Bone morphogenetic proteins in orthopaedic surgery

Bone morphogenetic proteins (BMPs) are growth factors which induce new bone formation. They are an increasingly important adjunct in the treatment of certain musculoskeletal disorders. Their underlying basic science and role in bone healing is explained. Delivery systems, safety issues and current evidence-based clinical applications of BMPs in orthopaedic surgery are described.     

Recent advances toward the clinical application of bone morphogenetic proteins in bone and cartilage repair

Inefficient healing of bony and cartilaginous defects is a common situation encountered by orthopedic surgeons. Enhancing the regenerative potential of bone and articular cartilage has the potential for profound applications in treatment of nonunions, large segmental bone and cartilage defects, and arthritis. The bone morphogenetic proteins (BMPs) encode a highly conserved class of signaling factors that possess the ability to induce ectopic cartilage and bone formation in vivo. Bone morphogenetic protein family members are expressed during limb development, endochondral ossification, and early fracture and cartilage repair. Loss-of-function and gain-of-function studies have demonstrated the necessity and sufficiency of these genes, respectively, in regulating both cartilage and bone development. Several recent animal studies have demonstrated the potential of BMPs to enhance spinal fusion, repair critical-size defects, accelerate union, and heal articular cartilage lesions. A limited number of clinical trials using BMPs in human beings have been reported, and these agents are currently available for clinical use within and outside the United States. Current challenges to be met are the development of efficient delivery systems to present BMP proteins or genes to target sites and to enhance their duration and function at these locations.     

The bone morphogenic protein

The molecular and cellular process to promote bone formation has been examined extensively in recent years in an attempt to minimize delayed unions and nonunions. Bone morphogenetic proteins (BMPs) have been determined to play an intricate role in the bone formation cascade. Over 14 BMPs have been isolated and more are being discovered as investigation progresses. BMP-2 and BMP-7 are being produced commercially for clinical use with specific indications. Continuing research is investigating the optimal carrier that will give the best results. This article reviews the most current information regarding BMPs.     

BMPs and the muscle–bone connection

Muscle and bone are two intimately connected tissues. A coordinated interplay between these tissues at mechanical levels is required for their development, function and ageing. Evidence is emerging that several genes and molecular pathways exert a pleiotropic effect on both muscle and bone. Bone morphogenetic proteins (BMPs) are secreted signal factors belonging to the transforming growth factor β (TGFβ) superfamily. BMPs have an essential role during bone and cartilage formation and maintenance. Recently, we and others have demonstrated that the BMP pathway also has a role in controlling adult skeletal muscle mass. Thus, BMPs become crucial regulators of both bone and muscle formation and homeostasis. In this review we will discuss the signalling downstream BMP and its role in muscle–bone interaction.This article is part of a Special Issue entitled “Muscle Bone Interactions”.     

Long-term effects of bone morphogenetic protein- based treatments in humans

Bone morphogenetic proteins (BMPs) are low-molecular-weight proteins of the transforming growth factor-beta (TGF-β) superfamily. In recent years, these growth and differentiation factors have been extensively researched for their multifunctional properties ranging from embryonic development to postnatal homeostasis. The defining ability of BMPs is the role they play in skeletal development and maintenance, especially the powerful osteoinductive activity for which these proteins are currently sought after. There are over 20 BMPs that have been discovered, with BMP-2 and BMP-7 currently being the only proteins of the group that are approved by the US Food and Drug Administration for clinical use as an autograft substitute for lumbar spinal interbody fusion procedures and for open tibial fractures with intramedullary nail fixation. BMP-2 has also been approved for use in dental bone grafting indications. However, a significant amount of off-label usage of these proteins has been reported, which has led to an industry approaching a billion dollars annually. In this review, we examine the long-term effects of BMPs as evidenced from in vitro, preclinical, and clinical studies.     

Interaction of bone morphogenetic proteins with cells of the osteoclast lineage: review of the existing evidence

The present review evaluates the existing scientific proofs of this supplementary role of the BMPs and summarises its clinical implications. Bone regeneration is a process consisting of bone formation and bone resorption, two different but closely coupling pathways, which in most circumstances proceed simultaneously. Plenty of evidence has also characterised the bone morphogenetic proteins (BMPs) as inducing factors of bone formation. However, there is also evidence that these multifunctioning proteins affect bone resorption and the osteoclast homeostasis utilising various pathways. The present review evaluates the existing scientific evidence of this supplementary role of the BMPs, and summarises its clinical implications. Note: This work is attributed to the Academic Unit, Trauma and Orthopaedic Surgery, Clarendon Wing, Leeds General Infirmary, Great George Street, Leeds, LS1 3EX, UK.     

