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Commentary and Perspective   |    
An Injectable BMP Cocktail for Fracture-Healing—A Study That Others Have Only ImaginedCommentary on an article by Thomas Lyon, MD, et al.: “Efficacy and Safety of Recombinant Human Bone Morphogenetic Protein-2/Calcium Phosphate Matrix for Closed Tibial Diaphyseal Fracture. A Double-Blind, Randomized, Controlled Phase-II/III Trial”
Cory Collinge, MD1
1 Fort Worth, Texas
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The author did not receive payments or services, either directly or indirectly (i.e., via his institution), from a third party in support of any aspect of this work. He, or his institution, has had a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. The author has not had any other relationships, or engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.


Copyright © 2013 by The Journal of Bone and Joint Surgery, Inc.
J Bone Joint Surg Am, 2013 Dec 04;95(23):e189 1-2. doi: 10.2106/JBJS.M.01179
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Bone morphogenetic proteins (BMPs) are important mediators of fracture repair. They include a group of bioactive proteins that are synthesized locally at a fracture site and work mostly by upregulating stem-cell differentiation, thereby stimulating bone formation. As such, BMPs are of major interest to orthopaedic surgeons as osteoinductive agents in patients with a difficult fracture in whom bone-healing is potentially compromised. Several BMPs, including recombinant human BMP-2 (rhBMP-2), have been characterized and synthesized via recombinant technology: bone formation is induced in a more or less dose-dependent fashion and may be given in quantities that vastly exceed physiologic amounts. rhBMP-2 has U.S. Food and Drug Administration approval for use in anterior lumbar spine fusions (2002) and for open tibial fractures (2004)1-3. A small number of studies have shown efficacy for achieving bone-healing in these areas, although recently the methodology of some of these studies has been called into question4.
Lyon et al. put together a fascinating study. Functionally, it is a well-designed randomized controlled trial of “injectable” BMP in closed tibial shaft fractures in patients treated with intramedullary nailing: the authors compared the radiographic and clinical healing in patients treated with injection at the fracture site, using two quantities of BMP-2 in calcium phosphate matrix, with that in controls (nailing only). The importance of this study, however, is that the ultimate goal of the study seems to be to design an injectable “cocktail” that will improve fracture-healing, by speeding up the healing process and minimizing the rate of nonunion. This goal has been the vision of surgeons and scientists much longer than the half century since Urist’s discovery of BMP5.
Unfortunately for all of us, the findings of the study indicate that the “cocktail” (as prepared) was unlikely to make a difference: the trial was shut down prematurely when a planned preliminary review demonstrated no treatment effect. There are a number of reasons these results may have been found. rhBMP-2 might not significantly affect healing in the optimal circumstances of closed fractures treated with the standard of care. Perhaps more likely though, the recipe needs to be refined to improve the cocktail’s effect. There are many variables in play here. For example, it is known that the efficacy of rhBMP-2 is carrier-dependent, and the authors suggest that the carrier may have allowed dispersal of the BMP away from the fracture site (seen radiographically). Additionally, changes in the preparation of the BMP product were made between this and prior clinical trials that may have altered clinical effects, although details of those changes are proprietary and thus unavailable.
Certainly, further studies that will investigate refined recipes for injectable materials to improve fracture-healing will come along, perhaps by the same study group. Their well-designed trial might be used as a model for future endeavors. Successful in finding a positive effect or not, the authors should also be commended for their impetus in actually studying what others have only imagined. Finally, a cautionary note must be acknowledged regarding the possibility for long-term problems with BMP usage: there are no ideal studies proving long-term safety. As we proceed with further investigations with BMPs, we must continue to maintain patient safety as a primary goal in their usage.
Aro  HT;  Govender  S;  Patel  AD;  Hernigou  P;  Perera de Gregorio  A;  Popescu  GI;  Golden  JD;  Christensen  J;  Valentin  A. Recombinant human bone morphogenetic protein-2: a randomized trial in open tibial fractures treated with reamed nail fixation. J Bone Joint Surg Am.  2011 May 4;93(  9):801-8.  Epub 2011 Mar 31.[CrossRef]
 
Jones  AL;  Bucholz  RW;  Bosse  MJ;  Mirza  SK;  Lyon  TR;  Webb  LX;  Pollak  AN;  Golden  JD;  Valentin-Opran  A; BMP-2 Evaluation in Surgery for Tibial Trauma-Allgraft (BESTT-ALL) Study Group. Recombinant human BMP-2 and allograft compared with autogenous bone graft for reconstruction of diaphyseal tibial fractures with cortical defects. A randomized, controlled trial. J Bone Joint Surg Am.  2006 Jul;88(  7):1431-41.[CrossRef]
 
Swiontkowski  MF;  Aro  HT;  Donell  S;  Esterhai  JL;  Goulet  J;  Jones  A;  Kregor  PJ;  Nordsletten  L;  Paiement  G;  Patel  A. Recombinant human bone morphogenetic protein-2 in open tibial fractures. A subgroup analysis of data combined from two prospective randomized studies. J Bone Joint Surg Am.  2006 Jun;88(  6):1258-65.[CrossRef]
 
Carragee  EJ;  Hurwitz  EL;  Weiner  BK. A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned. Spine J.  2011 Jun;11(  6):471-91.[CrossRef]
 
Urist  MR. Bone: formation by autoinduction. Science.  1965 Nov 12;150(  3698):893-9.[CrossRef]
 

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References

Aro  HT;  Govender  S;  Patel  AD;  Hernigou  P;  Perera de Gregorio  A;  Popescu  GI;  Golden  JD;  Christensen  J;  Valentin  A. Recombinant human bone morphogenetic protein-2: a randomized trial in open tibial fractures treated with reamed nail fixation. J Bone Joint Surg Am.  2011 May 4;93(  9):801-8.  Epub 2011 Mar 31.[CrossRef]
 
Jones  AL;  Bucholz  RW;  Bosse  MJ;  Mirza  SK;  Lyon  TR;  Webb  LX;  Pollak  AN;  Golden  JD;  Valentin-Opran  A; BMP-2 Evaluation in Surgery for Tibial Trauma-Allgraft (BESTT-ALL) Study Group. Recombinant human BMP-2 and allograft compared with autogenous bone graft for reconstruction of diaphyseal tibial fractures with cortical defects. A randomized, controlled trial. J Bone Joint Surg Am.  2006 Jul;88(  7):1431-41.[CrossRef]
 
Swiontkowski  MF;  Aro  HT;  Donell  S;  Esterhai  JL;  Goulet  J;  Jones  A;  Kregor  PJ;  Nordsletten  L;  Paiement  G;  Patel  A. Recombinant human bone morphogenetic protein-2 in open tibial fractures. A subgroup analysis of data combined from two prospective randomized studies. J Bone Joint Surg Am.  2006 Jun;88(  6):1258-65.[CrossRef]
 
Carragee  EJ;  Hurwitz  EL;  Weiner  BK. A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned. Spine J.  2011 Jun;11(  6):471-91.[CrossRef]
 
Urist  MR. Bone: formation by autoinduction. Science.  1965 Nov 12;150(  3698):893-9.[CrossRef]
 
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