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COPYRIGHT © 2004 BY THE JOURNAL OF BONE AND JOINT SURGERY, INCORPORATED

Use of Bone Morphogenetic

Proteins for
Musculoskeletal Applications
AN OVERVIEW
BY MICHAEL A. MONT, MD, PHILLIP S. RAGLAND, MD, BRIDGET BIGGINS, BA, GARY FRIEDLAENDER, MD,
TUSHAR PATEL, MD, STEPHEN COOK, MD, GRACIA ETIENNE, MD, PHD, ANDREW SHIMMIN, MD,
ROBYN KILDEY, BS, DAVID C. RUEGER, PHD, AND THOMAS A. EINHORN, MD

Introduction New insights into the nature of tion, other BMPs or BMP-combination

S
ince Marshall Urist’s original de- bone biology and the ability to manu- products are being evaluated clinically;
scription, in 1965, of the potential facture proteins through recombinant these include various isolates of ani-
of demineralized bone matrix to gene technology have led to the com- mal and human BMP implants, BMPx
induce bone formation, the medical mercialization of two BMPs: BMP-7 (Sulzer Biologics, Wheat Ridge, Colo-
community has anticipated the develop- (OP-1; Stryker, Kalamazoo, Michigan) rado), BMP-9, and others. While current
ment of osteogenic therapies1. Follow- and BMP-2 (Infuse; Medtronic Sofamor use is limited to approved applications in
ing this discovery, researchers sought to Danek, Memphis, Tennessee). In addi- the spine and the treatment of traumatic
identify and isolate these growth factors,
specifically bone morphogenetic pro-
teins (BMPs). Reddi and Huggins first
characterized these important molecules
involved in bone formation in 1973, and,
in 1982, Sampath and Reddi developed
a rat subcutaneous assay for BMP activ-
ity that measures bone formation2. They
found that BMPs initiate the bone-
healing cascade through the recruitment
of and interactions with mesenchymal
stem cells found in surrounding tissues,
including fascial planes, periosteum, pe-
ripheral blood, bone marrow, and can-
cellous bone. Several, but not all, of the
fifteen human BMPs described to date Fig. 1-A
have been found to bind to stem-cell re- Canine model showing a surgically created 2-cm defect.
ceptors, triggering proliferation and dif-
ferentiation, and to result in bone regen-
eration and repair.
Once various BMPs were success-
fully isolated, a variety of animal models
were used to test their efficacy in muscu-
loskeletal applications. Early studies in-
cluded bone-defect models as well as
models of cartilage development, spinal
fusion, and maxillofacial restoration.
The healing of critical-sized defects in
long bones was assessed in a variety of
animal species, including rabbits, sheep, Fig. 1-B
dogs, and primates3 (Figs. 1-A and 1-B). New bone formation was noted across all BMP-treated defects.
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Fig. 2-A Fig. 2-B Fig. 2-C Fig. 2-D

Figs. 2-A through 2-D Anteroposterior radiographs of a tibial nonunion. Fig. 2-A Open comminuted grade-II fracture of the left tibia. Fig. 2-B Prior
treatments included intramedullary rod fixation, autografting, a skin flap, and multiple irrigation and débridement procedures to treat infection. The
fracture failed to heal, and the patient was scheduled for an amputation of the leg. Fig. 2-C The nonunion healed after treatment with rhBMP, and
the bone was intact at five years. Fig. 2-D The union was sustained at ten years.

