Bone Morphogenic Proteins Development and Clinical Efficacy

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COPYRIGHT 2005 BY THE JOURNAL OF BONE AND JOINT SURGERY, INCORPORATED

Current Concepts Review

Bone Morphogenetic Proteins

DEVELOPMENT AND CLINICAL EFFICACYIN THE TREATMENT OF FRACTURES AND BONE DEFECTS

BYM.F. TERMAAT, MD, F.C. DENBOER, MD, PHD, F.C. BAKKER, MD, PHD,

P. PATKA, MD, PHD, ANDH.J.TH.M. HAARMAN, MD, PHD

Investigation performed at the Department of Surgery and Traumatology, VU University Medical Center, Amsterdam, The Netherlands

The discovery of bone morphogenetic proteins marks a major step forward in the understanding of bone physiol-ogy and in the development of advanced methods in skeletal surgery.

The cornerstones for successful growth-factor therapy in skeletal surgery remain biomechanical stability and bio-logical vitality of the bone providing an adequate environment for new bone formation.

Knowledge of the biological characteristics, mechanisms of action, and methods of delivery of growth factorswill become essential for skeletal surgeons.

The current clinical application of bone morphogenetic proteins is safe and efficacious as a result of a well-regulated cascade of events leading to bone formation.

Clinical trials have not yet determined whether different clinical indications each require a specific bone-tissue-engineering format or if a single pathway for stimulating bone-healing with growth factors is sufficient.

The treatment of fractures remains a challenge in skeletal sur-gery. Patients who have sustained trauma are often young and,consequently, the medical and socioeconomic costs of frac-tures are high1,2. As recently reported, the lifetime risk of frac-ture is one in two for males and one in three for females.These numbers are equivalent to the lifetime risk of coronaryartery disease and demonstrate that fractures are a substantialpublic health problem2. Although the majority of fracturesheal normally, between 5% and 10% of patients have impairedfracture-healing3.

The cornerstones for successful bone-healing are bio-mechanical stability and biological vitality of the bone pro-viding an environment in which new bone can form. Many

conditions, such as insufficient vascularization, infection,mechanical instability, and systemic diseases, can impairthis environment. Improving these conditions and preventingdetrimental factors should guide surgical strategies. Increasesin the understanding of bone physiology and advancements inbiotechnology have led to a new surgical therapy for control-ling and modulating bone-healing with growth factors.

Skeletal regeneration, or bone-healing, is a recapitula-tion of embryonic bone development, as bone heals throughthe generation of new bone rather than by forming scar tissue.Growth factors in the transforming growth factor-(TGF-)superfamily, including bone morphogenetic proteins (BMPs),

are the most intensively studied group of peptides involved inembryogenesis and in adult bone repair and are the mostpromising group of growth factors for use in the enhancementof bone repair. The effectiveness of applying BMPs has beenextensively investigated preclinically and has led to the clinicalintroduction of the most potent BMPs (BMP-2 and BMP-7).Because the application of growth factors will play an impor-tant role in future surgical strategies, knowledge of the biolog-ical characteristics, mechanisms of action, and methods ofdelivery will be essential.

Identification and Structure of BMPs

The phenomenon of bone induction, or osteoinduction, was

first described by Urist in 1965, after he made the key discov-ery that new bone formation occurred locally in rodents afterintramuscular implantation of bone cylinders decalcified withhydrochloric acid4. This phenomenon was ascribed to thepresence of a protein in bone matrix, which he named bonemorphogenetic protein5.

In the late 1980s, it was found that not a single proteinbut a group of proteins in the bone matrix was responsible forosteoinduction6,7. Since then, the structure of more than six-teen different human BMPs has been identified with the aid ofmolecular biology techniques7-10. The BMPs are designated asBMP-1 to BMP-16 and are divided into several subtypes, ac-

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T HE J O U R N A LOF B ON E & JOINT S U R G E R Y J BJ S .O RG

VO L U M E87-A NUMBER6 JU NE 2005

BON E M ORPHOGENETIC P ROTEINS

cording to structural similarity between the molecules withineach subfamily (Table I). With the exception of BMP-1, theBMPs belong to the transforming growth factor- (TGF-)superfamily, a group of growth and differentiation factors that

play an important role during embryogenesis and tissue repairin postnatal life7,8,10-14. The role of BMPs in bone formationduring embryonic development and in adult bone-healing hasbeen elucidated to a large extent15,16.

