Bone morphogenetic proteins in orthopaedic trauma surgery

Injury, Int. J. Care Injured 42 (2011) 730–734

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Injury journal homepage: www.elsevier.com/locate/injury

Review

Bone morphogenetic proteins in orthopaedic trauma surgery Evan Argintar *, Scott Edwards a, John Delahay a Georgetown University, PHC 1 – Dept Orthopedics, 3800 Reservoir Rd, Washington, DC 20007, United States

A R T I C L E I N F O

A B S T R A C T

Article history: Accepted 10 November 2010

Fracture healing describes the normal post-traumatic physiologic process of bone regeneration. Commonly, this complicated process occurs without interruption, however, certain clinical situations exist that may benefit from the usage of bone healing enhancement agents. Bone morphogenetic proteins (BMPs) assist in the process of bone healing by recruiting bone-forming cells to the area of trauma. The usage of BMP currently has two FDA-approved indications: (1) treatment of acute tibial fractures treated with intramedullary fixation and (2) treatment of long bone non-union. Despite this limited scope, off-label BMP usage continues to push the envelope for new applications. Although proven to be clinically successful, BMP use must be balanced with the large costs associated with their application. Regardless, more prospective randomised clinical trials must be conducted to validate and expand the role of BMP in the setting of trauma. ß 2010 Elsevier Ltd. All rights reserved.

Keywords: Bone morphogenetic protein (BMP) Trauma Fracture Indications

Contents Introduction . . . . . . . . . . Healing . . . . . . . . . . . . . . Acute application . . . . . . Chronic application . . . . Complications . . . . . . . . Financial considerations Future directions . . . . . . Summary . . . . . . . . . . . . Conflict of interest . . . . . References . . . . . . . . . . .

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Introduction Despite the relative success of normal fracture healing, roughly 5–10% of fractures that occur in the United States exhibit some degree of impaired repair.13 This healing delay may be attributed to inadequate reduction, insufficient vascular supply, instability, infection, the systemic state of the patient, and the very nature of insulting trauma. In many cases, there is no identifiable source. In these circumstances of sub-optimal bone healing, enhancement may be extremely beneficial. In 1965, Marshall R. Urist discovered the so-called bone induction principle. This theory postulated that bone matrix

* Corresponding author. Tel.: +1 301 442 2597; fax: +1 202 444 7856. E-mail addresses: [email protected] (E. Argintar), [email protected] (S. Edwards). a Tel.: +1 202 444 8677; fax: +1 202 444 7856. 0020–1383/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.injury.2010.11.016

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contained inducing agents that could help generate new bone formation when implanted into an extraskeletal site. Urist and his colleagues identified this factor as a protein that they named bone morphogenetic protein (BMP).38 Currently, nearly 20 structurally related BMPs have been discovered, and these proteins are known to be a part of the larger transforming growth factor-B (TGF-B) super-family of molecules. In 2008, more than $ 1.6 billion was spent on bone grafts and substitutes, with one-fifth spent on fracture management.30 Currently, only two BMP products, rhBMP-2 (INFUSE, Medtronic) and rhBMP-7 (OP-1, Stryker), are available for commercial clinical use. Although originally extracted from cadaveric specimens, to increase yields, these companies now produce BMP from recombinant gene technology. This has paved the way for companies to produce large quantities of specific BMPs that isolate the proteins believed to have the greatest potential for clinical use.

