选择性和非选择性环氧化酶-2抑制剂与实验性骨折愈合。短期治疗后效果的可逆性。

Selective and nonselective cyclooxygenase-2 inhibitors and experimental fracture-healing. Reversibility of effects after short-term treatment.

作者信息

Gerstenfeld L C, Al-Ghawas M, Alkhiary Y M, Cullinane D M, Krall E A, Fitch J L, Webb E G, Thiede M A, Einhorn T A

机构信息

Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Boston University Medical Center, 715 Albany Street, R-205, Boston, MA 02118, USA.

出版信息

J Bone Joint Surg Am. 2007 Jan;89(1):114-25. doi: 10.2106/JBJS.F.00495.

DOI:10.2106/JBJS.F.00495

PMID:17200318

Abstract

BACKGROUND

Cyclooxygenase-2-specific anti-inflammatory drugs (coxibs) and nonspecific nonsteroidal anti-inflammatory drugs have been shown to inhibit experimental fracture-healing. The present study tested the hypothesis that these effects are reversible after short-term treatment.

METHODS

With use of a standard model of fracture-healing, identical ED50 dosages of either a nonsteroidal anti-inflammatory drug (ketorolac), a coxib (valdecoxib), or vehicle (control) were orally administered to rats for either seven or twenty-one days and fracture-healing was assessed with biomechanical, histological, and biochemical analyses.

RESULTS

When healing was assessed at twenty-one days, the seven-day treatment produced only a trend for a higher rate of nonunion in valdecoxib and ketorolac-treated animals as compared with controls. No differences were observed at thirty-five days. The twenty-one-day treatment produced significantly more nonunions in valdecoxib-treated animals as compared with either ketorolac-treated or control animals (p < 0.05), but these differences disappeared by thirty-five days. The dose-specific inhibition of these drugs on prostaglandin E2 levels and the reversibility of the effects after drug withdrawal were assessed in fracture calluses and showed that ketorolac treatment led to twofold to threefold lower levels of prostaglandin E2 than did valdecoxib. Withdrawal of either drug after six days led to a twofold rebound in these levels by fourteen days. Histological analysis showed delayed remodeling of calcified cartilage and reduced bone formation in association with valdecoxib treatment.

CONCLUSIONS

Cyclooxygenase-2-specific drugs inhibit fracture-healing more than nonspecific nonsteroidal anti-inflammatory drugs, and the magnitude of the effect is related to the duration of treatment. However, after the discontinuation of treatment, prostaglandin E2 levels are gradually restored and the regain of strength returns to levels similar to control.

摘要

背景

环氧化酶-2特异性抗炎药物（coxibs）和非特异性非甾体抗炎药物已被证明会抑制实验性骨折愈合。本研究检验了以下假设：短期治疗后这些影响是可逆的。

方法

使用标准的骨折愈合模型，对大鼠口服相同半数有效剂量（ED50）的非甾体抗炎药物（酮咯酸）、coxib（伐地昔布）或赋形剂（对照），持续7天或21天，然后通过生物力学、组织学和生化分析评估骨折愈合情况。

结果

在21天时评估愈合情况，与对照组相比，接受7天治疗的伐地昔布和酮咯酸治疗组动物出现骨不连的发生率仅呈上升趋势。在35天时未观察到差异。与酮咯酸治疗组或对照组动物相比，接受21天治疗的伐地昔布治疗组动物出现明显更多的骨不连（p < 0.05），但这些差异在35天时消失。在骨折痂中评估了这些药物对前列腺素E2水平的剂量特异性抑制作用以及停药后作用的可逆性，结果显示酮咯酸治疗导致的前列腺素E2水平比伐地昔布低两到三倍。两种药物在给药6天后停药，到14天时这些水平会出现两倍的反弹。组织学分析显示，与伐地昔布治疗相关的钙化软骨重塑延迟且骨形成减少。