Physiology of BMPs

Osteoinductive ActivityOnly a subset of BMPs has the unique property of inducingde novo bone formation, or osteoinduction, by themselves16.BMP-2 through 7 and BMP-9 have been shown to have thisproperty17-26, meaning that these osteoinductive BMPs have thecapacity to provide the primordial signal for the differentia-tion of mesenchymal stem cells into osteoblasts. After ectopic

implantation (e.g., subcutaneously in rats or intramuscularlyin baboons), individual recombinant human (rh) BMPs in-duce endochondral bone formation. A typical sequence ofevents can be observed in endochondral bone formation in-duced by BMPs: recruitment and proliferation of monocytesand mesenchymal cells, differentiation into chondrocytes, hy-pertrophy of chondrocytes and calcification of the cartilagematrix, vascular invasion with associated osteoblast differen-tiation and bone formation, and finally remodeling of thenewly formed bone and bone marrow formation (Fig. 1)27-29.

Cheng et al. recently demonstrated, in mesenchymalprogenitor and osteoblastic cells infected by adenovirus-medi-

ated gene transfer of BMPs, the relative osteoinductivity of dif-ferent BMPs at various stages of the differentiation process26,30.BMP-2, 6, and 9 play an important role in the early phase ofthe differentiation of mesenchymal progenitor cells to pre-

osteoblasts, while most BMPs promote the terminal differen-tiation of these pre-osteoblasts to osteoblasts. These findingscould indicate that BMP-2, 6, and 9 may be more effectivein a situation in which pluripotent cells are present (e.g.,application of an autologous bone transplant or recruitmentfrom surrounding muscular tissue). In the clinical situation ofnormal fracture-healing, in which pre-osteoblasts are pre-dominantly present, the majority of the BMPs are adequatefor promoting osteogenesis. However, the clinical relevance ofthis cascade, in which different BMPs are important at varioussteps in the differentiation process leading to bone formation,remains unknown.

Interestingly, it has been demonstrated that the osteoin-

ductive activity of BMP-3 depends on the experimental condi-tions and the stage of differentiation, as described above.BMP-3 has been shown to be osteoinductive in vivo, but it canalso be inhibitory in the presence of other BMPs, such asBMP-2 and BMP-7, and it is a negative regulator of postnatalbone density in animal models26,30,31. Thus, BMP-3 appears tolack the stimulatory role of other BMPs, but these findingsalso illustrate that bone formation is the end-product of acomplex intracellular and extracellular signaling cascade inwhich BMPs may have contradictory roles at different stages32.

Although more BMP subtypes have been demonstratedto be osteoinductive, at present only rhBMP-2 and rhBMP-7

TABLE I Classification of BMPs*

BMP Subfamily BMP Molecule Synonym

BMP-2/4 BMP-2 BMP-2A

BMP-4 BMP-2B

BMP-3 BMP-3 Osteogenin

BMP-3B GDF-10

BMP-7 BMP-5

BMP-6 Vgr-1

BMP-7 OP-1

BMP-8 OP-2

BMP-8B OP-3

CDMP/GDF BMP-12 CDMP-3 or GDF-7

BMP-13 CDMP-2 or GDF-6

BMP-14 CDMP-1 or GDF-5

Miscellaneous BMP-9 GDF-2

BMP-10

BMP-11 GDF-11

BMP-15

BMP-16

*BMP-1 is not included because it is not a member of the TGF-superfamily. It is a proteinase involved in the processing of procollagen tocollagen28,113. GDF = growth differentiation factor, Vgr = vegetal related, OP = osteogenic protein, and CDMP = cartilage-derived morphoge-netic protein.



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have been developed and used for clinical applications26.

Receptors and Intracellular SignalingThe transforming growth factor- (TGF-) superfamily, ofwhich BMPs are members, consists of related subgroups, in-cluding TGF-, growth differentiation factors, activins and in-hibins, Mllerian inhibiting substance, and the BMPs33. BMPsexert their effects on cells by binding to specific membrane re-ceptors, analogous to the signaling by other members of theTGF-family. Specific binding of individual BMPs to these re-ceptor complexes leads to activation of the intracellular Smad-

signaling pathway that finally determines the outcome of thesignal.