injuries, early evidence suggests that BMPs may be clinically
useful in a variety of musculoskeletal applications, including
hip and knee arthroplasties, repair of soft-tissue defects (includ-
ing degenerative articular cartilage or intervertebral discs), and
treatment of osteonecrosis. The purposes of this review were (1)
to review current published and recently presented clinical data
on the use of recombinant human BMP-2 and 7 in specific
trauma and spinal fusion applications; (2) to identify important
clinically applied and relevant animal data that support future
directions for human trials to develop other BMPs or BMP de-
livery systems; and (3) to speculate, on the basis of reasonable
scientific evidence, on how BMPs may be used in the future to
improve the treatment of musculoskeletal conditions through
tissue-engineering.
Use of BMPs in Trauma Management
ost fractures and skeletal defects heal uneventfully; how-
M ever, delayed unions and nonunions remain a challenge
for the patient and the medical practitioner. In the first studies
of BMPs for fracture-healing, BMPs were extracted directly
from human bone. More recently, recombinant forms of BMP-
7 (OP-1 Implant; Stryker) and BMP-2 (Infuse; Medtronic Sofa-
mor Danek) were approved for a trauma indication: BMP-7
(OP-1) was approved for use for recalcitrant nonunions of long
bones and BMP-2, for acute open tibial fractures.
Prior to the development of recombinant BMPs, Johnson
et al. reported the first clinical studies of BMPs applied to fem-
oral nonunions in 19884. Twelve nonunions of the femoral
shaft were treated with a combination of internal fixation and
implants of purified human BMP (hBMP) with a noncollage-
nous protein carrier and with a polylactic acid copolymer.
Prior to hBMP treatment, the patients had undergone an aver-
age of 4.3 surgical attempts at repair. Union was obtained in
eleven of the twelve patients at an average of 4.7 months and
in one patient after repeat stabilization and implantation with
hBMP. Johnson et al. reported similar results after the treat-

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ment of four tibial nonunions two years later5. In another
study by these investigators, twenty-four of twenty-five resis-
tant long-bone nonunions treated with a composite of hBMP
and autolyzed, antigen-extracted allogeneic bone united at an
average of six months (range, three to fourteen months) and
one nonunion failed to unite because of a recurrent infec-
tion6. In 1998, this group reported on a one-stage lengthening
procedure to treat shortened femoral nonunions in which the
intercalary segmental defect was bridged with hBMP com-
posite alloimplants (partially purified hBMP and autolyzed,
antigen-extracted allogeneic human bone)7. These nonunions
were stabilized by plate osteosynthesis and lag screw fixa-
tion. Fourteen of fifteen nonunions healed within two years,
with an average increase in length of 2.8 cm (range, 1.5 to 5
cm). These investigators found similar results at an average of
fifty-five months after the treatment of thirty consecutive fem-
oral nonunions8.
These studies, which were performed without commer-
cially available BMPs, led several manufacturers to become in-
terested in the use of recombinant gene technology to
manufacture human BMPs. One of these, recombinant hu-
man BMP-7 (rhBMP-7), became the first BMP to be approved
Fig. 3-A
Fig. 3-A A thirty-three-year-old man with an open fracture of the proximal part of the femoral diaphysis. He
underwent eight procedures without obtaining fracture union. Fig. 3-B Bone union was evident at nine
months after treatment with rhOP-1.
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for clinical use when, in 2001, the OP-1 Implant (3.5 mg of
OP-1 and 1 g of collagen carrier) was granted marketing clear-
ance by the Food and Drug Administration (FDA) of the
United States for the treatment of recalcitrant nonunions of
long bones and was approved in Europe, Australia, and Can-
ada for various long-bone nonunion indications. Approval in
the United States was under a Humanitarian Device Exemp-
tion (HDE), an FDA approval that requires institutional re-
view board approval at medical centers where OP-1 is used
and that limits the total number of procedures performed to
fewer than 4000 per year. This approval followed a large, mul-
ticenter, prospective, randomized, controlled trial in which
122 patients with a total of 124 tibial nonunions were treated
with insertion of an intramedullary rod and either an OP-1
Implant or iliac crest autograft9. Outcomes assessment was
based on the severity of pain at the fracture site, ability to walk
with full weight-bearing, need for a reoperation, radiographic
evaluation of union, and physician satisfaction with the out-
come. The primary end point for success in this study was at
nine months following the surgical procedure. Eighty-one
percent of sixty-three tibiae treated with OP-1 and 85% of
sixty-one tibiae treated with autograft had a clinically success-
Fig. 3-B
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Fig. 4-A Fig. 4-B

