Enhancing Effects of a Prostaglandin EP4 Receptor Agonist on Recombinant Human Bone Morphogenetic Protein-2 Mediated Spine Fusion in a Rabbit Model

Abstract

An experimental animal study aimed at achieving posterolateral intertransverse process fusion with rhBMP-2 in combination with the local delivery of an EP4 receptor agonist. To determine whether an EP4 receptor agonist (EP4A) can reduce the amount of BMP required to achieve posterolateral spinal fusion in rabbits. In the clinic, BMP retaining implants are used for spinal fusion and the treatment of pseudarthrosis after long bone fracture. However, the requirement of high doses of BMP-2 for bone formation in humans makes the implants expensive and limits their use in the clinic. Previous studies in our laboratory using a new delivery system involving a synthetic polymer/beta-TCP powder composite had shown it was possible to reduce the total BMP-2 amount to 30 microg per fusion in a rabbit model. To further reduce the dose of BMP required for a successful fusion, we explored the use of a chemical compound to enhance the bone-inducing action of BMP-2. In order to prepare 1 implant to bridge the unilateral L5 and L6 transverse processes, 300 mg of polymer gel (PLA-DX-PEG block copolymer), 300 mg of beta-TCP powder, rhBMP-2 (7.5, 3.75, or 0 microg), with or without EP4A (45 microg) were mixed and manually shaped to resemble a rod. Through a posterolateral approach, 2 implants were placed on both sides (1 per side) by surgery in order to bridge the transverse processes of adult New Zealand white rabbits (n = 48). The lumbar vertebrae were recovered 6 weeks after surgery. The posterolateral fusion was examined by manual palpation, radiography, biomechanical testing, and histology. All of 8 rabbits that received 7.5 microg of BMP-2 and EP4A consistently showed fusion by significant amount of new bone formation. However, solid fusion was seen in only 3 of 8 rabbits that received 7.5 microg of BMP-2 without the EP4 receptor agonist. Local administration of an EP4 receptor agonist enhanced the bone-inducing activity of BMP-2 in a rabbit posterolateral lumbar spinal fusion model and as a result, the dose of BMP-2 required for this outcome was reduced by 50% compared with our previous report. The coadministration of this compound via a local delivery system may help to reduce the costs of spine fusion with use of BMP-2 in the clinic.