Bone morphogenetic proteins in orthopaedic trauma surgery

doi:10.1016/j.injury.2010.11.016

Injury

Volume 42, Issue 8, August 2011, Pages 730-734

https://doi.org/10.1016/j.injury.2010.11.016 Get rights and content

Abstract

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.

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 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.

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.

Section snippets

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

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,

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 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

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

Financial considerations

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

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

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

Conflict of interest

None.

References (40)

A.L. Bertone et al.
Adenoviral-mediated transfer of human BMP-6 gene accelerates healing in a rabbit ulnar osteotomy model
J Orthop Res
(2004)
L. David et al.
Emerging role of bone morphogenetic proteins in angiogenesis
Cytokine Growth Factor Rev
(2009)
P.V. Giannoudis et al.
Biological enhancement of bone healing with Bone Morphogenetic Protein-7 at the clinical setting of pelvic girdle non-unions
Injury
(2007)
K.U. Lewandrowski et al.
Vertebral osteolysis after posterior interbody lumbar fusion with recombinant human bone morphogenetic protein 2: a report of five cases
Spine J
(2007)
A.R. Vaccaro 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)
V. Alt et al.
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)
T.W. Axelrad et al.
Heterotopic ossification after the use of commercially available recombinant human bone morphogenetic proteins in four patients
J Bone Joint Surg Br
(2008)
V.M. Betz et al.
Healing of segmental bone defects by direct percutaneous gene delivery: effect of vector dose
Hum Gene Ther
(2007)
R. Bilic et al.
Osteogenic protein-1 (BMP-7) accelerates healing of scaphoid non-union with proximal pole sclerosis
Int Orthop
(2006)
M.R. Bong 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)

S. Boraiah et al.

Complications of recombinant human BMP-2 for treating complex tibial plateau fractures: a preliminary report

Clin Orthop Relat Res

(2009)

S.C. Chang et al.

Ex vivo gene therapy in autologous bone marrow stromal stem cells for tissue-engineered maxillofacial bone regeneration

Gene Ther

(2003)

Z. Dahabreh et al.

Giannoudis PV A cost analysis of treatment of tibial fracture nonunion by bone grafting or bone morphogenetic protein-7

Int Orthop

(2008)

S. Desmyter 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)

B. Dohin et al.

Enhancement of difficult nonunion in children with osteogenic protein-1 (OP-1): early experience

Clin Orthop Relat Res

(2009)

T.A. Einhorn

Current concepts review: enhancement of fracture healing

J Bone Joint Surg Am

(1995)

M. Fajardo et al.

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)

G.E. Friedlaender et al.

Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions

J Bone Joint Surg Am

(2001)

R. Garimella et al.

Expression and synthesis of bone morphogenetic proteins by osteoclasts: a possible path to anabolic bone remodeling

J Histochem Cytochem

(2008)

K.R. Garrison 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)

Cited by (71)