Figs. 4-A, 4-B, and 4-C Use of rhOP-1 in a posterolateral lumbar fusion. Fig. 4-A Intraoperative photograph of the posterolateral
lumbar fusion. Fig. 4-B Anteroposterior radiograph showing evidence of bone-bridging at twelve months.

ful result. Seventy-five percent of the tibiae treated with OP-1
and 84% of the tibiae treated with autograft were considered
to have radiographic evidence of healing. More than 20% of
the patients in the autograft group reported persistent donor-
site pain. The authors concluded that the OP-1 Implant is a
safe and effective treatment for tibial nonunions that provides
results comparable with those of autografting, without the
added morbidity of donor-site pain (Figs. 2-A through 2-D).
RhBMP-2 (Infuse) has also been studied in a human
clinical trial to evaluate its ability to accelerate healing of open
tibial shaft fractures and to reduce the need for secondary
intervention10. In this prospective, randomized, controlled,
single-blind study, 450 patients with an open tibial fracture
were randomized to one of three groups to receive (1) stan-

Fig. 4-C
Computed tomography image made at nine months postoperatively, showing complete bone-
bridging.

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Fig. 5-A
Figs. 5-A, 5-B, and 5-C Use of rhOP-1 with cortical strut graft. Fig. 5-A Intraoperative photograph
showing the strut in place.
dard care (intramedullary nail fixation and routine soft-tissue
management), (2) standard care and an implant containing 6
mg of rhBMP-2 applied to an absorbable collagen sponge, or
(3) standard care and an implant containing 12 mg of rhBMP-
2 applied to an absorbable collagen sponge. Four hundred and
twenty-one patients (94%) were available for the twelve-
month follow-up evaluation. The group treated with 12 mg of
BMP-2 had a 44% reduction in the risk of failure (p = 0.0005),
significantly fewer invasive interventions (p = 0.0264), and
significantly faster fracture-healing (p = 0.022) compared
with the patients in the control group. This trial resulted in re-
cent FDA approval of the use of Infuse with an intramedullary
nail for acute open tibial fractures.
Fig. 5-B
Histologic images showing superior incorporation of the BMP-augmented strut graft (Fig. 5-B) compared with the control (Fig. 5-C).
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Following the approval of the OP-1 Implant for treat-
ment of fractures, numerous postmarket research studies have
been completed. The largest of these was conducted in
Australia11, where the first 185 consecutive cases were fol-
lowed to evaluate general safety and efficacy. No serious ad-
verse events were reported in this series. Data were collected
from seventy-one surgeons in five states who treated patients
between August 1997 and December 1999 for a variety of skel-
etal disorders. Of particular interest were difficult nonunions
for which at least one iliac crest autograft procedure had
failed. Of the forty-two nonunions, thirty-one (74%) were
deemed clinically and radiographically united, with a mean of
5.6 months (range, three to fifteen months) until clinical
Fig. 5-C

