Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.
Clin Cancer Res. 2009 Sep 15;15(18):5829-39. doi: 10.1158/1078-0432.CCR-09-0426. Epub 2009 Sep 8.
The increasing incidence of osteonecrosis of the jaw and its possible association with high cumulative doses of bisphosphonate led us to study the effects of high doses of zoledronic acid (ZA) on bone remodeling.
Five-week-old C57BL6 mice were treated with saline or ZA weekly for 3 weeks at increasing doses (0.05-1 mg/Kg). Effects of ZA on bone remodeling were studied using standard assays.
We observed an increase in bone mineral density and content in treated animals at doses of 0.05 mg/Kg, which was not further enhanced at higher doses of ZA. Trabecular bone volume at the proximal tibia and the distal femur assessed by histomorphometry and microCT, respectively, increased significantly in ZA-treated groups. There was however no difference between 0.5 and 1 mg/kg, suggesting a ceiling effect for ZA. ZA led to decreased numbers of osteoclasts and osteoblasts per bone perimeter that paralleled a significant reduction of serum levels of TRAC5b and osteocalcin in vivo. Effects on osteoblasts were confirmed in in vitro assays. Mechanical testing of the femur showed increased brittleness in ZA-treated mice.
High doses of ZA inhibit both osteoclast and osteoblasts function and bone remodeling in vivo interfering with bone mechanical properties. No dose response was noted beyond 0.5 mg/kg suggesting that lower doses of ZA may be adequate in inhibiting bone resorption. Our data may help inform future studies of ZA use with respect to alternate and lower doses in the treatment of patients with cancer bone disease.
由于颌骨坏死的发病率不断上升，且其可能与双膦酸盐的高累积剂量有关，我们研究了唑来膦酸（ZA）高剂量对骨重建的影响。
5 周龄 C57BL6 小鼠每周用盐水或 ZA 处理 3 周，剂量递增（0.05-1mg/kg）。使用标准检测方法研究 ZA 对骨重建的影响。
我们观察到，在 0.05mg/kg 的剂量下，接受 ZA 治疗的动物的骨矿物质密度和含量增加，而在更高剂量的 ZA 下则没有进一步增加。通过组织形态计量学和 microCT 分别评估的近侧胫骨和远侧股骨的小梁骨体积均显著增加。然而，0.5 和 1mg/kg 之间没有差异，这表明 ZA 存在上限效应。ZA 导致每个骨周缘的破骨细胞和成骨细胞数量减少，这与体内 TRAC5b 和骨钙素血清水平的显著降低相平行。在体外实验中也证实了对成骨细胞的影响。股骨的力学测试显示，接受 ZA 治疗的小鼠脆性增加。
ZA 的高剂量抑制体内破骨细胞和成骨细胞的功能和骨重建，干扰骨的力学性能。在 0.5mg/kg 以上未观察到剂量反应，这表明较低剂量的 ZA 可能足以抑制骨吸收。我们的数据可能有助于为未来关于癌症骨病患者 ZA 替代和较低剂量使用的研究提供信息。
