Commentary & Perspective

Commentary & Perspective on
"Percutaneous Injection of Recombinant Human Bone Morphogenetic Protein-2 in a Calcium Phosphate Paste Accelerates Healing of a Canine Tibial Osteotomy"
by Ryland B. Edwards 3rd, DVM, MS, PhD, et al.

Commentary & Perspective by
Thomas A. Einhorn, MD*,
Department of Orthopaedic Surgery, Boston Medical Center, Boston, Massachusetts

On November 12, 1965, Marshall Urist published his classic article in which he described a property of demineralized bone matrix that had the ability to regenerate new bone¹. Subsequently, clinicians and scientists have anticipated the development of a bioactive compound that would make the difficulties associated with fracture-healing or spinal fusion things of the past. Although it took a bit longer than expected, the United States Food and Drug Administration recently cleared for marketing two recombinant human bone morphogenetic protein (rhBMP)-based products, rhBMP-7 (OP-1) for the treatment of recalcitrant nonunions of long bones and posterolateral lumbar spine fusions, and INFUSE Bone Graft (Medtronic Sofamor Danek, Memphis, Tennessee) for the treatment of open tibial fractures and single-level interbody fusions of the lumbar spine. While the FDA-approved uses of these products include additional restrictions (the need for Institutional Review Board approval for the use of OP-1 under a Humanitarian Device Exception; the use of INFUSE Bone Graft as a composite implant consisting of rhBMP-2, an absorbable collagen sponge, and a threaded titanium cage when used in the spine), the early reports on the use of these materials are encouraging^2,3,4. Except for the fact that the unit costs are high (ranging from $4900 to $5200 per implant), the current interest among orthopedic surgeons is strong. It seems that Marshall Urist's "magic bullet" is beginning to get some target practice.

In this issue of The Journal, another advance in BMP technology is addressed: the percutaneous injection of fractures with a calcium phosphate-based formulation⁵. Following on the heels of an article that my group published in the August 2003 issue of The Journal, in which rhBMP-2 was shown to stimulate fracture-healing in rats after percutaneous injection in an aqueous delivery vehicle⁶, this study takes the next step by the use of a delivery vehicle that may be more appropriate for human use.

The interest in developing an injectable BMP has been high ever since the stimulatory activity of this molecule for fracture-healing was recognized. Obvious examples of how this could be used clinically include the treatment of closed fractures that do not undergo operative intervention, the treatment of closed fractures that undergo operative intervention but in which the fracture site is not directly exposed, and the advancement of minimally invasive operative techniques in which introduction of a growth factor at the operative site can be accomplished with the tiniest of incisions. However, as with the use of any formulation of BMP, there is still a need to improve the human host response and to achieve a more consistent and reliable outcome. Ways to accomplish this may include enhancements in the activities of the molecules themselves, development of more optimal physiologic carriers for presenting the proteins to responding cells, or improvements in the kinetics of release and retention of the proteins in the tissues. The latter two possibilities may be addressed with an innovative injectable delivery vehicle.

The spectrum of delivery vehicles that are potentially useful for the administration of BMPs and other growth factors includes polylactic and polyglycolic acid carriers, hyaluronic acid gels, calcium phosphate-based pastes and cements, carboxymethyl cellulose substrates, and others⁷. Two recent reviews pointed to calcium phosphate-based products as showing great promise^8,9. The cements set under endothermic conditions and form poorly crystalline hydroxyapatite. The endothermic setting eliminates thermal damage to the proteins, and the calcium phosphate chemistry enhances protein-binding. Thus, while the poorly crystalline properties of these hydroxyapatites enhance their removal by osteoclasts and giant cells, minimizing their interference with fracture-healing and promoting the release of bound components, the resident time for the protein in the tissues is substantially greater than it would be if an aqueous delivery vehicle was used. Moreover, radio-opacity permits the surgeon to view the introduction, flow, and distribution of the material at the time of its injection—a potentially essential feature when BMPs are injected into a confined space involving adjacent vital structures.

