COX‐2 has a Critical Role During Incorporation of Structural Bone Allografts

Department of Orthopedics, The Center for Musculoskeletal Research, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Annals of the New York Academy of Sciences (Impact Factor: 4.38). 04/2006; 1068(1):532-42. DOI: 10.1196/annals.1346.012
Source: PubMed


Nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit cyclooxygenase (COX) activity, reduced pain and are commonly used in patients with skeletal injury. In this article we will also present data to show that selective COX-2 inhibitor delays allograft healing and incorporation. In contrast, local delivery of prostaglandin E2 (PGE2) enhanced bone formation at cortical bone graft junction. A 4-mm mid-diaphyseal segmental femoral defect was created and then repaired by frozen bone allograft of the same size. A 22-gauge metal pin was placed in the intramedullary cavity to stabilize the bone graft. Healing was evaluated weekly by X ray and by a semiquantitative histomorphometric analysis at 5 weeks postsurgery. Celecoxib (25 mg/kg/day) and Ketorolac (4 mg/kg/day) were administered daily for 2 weeks or 5 weeks. PGE2 was infused locally at a dose of 800 nmol/kg per day via osmotic minipump for 4 weeks. Inhibition of cyclooxygenase by daily administration of the Celecoxib or Ketorolac for 5 weeks reduced new bone ingrowth by about 60% (P < 0.05). The percentage of bony bridging in both drug-treated groups was significantly decreased at 5 weeks. Temporal administration of Celecoxib for 2 weeks also significantly reduced bone formation by 45% and withdrawal of the Celecoxib only led to slight recovery of bone formation at the graft side. In contrast to the inhibitory effects of NSAIDS, PGE2 infusion at the cortical bone junction increased bone formation by about twofold. These results demonstrated that COX-2 is essential for bone allograft incorporation. Furthermore, our data support the notion that COX-2-dependent PGE2 produced at the early stage of bone healing is prerequisite for efficient skeletal repair.

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    • "PGs are synthesized by osteoblasts in an auto-regulated fashion, controlling their own production, being abundant in bone matrix (Chikazu et al. 2011), capable of stimulating bone resorption and responsible for the controlling of events related to the processes of bone formation and repair by amplifying osteoblastic activity and positively acting in their differentiation (Einhorn 2002). Negative effects on the healing of allografts in mice femoral defects were reported with the administration of celecoxib (25 mg/Kg, daily), with a 60 % reduction of bone ingrowth after 2 weeks (O'Keefe et al. 2006). They are possible related to the interaction among the various chemical mediators released during inflammatory phase. "
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    ABSTRACT: Success of alveolar reconstructions using onlay autogenous block bone grafts depends on their adequate integration to the recipient bed influenced by a number of local molecules. Considering the fundamental role of cyclooxygenase (COX-2) in bone repair, the aim of this study was to analyze the effect of its inhibition in the integration of endochondral (EC) iliac crest, and intramembranous (IM) calvaria bone grafts. Thirty-two rabbits were divided into 4 groups: Calvaria Control (CC) and Iliac Control-treated with oral 0.9 % saline solution, and Calvarial-NSAID (C-NSAID) and Iliac-NSAID (I-NSAID) groups-treated with oral 6 mg/Kg non-steroidal anti-inflammatory drug etoricoxib. After 7, 14, 30 and 60 days the animals were euthanized and the specimens removed for histological, histomorphometric and immunohistochemistry analysis. At day 60, a tight integration of IM blocks could be seen with the presence of remodeling bone, whereas integration of EC grafts was mainly observed at the edges of the grafts. A significant higher percentage of bone matrix in the interface region of the CC grafts in comparison to C-NSAID only at day 14, whereas no differences were detected comparing the EC grafts. No differences were observed in Runx-2 and vascular endothelial growth factor (VEGF) immunolabeling when comparing CC and C-NSAID groups, while a significant weaker Runx-2 and VEGF labeling was detected in I-NSAID group at day 60. Although some influence was detected in osteogenesis, it is concluded that drug induced inhibition of COX-2 does not impair onlay bone grafts' healing of both embryologic origins in rabbits.
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    • "Reports of adverse effects on bone healing by NSAIDS led to the investigation of the effects by COX-2 inhibitors on bone healing. COX-2– dependent PGE 2 produced at the early stage of bone healing is a prerequisite for efficient skeletal repair [55]. A study on healing bone fractures showed a decrease in osteogenesis potential after the cells were treated with celecoxib [67]. "
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