Recombinant Human Bone Morphogenetic Protein-2: Use in Spinal Fusion Applications

Abstract

It has been several decades since Marshall Urist's discovery of osteoinductive activity within demineralized bone protein extracts. Initially described in Science in 1965 1, Dr. Urist's remarkable discovery, an unexpected byproduct of intended research on the competitive binding of radionucleotides during bone mineralization, suggested that morphogenetic activity resides among certain bone-matrix-derived proteins; this work continued with Urist's later identification of the active molecules as bone morphogenetic proteins 2,3. This was followed, in 1988, by the isolation of an individual protein, BMP-2, from a purified extract and its recombinant production 4. The long-awaited clinical use and commercial availability of bone morphogenetic proteins (BMPs) have only recently approached reality. Recombinant human bone morphogenetic protein-2 (rhBMP-2) has been tested for use in spinal fusion in several completed prospective, randomized clinical trials, beginning in 1997. After rhBMP-2 was demonstrated to be equivalent to autogenous iliac bone graft with regard to both fusion rate and clinical outcome 5, a scientific advisory panel convened by the Food and Drug Administration (FDA) advised that rhBMP-2 be approved as the first complete bone-graft substitute for spinal fusion. At this time, rhBMP-2 carried on a type-I collagen sponge is approved for use in conjunction with a tapered, threaded intervertebral fusion cage (LT-Cage; Medtronic Sofamor Danek, Minneapolis, Minnesota) for the clinical treatment of degenerative lumbar disc disease. Preclinical proof-of-concept, feasibility, and efficacy studies laid the groundwork that established certain parameters for the clinical use of rhBMP-2. Each successive spinal fusion study contributed to the evolution of the design and dose of the carrier/protein combination. The site-specific characteristics of spinal fusion led to the development of specific carrier/rhBMP-2 combinations. This paper documents the preclinical and clinical progress of the development of rhBMP-2 as a viable complete bone-graft substitute and is a tribute to the pioneering …