Off-label: The results of adjunctive bone morphogenetic protein for challenging femur fractures; a review of two cases
2024, Trauma Case Reports
Although bone morphogenetic proteins (BMPs) are used as an adjunct to promote healing, they may have unintended effects such as heterotopic ossification (HO). The literature is limited regarding the effect of using off-label BMPs for femur fractures.
We report two outcomes after off-label use of BMPs for the treatment of femur fractures and propose a possible explanation for the difference.
BMPs are critical osteoinductive factors in injured bone and muscle that facilitate bony healing. However, it may be important to recognize the potentially negative effects of adding BMP to bone graft material in certain cases to stimulate bone repair. We hope this case series helps surgeons consider the risks and benefits of using BMP for femur fractures, and therefore to decide with caution when BMP is indicated.
The bone morphogenetic protein 2 analogue L51P enhances spinal fusion in combination with BMP2 in an in vivo rat tail model
2024, Acta Biomaterialia
Bone morphogenic protein 2 (BMP2) is known to induce osteogenesis and is applied clinically to enhance spinal fusion despite adverse effects. BMP2 needs to be used in high doses to be effective due to the presence of BMP2 inhibitors. L51P is a BMP2 analogue that acts by inhibition of BMP2 inhibitors. Here, we hypothesized that mixtures of BMP2 and L51P could achieve better spinal fusion outcomes regarding ossification. To test whether mixtures of both cytokines are sufficient to improve ossification, 45 elderly Wistar rats (of which 21 were males) were assigned to seven experimental groups, all which received spinal fusion surgery, including discectomy at the caudal 4–5 level using an external fixator and a porous β-tricalcium phosphate (βTCP) carrier. These βTCP carriers were coated with varying concentrations of BMP2 and L51P. X-rays were taken immediately after surgery and again six and twelve weeks post-operatively. Histological sections and µCT were analyzed after twelve weeks. Spinal fusion was assessed using X-ray, µCT and histology according to the Bridwell scale by voxel-based quantification and a semi-quantitative histological score, respectively. The results were congruent across modalities and revealed high ossification for high-dose BMP2 (10 µg), while PBS induced no ossification. Low-dose BMP2 (1 µg) or 10 µg L51P alone did not induce relevant bone formation. However, all combinations of low-dose BMP2 with L51P (1 µg + 1/5/10 µg) were able to induce similar ossificationas high-dose BMP2. These results are of high clinical relevance, as they indicate L51P is sufficient to increase the efficacy of BMP2 and thus lower the required dose for spinal fusion.
Spinal fusion surgery is frequently applied to treat spinal pathologies. Bone Morphogenic Protein-2 (BMP2) has been approved by the U .S. Food and Drug Administration (FDA-) and by the “Conformité Européenne” (CE)-label. However, its application is expensive and high concentrations cause side-effects. This research targets the improvement of the efficacy of BMP2 in spinal fusion surgery.
The use of biological augments in fracture healing: where is the evidence?
2021, Orthopaedics and Trauma
Fracture non-union results in serious morbidity for patients and a financial burden on healthcare services. Fracture healing is a complex process that involves many chemical signalling molecules and cells. This complexity means there are many stages at which the healing pathway can theoretically be influenced by biologic adjuvants. Biologic adjuvants can be either osteoconductive, osteoinductive or osteogenic. Many laboratory studies have shown success in manipulating the signalling pathways involved in fracture healing. The majority of biologics serve to increase the presence of certain cytokines to stimulate bone forming cells; some agents involve effecting the delivery of early progenitor cells. There have been clinical trials involving multiple biologics, usually in the treatment of tibial non-unions. The clinical trials have shown very limited evidence to support the use of adjuvants in clinical practice. There is a consistent problem translating encouraging laboratory results into similar clinical results with the majority of agents, therefore there remains a lack of clinical evidence to support their use in everyday trauma practice.
Developing Bioreactors to Host Joint-Derived Tissues That Require Mechanical Stimulation
2019, Encyclopedia of Tissue Engineering and Regenerative Medicine: Volumes 1-3
Demographics of the Western Societies points toward an elderly population in need of research on replacement parts for joints and their components, such as the meniscus, cartilage, ligaments, tendons, and intervertebral discs. There is a lack of basic research to predict treatment options before degeneration or inflammation has progressed, and at late stages, when regeneration might not be an option anymore. Thus, to achieve a better understanding of the current specific problems in orthopedic research, there is a need for clinically relevant mechanobiological models. Animal experiments, especially those on large animals, are costly and, in some cases, doubtful as regards clinical translation. Ex vivo bioreactors that allow biomechanical loading are aimed to mimic the in vivo situation of critical joints that are prone to failure. These tissues often require unique adaptations prior and during organ culture as these are often under mechanical forces in situ. On the one hand, ex vivo organ cultures are limited in regarding the size and cell numbers that can be kept alive and the duration of experiments. However, a strong asset of these cultures is the use of primary human material, which is a chance to provide more translational relevant results. Within this book chapter, we give a brief history of general concepts for bioreactor constructions in the field of orthopedic research and give some recent examples for tendons, the knee joint and the intervertebral disc. We offer a summary of the current state of the art, pitfalls and limitations in the design and the future challenges.
Developing bioreactors to host joint-derived tissues that require mechanical stimulation
2019, Encyclopedia of Tissue Engineering and Regenerative Medicine
Demographics of the Western Societies points toward an elderly population in need of research on replacement parts for joints and their components, such as the meniscus, cartilage, ligaments, tendons, and intervertebral discs. There is a lack of basic research to predict treatment options before degeneration or inflammation has progressed, and at late stages, when regeneration might not be an option anymore. Thus, to achieve a better understanding of the current specific problems in orthopedic research, there is a need for clinically relevant mechanobiological models. Animal experiments, especially those on large animals, are costly and, in some cases, doubtful as regards clinical translation. Ex vivo bioreactors that allow biomechanical loading are aimed to mimic the in vivo situation of critical joints that are prone to failure. These tissues often require unique adaptations prior and during organ culture as these are often under mechanical forces in situ. On the one hand, ex vivo organ cultures are limited in regarding the size and cell numbers that can be kept alive and the duration of experiments. However, a strong asset of these cultures is the use of primary human material, which is a chance to provide more translational relevant results. Within this book chapter, we give a brief history of general concepts for bioreactor constructions in the field of orthopedic research and give some recent examples for tendons, the knee joint and the intervertebral disc. We offer a summary of the current state of the art, pitfalls and limitations in the design and the future challenges.
Osteogenesis by foamed and 3D-printed nanostructured calcium phosphate scaffolds: Effect of pore architecture
2018, Acta Biomaterialia
There is an urgent need of synthetic bone grafts with enhanced osteogenic capacity. This can be achieved by combining biomaterials with exogenous growth factors, which however can have numerous undesired side effects, but also by tuning the intrinsic biomaterial properties. In a previous study, we showed the synergistic effect of nanostructure and pore architecture of biomimetic calcium deficient hydroxyapatite (CDHA) scaffolds in enhancing osteoinduction, i.e. fostering the differentiation of mesenchymal stem cells to bone forming cells. This was demonstrated by assessing bone formation after implanting the scaffolds intramuscularly. The present study goes one step forward, since it analyzes the effect of the geometrical features of the same CDHA scaffolds, obtained either by 3D-printing or by foaming, on the osteogenic potential and resorption behaviour in a bony environment. After 6 and 12 weeks of intraosseous implantation, both bone formation and material degradation had been drastically affected by the macropore architecture of the scaffolds. Whereas nanostructured CDHA was shown to be highly osteoconductive both in the robocast and foamed scaffolds, a superior osteogenic capacity was observed in the foamed scaffolds, which was associated with their higher intrinsic osteoinductive potential. Moreover, they showed a significantly higher cell-mediated degradation than the robocast constructs, with a simultaneous and progressive replacement of the scaffold by new bone. In conclusion, these results demonstrate that the control of macropore architecture is a crucial parameter in the design of synthetic bone grafts, which allows fostering both material degradation and new bone formation.
Statement of Significance
3D-printing technologies open new perspectives for the design of patient-specific bone grafts, since they allow customizing the external shape together with the internal architecture of implants. In this respect, it is important to design the appropriate pore geometry to maximize the bone healing capacity of these implants. The present study analyses the effect of pore architecture of nanostructured hydroxyapatite scaffolds, obtained either by 3D-printing or foaming, on the osteogenic potential and scaffold resorption in an in vivo model. While nanostructured hydroxyapatite showed excellent osteoconductive properties irrespective of pore geometry, we demonstrated that the spherical, concave macropores of foamed scaffolds significantly promoted both material resorption and bone regeneration compared to the 3D-printed scaffolds with orthogonal-patterned struts and therefore prismatic, convex macropores.

