resulting from monthly intravenous zoledronic acid dosing, with changes being most dramatic at the mandible.

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