The Journal of Bone and Joint Surgery (American). 2005;87:1367-1378.
doi:10.2106/JBJS.D.02585
© 2005 The Journal of Bone and Joint Surgery, Inc.
Bone Morphogenetic Proteins
Development and Clinical Efficacy in the Treatment of Fractures and Bone Defects
M.F. Termaat, MD1,
F.C. Den Boer, MD, PhD2,
F.C. Bakker, MD, PhD1,
P. Patka, MD, PhD1 and
H.J.Th.M. Haarman, MD, PhD1
1 Department of Surgery and Traumatology, VU University Medical Center, P.O. Box
7057, 1007 MB Amsterdam, The Netherlands. E-mail address for M.F. Termaat:
mf.termaat{at}vumc.nl.
E-mail address for F.C. Bakker:
fc.bakker{at}vumc.nl.
E-mail address for P. Patka:
p.patka{at}vumc.nl.
E-mail address for H.J.Th.M. Haarman:
hjtm.haarman{at}vumc.nl
2 Department of Surgery, Sint Antonius Hospital, P.O. Box 2500, 3430 EM
Nieuwegein, The Netherlands. E-mail address:
frankdenboer{at}hotmail.com
Investigation performed at the Department of Surgery and Traumatology,
VU University Medical Center, Amsterdam, The Netherlands
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Abstract
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The discovery of bone morphogenetic proteins marks a major step forward in
the understanding of bone physiology and in the development of advanced
methods in skeletal surgery.
The cornerstones for successful growth-factor therapy in skeletal surgery
remain biomechanical stability and biological 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 factors will 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.
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Introduction
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The treatment of fractures remains a challenge in skeletal surgery.
Patients who have sustained trauma are often young and, consequently, the
medical and socioeconomic costs of fractures are
high1,2.
As recently reported, the lifetime risk of fracture is one in two for males
and one in three for females. These numbers are equivalent to the lifetime
risk of coronary artery disease and demonstrate that fractures are a
substantial public health
problem2. Although
the majority of fractures heal normally, between 5% and 10% of patients have
impaired
fracture-healing3.
The cornerstones for successful bone-healing are biomechanical stability
and biological vitality of the bone providing an environment in which new bone
can form. Many conditions, such as insufficient vascularization, infection,
mechanical instability, and systemic diseases, can impair this environment.
Improving these conditions and preventing detrimental factors should guide
surgical strategies. Increases in the understanding of bone physiology and
advancements in biotechnology have led to a new surgical therapy for
controlling and modulating bone-healing with growth factors.
Skeletal regeneration, or bone-healing, is a recapitulation of embryonic
bone development, as bone heals through the generation of new bone rather than
by forming scar tissue. Growth factors in the transforming growth
factor-ß (TGF-ß) superfamily, including bone morphogenetic proteins
(BMPs), are the most intensively studied group of peptides involved in
embryogenesis and in adult bone repair and are the most promising group of
growth factors for use in the enhancement of bone repair. The effectiveness of
applying BMPs has been extensively investigated preclinically and has led to
the clinical introduction of the most potent BMPs (BMP-2 and BMP-7). Because
the application of growth factors will play an important role in future
surgical strategies, knowledge of the biological characteristics, mechanisms
of action, and methods of delivery will be essential.
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Identification and Structure of BMPs
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The phenomenon of bone induction, or osteoinduction, was first described by
Urist in 1965, after he made the key discovery that new bone formation
occurred locally in rodents after intramuscular implantation of bone cylinders
decalcified with hydrochloric
acid4. This
phenomenon was ascribed to the presence of a protein in bone matrix, which he
named bone morphogenetic
protein5.
In the late 1980s, it was found that not a single protein but a group of
proteins in the bone matrix was responsible for
osteoinduction6,7.
Since then, the structure of more than sixteen different human BMPs has been
identified with the aid of molecular biology
techniques7-10.
The BMPs are designated as BMP-1 to BMP-16 and are divided into several
subtypes, according to structural similarity between the molecules within each
subfamily (Table I). With the
exception of BMP-1, the BMPs belong to the transforming growth factor-ß
(TGF-ß) superfamily, a group of growth and differentiation factors that
play an important role during embryogenesis and tissue repair in postnatal
life7,8,10-14.
The role of BMPs in bone formation during embryonic development and in adult
bone-healing has been elucidated to a large
extent15,16.