Signaling by the TGF- family occurs through type-Iand type-II serine/threonine kinase receptors, of which severalsubmembers have been identified. Each member of the TGF-family, including the BMPs, binds to a characteristic combi-nation of type-I and II receptors, which assembles a phospho-rylated complex. Subsequently, this complex phosphorylatesand activates receptor-regulated Smads (R-smads: Smad 1, 5,and 8 for BMPs). The Smad pathway is regulated by mediatorSmads (Smad 4 for BMPs), inhibitory Smads (I-Smads: Smad

Fig. 1

Illustration of the mechanisms of action of BMPs in bone repair. A typical sequence of events can be observed in endochondral bone formation in-

duced by BMPs: recruitment and proliferation of monocytes and mesenchymal cells, differentiation into chondrocytes, calcification of the cartilage

matrix, vascular invasion with associated osteoblast differentiation and bone formation, and remodeling of the newly formed bone. + = stimulating

effect, BM = basement membrane, BMPs = bone morphogenetic proteins, TGF-= transforming growth factor-, IL-1 = interleukin-1, IL-6 = interleukin-

6, FGF = fibroblast growth factor, and PDGF = platelet-derived growth factor.



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6 and 7), Smad binding proteins, and protein degradation34-37.The complex of Smad proteins are nuclear effectors, and theydetermine the outcome of the signal by activating or repress-ing target genes in the nucleus and they change the cellular

activity, including growth, differentiation, and extracellularmatrix synthesis (Fig. 2)38-40.Growth and differentiation factors such as the BMPs

play an essential role in cellular functioning but require atempering of their signal for coordinated bone formationand remodeling. This is achieved by feedback mechanisms:extracellularly by antagonists (i.e., noggin) and intracellularlyby inhibition and modulation of the Smad-signaling path-way41. Little is known about the downstream nuclear factors

that inhibit or stimulate the intracellular BMP signal. Hence,BMP signaling is a complex cascade with many levels of mu-tual interactions of the signal at extracellular, membranous,cytoplasmic, and nuclear levels15.

Preclinical Research with BMPs

Biological Activity of BMPsThe production of individual recombinant human BMPs (rh-BMPs) by biotechnology companies led to two importantconclusions. First, single BMPs are osteoinductive by them-selves. Second, the osteoinductivity of a single BMP has adose-response ratio42,43.

Patient characteristics do not determine the efficacy of

Fig. 2

BMP signaling pathway revealing multiple regulation mechanisms at the extracellular, membranous, cytoplasmic, and nuclear levels. BMPs bind to

a characteristic combination of type-I and II receptors, which assembles a phosphorylated complex. Subsequently, this complex phosphorylates and

activates receptor-regulated Smads (R-smads: Smad 1, 5, and 8 for BMPs). The Smad pathway is regulated by mediator Smads (Smad 4 for BMPs),

inhibitory Smads (I-Smads: Smad 6 and 7), Smad binding proteins (SBP), and protein degradation. The final complex of Smad proteins are nuclear

effectors, which determine the outcome of the signal by activating or repressing target genes in the nucleus and change the cellular activity, includ-

ing growth, differentiation, and extracellular matrix synthesis. BMPs = bone morphogenetic proteins, and P = phosphorylation.



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the dose of BMPs, as these proteins act locally. Therefore, theconcentration of BMPs at the site of implantation is moreimportant than the total dose of the BMP. The dose of BMPsmust overcome a threshold before they can effectively induce

bone formation. If the dose of BMPs is too low there will beinadequate bone formation, and if it is too high there will bemore bone formation and more rapid osteoinduction thandesired43. This increased bone formation eventually results indirect (intramembranous) ossification, bypassing the inter-mediate phase of endochondral ossification that occurs whenlower doses are used. However, with high doses of BMPs,initial localized resorption of bone can be seen as a result ofincreased osteoclastic activity, as BMPs also stimulate osteo-clastogenesis and osteoclastic activity41,44,45. At this point, ahigher dose of BMPs has no effectiveness, as the upper bor-der, after which no further acceleration of bone formationoccurs, has been reached43,46,47. Local overdoses of BMPs couldbe expected to lead to heterotopic ossification, but this phe-

nomenon has not been shown to occur under physiologicalconditions. In a mouse model of BMP-4-induced heterotopicossification, Glaser et al. demonstrated in vivo that hetero-topic ossification in fibrodysplasia ossificans progressiva maynot be due to the genetic overexpression of BMP-4 but ratherto the underexpression of the extracellular antagonist ofBMPs, noggin48. Excessive ossification in this animal modelcould be prevented by local delivery of noggin, illustratingthe highly regulated negative feedback mechanisms for BMPsthat prevent abnormal or heterotopic bone formation evenwith high doses.