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Fig. 6-A
Figs. 6-A and 6-B Five-millimeter, 6-mm-deep defects in the femoral condyles. Fig. 6-A A section showed organized formation of new cartilage and
subchondral bone in a knee defect treated with OP-1 (toluidine blue, ×25). Fig. 6-B A specimen taken from the control group, in which the defect
was unfilled, showed minimal evidence of cartilage or subchondral bone regeneration (toluidine blue, ×25).
union and a mean of 5.9 months (range, three to fifteen
months) until radiographic union (Figs. 3-A and 3-B). Nine
cases were considered failures, and two patients were lost to
follow-up. Of the nine failures, seven were associated with
comorbidity factors known to retard or prevent new bone
formation (infection, osteogenesis imperfecta, rheumatoid ar-
thritis, and failure of fixation). Several smaller studies have
yielded similar results supporting the efficacy and safety of
BMP treatments for a variety of trauma applications, includ-
ing recalcitrant nonunions, fresh fractures, and malunions12-14.
Current BMP formulations require an open procedure
to apply the BMP and graft material to the fracture site. How-
ever, recent preclinical research has highlighted the potential
ability to utilize percutaneous injection of these proteins to ac-
celerate fracture repair. Einhorn et al. recently reported the re-
sults of a study of a single percutaneous injection of rhBMP-2
into a closed fracture site in 144 male Sprague-Dawley rats15.
Torsional biomechanical testing indicated that the stiffness of
the BMP-2-treated fracture sites was twice that in the control
group at the two, three, and four-week time-points. At four
weeks, the stiffness and strength of the rhBMP-2-treated frac-
ture sites were equal to those of the intact contralateral fem-
ora, whereas the controls were significantly weaker than the
intact femora (p < 0.005). The results of this study indicated
that a single percutaneous injection of rhBMP-2 accelerated
fracture-healing and callus formation. In another recent study,
Edwards et al. confirmed these findings in a larger animal spe-
cies; they found that injection of rhBMP-2 in a rapidly resorb-
able calcium phosphate paste in a canine tibial osteotomy
model accelerated bone-healing16.
Utilizing novel regional gene-therapy techniques, Lie-
berman et al.17 used BMP-2-producing bone-marrow cells
with adenoviral gene transfer to treat rats with segmental fem-
oral defects. They compared these results with those of treat-
ment with rhBMP-2 and those in three control groups (defects
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Fig. 6-B
treated with demineralized bone matrix, those treated with β-
galactosidase-transduced bone-marrow cells, and untreated
defects). Both BMP groups showed rapid healing of the de-
fects, with twenty-two of twenty-four defects in the gene
therapy group and all defects in the rhBMP-2 group healing
at two months as measured radiographically. Only one of
thirty-two defects in the three control groups healed. The au-
thors demonstrated the feasibility and efficacy of using a
gene-therapy technique to deliver BMP-2-producing bone-
marrow cells. Using a similar technique, this group also
treated the hindlimbs of mice with helper-dependent aden-
oviral vector-producing BMP-2 and found enhanced bone re-
pair (orthotopic bone formation)18.
Use of BMPs in Spinal Applications
hile the use of BMPs has been evaluated in numerous
W models, spinal applications continue to receive much
interest as the population ages and degenerative disc disease
becomes increasingly prevalent. Numerous preclinical and
clinical studies have been conducted to evaluate the ability of
BMPs to promote both posterolateral and interbody fusions of
the spine19,20.
Infuse (rhBMP-2) for the treatment of degenerative disc
disease was tested in a randomized, controlled trial21. The
FDA granted approval for use of Infuse for single-level ante-
rior lumbar interbody fusions in 2002. Two hundred and
eighty-one patients underwent interbody fusion with use of
two fusion cages and either Infuse (rhBMP-2 on an absorb-
able collagen sponge) or autogenous iliac-crest bone graft. At
twenty-four months, 94.5% of 145 patients who had received
the rhBMP-2 had fusion, whereas the fusion rate in the con-
trol group of 136 patients was 88.7%. At the six, twelve, and
twenty-four-month intervals, the Oswestry, back pain, and
leg pain scores and the neurological status had improved in
both treatment groups.
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A recent pilot study was designed to evaluate the feasi-
bility and safety of utilizing rhOP-1 Putty (3.5 mg of rhOP-1,
1 g of collagen carrier, and 230 mg of carboxymethylcellulose)
as a substitute for iliac crest bone graft in posterolateral
fusion22. Thirty-six patients with symptomatic spinal stenosis
and associated single-level degenerative spondylolisthesis
(grade I or grade II) were enrolled to receive rhOP-1 or au-