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Physiology of BMPs
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Osteoinductive Activity
Only a subset of BMPs has the unique property of inducing de novo bone
formation, or osteoinduction, by
themselves16. BMP-2
through 7 and BMP-9 have been shown to have this
property17-26,
meaning that these osteoinductive BMPs have the capacity to provide the
primordial signal for the differentiation of mesenchymal stem cells into
osteoblasts. After ectopic implantation (e.g., subcutaneously in rats or
intramuscularly in baboons), individual recombinant human (rh) BMPs induce
endochondral bone formation. A typical sequence of events can be observed in
endochondral bone formation induced by BMPs: recruitment and proliferation of
monocytes and mesenchymal cells, differentiation into chondrocytes,
hypertrophy of chondrocytes and calcification of the cartilage matrix,
vascular invasion with associated osteoblast differentiation and bone
formation, and finally remodeling of the newly formed bone and bone marrow
formation (Fig.
1)27-29.
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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 induced 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-ß =
transforming growth factor-ß, IL-1 = interleukin-1, IL-6 = interleukin-6,
FGF = fibroblast growth factor, and PDGF = platelet-derived growth factor.
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Cheng et al. recently demonstrated, in mesenchymal progenitor and
osteoblastic cells infected by adenovirus-mediated gene transfer of BMPs, the
relative osteoinductivity of different BMPs at various stages of the
differentiation
process26,30.
BMP-2, 6, and 9 play an important role in the early phase of the
differentiation of mesenchymal progenitor cells to pre-osteoblasts, while most
BMPs promote the terminal differentiation of these pre-osteoblasts to
osteoblasts. These findings could indicate that BMP-2, 6, and 9 may be more
effective in a situation in which pluripotent cells are present (e.g.,
application of an autologous bone transplant or recruitment from surrounding
muscular tissue). In the clinical situation of normal fracture-healing, in
which pre-osteoblasts are predominantly present, the majority of the BMPs are
adequate for promoting osteogenesis. However, the clinical relevance of this
cascade, in which different BMPs are important at various steps in the
differentiation process leading to bone formation, remains unknown.
Interestingly, it has been demonstrated that the osteoinductive activity of
BMP-3 depends on the experimental conditions and the stage of differentiation,
as described above. BMP-3 has been shown to be osteoinductive in vivo, but it
can also be inhibitory in the presence of other BMPs, such as BMP-2 and BMP-7,
and it is a negative regulator of postnatal bone density in animal
models26,30,31.
Thus, BMP-3 appears to lack the stimulatory role of other BMPs, but these
findings also illustrate that bone formation is the end-product of a complex
intracellular and extracellular signaling cascade in which BMPs may have
contradictory roles at different
stages32.
Although more BMP subtypes have been demonstrated to be osteoinductive, at
present only rhBMP-2 and rhBMP-7 have been developed and used for clinical
applications26.
Receptors and Intracellular Signaling
The transforming growth factor-ß (TGF-ß) superfamily, of which
BMPs are members, consists of related subgroups, including TGF-ß, growth
differentiation factors, activins and inhibins, Müllerian inhibiting
substance, and the
BMPs33. BMPs exert
their effects on cells by binding to specific membrane receptors, analogous to
the signaling by other members of the TGF-ß family. Specific binding of
individual BMPs to these receptor complexes leads to activation of the
intracellular Smad-signaling pathway that finally determines the outcome of
the signal.
Signaling by the TGF-ß family occurs through type-I and type-II
serine/threonine kinase receptors, of which several submembers have been
identified. Each member of the TGF-ß family, including the BMPs, binds 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, and protein
degradation34-37.
The complex of Smad proteins are nuclear effectors, and they determine the
outcome of the signal by activating or repressing target genes in the nucleus
and they change the cellular activity, including growth, differentiation, and
extracellular matrix synthesis (Fig.
2)38-40.
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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, including growth,
differentiation, and extracellular matrix synthesis. BMPs = bone morphogenetic
proteins, and P = phosphorylation.
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Growth and differentiation factors such as the BMPs play an essential role
in cellular functioning but require a tempering of their signal for
coordinated bone formation and remodeling. This is achieved by feedback
mechanisms: extracellularly by antagonists (i.e., noggin) and intracellularly
by inhibition and modulation of the Smad-signaling
pathway41. 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 mutual interactions of the signal at extracellular, membranous,
cytoplasmic, and nuclear
levels15.