The dose of BMP needed for clinical efficacy must over-come a threshold, and the dose-response curve becomes

steeper as one progresses from rodent to nonhuman primatemodels. The latter species, which is most closely related to hu-mans, was used to derive the human therapeutic dosage of 3.5mg/4 mL of sterile saline solution or 0.88 mg/mL of sterile sa-line solution for rhBMP-7 and 12 mg/8 mL of sterile water or1.50 mg/mL of sterile water for rhBMP-2. RhBMPs are expen-sive and are used in current clinical applications at concentra-tions that are ten to 1000-fold higher than those of nativeBMPs. These high doses of BMPs are used in an attempt toproduce a clinical effect comparable with that shown to beosteoinductive in animal studies. The strongly regulated sig-naling mechanisms and the rapid local and systemic clear-ance of BMPs in higher species also necessitate higher doses. It

has also been assumed that higher species have fewer respond-ing cells than do lower species. This raises important ques-tions regarding combination therapies of BMPs and thedevelopment of advanced delivery systems that are more effi-cient and, not unimportantly, more cost-effective.

Delivery Systems for BMPs

In the early 1990s, a major hurdle was cleared with the isola-tion, identification, and understanding of the physiologicalmechanisms of BMPs. However, it became evident that localapplication of BMPs is essential, as their systemic clearance ishigh. The natural delivery system of BMPs (i.e., bone matrix)

is highly effective, as the proteins are incorporated into a ma-trix that serves as a reservoir49. As mentioned above, the bio-logical activity of rhBMPs shows a dose-response relationshipand, to increase the osteoinductive response, the activity must

be maintained over a period of time. However, local tissueclearance of rhBMPs is rapid. Studies of animal fracture mod-els have demonstrated that BMPs can be efficacious when ad-ministrated locally in a formulation buffer50-53. Despite this, ithas become evident that bone repair is not efficiently stimu-lated in larger animal models, as the BMPs are not retained atthe repair site for a sufficient period of time. Research hasbeen concentrated on how to deliver these proteins efficientlyat the site of implantation by varying the delivery systems. Theneed to develop an adequate delivery system for BMPs hashampered their clinical application54. In general, delivery ofgrowth factors has been attempted through two approaches:(1) protein therapy, in which a recombinant protein is deliv-ered directly to the regeneration site with or without a carrier

matrix, and (2) gene therapy, in which a protein is deliveredindirectly by its encoding gene.

CarriersAn ideal carrier material should be biocompatible, biodegrad-able, and osteoconductive. The kinetics of a carrier have a pro-found effect on the speed and efficacy of bone induction. Theprimary function of these delivery materials is to increase theefficacy of BMPs by preventing rapid diffusion of the induc-tive agent away from the implant site and by providing a sus-tained release of the protein55. With the use of a buffer deliverysystem,


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osteoconductive matrix for the ingrowth of newly formedbone by promoting the deposition of minerals and by bindingnoncollagenous matrix proteins that initiate mineralization80.The rhBMPs available for clinical applications are delivered

in a type-I bovine collagen carrier, either a collagen sponge(used with BMP-2) or collagen particles (used with BMP-7).The current clinical collagen carriers release BMPs in a bulkmanner and require high doses of BMPs to produce an effect.Collagen-based carriers are effective for the current first-generation products, but they will need to be substantially im-proved in order to achieve clinical efficacy at lower doses and,therefore, at lower cost. It remains unknown if a sustained re-lease of BMPs is required throughout the bone-healing pro-cess, and this question must be elucidated by future research.

Gene Therapy

The limitations associated with current carrier materials, suchas immunological reactions and the inability to provide sus-

tained release of BMPs, have led to the development of ad-vanced approaches for the delivery of BMPs81. There are twoways to deliver the required BMP gene to the regeneration site:it can be delivered directly to the tissue so that host cells aretransfected and express the protein (in vivo transduction)82-85,and it can be delivered through transfection of cultured cells,which are implanted at the regeneration site (in vitro trans-duction) and subsequently express the protein83,86-91. The extra-cellular signaling pathway of the BMPs advocates for the latter,in vitro, approach, as this technique provides a well-controlledtransduction of the gene in a specific cell population that willexpress the protein at the required site. Despite the potentialfor using gene therapy to express growth factors, questions

concerning the safety of employing viral vectors and the influ-ence of immunological reactions to viral proteins need to beaddressed before clinical application can be considered.