Growth factors in bone

Bone contains several growth factors, including bone morphogenetic proteins (BMPs), transforming growth factor beta (TGF-beta), insulin-like growth factors I and II (IGF-I and IGF-II), platelet derived growth factor (PDGF) and basic and acidic fibroblast growth factor (bFGF and aFGF). Spatial and temporal variations in the expression and secretion of the various growth factors have been demonstrated in osteoblastic cultures and in various experimental and clinical in vivo models, including fracture healing in humans. Local application of various growth factors influences proliferation, differentiation and protein synthesis in osteoblastic cultures and bone formation in different animal models, including experimental fractures and skeletal defects. The BMPs are the only growth factors known to provoke bone formation heterotopically by making undifferentiated mesenchymal cells differentiate into osteoblasts (osteoinduction). BMPs and other growth factors, soon to become commercially available for clinical use, need a delivery system for their sustained release, as the factors are otherwise rapidly absorbed. Some existing systems inhibit bone formation by inducing chronic inflammation or physically by unresorbed carrier obstructing bone formation. New delivery systems are being investigated.     

Clinical applications of bone morphogenetic proteins: current evidence

Bone morphogenetic proteins (BMPs) were first described by Dr. Marshall Urist in 1965. Since 1988 a series of clinical studies and randomized clinical trials have evaluated the application of these molecules in humans. A comprehensive review of 30 clinical studies was performed to elicit the existing evidence of the English orthopaedic literature. BMPs appear to be efficacious as the reported success rates are equivalent and perhaps superior to those achieved with the gold standard methods of autografting. Clinical safety assessments have been even more encouraging with just a few reports of adverse events related to their use in clinical practice. There are certain controversies on the presented results of all the reviewed clinical series, which reflect the complexity of the osteoinductive and osteoconductive role of the BMPs, the ongoing quest for optimization of the dosing schemes and delivery carriers, as well as the multifactorial interactions during bone formation and remodeling.     

The family of bone morphogenetic proteins

The family of bone morphogenetic proteins. Bone morphogenetic proteins (BMPs) are secreted signaling molecules belonging to the transforming growth factor-beta (TGF-beta) superfamily of growth factors. The first BMPs were originally identified by their ability to induce ectopic bone formation when implanted under the skin of rodents. In this ectopic overexpression assay, there was a recapitulation of all the events occurring during skeletogenesis. This latter aspect indicated that these molecules could play important roles during development. More than 30 BMPs have been identified to date. The study of their expression pattern as well as the analysis of spontaneously mutated or genetically depleted mice have demonstrated a much broader range of function. These activities are mainly localized at sites of epithelial-mesenchymal interactions, including but not restricted to the skeleton. This review presents our current knowledge about the functions of BMPs during skeleton development as well as in many other biologic processes.     

Einsatz von Bone-morphogenetic Protein-7 (BMP-7) in der Behandlung von Pseudarthrosen der oberen und unteren Extremität

Bone morphogenetic proteins (BMPs) are bone growth factors, which regulate bone formation during fetal development and bone repair after injury in postfetal life. Since 1992 BMP-7 has been produced by recombinant technique (rhBMP-7). Numerous animal models and clinical trials have shown that rhBMP-7 can induce de novo bone formation in segmental defects of bones and in cases of nonunion. Since 2001 rhBMP-7 has been approved for treatment of tibial nonunion in Europe. The effect of rhBMP-7 is comparable to the clinical and radiological results achieved with bone autografts. The problem of donor site morbidity (which occurs in up to 20% of all cases) is eliminated by the use of BMP-7. Long-term results and experience in clinical practice are not yet available.     

Discovery and development of BMPs

In the early 1970s, the isolation and identification of bone morphogenetic proteins (BMPs) was a major breakthrough for the understanding of the distinct biological events occurring during bone formation. Not surprising, since their discovery, BMPs have been perhaps one of the most intensively studied group of factors in various physiological processes. The prompt development of recombinant BMPs and various delivery methods made BMPs currently available for clinical use. Research and clinical studies on BMPs are ongoing, aiming to refine further our understanding of their activities in vivo and to optimise and expand their clinical use in humans.     

Successful Spinal Fusion by E. coli-derived BMP-2-adsorbed Porous β-TCP Granules: A Pilot Study

Bone morphogenetic proteins (BMPs) were originally identified as osteoinductive proteins. With cloning of BMP genes, studies of BMPs and their clinical application have advanced. However, with increasing clinical applications, drug delivery systems and production costs have become more important issues. To address these issues, we asked whether E. coli-derived rhBMP-2 (E-BMP-2)-adsorbed porous β-TCP granules could achieve posterolateral lumbar fusion in a rabbit model similar to autogenous bone grafts. Lumbar spinal fusion masses were evaluated by 3-D computed tomography, mechanical testing, and histological analyses 8 weeks after surgery. By these measures E-BMP-2-adsorbed β-TCP granules achieved lumbar spinal fusion in dose-dependent fashion in a rabbit model as well as autogenous bone graft. Our preliminary findings suggest E-BMP-2-adsorbed porous β-TCP could be a novel, effective alternative to autogenous bone grafting for generating new bone and promoting regenerative repair of bone, and potentially utilizable in the clinical setting for treating spinal disorders.     

