Effects of indomethacin and local prostaglandin E_2 on fracture healing in rabbits

摘要

Indomethacin inhibits the prostaglandin synthesis and is used as an anti-inflammatory drug. Systemic indomethacin treatment inhibits the overall fracture healing process in stable as well as unstable fracture models in rats and rabbits assessed by increased angulation in unstable fractures and reduced strength development in stable fractures. The strength development is an overall indicator of the fracture healing process whereas hemodynamics, callus formation, and remodeling must be analyzed and understood in combination with many factors. It has not been possible to discover direct effects of indomethacin on bone blood flow, but increased blood flow 2 weeks after a plated osteotomy and a later increase indicate that indomethacin delays healing. This is further supported by a reduced RAP in the adjacent cortical bone and reduced BMC in the diaphyseal bone after indomethacin treatment of a plated osteotomy in rabbits. However, at unstable conditions the effect of indomethacin treatment on the BMC is not clear. Local infusion of PGE_2 to a plated tibial osteotomy in rabbits causes the formation of an abnormal callus with a low mineral content and biomechanical strength. The effects seem to be direct effects and not a modulation of the fracture repair process. In intact rat bone PGE_2 seems to enhance the remodeling process and to increase the bone mass. Similarly PGE_2 infusion to a periosteal defect increases the RAP, but PGE_2 infusion to an osteotomy with concomitantly increased RAP in the adjacent cortical bone, did not seem to have measurable effect over that caused by the fracture. The effects of PGE_2 may in part be mediated by IGF-I, which was found to increase in periosteal tissue during local PGE_2 stimulation. This observation provides in vivo confirmation of the in vitro observation that PGE_2 stimulates IGF-I.