The role of cyclo-oxygenase-2 during fracture healing

The initial phase of fracture healing is the inflammatory phase. Cyclooxygenase-2 (COX-2) is induced at sites of inflammation and is responsible for the production of prostaglandins. The effects of prostaglandins on fracture healing are not clearly understood, since they both stimulate bone formation and resorption.;The initial study focused on the effects of long-term or continuous inhibition of COX-2 during fracture healing. The study examined the effect of the COX-2 specific inhibitors, celecoxib and rofecoxib in a rat closed femur fracture model. The histologic observations revealed that the morphology of the callus is altered by celecoxib and rofecoxib. The mechanical data of the rofecoxib-treatment group showed a marked reduction in material and structural properties at all time points. The visual inspection data of the rofecoxib group showed fibrous non-unions. The celecoxib-treatment group had mechanical properties similar to the control femora, but failed as fibrous non-unions. The indomethacin-treatment group had diminished mechanical properties, but did fail as unions.;The second study focused on the effects of COX-2 inhibition during the early phases of fracture healing. The animals were treated with different doses of celecoxib or treated for different periods before or after fracture. The celecoxib dose of 2 mg/kg/day reduced mechanical properties and caused a significant increase in non-unions. Similarly, treatment with celecoxib 4 mg/kg/day for 5 days reduced mechanical properties. Celecoxib therapy prior to fracture did not affect materials properties.;The third study was to determine the effect of celecoxib treatment on the production of prostaglandin E2 within the fracture callus at 4 days post-fracture. Celecoxib treatment reduced fracture callus prostaglandin E2 levels by almost 61%. The final study focused on the effects of COX-2 inhibition on the cellular proliferation with in the fracture callus. No peak in the cellular proliferation rate (BrdU + / total) was observed in the celecoxib treated animals. However the cellular proliferation rate peaked at day 4 post-fracture in control animals. With the use of a closed femur fracture model, it was possible to determine that COX-2 is essential for fracture healing. The experimental results indicate that COX-2-specific NSAID therapy significantly impairs fracture healing.