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Preclinical Research with BMPs
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Biological Activity of BMPs
The production of individual recombinant human BMPs (rhBMPs) by
biotechnology companies led to two important conclusions. First, single BMPs
are osteoinductive by themselves. Second, the osteoinductivity of a single BMP
has a dose-response
ratio42,43.
Patient characteristics do not determine the efficacy of the dose of BMPs,
as these proteins act locally. Therefore, the concentration of BMPs at the
site of implantation is more important than the total dose of the BMP. The
dose of BMPs must overcome a threshold before they can effectively induce bone
formation. If the dose of BMPs is too low there will be inadequate bone
formation, and if it is too high there will be more bone formation and more
rapid osteoinduction than
desired43. This
increased bone formation eventually results in direct (intramembranous)
ossification, bypassing the intermediate phase of endochondral ossification
that occurs when lower doses are used. However, with high doses of BMPs,
initial localized resorption of bone can be seen as a result of increased
osteoclastic activity, as BMPs also stimulate osteoclastogenesis and
osteoclastic
activity41,44,45.
At this point, a higher dose of BMPs has no effectiveness, as the upper
border, after which no further acceleration of bone formation occurs, has been
reached43,46,47.
Local overdoses of BMPs could be expected to lead to heterotopic ossification,
but this phenomenon has not been shown to occur under physiological
conditions. In a mouse model of BMP-4-induced heterotopic ossification, Glaser
et al. demonstrated in vivo that heterotopic ossification in fibrodysplasia
ossificans progressiva may not be due to the genetic overexpression of BMP-4
but rather to the underexpression of the extracellular antagonist of BMPs,
noggin48. Excessive
ossification in this animal model could be prevented by local delivery of
noggin, illustrating the highly regulated negative feedback mechanisms for
BMPs that prevent abnormal or heterotopic bone formation even with high
doses.
The dose of BMP needed for clinical efficacy must overcome a threshold, and
the dose-response curve becomes steeper as one progresses from rodent to
nonhuman primate models. The latter species, which is most closely related to
humans, was used to derive the human therapeutic dosage of 3.5 mg/4 mL of
sterile saline solution or 0.88 mg/mL of sterile saline solution for rhBMP-7
and 12 mg/8 mL of sterile water or 1.50 mg/mL of sterile water for rhBMP-2.
RhBMPs are expensive and are used in current clinical applications at
concentrations that are ten to 1000-fold higher than those of native BMPs.
These high doses of BMPs are used in an attempt to produce a clinical effect
comparable with that shown to be osteoinductive in animal studies. The
strongly regulated signaling mechanisms and the rapid local and systemic
clearance of BMPs in higher species also necessitate higher doses. It has also
been assumed that higher species have fewer responding cells than do lower
species. This raises important questions regarding combination therapies of
BMPs and the development of advanced delivery systems that are more efficient
and, not unimportantly, more cost-effective.
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Delivery Systems for BMPs
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In the early 1990s, a major hurdle was cleared with the isolation,
identification, and understanding of the physiological mechanisms of BMPs.
However, it became evident that local application of BMPs is essential, as
their systemic clearance is high. The natural delivery system of BMPs (i.e.,
bone matrix) is highly effective, as the proteins are incorporated into a
matrix that serves as a
reservoir49. As
mentioned above, the biological activity of rhBMPs shows a dose-response
relationship and, to increase the osteoinductive response, the activity must
be maintained over a period of time. However, local tissue clearance of rhBMPs
is rapid. Studies of animal fracture models have demonstrated that BMPs can be
efficacious when administrated locally in a formulation
buffer50-53.
Despite this, it has become evident that bone repair is not efficiently
stimulated in larger animal models, as the BMPs are not retained at the repair
site for a sufficient period of time. Research has been concentrated on how to
deliver these proteins efficiently at the site of implantation by varying the
delivery systems. The need to develop an adequate delivery system for BMPs has
hampered their clinical
application54. In
general, delivery of growth factors has been attempted through two approaches:
(1) protein therapy, in which a recombinant protein is delivered directly to
the regeneration site with or without a carrier matrix, and (2) gene therapy,
in which a protein is delivered indirectly by its encoding gene.