Bone morphogenetic proteins in bone tumors

Bone morphogenetic proteins (BMPs), inducers of ectopic bone formation in vivo, are present in a number of osteosarcomas. BMPs are responsible for reactive bone formation, including periosteal reactions by normal osteoblasts, rather than production of tumorous osteoid by tumor cells. Osteosarcomas producing BMPs contain less-differentiated mesenchymal cells, resulting in a poorer prognosis for those patients. BMPs are also expressed in malignant fibrous histiocytomas (MFHs) of bone and dedifferentiated chondrosarcomas exhibiting undifferentiated features. However, BMPs in MFH do not show any osteoinductive activity in vivo, suggesting that those BMPs may be inactive forms and have additional functions unrelated to bone formation. Among benign bone tumors, BMPs are expressed in osteoid osteomas or osteoblastomas and effect reactive bone formation such as a surrounding sclerosis. BMPs and a BMP receptor (BMPRIB) are also detected in the cartilage cap in osteochondroma, suggesting that BMP signaling via BMPRIB might be involved in the pathogenesis of osteochondroma. Clinically, BMPs have utility as diagnostic and prognostic markers for characterizing the stage of differentiation of mesenchymal cells and mesenchymal tumors, and they may be of value in predicting the prognosis of sarcoma patients. This article reviews the accumulated information on BMPs in bone tumors, including the most recent findings, and discusses the biological and clinical significance of BMPs in bone tumors.Presented at the 36th Annual Musculoskeletal Tumor Meeting of the Japanese Orthopaedic Association, Kobe, Japan, July 2003     

Critical analysis and efficacy of BMPs in long bones non-union

Non-union of long bone fractures is considered as multifactorial. The management of this entity continues to be difficult often requiring multiple procedures with unpredictable results. Bone morphogenetic proteins (BMPs) are power agents being used in the clinical setting for a variety of pathological conditions where tissue regeneration is required. This article analyses the currently existing evidence of the efficacy of BMPs for the management of non-union of long bone fractures.     

BMP4 is dispensable for skeletogenesis and fracture-healing in the limb

Bone morphogenetic proteins (BMPs) are potent bone-forming agents that show clinical efficacy when used in patients to augment fracture-healing. Molecular profiling of fracture tissues has confirmed that BMPs 2, 3, 4, 5, 6, and 7 are expressed during the healing process, and it has identified a specific temporal pattern of expression for each BMP. Mice engineered to express increased levels of BMP antagonists have fragile bones that are prone to fracture, suggesting that BMPs not only mediate bone formation in the context of repair, but may also have a role in maintaining adult bone. In this study, mice carrying floxed Bmp4 alleles were bred with Prx1-cre transgenic mice to establish limb-specific removal of Bmp4. We compared these mice to mice in which Bmp2 was specifically deleted from the limb, and we then assessed limb skeletogenesis and fracture-healing. Limb skeletogenesis occurs normally in the absence of BMP4, and postnatal skeletal growth was also unaffected when BMP4 was removed. When mice lacking BMP4 were challenged to repair fractures, they were able to mount a successful healing response. We concluded that BMP4 is not required for formation of the limb skeleton and that femur fracture-healing is unaffected by the absence of BMP4. This study demonstrates that BMP4 is not required for bone formation and function in the limb, giving us further insights into the utility of recombinant human BMPs as therapeutic agents.     

Bone morphogenetic proteins in clinical applications

The role of bone morphogenetic proteins (BMPs) in bone healing has been shown in numerous animal models. To date, at least 20 BMPs have been identified, some of which have been shown in vitro to stimulate the process of stem cell differentiation into osteoblasts in human and animal models. Having realized the osteoinductive properties of BMPs and having identified their genetic sequences, recombinant gene technology has been used to produce BMPs for clinical application - most commonly, as alternatives or adjuncts in the treatment of cases in which fracture healing is compromised. BMP-2 and BMP-7 are approved for clinical use in open fractures of long bones, non-unions and spinal fusion. However, despite significant evidence of their potential benefit to bone repair and regeneration in animal and preclinical studies, there is, to date, a dearth of convincing clinical trials. The purpose of this paper is to give a brief overview of BMPs and to critically review the clinical data currently available on the use of BMP-2 and BMP-7 in fracture healing.     

