Copyright © 2006 by The Journal of Bone and Joint Surgery, Inc.
Commentary & Perspective
Commentary & Perspective by
Peter Kloen, MD, PhD*,
Department of Orthopedic Surgery, Academisch Medisch Centrum, Amsterdam, The Netherlands
Bone morphogenetic proteins (BMPs) play pivotal roles in the embryogenesis, development, and repair of the skeletal system. An enormous body of research that began with Marshall Urist's initial discovery of these proteins in 1965 led to the recent approval by the United States Food and Drug Administration of two BMP isoforms for limited clinical use to generate bone: rhBMP-2 and rhBMP-7 (osteogenic protein [OP-1]).
After impressive results were seen in numerous preclinical studies, the greatly anticipated clinical application of BMPs in orthopaedic surgery is now under way. To date, most clinical studies for BMPs have been restricted to applications in spinal surgery, and these studies seem to confirm that BMP increases bone formation and can accelerate spinal fusion. On the other hand, convincing data on the efficacy of BMPs in trauma (fracture-healing and bone regeneration in defects and/or nonunions) have been less forthcoming. What are the important differences between healing of a long-bone fracture and trying to obtain spinal fusion? In the spine, we expect BMP to produce bone where initially there was none. This is exactly what characterizes a BMP, that is, the ability to produce bone at an ectopic (nonosseous) location. However, in fractures and nonunions, we expect BMP to accelerate or restart a healing response where there was bone before (osseous location). Fracture healing is a biologically complex process with thousands of genes involved. Hence, following fracture, all components of the BMP-signaling cascade are likely to be already present, as confirmed by us recently, suggesting that a single exogenous BMP might not be the "magic bullet" we and our patients have hoped for1. Another factor that may be driving the different success rates observed to date with BMPs in spinal and trauma surgery is the presence of a consistently more responsive cell population in certain areas of the spine (e.g., posterolateral gutters), leading to more predictable results.
Obviously, one of the obstacles to completing a randomized controlled trial is the large number of patients needed, especially in a population of patients with long-bone fractures of very diverse circumstances. To complete a randomized controlled trial on the use of BMP in trauma will thus require a long inclusion period or a large number of participating centers.
Two randomized controlled trials on the use of BMP in the treatment of tibial fractures have been published to date2,3. Although widely quoted, both have experimental design flaws4. To the best of my knowledge, the current study by Jones et al. is the third randomized controlled trial to address the use of a BMP in tibial fractures. Each of the thirty patients (fifteen in each group) in their study had a residual cortical defect after initial fracture fixation and underwent a staged reconstruction with either autogenous cancellous bone graft (the gold standard) or rhBMP-2/absorbable collagen sponge and allograft bone chips. In the latter treatment, the rhBMP-2 is the presumed osteoinductor, whereas the allograft has only limited—if any—osteoinductive capacity and merely functions as osteoconductor. The outcome was based on unblinded clinical and partially blinded radiographic evaluation. The authors concluded that rhBMP-2/absorbable collagen sponge and allograft is safe and is as effective as autogenous cancellous bone-grafting. Given the lack of complications in the rhBMP-2 group, their conclusion on safety seems correct, albeit in a very small number of patients. Safety studies for new drugs need to include many patients because complications are rarer than observed treatment effects. This study was powered on efficacy, not on safety. As far as the efficacy of rhBMP-2/allograft is concerned, however, there is a lack of proper controls to isolate the effects of rhBMP-2. The main conclusion to be drawn from this paper is that this particular combination of rhBMP-2/absorbable collagen sponge and allograft is tolerated well at this location and that in this limited experience there seems to be no difference in measured outcome as compared to autologous bone graft.
One of the enigmas about the use of BMP in clinical practice is why such large quantities of the protein seem to be needed to get a specific—if any—effect. The amount of BMP in native bone is on the order of 1 to 2 μg of BMP/kg of cortical bone, whereas the total dosage of rhBMP-2 used in this study is 12 mg. This dosage thus equals the amount stored in at least 6000 kg (!) of native cortical bone. This amount dwarfs the 39 cc average volume of cancellous bone that was used in the control group with apparently the same results. Why is it that rhBMP-2 is so much less efficient? Do we expect too much from a single protein? Are we missing something? There are literally thousands of genes that are either up-regulated or down-regulated during fracture healing. In addition, mechanisms of regulation of BMP signaling crosstalk with other signaling pathways and their roles are still incompletely understood. The idea of successfully manipulating the extremely complex process of bone-healing through the use of a supraphysiological dose of a single factor may be naive.