Carriers
An ideal carrier material should be biocompatible, biodegradable, and
osteoconductive. The kinetics of a carrier have a profound effect on the speed
and efficacy of bone induction. The primary function of these delivery
materials is to increase the efficacy of BMPs by preventing rapid diffusion of
the inductive agent away from the implant site and by providing a sustained
release of the
protein55. With the
use of a buffer delivery system, <5% of the BMP dose remains at the
application site, whereas combinations of BMPs with gelatin foam, collagen, or
calcium phosphate pastes increase the retention to 15% to
55%56. The carrier
provides an osteoconductive matrix that stabilizes the release of BMPs and
thereby lowers the required
dose57. Additional
research is still required to determine the optimal type of carrier material
for the delivery of BMPs for particular clinical indications. For the
treatment of fracture repair, the delivery must be coupled with a carrier that
degrades rapidly, to meet the rate of new bone formation so that remaining
carrier material does not compromise the healing. For the treatment of
nonunions and for spinal fusion, the carrier characteristics have to include a
slow release of BMPs, with sufficient residence time and osteoconductive
matrix support for osteogenic cell infiltration and the prevention of
encroaching soft
tissue55.
Many different carrier materials have been used in animal experiments.
These include demineralized collagenous bone
matrix50,58-60,
collagen
products55,58,61,
resorbable polymers such as
polylactide62,63
and
polylactide-co-glycolide64-68,
gelatin
hydrogels69,70,
calcium phosphate ceramics such as tricalcium
phosphate71,72
and
hydroxyapatite73,74,
resorbable calcium phosphate cement
(alpha-BSM)75, and
combinations of these
materials76-79.
Collagen-based carriers possess the appropriate characteristics, as type-I
collagen, the main component of bone matrix, is biocompatible and
bioresorbable. Collagen provides an osteoconductive matrix for the ingrowth of
newly formed bone by promoting the deposition of minerals and by binding
noncollagenous 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 bulk manner 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 improved in order to achieve
clinical efficacy at lower doses and, therefore, at lower cost. It remains
unknown if a sustained release of BMPs is required throughout the bone-healing
process, and this question must be elucidated by future research.
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Gene Therapy
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The limitations associated with current carrier materials, such as
immunological reactions and the inability to provide sustained release of
BMPs, have led to the development of advanced approaches for the delivery of
BMPs81. There are
two ways to deliver the required BMP gene to the regeneration site: it can be
delivered directly to the tissue so that host cells are transfected 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 transduction) and subsequently
express the
protein83,86-91.
The extracellular signaling pathway of the BMPs advocates for the latter, in
vitro, approach, as this technique provides a well-controlled transduction of
the gene in a specific cell population that will express the protein at the
required site. Despite the potential for using gene therapy to express growth
factors, questions concerning the safety of employing viral vectors and the
influence of immunological reactions to viral proteins need to be addressed
before clinical application can be considered.
Local and Systemic Safety
Ectopic bone formation and bone overgrowth after implantation has been one
of the major concerns about clinical application of BMPs in humans. Also,
systemic effects after local implantation, such as immunogenicity and
carcinogenicity, have been evaluated intensively.
Excessive local bone formation has been reported only after the use of very
high BMP doses, and it varies among species. Also, the excessive bone
formation has been followed by eventual remodeling to the normal bone
contour42.
Moreover, bone formation requires the presence of mesenchymal cells expressing
receptors for BMP, and these are unregulated only in specific clinical
settings such as after
injury92. When BMPs
are used in the current therapeutic dosages, there seems to be a negligible
risk of excessive bone formation at the implantation
site93-96.
Animal studies have demonstrated that, as a result of rapid clearance,
systemic concentrations of rhBMPs are virtually undetectable after intravenous
delivery. To our knowledge, studies of the use of rhBMPs in humans have not
demonstrated any systemic toxicity thus
far93,97-100.
Currently used collagen carrier materials are immunogenic and induce the
formation of antibodies. In recent clinical studies of small series,
antibodies against BMPs developed in 6% to 10% of patients and antibodies
against type-I bovine collagen developed in 5% to
20%93,96.
In a study by Govender et al., the number of patients with an immunogenic
reaction increased from one to nine when the dose of rhBMP-2 was increased
from 0.75 to 1.50
mg/mL96. The
antibody titers were low and transient, and this sensitization was not
reported to have any adverse effects on the bone-healing
process93,96.