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Much attention has focused on the ability of BMP to stimulate new bone growth. In the setting of trauma, BMP is utilised to augment fracture repair and treat delayed union and nonunion. Both commercially available options come with a collagen carrier. This delivery system both provides a scaffolding system that allows bony in-growth, as well keeps the liquid-BMP media concentrated in the point of interest. Although the process of healing is dynamic, as the collagen carrier dissolves, the BMP similarly decreases in concentration over a period of weeks. This allows ample time for the chemotaxis of bone-forming mesenchymal stems cells (MSCs) to be recruited to the area of healing. The technique of BMP application is still evolving. In sites of nonunion, all fibrous, necrotic, and sclerotic tissues should be debrided from the fracture site, such that the BMP-collagen carrier unit can be placed well apposed to the bone. Prior to BMP application, definitive fixation should be achieved, and attention should be paid to haemostasis, which when uncontrolled, could dislodge the BMP graft. The BMP should be applied adjacent to the viable tissue in a quantity sufficient to fill any bone defects, bridge fracture comminution, and be in contact with both proximal and distal fracture fragments (Fig. 1). The geometry of the graft (folded, rolled, wrapped) should be dictated by the constraints of bony defects. Once implanted, local irrigations should be avoided, and soft tissue closure around the BMP collagen graft is essential to maximise local BMP concentrations. If needed, drains should be placed remotely. BMP should be used a biological adjunct only; these grafts offer no mechanical strength at all. Adjuncts used in fracture management can be classified in several ways. Osteoinductive materials contain agents capable of recruiting bone-forming MSCs. Osteoconductive substances act as scaffolding for in-growth of new bone and vascular tissue. Osteogenic substances already contain cells that are able to directly generate bone. Bone graft enhancers provide additional biological activity for stimulation of bone healing. By these definitions, BMPs are considered to be osteoinductive enhancers for fracture management. Healing Fracture healing describes the physiologic restoration of bone tissue after injury. This specialised process normally regenerates bone in a well-orchestrated biological process that restores skeletal integrity. BMPs are known to play an important role in this normal healing process. During the initial inflammatory stage of fracture healing, BMPs quickly emerge as the central regulatory transcription factors involved in coordinating injury repair. The initial chondrogenic phase of endochondral bone healing appears to be dominated by BMP 2, 3, 4, 5 and 6. Additionally, BMP 7 and 8 emerge more specifically in the later osteogenic phase of fracture healing. This complicated process is regulated by a combination of autofeedback loops and naturally occurring BMP inhibitors.28 Evidence exists that BMPs may additionally interact with cells of the osteoclast lineage, and this relationship may have implications on both bone formation as well as bone resorption.20,34 This coupling has been found in mice models, and may suggest that osteoclast cells may have an important role in regulating bone-forming cells needed for normal fracture repair.16,40 Specific BMP subtypes are now being identified as having important roles in angiogenesis regulation. Mutations in genes encoding components of the BMP signalling pathway have been linked to two specific genetic vascular diseases.10 The BMP pathway may target genes that play a role in blood vessel formation.32 Although vasculogensic stimulating properties of BMP are better studied in the embryo, further investigation into

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these pathways functioning in adults may contribute to novel therapies in vascular disease.33 Although two commercially available products exist, it is still unclear if BMP-2 or BMP-7 might individually be better suited to treat specific pathologic situations. Clearly, each BMP has a unique role in fracture healing, with specific BMP concentrations occurring at different periods of tissue recovery. The significance of these differences must be further investigated to help identify situations that might benefit from BMP-specific treatment. It is the complicated balance of BMPs and several naturally BMP antagonists that may serve as one intrinsic source for the development of pathologic fracture healing.14 Kwong et al. sampled BMPs and BMP inhibitors from intraoperative human fractures, that upon follow-up, were determined to be normal or to become nonunion. These authors found a significant reduction in BMP 2 and 12 expression in the cartilaginous areas of non-healing fracture.26 Identifying the cause of pathologic healing can optimise successful treatment of nonunion. Traditionally, hypertrophic nonunions occur as a result of inadequate mechanical stability, whilst atrophic nonunion occurs as a consequence of inadequate biological healing. By these criteria, BMP seemingly would be best suited for treatment of atrophic nonunion, as BMP would help attract the needed biological stimuli required for normal fracture healing. Unfortunately, current studies fail to stratify nonunion by aetiology, and instead, treat all nonunions with fixation revision as well as additional of biological adjunct. Acute application Much of the original work on the efficacy of BMP in the setting of trauma is rooted in spinal arthrodesis literature.39 These early studies helped pave the way for the application of BMP in acute and chronic fracture management. The BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) study reported on the results in a large multicenter, prospective, randomised, controlled study on the use of INFUSE. Here, 450 patients with open tibial fractures were initially managed with irrigation, debridement, and intramedullary nail placement. At wound closure, patients were randomised to receive normal closure without BMP, or closure with BMP-2 on an absorbable collagen sponge. The group treated with highest BMP concentrations demonstrated fewest secondary interventions, accelerated time to union, improved wound healing, and a reduced infection rate.21 In a subgroup analysis, Swiontkowski et al. found that the addition of rhBMP-2 to the treatment of type-III open tibial fractures significantly reduced the frequency of bone-grafting procedures and other secondary interventions.35 In a smaller prospective study, Jones et al. compared tibial fractures with cortical defects treated with autogenous bone graft or allograft treated with onlay rhBMP-2 on an absorbable collagen sponge. Here, equivalent healing rates and intraoperative blood loss was demonstrated.22 A similar study to the BESST, McKee et al. compared open tibial fractures treated with either standard closure or 3.4 mg of BMP-7. In the 124 patients evaluated, those treated with BMP had decreased secondary interventions, and improvement in function postoperatively at one year.29 Chronic application Despite the limited indication for BMP use in acute fracture management, extensive clinical investigation has focused on the management of delayed union and nonunion. In a multicenter study on 122 patients, Friedlaender et al. prospectively randomised patients with tibial nonunion to receive autograft or rhBMP-7