The indications and use of bone morphogenetic proteins in foot, ankle, and tibia surgery

Tissue engineering is an area of rapid growth. Tissue engineering in orthopedic surgery involves the use of growth factors, mesenchymal stem cells, and scaffolds, individually or in combination, toward the growth and restoration of various musculoskeletal tissues, such as ligaments, tendons, muscles, nerves, and bone. These advances are constantly evolving in foot and ankle surgery as well. Bone morphogenetic proteins (BMPs) have played an integral role in the advancement of tissue engineering strategies across multiple orthopedic subspecialities and have proved to play a role in the development of bone and musculoskeletal tissues. BMPs have recently been applied in several areas of foot and ankle surgery, including acute fracture augmentation, nonunions, and arthrodesis, with promising results. This article reviews the key aspects of clinical translation of strategies in tissue engineering as well as current applications and results of BMP use in tibia, foot, and ankle surgery. Future applications of BMP and novel materials in foot and ankle surgery are also reviewed.     

The use of bone morphogenetic protein in spine fusion

Background contextBecause pseudarthrosis remains a clinically significant complication after spinal arthrodesis, the role of recombinant bone morphogenetic proteins (BMPs) is continually evaluated in spine surgery.PurposeThis article reviews the important literature in clinical research involving the use of BMPs in the augmentation of spinal fusion.Study design/settingReview article.MethodsA literature search was performed via MEDLINE through PubMed with the dates January 1960 to July 2007 using the keywords “bone morphogenetic protein, BMP, spinal arthrodesis, and/or bone healing.” Pertinent preclinical and clinical publications were chosen based on relevance and quality for inclusion in this study.ResultsPublications focused on the historical context and potential clinical applications using BMP were selected to delineate the risks, benefits, and current indications for the augmentation of spinal arthrodesis.ConclusionsAlthough multiple commercially available recombinant BMPs have demonstrated clinical success in interbody and posterolateral fusions, the associated costs preclude its routine use in spinal arthrodesis. The spine surgeon must assess each patient individually based on age, bone quality, diagnosis, comorbidities, and risks of nonunion to determine the cost effectiveness of the use of BMP to augment spinal fusion.     

What bone graft substitutes should we use in post-traumatic spinal fusion?

Surgical treatment of spinal fractures consists of postural reduction and segmental arthrodesis, together with an eventual performance of spinal canal decompression. Spinal arthrodesis consists of the combination of a hardware system for mechanical stabilisation together with a biological substance for enhancement of bone formation. To date, autologous graft is the only biological substance demonstrated to possess osteogenic properties. Cancellous bone graft has greater cellular activity than cortical graft, whereas cortical graft is stronger. Consequently, according to biological and biomechanical properties of autograft, spinal posterior arthrodesis is better enhanced by cancellous autograft, whereas anterior interbody tricortical bone is more suitable for anterior fusion. Allograft does not cause harvesting complications as autograft does, and also its amount is theoretically unlimited; nevertheless the rate of bone fusion facilitated by allograft is far from that enhanced by autograft given that allograft has no osteoprogenitor cells. There is little evidence on the efficacy of demineralised bone matrix for spinal fusion. Bone morphogenetic proteins (BMPs) are in use in spinal surgery, but their exact role with respect to type, dose, and carrier, together with their cost-effectiveness, need further clinical delineation. Calcium phosphate compounds appear to be good as carriers; however, they have no osteoinductive or osteogenic properties. Current clinical literature seem to indicate their usefulness for bony fusion in spinal surgery, when combined with bone marrow aspirate or used as an extender for autologous bone graft. Age, length of fusion, location, and concurrent diseases should be definitive for fusion outcome; papers on spinal arthrodesis should neatly stratify these variables. Unfortunately, since that is not the rule, conclusions drawn from current literature are very unreliable. Autograft remains the gold standard, and cancellous bone is advisable in posterolateral approaches, whereas tricortical iliac crest autograft appears appropriate for interbody support. In longer segments, its expansion with BMPs looks safe at least. Basic knowledge has been achieved from animal experiments, and clinical application of the findings to humans should be done very cautiously; in any case, both anterior and posterior arthrodesis must be protected with instrumentation used according to appropriate biomechanical principles. A combination of failure of the correct graft together with proper instrumentation will result in poorer outcome, even if the right graft is used.     

Clinical applications of BMPs

Bone morphogenetic proteins (BMPs) are polypeptides discovered by Marshall Urist in 1965 and later defined by his co-workers as multifunctional cytokines involved in osteoinduction. They are members of the transforming growth factor-beta superfamily with the exception of the BMP-1. Till now at least 20 BMPs have been identified and studied, but only BMP 2, 4 and 7 have been able in vitro to stimulate the entire process of stem cell differentiation into osteoblastic mature cells. After in vitro studies BMPs have been tested in preclinical and clinical studies, showing their definite potential in osteoinduction and have been approved for clinical use in open fracture of long bones, non-unions and vertebral arthrodesis. But more clinical use of these molecules is under investigation and the possibility of using gene therapy in selected pathologies seems the most appealing.