Dose and Time-Dependent Effects of Cyclooxygenase-2 Inhibition on Fracture-Healing

Department of Orthopaedics, UMDNJ-New Jersey Medical School, MSB G580/ORTHO, 185 South Orange Avenue, Newark, NJ 07103, USA.
The Journal of Bone and Joint Surgery (Impact Factor: 5.28). 03/2007; 89(3):500-11. DOI: 10.2106/JBJS.F.00127
Source: PubMed


Fracture-healing is impaired in mice lacking a functional cyclooxygenase-2 (COX-2) gene or in rats continuously treated with COX-2 inhibitors. These observations indicate that COX-2 is a critical regulator of fracture repair. Nonsteroidal anti-inflammatory drugs are commonly used to treat pain associated with musculoskeletal trauma and disease. Nonsteroidal anti-inflammatory drugs inhibit COX-2 function and in so doing can impair fracture-healing. The goal of the present study was to determine how variations in nonsteroidal anti-inflammatory drug therapy ultimately affect fracture-healing.
Closed femoral fractures were made in female Sprague-Dawley rats. The rats were treated with different doses of celecoxib (a COX-2-selective nonsteroidal anti-inflammatory drug) or were treated for different periods before or after fracture with celecoxib. Eight weeks after the fracture, healing was assessed with radiography and destructive torsional mechanical testing. The effect of celecoxib treatment on fracture callus prostaglandin E2 and F(2alpha) levels was determined as a measure of cyclooxygenase activity.
Celecoxib doses as small as 2 mg/kg/day reduced fracture callus mechanical properties and caused a significant increase in the proportion of nonunions. Similarly, treatment with celecoxib at a dose of 4 mg/kg/day for just five days reduced fracture callus mechanical properties and significantly increased the proportion of nonunions. Conversely, celecoxib therapy prior to fracture or initiated fourteen days after fracture did not significantly increase the proportion of nonunions. Celecoxib treatment at a dose of 4 mg/kg/day reduced fracture callus prostaglandin E2 and F(2alpha) levels by >60%.
COX-2-selective nonsteroidal anti-inflammatory drug therapy during the early stages of fracture repair significantly reduced fracture callus mechanical properties at later stages of healing and increased the proportion of nonunions in this animal model.

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    • "Numerous studies have shown traditional NSAIDs may inhibit bone metabolism and healing,[2122] but there are numerous controversies and also little is known about the alleged inhibitory effects of the newer COX-2 inhibitors on this process.[232425] Therefore, the role of COX-2 in bone regeneration needs to be better defined in order to further elucidate the impact of NSAIDs on bone healing.[26] "
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    ABSTRACT: Background: Osteoclastogenesis is coordinated by the interaction of members of the tumor necrosis factor (TNF) superfamily: Receptor activator of nuclear factor-κB ligand (RANKL) and Osteoprotegerin (OPG). The aim of this study was to compare the effect of two different types of non-steroidal anti-inflammatory drugs (NSAIDs) on the RANKL/OPG balance during the healing of the alveolar process. Materials and Methods: This was an experimental study, carried on 45 male Wistar rats (200 ± 25 g, 8-10 weeks old). After extraction of the right maxillary first molar, 15 rats received 5 mg/kg/day of diclofenac and 15 rats received 15 mg/kg/day of celecoxib and 15 rats received normal saline. The animals were sacrificed 7, 14 and 21 days after tooth extraction. The number of osteoclasts, OPG and RANKL messenger ribonucleic acid expression were determined by tartrate-resistant acid phosphate (TRAP) staining and polymerase chain reaction (PCR) respectively. The data were analyzed by one-way ANOVA followed by Tukey's post-hoc test. Values of P < 0.05 were considered significant. Results: On days 7, 14 and 21 the ratio of RANKL/OPG in the control group was higher than diclofenac and celecoxib groups. TRAP immunolabeling of the control group was more than diclofenac group on day 7 and was more than celecoxib group on day 14. On day 21, no significant differences were noted among the three studied groups. Conclusion: Both drugs affect RANKL/OPG gene expression and also osteoclastogenesis in alveolar socket during the experimental period of 21 days.
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    • "Ibuprofen and indomethacin can slow the process of bone healing,10 while celecoxib11 , 12 and acetominofen12 , 13 did not influence this process. Simon and O'Connor,14 on the other hand, reported that celecoxib significantly reduces mechanical properties of the callus in the early stages of repair of fractures and increases the proportion of pseudoarthrosis in later stages. "
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    ABSTRACT: OBJECTIVE: To evaluate the effect of dipyrone on healing of tibial fractures in rats. METHODS: Fourty-two Wistar rats were used, with mean body weight of 280g. After being anesthetized, they were submitted to closed fracture of the tibia and fibula of the right posterior paw through manual force. The rats were randomly divided into three groups: the control group that received a daily intraperitoneal injection of saline solution; group D-40, that received saline injection containing 40mg/Kg dipyrone; and group D-80, that received saline injection containing 80mg/Kg dipyrone. After 28 days the rats were sacrificed and received a new label code that was known by only one researcher. The fractured limbs were then amputated and X-rayed. The tibias were disarticulated and subjected to mechanical, radiological and histological evaluation. For statistical analysis the Kruskal-Wallis test was used at a significance level of 5%. RESULTS: There wasn't any type of dipyrone effect on healing of rats tibial fractures in relation to the control group. CONCLUSION: Dipyrone may be used safely for pain control in the treatment of fractures, without any interference on bone healing. Level of Evidence II, Controlled Laboratory Study.
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    • "Animal studies performed with COX-2 knockout mice revealed that the activity of the COX-2 enzyme has an important role in osteogenesis [32, 40]. Fracture sites in wild-type animals showed delayed bone healing when they were treated with COX-2 inhibitors for a very long time with a high dose [8, 11, 23, 32, 33]. Although these data could explain that PGE2 is an essential molecule in fracture healing, the question still remains concerning why there is no clear evidence for delayed fracture healing as a result of COX-2 inhibitor treatment in clinical use. "
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