Local and Systemic SafetyEctopic bone formation and bone overgrowth after implanta-tion has been one of the major concerns about clinical appli-cation of BMPs in humans. Also, systemic effects after localimplantation, such as immunogenicity and carcinogenicity,have been evaluated intensively.

Excessive local bone formation has been reported onlyafter the use of very high BMP doses, and it varies among spe-cies. Also, the excessive bone formation has been followed by

eventual remodeling to the normal bone contour42

. Moreover,bone formation requires the presence of mesenchymal cellsexpressing receptors for BMP, and these are unregulated onlyin specific clinical settings such as after injury92. When BMPsare used in the current therapeutic dosages, there seems to bea negligible risk of excessive bone formation at the implanta-tion site93-96.

Animal studies have demonstrated that, as a result ofrapid clearance, systemic concentrations of rhBMPs are virtu-ally undetectable after intravenous delivery. To our knowledge,studies of the use of rhBMPs in humans have not demon-strated any systemic toxicity thus far93,97-100.

Currently used collagen carrier materials are immuno-genic and induce the formation of antibodies. In recent clini-cal studies of small series, antibodies against BMPs developedin 6% to 10% of patients and antibodies against type-I bovine

collagen developed in 5% to 20%

93,96

. In a study by Govenderet al., the number of patients with an immunogenic reactionincreased from one to nine when the dose of rhBMP-2 was in-creased from 0.75 to 1.50 mg/mL96. The antibody titers werelow and transient, and this sensitization was not reported tohave any adverse effects on the bone-healing process93,96. It isimportant to realize that, although sensitization was observedin a minority of the patients in these first clinical studies, thepresence of antibodies was positively correlated with higherdoses of both BMP and collagen. It remains unknown whatimmunogenic reactions will occur when even higher doses ofBMPs or collagen are applied for the first time in a patient orfor a second time in a previously sensitized patient.

The long-term effects and possible genetic alterations

due to the application of BMPs in humans remain unknown.In vitro and in vivo studies to date have not demonstrated anyevidence of carcinogenicity, and they have even demonstratedan antiproliferative effect on human tumors101,102. We are notaware of any clear published data on the application of BMPsduring human pregnancy or the effect on embryonic or ado-lescent development. Therefore, pregnancy is a contraindica-tion to the use of BMPs, and applications in children must beconsidered carefully.

Clinical Applications and

Efficacy of BMPs (Table II)

Clinical Efficacy of BMPs for

Stimulating Fracture-HealingIt is surprising that the effects of BMPs on fractures, poten-tially the most common clinical indication, have been studiedonly to a limited extent. BMPs and their receptors are unregu-lated during the fracture-healing process92,103. Animal modelshave demonstrated that fracture-healing can be accelerated bythe local administration of rhBMPs50,52,58,103,104. The primary goalof the use of BMPs in fresh (open) fractures is to enhance thefracture-healing process in order to reduce the rate of second-ary interventions and thus to shorten the healing time96.

Riedel and Valentin-Opran performed what we believewas the first feasibility study of the application of rhBMP-2bound to an absorbable collagen sponge in patients with a fresh

open tibial fracture105

. This clinical trial demonstrated that im-plantation of rhBMP is surgically feasible and safe, and mostpatients had primary healing without secondary interventions.

The BESTT study group evaluated the application ofrhBMP-2 in an absorbable collagen sponge (ACS) in open tib-ial fractures with the primary end point for efficacy definedas the percentage of patients requiring secondary interventionwithin twelve months96. The patients were randomized tothree treatment groups. Group I (147 patients) had fracturetreatment with open reduction and internal fixation (the stan-dard care) and was considered to be the control group, GroupII (145 patients) had standard care with the addition of 0.75



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six patients treated with the type-I collagen carrier alone hadbone formation. We believe that this was the first evidence ofthe osteoinductive capacity and effectiveness of rhBMP-7 inhumans.

