O'Connor J Patrick, Capo John T, Tan Virak, Cottrell Jessica A, Manigrasso Michaele B, Bontempo Nicholas, Parsons J Russell
Department of Biochemistry, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ, USA.
Acta Orthop. 2009 Oct;80(5):597-605. doi: 10.3109/17453670903316769.
Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) activity, which is the rate-limiting enzyme in the synthesis of prostaglandins. Previous studies have indicated that NSAID therapy, and in particular NSAIDs that specifically target the inflammatory cyclooxygenase (COX-2), impair bone healing. We compared the effects of ibuprofen and rofecoxib on fibula osteotomy healing in rabbits to determine whether nominal, continuous inhibition of COX-2 with rofecoxib would differentially affect fracture healing more than cyclical inhibition of COX-2 using ibuprofen, which inhibits COX-1 and COX-2 and has a short half-life in vivo.
Bilateral fibula osteotomies were done in 67 skeletally mature male New Zealand white rabbits. The rabbits were treated with placebo, rofecoxib (12.5 mg once a day), or ibuprofen (50 mg 3 times a day) for 28 days after surgery. Plasma ibuprofen levels were measured by HPLC analysis. Bone healing was assessed by histomorphometry at 3 and 6 weeks after osteotomy, and at 6 and 12 weeks by torsional mechanical testing.
Plasma ibuprofen levels peaked and declined between successive doses. Fracture callus morphology was abnormal in the rofecoxib-treated rabbits and torsional mechanical testing showed that fracture healing was impaired. Ibuprofen treatment caused persistence of cartilage within the fracture callus and reduced peak torque at 6 weeks after osteotomy as compared to the fibulas from the placebo-treated rabbits. In the specimens allowed to progress to possible healing, non-union was seen in 5 of the 26 fibulas from the rofecoxib-treated animals as compared to 1 of 24 in the placebo group and 1 of 30 in the ibuprofen treatment group.
Continuous COX-2 inhibition as modeled by rofecoxib treatment appears to be more deleterious to fracture repair than cyclical cyclooxygenase inhibition as modeled by ibuprofen treatment. Ibuprofen treatment appeared to delay bone healing based upon the persistence of cartilage within the fracture callus and diminished shear modulus. Despite the ibuprofen-induced delay, rofecoxib treatment produced worse fracture (osteotomy) healing than ibuprofen treatment.
非甾体抗炎药（NSAIDs）抑制环氧化酶（COX）活性，而COX是前列腺素合成中的限速酶。既往研究表明，NSAID治疗，尤其是特异性靶向炎症性环氧化酶（COX-2）的NSAIDs，会损害骨愈合。我们比较了布洛芬和罗非昔布对兔腓骨截骨愈合的影响，以确定使用罗非昔布对COX-2进行持续、名义上的抑制是否比使用布洛芬对COX-2进行周期性抑制更能差异性地影响骨折愈合，布洛芬可抑制COX-1和COX-2，且在体内半衰期较短。
对67只骨骼成熟的雄性新西兰白兔进行双侧腓骨截骨术。术后28天，这些兔子分别接受安慰剂、罗非昔布（12.5mg，每日1次）或布洛芬（50mg，每日3次）治疗。通过高效液相色谱分析测定血浆布洛芬水平。在截骨术后3周和6周通过组织形态计量学评估骨愈合情况，并在6周和12周通过扭转力学测试进行评估。
连续给药期间，血浆布洛芬水平先达到峰值然后下降。罗非昔布治疗组的兔骨折痂形态异常，扭转力学测试显示骨折愈合受损。与安慰剂治疗组的腓骨相比，布洛芬治疗导致骨折痂内软骨持续存在，并在截骨术后6周降低了峰值扭矩。在允许进展至可能愈合的标本中，罗非昔布治疗组的26根腓骨中有5根出现骨不连，而安慰剂组24根中有1根，布洛芬治疗组30根中有1根。
罗非昔布治疗所模拟的COX-2持续抑制似乎比布洛芬治疗所模拟的环氧化酶周期性抑制对骨折修复更具损害性。基于骨折痂内软骨的持续存在和剪切模量降低，布洛芬治疗似乎延迟了骨愈合。尽管布洛芬导致延迟，但罗非昔布治疗产生的骨折（截骨）愈合情况比布洛芬治疗更差。