A major advantage of an injectable osteogenic agent is the ability to time its administration for optimal effect. As was shown by Seeherman et al.¹⁰, administration of rhBMP-2 one week after injury in a nonhuman primate fibular osteotomy model was more osteogenic than was exposure of the fracture to the protein at the time of the initial injury. The reasons for this result, while not fully understood, might be explained by a greater number of responding cells at the fracture site several days after the initiation of a proliferative response to injury, a more favorable microenvironment for healing after the initial inflammatory response has subsided, or perhaps a direct stimulation of cells that have already begun to make bone.

Calcium phosphate-based cements are beginning to receive heightened attention for their use as adjuncts in fracture-fixation as well as in the delivery of bioactive molecules. One recent innovation has been the incorporation of growth factors in microspheres embedded in the calcium phosphate structure. An associated advantage is that the release kinetics may be better controlled because the protein is not distributed throughout the mass of cement but rather in discrete packages, contained as microspheres.

As this field continues to evolve and better clinical results are achieved through advanced discovery, improved delivery, and modification of host responsiveness, orthopaedic surgeons must be reminded that attention to principles of orthopaedic management are still paramount in delivering the highest quality of care. As an example, although BMP injection into a delayed union may boost its healing potential, treatment of a nonunion should not be attempted until the underlying cause of failure is identified and corrected. The use of BMPs and other growth factors will not compensate for inadequate fracture reduction, stabilization, or traumatic handling of soft tissues. Simply stated, these technologies will not make bad surgeons good; they will make good surgeons better.

*The author did not receive grants or outside funding in support of his research or preparation of this manuscript. The author received payments or other benefits or a commitment or agreement to provide such benefits from commercial entities (Stryker Biotech and Wyeth Research). No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the author is affiliated or associated.

References

1. Urist MR. Bone: formation by autoinduction. Science. 1965;150:893-9.
2. Friedlaender GE, Perry CR, Cole JD, Cook SD, Cierny G, Muschler GF, Zych GA, Calhoun JH, LaForte AJ, Yin S. Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. J Bone Joint Surg Am. 2001;83 (Suppl 1 [Pt 2]):S151-8.
3. Burkus JK, Gornet MF, Dickman CA, Zdeblick TA. Anterior lumbar interbody fusion using rhBMP-2 with tapered interbody cages. J Spinal Disord Tech. 2002;15:337-49.
4. Burkus JK, Heim SE, Gornet MF, Zdeblick TA. Is INFUSE bone graft superior to autograft bone? An intergrated analysis of clinical trials using the LT-CAGE lumbar tapered fusion device. J Spinal Disord Tech. 2003;16:113-22.
5. Edwards RB 3rd, Seeherman HJ, Bogdanske JJ, Devitt J, Vanderby R Jr, Markel MD. Percutaneous injection of recombinant human bone morphogenetic protein-2 in a calcium phosphate paste accelerates healing of a canine tibial osteotomy. J Bone Joint Surg Am. 2004;86:1425-38.
6. Einhorn TA, Majeska RJ, Mohaideen A, Kagel EM, Bouxsein ML, Turek TJ, Wozney JM. A single percutaneous injection of recombinant human bone morphogenetic protein-2 accelerates fracture repair. J Bone Joint Surg Am. 2003;85:1425-35.
7. Seeherman H. The influence of delivery vehicles and their properties on the repair of segmental defects and fractures with osteogenic factors. J Bone Joint Surg Am. 2001;83(Suppl. 1 [Pt 2]):S79-81.
8. Seeherman H, Wozney J, Li R. Bone morphogenetic protein delivery systems. Spine. 2002;27(16 Suppl 1):S16-23.
9. Seeherman H, Li R, Wozney J. A review of preclinical program development for evaluating injectable carriers for osteogenic factors. J Bone Joint Surg Am. 2003;85(Suppl 3):96-108.
10. Seerherman H, Li R, Blake C, Bouxsein M, Cooper J, Gavin D, Li XJ, Wozney JM. A single injection of rhBMP-2/calcium phosphate paste given one week after surgery accelerates healing by 50% in a non-human primate fibula osteotomy model. Trans Orthop Res Soc. 2002;48:237.

Copyright © 2004 by the The Journal of Bone and Joint Surgery, Inc.