Friedlaender et al. assessed the efficacy of rhBMP-7bound to type-I collagen (an OP-1 [osteogenic protein-1]implant) for the treatment of established tibial nonunions bycomparing it with autologous bone-grafting, the so-calledgold standard of treatment93. The union rate was similar in thetwo groups, which also did not differ with regard to clinical orradiographic healing characteristics. Although comparativeefficacy was demonstrated, the goal of the BMP therapy, ahigher healing rate, was not achieved. Unfortunately, the au-thors did not conduct a power analysis for their study, and thelack of differences between the groups may have been the re-sult of a type-II statistical error. It is interesting to speculatethat the rhBMP-7 might have been more effective, as the per-centage of patients with atrophic nonunion was higher in the

rhBMP-7 group (41%) than it was in the group treated withautologous bone-grafting (25%). However, no statistical anal-ysis with adjustment for atrophic nonunion was performed.Also, the authors chose a difficult population of patients withnonunion to study, as the majority had had prior bone-graftingand intramedullary rod fixation before inclusion in the studyand this could have resulted in heterogeneity of the results.Another factor causing heterogeneity may have been the factthat clinical and radiographic assessment of successful bone-healing is extremely difficult and subjective in such patients115.Friedlaender et al. did show that the risk of infection at theimplantation site was significantly lower in the rhBMP-7group than it was in the group treated with autologous bone-

grafting (p = 0.002). The authors concluded that BMPs couldbe deemed an effective alternative to autografting if the mor-bidity associated with harvesting of the graft is taken intoconsideration93.

Clinical Efficacy of BMPs in Spinal FusionThe acceleration of spinal fusion has been extensively studiedafter animal experiments demonstrated that BMPs can beused as a replacement for, or an augmentation of, autologousbone-grafting46,116-119. BMPs have been evaluated to determinetheir osteoinductive potential in posterolateral intertransverseand interbody fusions. Nonunion or failure to achieve a solidbone fusion still occurs in up to 35% of patients treated with

spinal fusion120

.Burkus et al. investigated the use of rhBMP-2/ACS tostimulate spinal fusion in a cohort of 279 patients with degen-erative disc disease. In two prospective randomized trials, theeffectiveness, safety, and rates of osteoinduction following an-terior lumbar interbody fusion with use of rhBMP-2/ACSwere compared with those following fusion with autologousbone graft, with both substances placed in the hollow centralportion of an LT-Cage121,122. Plain radiographs and computedtomographic scans were used to evaluate the pattern of os-teoinduction in the interbody space and the progression offusion at six, twelve, and twenty-four months. All patients

treated with the rhBMP-2/ACS demonstrated evidence of os-teoinduction at six months. At twenty-four months, the fu-sion was successful in 94.5% of the patients in the BMP-2group and 88.7% of those in the control group. This difference

was not significant. In another study, Burkus et al. investigatedthe efficacy of rhBMP-2 for enhancing the incorporation ofthreaded cortical allografts in forty-two patients123. At twelvemonths, interbody fusion was demonstrated in 100% of theBMP-2 group compared with 89.5% of the control group.These studies demonstrated the effectiveness of BMPs in spi-nal fusion and the potential for eliminating the harvest ofautograft121-123.

In a randomized trial, Johnsson et al. compared the efficacyof rhBMP-7 with that of autologous bone-grafting for achievingposterolateral fusion in twenty patients94. The radiostereometricand radiographic results at twelve months showed no signifi-cant difference between the two methods of fusion.

A major concern about the use of BMPs to enhance

spinal fusion is the risk of bone overgrowth or heterotopic os-sification leading to spinal or foraminal stenosis. In a laminec-tomy defect model with a dural defect in dogs, Meyer et al.found no evidence of abnormal mineralization within the the-cal sac or in the spinal cord after treatment with rhBMP-2124.However, caution with regard to the use of the BMPs shouldbe exercised in cases of dural defects, even after repair. Rh-BMP-7 has been approved by the Food and Drug Administra-tion for use with lumbar interbody spinal fusion cages in theUnited States. These cages have the advantage of providingproper containment of the BMP and offering resistance to ax-ial loading.

When BMPs are used in spinal surgery, the key consid-

erations are accurate placement of the BMP at the fusion site,retention of the BMP by the carrier, securing hemostasis toprevent dilution of the BMP, and limiting the exposure ofbone beyond the fusion area. It remains difficult to assess theclinical outcomes of the use of BMPs in spinal fusion, asobjective standards for successful fusion are not available.Current evidence indicates that BMPs can be used safely andeffectively when the above conditions have been met.