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Fig. 1. BMP on collagen graft: ready to be applied to femoral nonunion.

in a bovine bone-derived type-1 collagen-particle delivery vehicle. Results showed statistical equivalence between both groups with regard to union (clinical and radiographic) despite the higher amount of smokers found in the BMP treated study population.15 Belgian clinicians retrospectively evaluated 62 tibial nonunions

treated with BMP-7, and found a clinical healing rate of 79.6% and a radiographic healing rate of 84.9% at an average of 230 days.11 Kanakaris et al. demonstrated fracture healing of 89.7% in tibial non-unions treated with BMP-7 and fixation revision.23 These same authors achieved 86.6% fusion in 30 patients treated with BMP-7 for femoral non-union.24 Documented prospective success of BMP-7 has also extended to treatment of upper extremity trauma. In evaluating scaphoid nonunion, Bilic et al. used BMP-7 and found reduced radiographic healing times as well as improved performance when used with autograft and allograft.5 Bong et al. achieved 100% union with application of BMP-7 and fixation revision in 17 cases of humeral nonunion.6 Unpublished data from our institution found clinical and radiographic union was achieved with BMP-2 application and fixation revision of 7 of 11 patients with humeral non-unions. These authors concluded factors associated with failure of union with BMP-2 were large bony defects (greater than 4 cm) and poor soft-tissue vascularity surrounding the nonunion site. Treatment has also extended to management of other non-long bone fractures. Giannoudis et al. reviewed the application of BMP7 in the setting pelvic post-traumatic nonunion and post-partum pelvic instability. He found fusion was achieved in 89% of the patients, with 78% of the patients reporting excellent or good results.18 Few studies have evaluated BMP application on a more generalised scale. Moghaddam et al. reported their experience of 53 patients treated for atrophic non-union with BMP-7 on a collagen carrier. The non-unions were localised to the femur (21), tibia (26), humerus (3), and forearm (7). In 12 cases, BMP-7 was applied in isolations, without change in fixation. At 6 months follow-up, 82% of the patients demonstrated clinical and radiographic fracture healing.31 When used concurrently with autograft, BMP may synergistically work to produce union. Giannoudis et al. combined these two substances to treat a multitude of long-bone nonunions, and found 100% union in 45 patients.19 BMP use has formally been evaluated in the adult population, however, off-label use has included paediatric non-union cases. Dohin et al. found that a single dose of BMP-7 mixed with a bovine collagen carrier generated clinical and radiographic fracture union in 17 of 23 paediatric patients with symptomatic long-bone nonunions.12 Complications With several complications now identified with the use of BMP in spinal arthrodesis, reports are now being recognised in fracture literature. Boraiah et al. evaluated complications associated with the use of BMP-2 in complex tibial plateau fractures. In this study, 10 of 17 patients developed heterotopic ossification, and four of these patients required additional operative interventions for ectopic bone removal.7 This development of heterotopic ossification has also been found with use of BMP-7.2 Unpublished data from our institution found three patients that developed a reaction to the BMP-2 consisting of erythema and oedema for treatment of humeral nonunion. This could suggest that soft tissue reactivity to BMP-2 may be heightened in the upper extremity (Fig. 2). Although previously not described clinically in the setting of trauma, BMP use in the spine,27 as well as in vitro animal models have documented bone resorption as a consequence of BMP-induced osteoclastic stimulation.36 Financial considerations

Fig. 2. Local inflammation at site of BMP application.

