Cancer Treatment Dosing Regimens of Zoledronic Acid Result in Near-Complete Suppression of Mandible Intracortical Bone Remodeling in Beagle Dogs
Cancer Treatment Dosing Regimens of Zoledronic Acid Result in Near-Complete Suppression of Mandible Intracortical Bone Remodeling in Beagle Dogs
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DOI：
10.1359/jbmr.090713
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发表时间：
2010-01-01
影响因子：
6.2
通讯作者：
Burr, David B.
中科院分区：
文献类型：
--
作者：
Allen, Matthew R.;Kubek, Daniel I.;Burr, David B.
用于癌症治疗的双膦酸盐剂量大大高于用于骨质疏松症的剂量。关于这些高剂量对组织水平重塑抑制的影响知之甚少。本研究的目的是评估唑来膦酸的癌症给药方案对不同骨骼部位组织水平骨重建的影响。卵巢成熟的雌性比格犬每月静脉输注溶剂（VEH，生理盐水）或唑来膦酸（ZOL，0.067 mg/kg）;另一组动物每日口服阿仑膦酸钠（ALN，0.2 mg/kg/天）。ZOL和ALN的剂量（以毫克/千克计）分别与用于癌症和骨质疏松症的剂量一致。处理3个月或6个月后，对动物实施安乐死，并对下颌骨、肋骨和胫骨进行动态骨组织学处理。任何动物的下颌骨均无口腔病变或骨基质坏死的证据。3个月后，与VEH相比，ZOL（-95%）显著抑制了下颌骨皮质内骨重建的速率;到6个月时，与VEH相比，ZOL几乎完全抑制（-99%）。与VEH相比，ZOL在3个月（-83%）和6个月（-85%）时还显著抑制了肋骨皮质的重塑; ZOL治疗的胫骨皮质骨形成率无显著性降低（-68%至-75%）。在下颌骨和肋骨处，ZOL治疗动物的重塑抑制显著大于ALN治疗动物; ALN和VEH在任何部位的任何评估参数均无差异。在骨骼部位之间进行比较，在具有较高重塑的部位，ZOL治疗的重塑抑制的绝对水平显著更高，而这些部位之间的降低百分比相似。这些结果证明了每月静脉注射唑来膦酸几乎完全抑制了皮质内重塑，其中下颌骨的变化最显著。(C)2010年美国骨与矿物质研究学会。
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. (C) 2010 American Society for Bone and Mineral Research.