It is important to realize that, although sensitization was observed in a
minority of the patients in these first clinical studies, the presence of
antibodies was positively correlated with higher doses of both BMP and
collagen. It remains unknown what immunogenic reactions will occur when even
higher doses of BMPs or collagen are applied for the first time in a patient
or for 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 any evidence of carcinogenicity, and they have even
demonstrated an antiproliferative effect on human
tumors101,102.
We are not aware of any clear published data on the application of BMPs during
human pregnancy or the effect on embryonic or adolescent development.
Therefore, pregnancy is a contraindication to the use of BMPs, and
applications in children must be considered carefully.
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Clinical Applications and Efficacy of BMPs (Table II)
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Clinical Efficacy of BMPs for Stimulating Fracture-Healing
It is surprising that the effects of BMPs on fractures, potentially the
most common clinical indication, have been studied only to a limited extent.
BMPs and their receptors are unregulated during the fracture-healing
process92,103.
Animal models have demonstrated that fracture-healing can be accelerated by
the local administration of
rhBMPs50,52,58,103,104.
The primary goal of the use of BMPs in fresh (open) fractures is to enhance
the fracture-healing process in order to reduce the rate of secondary
interventions and thus to shorten the healing
time96.
Riedel and Valentin-Opran performed what we believe was the first
feasibility study of the application of rhBMP-2 bound to an absorbable
collagen sponge in patients with a fresh open tibial
fracture105. This
clinical trial demonstrated that implantation of rhBMP is surgically feasible
and safe, and most patients had primary healing without secondary
interventions.
The BESTT study group evaluated the application of rhBMP-2 in an absorbable
collagen sponge (ACS) in open tibial fractures with the primary end point for
efficacy defined as the percentage of patients requiring secondary
intervention within twelve
months96. The
patients were randomized to three treatment groups. Group I (147 patients) had
fracture treatment with open reduction and internal fixation (the standard
care) and was considered to be the control group, Group II (145 patients) had
standard care with the addition of 0.75 mg/mL of rhBMP-2/ACS, and Group III
(145 patients) had standard care with the addition of 1.50 mg/mL of
rhBMP-2/ACS. The percentages of patients requiring secondary intervention were
46%, 37%, and 26%, respectively; thus, the percentages were lower in both
groups treated with rhBMP-2. Compared with the control group, the group
treated with 1.50 mg/mL of rhBMP-2 had a significant (44%) reduction in the
rate of secondary interventions (p = 0.0005) and a significantly shorter
healing time (145 compared with 184 days, p = 0.0022). A noteworthy limitation
of the study was an imbalance in the use of unreamed and reamed nailing, with
the latter favored in the rhBMP-2-treated groups. As multiple regression
analyses indicated that both reaming and rhBMP-2 independently affected the
primary outcome of the fracture treatment, the authors considered it
appropriate to pool subgroups to assess the overall efficacy of rhBMP-2. Also,
there was a risk of verification bias in this study because the treating
surgeon, who was not blinded to the treatment assignment, performed the final
clinical and radiographic assessments of fracture union. The implantation of
rhBMP-2/ACS significantly reduced the rate of infections in patients with a
Gustilo-Anderson type-IIIA or IIIB open fracture (p = 0.0219). The authors
attributed this observation to increased fracture stability and increased
vascular supply, both of which enhanced soft-tissue
healing106.
A randomized clinical trial of the use of rhBMP-7 to stimulate healing of
fresh open fractures is ongoing, and the preliminary results were recently
presented by McKee et
al.107. Overall,
124 patients with an open tibial shaft fracture were randomized either to a
group treated with the addition of rhBMP-7 in a type-I collagen carrier at the
fracture site or to a control group treated with normal wound closure. In this
preliminary report, the number of secondary interventions was lower in the
rhBMP-7 group than it was in the control group (12% and 27%,
respectively).
Clinical Efficacy of BMPs in the Treatment of Bone Defects and Nonunions
Extensive preclinical data have demonstrated the potential for BMPs to
induce healing of critically sized defects—i.e., defects that cannot
heal without exogenous osteogenic
stimulation61,108.
In animal models with such segmental defects, the results of BMP were
equivalent to or better than those of autologous bone-grafting, the standard
treatment of bone defects and nonunions in clinical
practice61,76,108-110.
These findings demonstrated the potential for BMPs to be used as an
alternative to autologous bone-grafting. This potential has been investigated
intensively in recent years as bone-graft harvest causes morbidity, such as
persistent pain, numbness, or hypersensitivity at the donor
site111.