The proven benefit of BMP must be weighed against its exorbitant cost. Costs of commercially available BMP are volumedependant, but large volumes can cost $ 5000. Conversely, the

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potential costs of additional surgical treatments for long-bone non-union, coupled with the financial societal burden of prolonged work absence is expensive, and should not be ignored.25 Using the German healthcare model, Alt et al. found that the overall savings achieved by rhBMP-2 treatment in open tibia fractures offset the upfront price of rhBMP-2, and led to net savings for health insurance companies.1 This support was echoed by Garrison et al. who suggested the cost-effectiveness of additional BMP may be improved if the price of BMP is reduced or if BMP is mainly used in severe cases.17 Similarly, Dahabreh et al. found rhBMP-7 to be cost-effective in the treatment of tibial nonunion.9 All of these European studies suggest that the usage of BMP may have a legitimate economical role in fracture care. This demands further exploration within the medical infrastructure in the United States. Future directions The future of fracture management will be linked with the optimisation of biological adjuncts coupled with the development of novel strategies for specific agent delivery. Although current research is dominated by BMP investigation, manipulation of naturally occurring BMP inhibitors may offer a promising technique to optimising fracture healing.37 Animal models have demonstrated successful fusion after percutaneous administration of BMP.4 Viral vectors offer another minimally invasive way of delivering and stimulating bone healing by genetic transfer.3 Application of BMP may also prove vital for the tissue regeneration of the musculoskeletal system.8 Summary Although the application of BMP is promising, it is important to reiterate that most fractures heal uneventfully without complications. Proper treatment rests with both the proper identification of fractures (and patients) that may benefit from BMP application, coupled with an understanding of the injury-specific local biological and/or structural needs necessary to achieve effective fracture healing. The majority of current clinical evidence supporting use of BMPs is dominated by retrospective analysis, and many off-label usages are currently being practised. Despite the clear FDA indications that exist, BMPs have exorbitant prices that most be examined and balanced with their cost effectiveness. BMPs clearly offer a technology that greatly enhances the management of musculoskeletal injuries, however, there still is a great need for continued prospective randomised controlled studies to standardise fracture treatment, optimise fracture healing, and develop novel therapies. Conflict of interest None. References 1. Alt V, Heissel A. Economic considerations for the use of recombinant human bone morphogenetic protein-2 in open tibial fractures in Europe: the German model. Curr Med Res Opin 2006;22(Suppl. 1):S19–22. 2. Axelrad TW, Steen B, Lowenberg DW, et al. Heterotopic ossification after the use of commercially available recombinant human bone morphogenetic proteins in four patients. J Bone Joint Surg Br 2008;90(December (12)):1617–22. 3. Bertone AL, Pittman DD, Bouxsein ML, et al. Adenoviral-mediated transfer of human BMP-6 gene accelerates healing in a rabbit ulnar osteotomy model. J Orthop Res 2004;22(November (6)):1261–70. 4. Betz VM, Betz OB, Glatt V, et al. Healing of segmental bone defects by direct percutaneous gene delivery: effect of vector dose. Hum Gene Ther 2007;18(October (10)):907–15.

