Gasser Jürg A, Ingold Peter, Venturiere Andrea, Shen Victor, Green Jonathan R
Novartis Institutes for Biomedical Research, Basel, Switzerland.
J Bone Miner Res. 2008 Apr;23(4):544-51. doi: 10.1359/jbmr.071207.
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.
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.
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.
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.
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.
目前的双膦酸盐疗法可有效预防绝经后女性的骨质流失。我们研究了单次静脉注射唑来膦酸（ZOL）对去卵巢大鼠的影响。对骨质流失的保护作用呈剂量依赖性，可持续长达32周，这为ZOL每年一次静脉给药方案治疗绝经后骨质疏松症提供了理论依据。
每年一次静脉注射5毫克唑来膦酸（ZOL）可增加骨密度（BMD）并降低低骨密度绝经后女性骨折发生率。本研究的主要目的是确定单次剂量ZOL在去卵巢大鼠（绝经后骨质减少动物模型）中的骨保护作用持续时间。次要目的是确定对骨转换和力学性能的影响。
雌性Wistar大鼠（每组10只）在双侧卵巢切除术前4天接受单次静脉注射ZOL 0.8、4、20、100或500微克/千克，阿仑膦酸钠200微克/千克或等渗盐水。假手术对照组用盐水预处理。在32周内每隔4周测量松质骨和皮质骨的质量和密度（pQCT）。在32周时还评估了骨结构（microCT）、骨形成动力学（基于荧光染料标记的组织形态计量学）以及压缩试验中的生物力学强度。
ZOL≥4微克/千克对总骨密度、ZOL≥20微克/千克对皮质骨密度、ZOL≥4微克/千克对松质骨密度，可使与卵巢切除相关的骨密度损失在32周内显著减轻（与去卵巢对照组相比，p<0.01）。200微克/千克阿仑膦酸钠与20微克/千克ZOL效力相当。ZOL剂量依赖性地减轻了与卵巢切除相关的小梁结构参数下降。200微克/千克阿仑膦酸钠与20微克/千克ZOL相当。骨吸收标志物TRACP5b表明，即使在最低剂量0.8微克/千克时，ZOL相对于去卵巢大鼠也能短暂抑制破骨细胞活性升高，而在100 - 500微克/千克时，在整个32周的研究期间相对于去卵巢对照组效果显著。20微克/千克ZOL对骨形成参数无显著影响，但100 - 500微克/千克ZOL可使其显著降低。200微克/千克阿仑膦酸钠与100微克/千克ZOL相当。ZOL使卵巢切除后骨强度参数得到剂量相关的改善。200微克/千克阿仑膦酸钠与20微克/千克ZOL效力相似。
单次静脉注射ZOL在去卵巢大鼠中的骨保护作用持续时间和程度呈剂量依赖性，可持续长达32周。与阿仑膦酸钠相比，ZOL在预防骨质流失方面效力高10倍。这些数据支持使用每年一次静脉注射ZOL给药方案治疗骨质疏松症。