View all citing articles on Scopus

^a: Tel.: +1 202 444 8677; fax: +1 202 444 7856.

View full text

ReviewBone morphogenetic proteins in orthopaedic trauma surgery

Abstract

Introduction

Section snippets

Healing

Acute application

Chronic application

Complications

Financial considerations

Future directions

Summary

Conflict of interest

J Orthop Res

Cytokine Growth Factor Rev

Injury

Spine J

Spine J.

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

Heterotopic ossification after the use of commercially available recombinant human bone morphogenetic proteins in four patients

J Bone Joint Surg Br

Healing of segmental bone defects by direct percutaneous gene delivery: effect of vector dose

Hum Gene Ther

Osteogenic protein-1 (BMP-7) accelerates healing of scaphoid non-union with proximal pole sclerosis

Int Orthop

Osteogenic protein-1 (bone morphogenic protein-7) combined with various adjuncts in the treatment of humeral diaphyseal nonunions

Bull Hosp Joint Dis

Complications of recombinant human BMP-2 for treating complex tibial plateau fractures: a preliminary report

Clin Orthop Relat Res

Ex vivo gene therapy in autologous bone marrow stromal stem cells for tissue-engineered maxillofacial bone regeneration

Gene Ther

Giannoudis PV A cost analysis of treatment of tibial fracture nonunion by bone grafting or bone morphogenetic protein-7

Int Orthop

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

Enhancement of difficult nonunion in children with osteogenic protein-1 (OP-1): early experience

Clin Orthop Relat Res

Current concepts review: enhancement of fracture healing

J Bone Joint Surg Am

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

Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions

J Bone Joint Surg Am

Expression and synthesis of bone morphogenetic proteins by osteoclasts: a possible path to anabolic bone remodeling

J Histochem Cytochem

Clinical effectiveness and cost-effectiveness of bone morphogenetic proteins in the non-healing of fractures and spinal fusion: a systematic review

Health Technol Assess

Review
Bone morphogenetic proteins in orthopaedic trauma surgery