Little David G, Smith Nicholas C, Williams Paul R, Briody Julie N, Bilston Lynne E, Smith Elisabeth J, Gardiner Edith M, Cowell Christopher T
Orthopaedic Research and Biotechnology, Children's Hospital at Westmead, Sydney, NSW, Australia.
J Bone Miner Res. 2003 Jul;18(7):1300-7. doi: 10.1359/jbmr.2003.18.7.1300.
Prolonged healing times and stress-shielding osteopenia remain problematic in distraction osteogenesis. In this study of 30 rabbits, zoledronic acid increased regenerate volume, mineralization, and tibial strength and prevented osteopenia over a 6-week period. Translation to the clinical setting, if safe, could improve outcomes in distraction osteogenesis in children.
Because the external fixators for limb lengthening and reconstruction are designed to control the positions of bone fragments accurately, they also produce stress-shielding effects on the forming regenerate and surrounding bone. Osteopenia, leading to refracture and limitations on rehabilitation, are common consequences, potentially increasing morbidity and detracting from final clinical outcome.
We examined the effect of zoledronic acid on distraction osteogenesis in 42 immature male NZW rabbits. The model chosen results in reliable regenerate formation and stress-shielding osteopenia. Fourteen animals received either Saline, zoledronic acid 0.1 mg/kg at surgery (ZOL), or another dose 2 weeks postoperatively (Redosed ZOL). Rabbits underwent DXA for bone mineral content and bone mineral density in regenerate and surrounding segments of operated and contralateral tibias. After death at 6 weeks, 30 pairs of tibias underwent quantitative computerized tomography (QCT) and four-point bend testing, and 12 were examined by histomorphometry. The study was powered at 0.8 to show differences of 1.3 SDs for mineral and mechanical parameters.
Osteopenia observed in tibias of the Saline group was absent in ZOL and Redosed ZOL tibias, the latter exhibiting higher bone mineral density and bone mineral content over contralateral regions (p < 0.01). Regenerate bone mineral content was higher in ZOL and Redosed ZOL versus Saline groups at 4 and 6 weeks (p < 0.01). Cross-sectional area was 49% and 59% greater at 6 weeks in ZOL and Redosed ZOL regenerates compared with the Saline group (p < 0.01). ZOL and Redosed ZOL tibias were 29% and 89% stronger by four-point bending than the Saline group (p < 0.01). Histomorphometry in the regenerate of ZOL and Redosed ZOL groups revealed higher trabecular bone volume and trabecular number compared with the Saline group (p < 0.001).
Zoledronic acid administration led to significantly greater bone area, mineral content, strength, and trabecular number with reduced stress-shielding osteopenia in this model of distraction osteogenesis. These data suggest that intraoperative and postoperative zoledronic acid administration could improve outcomes in children undergoing limb lengthening.
在牵张成骨术中，愈合时间延长和应力遮挡性骨质减少仍然是问题。在这项对30只兔子的研究中，唑来膦酸在6周时间内增加了再生骨量、矿化程度和胫骨强度，并预防了骨质减少。若能安全地转化到临床应用中，可能会改善儿童牵张成骨术的治疗效果。
由于用于肢体延长和重建的外固定器旨在精确控制骨碎片的位置，它们也会对正在形成的再生骨和周围骨骼产生应力遮挡效应。骨质减少会导致再骨折和康复受限，是常见的后果，可能会增加发病率并影响最终的临床结果。
我们研究了唑来膦酸对42只未成熟雄性新西兰白兔牵张成骨的影响。所选用的模型能可靠地形成再生骨并导致应力遮挡性骨质减少。14只动物分别接受生理盐水、手术时给予0.1mg/kg唑来膦酸（ZOL）或术后2周给予另一剂量（再次给药ZOL）。兔子接受双能X线吸收法（DXA）检测手术侧和对侧胫骨再生骨及周围节段的骨矿物质含量和骨矿物质密度。6周后处死兔子，30对胫骨进行定量计算机断层扫描（QCT）和四点弯曲试验，12只进行组织形态计量学检查。该研究的检验效能为0.8，以显示矿物质和力学参数有1.3个标准差的差异。
生理盐水组胫骨中观察到的骨质减少在ZOL组和再次给药ZOL组的胫骨中未出现，后者在对侧区域表现出更高的骨矿物质密度和骨矿物质含量（p<0.01）。在4周和6周时，ZOL组和再次给药ZOL组的再生骨矿物质含量高于生理盐水组（p<0.01）。与生理盐水组相比，ZOL组和再次给药ZOL组在6周时再生骨的横截面积分别大49%和59%（p<0.01）。通过四点弯曲试验，ZOL组和再次给药ZOL组的胫骨比生理盐水组分别强29%和89%（p<0.01）。ZOL组和再次给药ZOL组再生骨的组织形态计量学显示，与生理盐水组相比，小梁骨体积和小梁数量更高（p<0.001）。
在这个牵张成骨模型中，给予唑来膦酸导致骨面积、矿物质含量、强度和小梁数量显著增加，同时应力遮挡性骨质减少。这些数据表明，术中及术后给予唑来膦酸可能会改善接受肢体延长手术儿童的治疗效果。