Another unsolved issue is which, if any, BMP is the optimal growth factor to promote fracture healing. A combination of more than one BMP might be better than a single one. Testing more than one growth factor at a time in a clinical trial is, however, exceedingly complex. Clinical trials that test a cocktail of BMP-2 and BMP-7 may prove to be difficult, given that the commercial rights are owned by two competing companies (the current authors fail to mention or even reference BMP-7 [OP-1]).
Another problem that must be solved is that optimal bone induction by BMP seems to depend on implant location. A viable muscular bed (e.g., during posterolateral bone-grafting in spine) seems to provide a more favorable environment for osteogenic differentiation in the presence of exogenous BMP. The presence or lack of a viable muscular bed may make some applications less likely to succeed than others. For instance, there usually is no circumferential presence of healthy muscle in severe (open) tibial fractures, which would suggest that BMPs might have a less powerful effect on bone induction in tibial fractures than elsewhere.
Finally, two recent publications provide some negative evidence on the clinical use of BMPs in select applications involving allografts. Pradhan et al. presented data in Spine that suggested that rhBMP-2 caused an aggressive resorption of femoral ring allografts used for anterior lumbar interbody fusion in human patients5. Another clinical study on the use of BMP-7 in impaction allografting in hip revisions also failed to show any benefit6.
Given what we do know about the important role of BMPs in bone development and formation, there is little doubt that BMPs will have a future role in the armamentarium of the trauma surgeon. At this stage, however, the data proving their effect on fracture healing and in treatment of nonunion and/or defects in humans are not overwhelming. We should not forget that clinical application of these compounds is still in its infancy. Improvements in its carriers, the ability to deliver them in a more controlled fashion (e.g., gene therapy), and a better understanding of its mechanisms, target cells, and gene responses will undoubtedly earn BMPs a role in operative treatment of fractures. Studies such as that of Jones et al. help in the sense that they further document important data about actual patient response under current protocols. These authors should be congratulated on their work, but we should all keep in mind that there is much more work to be done. This being the era of nanotechnology, genomics, and proteomics, it will only be a matter of time before the orthopaedic traumatologist will modulate fracture repair not only with hardware but also at the cellular level.
*The author did not receive grants or outside funding in support of his research for or preparation of this manuscript. He did not receive payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. 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. Kloen P, Doty SB, Gordon E, Rubel IF, Goumans M-J, Helfet DL. Expression and activation of the BMP-signaling components in human fracture nonunions. J Bone Joint Surg Am. 2002;84:1909-18.
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):S151-61.
3. Govender S, Csimma C, Genant HK, Valentin-Opran A, Amit Y, Arbel R, Aro H, Atar D, Bishay M, Borner MG, Chiron P, Choong P, Cinats J, Courtenay B, Feibel R, Geulette B, Gravel C, Haas N, Raschke M, Hammacher E, van der Velde D, Hardy P, Holt M, Josten C, Ketterl RL, Lindeque B, Lob G, Mathevon H, McCoy G, Marsh D, Miller R, Munting E, Oevre S, Nordsletten L, Patel A, Pohl A, Rennie W, Reynders P, Rommens PM, Rondia J, Rossouw WC, Daneel PJ, Ruff S, Ruter A, Santavirta S, Schildhauer TA, Gekle C, Schnettler R, Segal D, Seiler H, Snowdowne RB, Stapert J, Taglang G, Verdonk R, Vogels L, Weckbach A, Wentzensen A, Wisniewski T; BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group. Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J Bone Joint Surg Am. 2002;84:2123-34.
4. Westerhuis RJ, van Bezooijen RL, Kloen P. Use of bone morphogenetic proteins in traumatology. Injury. 2005;36:1405-12.
5. Pradhan BB, Bae HW, Dawson EG, Patel VV, Delamarter RB. Graft resorption with the use of bone morphogenetic protein: lessons from anterior lumbar interbody fusion using femoral ring allografts and recombinant human bone morphogenetic protein-2. Spine. 2006;31:E277-84.
6. Karrholm J, Hourigan P, Timperley J, Razaznejad R. Mixing bone graft with OP-1 does not improve cup or stem fixation in revision surgery of the hip: 5-year follow-up of 10 acetabular and 11 femoral study cases and 40 control cases. Acta Orthop. 2006;77:39-48.
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