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5. Bilic R, Simic P, Jelic M, et al. Osteogenic protein-1 (BMP-7) accelerates healing of scaphoid non-union with proximal pole sclerosis. Int Orthop 2006;30:128–34. 6. Bong MR, Capla EL, Egol KA, et al. Osteogenic protein-1 (bone morphogenic protein-7) combined with various adjuncts in the treatment of humeral diaphyseal nonunions. Bull Hosp Joint Dis 2005;63(1–2):20–3. 7. Boraiah S, Paul O, Hawkes D, et al. Complications of recombinant human BMP-2 for treating complex tibial plateau fractures: a preliminary report. Clin Orthop Relat Res 2009;467(December (12)):3257–62. 8. Chang SC, Chuang HL, Chen YR, et al. Ex vivo gene therapy in autologous bone marrow stromal stem cells for tissue-engineered maxillofacial bone regeneration. Gene Ther 2003;10(November (24)):2013–9. 9. Dahabreh Z, Calori GM, Kanakaris NK, Nikolaou VS. Giannoudis PV A cost analysis of treatment of tibial fracture nonunion by bone grafting or bone morphogenetic protein-7. Int Orthop )2008;(December 4). 10. David L, Feige JJ, Bailly S. Emerging role of bone morphogenetic proteins in angiogenesis. Cytokine Growth Factor Rev 2009;20(June (3)):203–12. 11. Desmyter S, Goubau Y, Benahmed N, et al. The role of bone morphogenetic protein-7 (Osteogenic Protein-1) in the treatment of tibial fracture non-unions. An overview of the use in Belgium. Acta Orthop Belg 2008;74(August (4)):534–7. 12. Dohin B, Dahan-Oliel N, Fassier F, Hamdy R. Enhancement of difficult nonunion in children with osteogenic protein-1 (OP-1): early experience. Clin Orthop Relat Res 2009;467(December 12):3230–8. 13. Einhorn TA. Current concepts review: enhancement of fracture healing. J Bone Joint Surg Am 1995;77A(6):940–56. 14. Fajardo M, Liu CJ, Egol K. Levels of expression for BMP-7 and several BMP antagonists may play an integral role in a fracture nonunion: a pilot study. Clin Orthop Relat Res 2009;467(December (12)):3071–8. 15. Friedlaender GE, Perry CR, Cole JD, et al. Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. J Bone Joint Surg Am 2001;83-A(Suppl. 1 (Pt 2)):S151–8. 16. Garimella R, Tague SE, Zhang J, et al. Expression and synthesis of bone morphogenetic proteins by osteoclasts: a possible path to anabolic bone remodeling. J Histochem Cytochem 2008;56(June (6)):569–77. 17. Garrison KR, Donell S, Ryder J, et al. Clinical effectiveness and cost-effectiveness of bone morphogenetic proteins in the non-healing of fractures and spinal fusion: a systematic review. Health Technol Assess 2007;11(August (30)). 1– 150, iii–iv. 18. Giannoudis PV, Psarakis S, Kanakaris NK, Pape HC. Biological enhancement of bone healing with Bone Morphogenetic Protein-7 at the clinical setting of pelvic girdle non-unions. Injury 2007;38(September (Suppl. 4)):S43–8. 19. Giannoudis PV, Kanakaris NK, Dimitriou R, et al. The synergistic effect of autograft and BMP-7 in the treatment of atrophic nonunions. Clin Orthop Relat Res 2009;467(December (12)):3239–48. 20. Giannoudis PV, Kanakaris NK, Einhorn TA. Interaction of bone morphogenetic proteins with cells of the osteoclast lineage: review of the existing evidence. Osteoporos Int 2007;18(December (12)):1565–81. 21. Govender S, Csimma C, Genant HK, et al. 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-A(December (12)):2123–34. 22. Jones AL, Bucholz RW, Bosse MJ, et al. 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;88(July (7)):1431–41. 23. Kanakaris NK, Calori GM, Verdonk R, et al. Application of BMP-7 to tibial nonunions: a 3-year multicenter experience. 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McKee MD, Schemitsch EH, Waddell JP, et al. The effect of human recombinant bone morphogenic protein (RHBMP-7) on the healing of open tibial shaft fractures: results of a multi-center, prospective, randomized clinical trial. In: Proceedings of the 18th Annual Meeting of the Orthopaedic Trauma Association; 2002. p. 157–8. 30. Mendenhall S. Orthopedic Network News, vol. 19, Number 4. October 2008. 31. Moghaddam A, Elleser C, Biglari B, et al. Clinical application of BMP 7 in long bone non-unions. Arch Orthop Trauma Surg 2010;130(January (1)):71–6. 32. Moreno-Miralles I, Schisler JC, Patterson C. New insights into bone morphogenetic protein signaling: focus on angiogenesis. Curr Opin Hematol 2009;(May (3)):195–201. 33. Moser M, Patterson C. Bone morphogenetic proteins and vascular differentiation: BMPing up vasculogenesis. Thromb Haemost 2005;94(October (4)):713–8.

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37. Tsialogiannis E, Polyzois I, Oak Tang Q, et al. Targeting bone morphogenetic protein antagonists: in vitro and in vivo evidence of their role in bone metabolism. Expert Opin Ther Targets 2009;13(January (1)):123–37. 38. Urist MR. A morphogenetic matrix for differentiation of bone tissue. Calcified Tissue Res 1970;(Suppl.):98–101. 39. Vaccaro AR, Whang PG, Patel T, et al. The safety and efficacy of OP-1 (rhBMP-7) as a replacement for iliac crest autograft for posterolateral lumbar arthrodesis: minimum 4-year follow-up of a pilot study. Spine J 2008;8(3):457–65. 40. Wutzl A, Brozek W, Lernbass I, et al. Bone morphogenetic proteins 5 and 6 stimulate osteoclast generation. J Biomed Mater Res A 2006;77(April (1)):75–83.