InfectionOf particular interest are the findings of reduced rates of in-fection after treatment of fresh fractures and nonunions withBMPs. These findings may be explained by the increased

stability created by the enhanced osteoinduction and the ac-companying increase in the local vascular supply. Studies ofanimals have also demonstrated the potential of BMPs to in-duce bone formation in infected osseous sites, thus providingincreased callus stability125,126. This is important because insta-bility of the fracture site has been shown to affect the healingand progression of bone infections127.

AngiogenesisOsteogenesis and angiogenesis are known to be mutually in-terdependent, and BMPs have been demonstrated in vesselsduring bone repair128-130. Ramoshebi and Ripamonti showed



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that implantation of BMP-7 stimulates the growth of angio-genic sprouts toward the implant131. Although the exact mech-anisms remain unknown, BMPs seem to vitalize the bone siteby stimulating osteogenesis, the resorption of damaged bone,

and angiogenesis.

Overview

The discovery of BMPs marked a major step forward in theunderstanding of bone physiology and in the development ofadvanced methods of skeletal bone surgery. These growth anddifferentiation factors have a unique potential to induce newbone formation, even at extraskeletal sites. It has taken almostforty years since the initial discovery of these growth factors byUrist4 for them to become available for clinical application.The successful application of BMPs depends on elucidationof the optimal therapeutic dosage, delivery system, and localconditions for bone repair, and these factors are still under in-vestigation. Basic surgical management to provide adequate

environmental conditions of the implantation site, such assoft-tissue coverage, host-bed vitality, and biomechanical sta-bility, remains essential.

Prospective clinical trials of BMP-2 and BMP-7 for thetreatment of fractures and nonunions, respectively, haveshown solid outcomes. Clinical trials, although still limitedin number compared with preclinical studies, have demon-strated that BMPs are effective and safe for human applica-tion and have an efficacy comparable with that of autologousbone-grafting.

Growth-factor therapy with BMPs offers a new surgicalapproach that can augment or even replace bone-grafting pro-cedures. However, it must be noted that treatment of fresh

fractures with BMP in humans did not result in a significantlyhigher rate of bone-healing compared with that yielded bycurrent treatment techniques such as autologous bone-grafting.This finding is in strong contrast to the preclinical results inanimal studies. BMPs must be given in much higher doses toaccomplish osteoinductive activity in humans.

The first clinical studies of BMP-2 and 7 have demon-strated that bone formation is not always consistent. Possible

explanations for this are the relative osteoinductivity of theapplied BMPs in the presence of responding cells and the timeat which the BMPs are presented locally by their carrier. Anincreased understanding of these mechanisms and additional

research are still needed to develop better carrier systems andpossible combination therapies with other BMPs or growthfactors.

Future preclinical and clinical research must clarify is-sues regarding the relative effectiveness of BMPs, the interac-tion between BMP subtypes, and the characteristics ofresponding cells in much greater detail. BMPs have great clini-cal potential, but in the next decades we will have to discernwhether there is a single pathway to efficient bone-healingor whether different clinical situations require specific bone-tissue-engineering formats.

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M.F. Termaat, MD

F.C. Bakker, MD, PhDP. Patka, MD, PhDH.J.Th.M. Haarman, MD, PhDDepartment of Surgery and Traumatology, VU University MedicalCenter, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. E-mailaddress for M.F. Termaat: [email protected]. E-mail address for F.C.Bakker: [email protected]. E-mail address for P. Patka:[email protected]. E-mail address for H.J.Th.M. Haarman:[email protected]

F.C. Den Boer, MD, PhDDepartment of Surgery, Sint Antonius Hospital, P.O. Box 2500, 3430 EMNieuwegein, The Netherlands. E-mail address: [email protected]

The authors did not receive grants or outside funding in support of theirresearch or preparation of this manuscript. They did not receive pay-ments or other benefits or a commitment or agreement to provide suchbenefits from a commercial entity. No commercial entity paid ordirected, or agreed to pay or direct, any benefits to any research fund,foundation, educational institution, or other charitable or nonprofitorganization with which the authors are affiliated or associated.

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Bone Morphogenic Proteins Development and Clinical Efficacy

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