Parameters for Lithium Treatment Are Critical in Its Enhancement of Fracture-Healing in Rodents
Parameters for Lithium Treatment Are Critical in Its Enhancement of Fracture-Healing in Rodents
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DOI：
10.2106/jbjs.n.00057
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发表时间：
2014-12-03
影响因子：
5.3
通讯作者：
Nam, Diane
中科院分区：
文献类型：
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作者：
Bernick, Joshua;Wang, Yufa;Nam, Diane
背景：锂是一种治疗双相情感障碍的药物，临床上没有用于骨折治疗的迹象，但有报道称它对骨生物学有积极影响。据推测，锂对骨骼健康有益的剂量可能远低于双相情感障碍患者精神药物益处所需的剂量。使用啮齿动物骨折模型进行临床前研究，以确定锂作为骨折护理新疗法的最低有效剂量、最佳治疗开始时间和最佳治疗持续时间。方法：采用实验设计方法评估剂量、治疗开始时间和治疗持续时间的参数。对闭合性股骨干骨折进行破坏性扭转力学测试和基于显微计算机断层扫描的图像分析。结果：低剂量(每天每公斤体重20毫克)、较晚开始锂治疗(骨折后7天)和较长治疗时间(两周)的锂治疗组合可使骨折愈合最大化，最大屈服扭矩较未治疗和假治疗对照组增加46%(481.1+/-104.0 N-mm比329.9+/-135.8 N-mm；p=0.04)。实验设计分析表明，治疗开始的时间是改善骨折愈合的最有影响的参数，与起病较早的患者(骨折后三天)相比，起病较晚(骨折后7天)的股骨显示出显著的最大屈服扭矩增加(21%)(p=0.01)。结论：起病较晚的锂显著促进股骨骨折的愈合。趋势表明，较低的剂量和较长的疗程对骨折修复也有积极的影响。
Background: Lithium, a treatment for bipolar disorder, is not clinically indicated for use in fracture management but has been reported to positively influence bone biology. It is hypothesized that lithium dosing for beneficial effects on bone health may be much lower than the dosing required for psychotropic benefits in patients with bipolar disorder. A preclinical study with a rodent fracture model was utilized to best define the lowest effective dose, best timing of treatment onset, and optimal treatment duration for the use of lithium as a new treatment in fracture care.Methods: A design-of-experiments approach was used to assess the parameters of dose, timing of treatment onset, and treatment duration. Closed femoral shaft fractures were generated and analyzed with use of destructive torsional mechanical testing and microcomputed tomography-based image analysis. Eleven different outcome measures were quantified, with maximum yield torque as the primary study outcome, to assess the quality of long-bone fracture-healing.Results: Fracture-healing was maximized with a lithium treatment combination of a low dose (twenty milligrams per kilogram of body weight per day), later onset of lithium treatment (seven days after fracture), and longer treatment duration (two weeks), with maximum yield torque displaying a 46% increase compared with nontreated and sham-treated controls (481.1 +/- 104.0 N-mm compared with 329.9 +/- 135.8 N-mm; p = 0.04). Design-of-experiments analysis determined the timing of treatment onset to be the most influential parameter for improving fracture-healing, with femora treated at a later onset (seven days after fracture) showing a significant (21%) increase in maximum yield torque compared with those treated at an earlier onset (three days after fracture) (p = 0.01).Conclusions: A later onset of lithium administration significantly improved femoral fracture-healing. Trends indicated that a lower dose and longer treatment duration also had a positive effect on fracture repair.