The December 2002 issue of the American volume of The Journal carried an article by Govender et al. reporting the results of the BESTT (BMP-2 Evaluation in Surgery for Tibial Trauma) study group on the effects of recombinant human bone morphogenetic protein-2 (rhBMP-2) in the treatment of open tibial fractures. That study, which randomized 450 patients with open tibial fractures to either the then current standard of care, consisting of irrigation and débridement and definitive treatment with an intramedullary nail, or that same treatment in conjunction with implantation of either 0.75 mg/mL of rhBMP-2 or 1.50 mg/mL of rhBMP-2 on an absorbable collagen sponge, showed a significant reduction (p = 0.0005) in the number of secondary interventions within twelve months in the group that was treated with the higher dose of rhBMP-21. Based on these results, the United States Food and Drug Administration, in April 2004, granted approval for the 1.50 mg/mL concentration of rhBMP-2 on an absorbable collagen sponge in the treatment of acute, open tibial fractures that have been stabilized with an intramedullary nail.
During approximately the same time period in which that study was performed, a parallel investigation was conducted at ten level-1 trauma centers in the United States and included sixty patients. The results from that study also implied a reduction in the rate of secondary interventions when rhBMP-2 was used in patients who were managed with an intramedullary nail. Because the results of that study have not been reported, most surgeons are unaware of them. In order to extract information from these studies with regard to which patients benefit most from this intervention, in this issue of The Journal, Swiontkowski et al. report on individual subgroup analyses of the effects of rhBMP-2 on clinical outcomes in the Gustilo-Anderson type-IIIA or IIIB open fractures and those fractures treated with reamed intramedullary nailing. The results show that the addition of rhBMP-2 to the treatment of type-IIIA or IIIB open tibial fractures can significantly reduce (p = 0.0005) the frequency of additional bone-grafting procedures and other secondary interventions within twelve months after definitive wound closure for the original injury. Although there was a mild trend for a similar effect in the patients who underwent reamed intramedullary nailing, no significant difference was found between the control group and the rhBMP-2-treated group.
So how does this new information advance our knowledge over what we already know from the December 2002 publication? To my thinking, the answer is straightforward. Because reamed intramedullary nailing of the tibia was performed in open fractures of types I through IIIB, the results show that the beneficial effects of rhBMP-2 are more evident in the most severe fractures (types IIIA and IIIB) and while this protein may also have a role to play in the less severe open fractures of the tibia, those beneficial effects are not as evident or pronounced.
Over the past three years, orthopaedic surgeons have been slow to respond to the potential use of rhBMP-2 in the treatment of open tibial fractures. Although the reasons for this are unclear, there are two possible explanations. First, as with any new technology, it takes time before the message is delivered, widely disseminated, and enacted. Second, in an era of cost-consciousness and sensitivity, anything that greatly increases the cost of medical care is highly scrutinized. Considering that a unit of rhBMP-2 (indicated for the treatment of an open tibial fracture) costs in the range of $5,000, surgeons have appropriately questioned if use of this protein is cost-effective. However, a cost analysis specifically addressing the use of rhBMP-2 in type IIIA and IIIB fractures has been performed, and a significant cost savings was demonstrated2.
It has been more than forty years since Marshall R. Urist first made the discovery of the osteoinductive substance in the extracellular matrix of bone that has the ability to regenerate bone in a nonskeletal site. Since that time, intensive research has been performed to understand the biology of this effect and to harness it in a way that may have a therapeutic impact in patients. Many of the preliminary investigations involved the development of animal models to test the ability of various BMPs to produce desired effects. However, despite the use of so-called critical size defects to stimulate nonunions or surgically planned osteotomies to stimulate open fractures, no animal model adequately mimics the conditions associated with clinical conditions. Indeed, in open fractures, the energy transmitted to the fracture site, the extent of the trauma that is sustained, the potential inoculation by bacterial organisms, the acute immune suppression produced by the injury, and other less well understood effects produce a unique setting that cannot be replicated in an animal. Type IIIA and IIIB open tibial fractures in particular represent a special subset of injuries. Thus, there is no substitute for clinical research, and the types of data reported in this subgroup analysis provide the best information available to help surgeons make critical decisions in the care of patients.
A vitally important question is whether the scientific observations on the effects of BMPs in animal systems would necessarily translate into their therapeutic use in patients. Just because an extracted or recombinant protein regenerates bone in a healthy animal does not necessarily mean it will enhance skeletal repair in the setting of a challenged fracture-healing environment. Indeed, while the success associated with the use of rhBMP-2 in patients who undergo single-level interbody lumbar spinal fusion has now been well-established, that too is a normal healing environment, and the success of the protein under those conditions does not necessarily support its use in the management of severe skeletal injuries. Thus, this report by Swiontkowski et al. provides important knowledge on the use of rhBMP-2 in conditions in which skeletal healing is challenged.
Other BMPs are currently under investigation, and at least one, OP-1 (osteogenic protein-1), which is also known as BMP-7, has achieved limited approval from the United States Food and Drug Administration under a Humanitarian Device Exemption for the treatment of recalcitrant nonunions of long bones in which the use of autologous bone graft is not feasible. Other technologies, such as the use of systemic drugs to enhance fracture-healing, are currently under investigation. The challenges to bringing these technologies to patients lie primarily in the ability of clinical investigators to demonstrate efficacy and in the ability of the companies that develop them to provide the product at an affordable price. However, surgeons must recognize that cost-effectiveness is related to efficacy; if clinical trials demonstrate that these new treatments are clearly superior to the current standards of care and if cost analyses favor the new technology, serious consideration should be given to offering these treatments to our patients, despite the apparent price tag.
*The author did not receive grants or outside funding in support of their research for or preparation of this manuscript. The author received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity (Stryker Biotech, Wyeth Research). In addition, a commercial entity (Stryker Biotech, Wyeth Research) paid or directed, or agreed to pay or direct, benefits to a research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.
1. 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.
2. Jones AL, Swiontkowski MF, Polly DW, Duff SB, Ackerman SJ. Use of rhBMP-2 in the treatment of open tibial shaft fractures: do improved clinical outcomes outweigh the additional expense of rhBMP-2? Presented as a poster exhibit at the Annual Meeting of the Orthopaedic Trauma Association; 2004 Oct 8-10; Hollywood, FL.