In the late 1980s and early 1990s, Johnson et al. evaluated several small
series of patients in whom resistant non-unions and segmental long-bone
defects had been treated with human BMP
(hBMP)112-114.
As recombinant BMPs were not yet available, a purified mixture of BMP proteins
(hBMP) was used, in combination with insoluble noncollagenous proteins; both
were derived from human donor bone. At that point in time, the risk of
immunogenicity associated with alloimplants was becoming apparent. Also, it
remained unknown which specific proteins were responsible for the
osteoinductive activity and how this activity should be managed to develop an
applicable clinical product. However, these were the first studies to assess
purified BMPs clinically, and they demonstrated that these alloimplants were
tolerated and could be useful in the management of difficult nonunions.
To our knowledge, Geesink et al. were the first to demonstrate, in a
clinical model, that recombinant BMPs can induce healing of cortical bone
defects in
humans99. RhBMP-7
bound to collagen particles was shown to be effective in five of six patients
with a critically sized fibular defect. Only three of six patients treated
with the type-I collagen carrier alone had bone formation. We believe that
this was the first evidence of the osteoinductive capacity and effectiveness
of rhBMP-7 in humans.
Friedlaender et al. assessed the efficacy of rhBMP-7 bound to type-I
collagen (an OP-1 [osteogenic protein-1] implant) for the treatment of
established tibial nonunions by comparing it with autologous bone-grafting,
the so-called gold standard of
treatment93. The
union rate was similar in the two groups, which also did not differ with
regard to clinical or radiographic healing characteristics. Although
comparative efficacy was demonstrated, the goal of the BMP therapy, a higher
healing rate, was not achieved. Unfortunately, the authors did not conduct a
power analysis for their study, and the lack of differences between the groups
may have been the result of a type-II statistical error. It is interesting to
speculate that the rhBMP-7 might have been more effective, as the percentage
of patients with atrophic nonunion was higher in the rhBMP-7 group (41%) than
it was in the group treated with autologous bone-grafting (25%). However, no
statistical analysis with adjustment for atrophic nonunion was performed.
Also, the authors chose a difficult population of patients with nonunion to
study, as the majority had had prior bone-grafting and intramedullary rod
fixation before inclusion in the study and this could have resulted in
heterogeneity of the results. Another factor causing heterogeneity may have
been the fact that 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 the implantation
site was significantly lower in the rhBMP-7 group than it was in the group
treated with autologous bone-grafting (p = 0.002). The authors concluded that
BMPs could be deemed an effective alternative to autografting if the morbidity
associated with harvesting of the graft is taken into
consideration93.
Clinical Efficacy of BMPs in Spinal Fusion
The acceleration of spinal fusion has been extensively studied after animal
experiments demonstrated that BMPs can be used as a replacement for, or an
augmentation of, autologous
bone-grafting46,116-119.
BMPs have been evaluated to determine their osteoinductive potential in
posterolateral intertransverse and interbody fusions. Nonunion or failure to
achieve a solid bone fusion still occurs in up to 35% of patients treated with
spinal
fusion120.
Burkus et al. investigated the use of rhBMP-2/ACS to stimulate spinal
fusion in a cohort of 279 patients with degenerative disc disease. In two
prospective randomized trials, the effectiveness, safety, and rates of
osteoinduction following anterior lumbar interbody fusion with use of
rhBMP-2/ACS were compared with those following fusion with autologous bone
graft, with both substances placed in the hollow central portion of an
LT-Cage121,122.
Plain radiographs and computed tomographic scans were used to evaluate the
pattern of osteoinduction in the interbody space and the progression of fusion
at six, twelve, and twenty-four months. All patients treated with the
rhBMP-2/ACS demonstrated evidence of osteoinduction at six months. At
twenty-four months, the fusion was successful in 94.5% of the patients in the
BMP-2 group and 88.7% of those in the control group. This difference was not
significant. In another study, Burkus et al. investigated the efficacy of
rhBMP-2 for enhancing the incorporation of threaded cortical allografts in
forty-two
patients123. At
twelve months, interbody fusion was demonstrated in 100% of the BMP-2 group
compared with 89.5% of the control group. These studies demonstrated the
effectiveness of BMPs in spinal fusion and the potential for eliminating the
harvest of
autograft121-123.
In a randomized trial, Johnsson et al. compared the efficacy of rhBMP-7
with that of autologous bone-grafting for achieving posterolateral fusion in
twenty patients94.
