Selective and nonselective cyclooxygenase-2 inhibitors and experimental fracture-healing - Reversibility of effects after short-term treatment
Selective and nonselective cyclooxygenase-2 inhibitors and experimental fracture-healing - Reversibility of effects after short-term treatment
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DOI：
10.2106/jbjs.f.00495
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发表时间：
2007-01-01
影响因子：
5.3
通讯作者：
Einhorn, T. A.
中科院分区：
文献类型：
--
作者：
Gerstenfeld, L. C.;Al-Ghawas, M.;Einhorn, T. A.
背景资料：环氧合酶-2特异性抗炎药（coxibs）和非特异性非甾体抗炎药已被证明可抑制实验性溃疡愈合。本研究验证了这些影响在短期治疗后是可逆的假设。方法：使用标准的创伤愈合模型，给予相同的ED 50剂量的非甾体抗炎药（酮咯酸），一种coxib（伐地考昔）或赋形剂（对照）口服给药大鼠7天或21天，用生物力学，组织学，结果：当在第21天评估愈合时，与对照组相比，在伐地考昔和酮咯酸治疗的动物中，7天的治疗仅产生了更高的不愈合率的趋势。在第35天未观察到差异。与酮咯酸治疗组或对照组动物相比，伐地昔布治疗组动物在21天的治疗中产生了显著更多的骨不连（p < 0.05），但这些差异在35天后消失。在骨折骨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和停药后效应的可逆性，结果表明酮咯酸治疗导致前列腺素E2水平比伐地昔布低2 - 3倍。6天后停用任何一种药物，14天后这些水平都会反弹两倍。组织学分析表明，延迟重塑的钙化软骨和减少骨形成与valdecoxib treatment.Conclusions：环氧合酶-2特异性药物抑制骨愈合超过非特异性非甾体类抗炎药，效果的大小与治疗时间有关。然而，在停止治疗后，前列腺素E2的水平逐渐恢复和恢复的强度返回到水平类似于control.Clinical Relevance：虽然动物研究表明，非甾体类抗炎药和昔布抑制骨修复，有没有临床报告与1级证据支持这些发现。由于大多数患者在疼痛消退后停止这些药物，因此确定抑制作用是否可逆非常重要。目前的动物研究证实，抑制环氧合酶2会损害创面愈合，其作用取决于治疗的剂量和持续时间。然而，骨痂中前列腺素水平的降低随着药物停药而反弹，并且愈合骨折的机械完整性的损伤在短期治疗后逆转。
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.Clinical Relevance: While animal studies have suggested that both nonsteroidal anti-inflammatory drugs and coxibs inhibit bone repair, there have been no clinical reports with Level-1 evidence to support these findings. Because most patients discontinue these medications when pain has subsided, it is important to determine whether the inhibitory effects are reversible. The present animal study confirms that inhibition of cyclooxygenase 2 impairs fracture-healing and that the effects are dependent on both the dose and duration of treatment. However, the reduced prostaglandin levels in callus rebound with drug withdrawal, and the impairment in the mechanical integrity of the healing fractures is reversed after short-term treatment.