It has been 37 years since Marshall Urist first described the ability of bone-derived proteins to induce bone formation in animals. Through the efforts of multiple scientists and clinicians, several osteoinductive proteins are on the threshold of availability for clinical use. This issue focuses on the three such proteins, which have progressed through the developmental process sufficiently to have human clinical trial data. These three osteoinductive proteins are recombinant human bone morphogenetic protein-2 (rhBMP-2); recombinant human bone morphogenetic protein-7 (rhBMP-7), also called recombinant human osteogenic protein-1 (rhOP-1); and a highly purified extract from a mixture of bovine bone morphogenetic proteins (bovine BMP extract). Small amounts of BMP also may be present in some demineralized bone matrix (DBM) preparations. However, the concentration of BMPs in DBM is not thought to be sufficient for it to be a complete substitute for autogenous bone graft in the more challenging healing environments.
Although numerous proteins are involved in bone formation, only select BMPs are capable of inducing bone formation in an ectopic location. Osteoinduction is defined as the ability of a protein or gene to mediate the induction of bone formation singularly in a nonbony location. In contrast, osteoconduction is defined as the ability of a material to act as a scaffold for new bone formation in a bony environment in the absence of implanted osteoinductive factors. That is, such material no intrinsic ability to induce bone formation independently. Osteoconductive materials may be used to deliver osteoinductive factors in a bony or nonbony environment. Some materials that do not contain osteoinductive factors can facilitate bone formation in a nonbony environment more actively than purely osteoconductive materials. In this discussion these substances are defined as osteopromotive.
One primary determinant of an osteoinductive factor’s success or failure is the amount of protein implanted. Unfortunately, there has been no standard method of reporting the amount of growth factor used. Instead of simple report on the overall dose, the most predictive parameter for efficacy appears to be the concentration of osteoinductive factor expressed as milligrams of protein per unit volume of the total implant. Using this method, there generally is a threshold concentration below which no bone or variable amounts of bone are induced and above which consistent bone induction may be observed. This threshold may be different for different osteoinductive factors, different carrier matrices, different anatomic locations, and even different animal species. In addition, this threshold may need to be raised in the face of systemic healing challenges such as smoking, corticosteroids, chemotherapeutic agents, and diabetes mellitus. Above the concentration threshold, the volume implanted will determine the amount of bone formed, and the shape of the carrier will determine the geometry.
Clinical application of osteoinductive factors is in its infancy, and this issue of Spine aims to provide the practicing spinal surgeon with the basic information needed to avoid the pitfalls that undoubtedly lie ahead as BMPs move into widespread clinical use. The articles cover the basic science as well as the preclinical and clinical information available. A panel of international experts has been assembled in an attempt to define standard nomenclature, and to propose minimum elements for meeting the burden of proof needed to ensure safe clinical application.
Spine surgeons need to become comfortable with more than just bones and metal. The ability to manipulate the cellular environment soon will be incorporated into every operating room. The age of BMP has arrived. We must embrace it, respect it and apply it with appropriate care and caution.