The radiostereometric and radiographic results at twelve months showed no
significant 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 ossification leading to spinal or foraminal
stenosis. In a laminectomy 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 should be exercised in
cases of dural defects, even after repair. RhBMP-7 has been approved by the
Food and Drug Administration for use with lumbar interbody spinal fusion cages
in the United States. These cages have the advantage of providing proper
containment of the BMP and offering resistance to axial loading.
When BMPs are used in spinal surgery, the key considerations are accurate
placement of the BMP at the fusion site, retention of the BMP by the carrier,
securing hemostasis to prevent dilution of the BMP, and limiting the exposure
of bone beyond the fusion area. It remains difficult to assess the clinical
outcomes of the use of BMPs in spinal fusion, as objective standards for
successful fusion are not available. Current evidence indicates that BMPs can
be used safely and effectively when the above conditions have been met.
Infection
Of particular interest are the findings of reduced rates of infection after
treatment of fresh fractures and nonunions with BMPs. These findings may be
explained by the increased stability created by the enhanced osteoinduction
and the accompanying increase in the local vascular supply. Studies of animals
have also demonstrated the potential of BMPs to induce bone formation in
infected osseous sites, thus providing increased callus
stability125,126.
This is important because instability of the fracture site has been shown to
affect the healing and progression of bone
infections127.
Angiogenesis
Osteogenesis and angiogenesis are known to be mutually interdependent, and
BMPs have been demonstrated in vessels during bone
repair128-130.
Ramoshebi and Ripamonti showed that implantation of BMP-7 stimulates the
growth of angiogenic sprouts toward the
implant131.
Although the exact mechanisms remain unknown, BMPs seem to vitalize the bone
site by stimulating osteogenesis, the resorption of damaged bone, and
angiogenesis.
|
Overview
|
|---|
The discovery of BMPs marked a major step forward in the understanding of
bone physiology and in the development of advanced methods of skeletal bone
surgery. These growth and differentiation factors have a unique potential to
induce new bone formation, even at extraskeletal sites. It has taken almost
forty years since the initial discovery of these growth factors by
Urist4 for them to
become available for clinical application. The successful application of BMPs
depends on elucidation of the optimal therapeutic dosage, delivery system, and
local conditions for bone repair, and these factors are still under
investigation. Basic surgical management to provide adequate environmental
conditions of the implantation site, such as soft-tissue coverage, host-bed
vitality, and biomechanical stability, remains essential.
Prospective clinical trials of BMP-2 and BMP-7 for the treatment of
fractures and nonunions, respectively, have shown solid outcomes. Clinical
trials, although still limited in number compared with preclinical studies,
have demonstrated that BMPs are effective and safe for human application and
have an efficacy comparable with that of autologous bone-grafting.
Growth-factor therapy with BMPs offers a new surgical approach that can
augment or even replace bone-grafting procedures. However, it must be noted
that treatment of fresh fractures with BMP in humans did not result in a
significantly higher rate of bone-healing compared with that yielded by
current treatment techniques such as autologous bone-grafting. This finding is
in strong contrast to the preclinical results in animal studies. BMPs must be
given in much higher doses to accomplish osteoinductive activity in
humans.
The first clinical studies of BMP-2 and 7 have demonstrated that bone
formation is not always consistent. Possible explanations for this are the
relative osteoinductivity of the applied BMPs in the presence of responding
cells and the time at which the BMPs are presented locally by their carrier.
An increased understanding of these mechanisms and additional research are
still needed to develop better carrier systems and possible combination
therapies with other BMPs or growth factors.
Future preclinical and clinical research must clarify issues regarding the
relative effectiveness of BMPs, the interaction between BMP subtypes, and the
characteristics of responding cells in much greater detail. BMPs have great
clinical potential, but in the next decades we will have to discern whether
there is a single pathway to efficient bone-healing or whether different
clinical situations require specific bone-tissue-engineering formats.
|
Acknowledgments
|
|---|
The authors did not receive grants or outside funding in support of their
research or preparation of this manuscript. They did not receive payments or
other benefits or a commitment or agreement to provide such benefits from a
commercial entity. No commercial entity paid or directed, or agreed to pay or
direct, any benefits to any research fund, foundation, educational
institution, or other charitable or nonprofit organization with which the
authors are affiliated or associated.
|
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Abstract
Introduction