tograft. Clinical outcomes were measured with use of Oswe-
stry and Short Form-36 (SF-36) surveys and visual analogue
scales, and radiographic outcomes were measured by two in-
dependent radiologists, blinded to the type of treatment, who
used digital calipers to assess bridging bone on anteroposte-
rior radiographs and stability on flexion and extension radio-
graphs. At twenty-four months, sixteen of seventeen patients
in the rhOP-1 group and six of ten in the autograft group were
considered to have clinical success, whereas eleven patients in
the rhOP-1 group and four in the autograft group were con-
sidered to have radiographic evidence of success. No adverse
events related to the use of rhOP-1 were noted (Figs. 4-A, 4-B,
and 4-C). These preliminary results support the safety and ef-
fectiveness of rhOP-1 Putty as a replacement for iliac crest au-
tograft in human posterolateral lumbar fusion. The results of
this study led to the recent approval of rhOP-1 Putty by the
Fig. 7-A
Fig. 7-B
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FDA for revision posterolateral fusion under a Human Device
Exemption.
Bovine BMPx (a composite of collagen and purified bo-
vine BMP extract) has recently been tested in animal models for
use in spinal arthrodesis23. Use of this product led to a 100% spi-
nal fusion rate in a rabbit model, which was twice the rate of fu-
sion following use of autograft in a rhesus macaque monkey
model. The authors concluded that the bovine BMP extract was
safe and as effective as an autograft for posterolateral intertrans-
verse process fusion. Clinical studies are now under way.
The efficacy of BMP treatments and associated costs of
manufacturing and development have supported the need to
analyze cost-effectiveness of these sometimes expensive treat-
ments. In an ongoing study at the University of Toronto,
rhOP-1 Putty is being evaluated as an adjunct to autologous
bone graft in patients who are at high risk for failure of cervi-
cal and lumbar arthrodesis24. In that study, the documented
medical risk factors include mucopolysaccharide deficiency
syndrome, adrenal insufficiency, rheumatoid arthritis, morbid
obesity, and heavy smoking (more than three packs per day)
with a previous pseudarthrosis. Preliminary data have been
reported on the first nine patients, who had a total of five cer-
vical and four lumbar procedures. All of these patients had ra-
Use of rhOP-1 in a rabbit degenerative disc
model. The injection of rhOP-1 induced a res-
toration of disc height at six weeks. The disc
space in the control group is narrowed (Fig.
7-A; red line) compared with the disc space
maintained with the use of rhOP-1 (Fig. 7-B;
red line).
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Fig. 8-A
Preoperative radiograph of a twenty-seven-year-old man with osteone-
crosis and early collapse of the femoral head.
diographic evidence of a solid fusion after three months of
follow-up. On the basis of the early results of this study, rhOP-
1 Putty appears to be a safe and cost-effective adjunct in pro-
moting osseous fusion in patients with documented medical
risk factors for failure of fusion.
Use of BMPs in Total Joint Arthroplasty
he number and complexity of total joint arthroplasties
T continue to increase. The challenges of complex total hip
Fig. 8-B
Fig. 8-B Intraoperative photograph of the femoral head, showing minimal cartilage damage despite post-collapse disease seen radiographically.
Fig. 8-C Trapdoor created with an oscillating saw.
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arthroplasty include bone loss, cortical perforation, defects in
the interface between the porous coating and the host bone,
and periprosthetic fracture25-27. The additional operative time,
limited supply of autologous bone, and morbidity associated
with harvesting autogenous bone graft have resulted in the use
of various types of allografts. Contained defects can be man-
aged effectively with morselized cancellous allograft28. Al-
though use of allograft bone can lead to healing of defects,
prosthetic ingrowth may not occur, thus limiting the stability
of the system. Allograft bone has always been an attractive al-
ternative to autograft bone because it supports bone forma-
tion, its supply is less limited, and restoration of large
structural defects is possible. However, allograft bone, mor-
selized or bulk, does not have the osteoinductive capacity of
autograft bone29-31 and may have a relatively low capacity to in-
corporate with the host bone32,33. Bone morphogenetic pro-
teins alone or in combination with other regulatory molecules
or allogeneic bone may induce new bone formation more ef-
fectively than autograft3,34-36 in certain arthroplasty settings. Al-
though calcium phosphate and hydroxyapatite coatings can
augment ingrowth of bone into porous surfaces, they do not
have the ability to induce bone growth in large defects37-41. It is
possible that BMPs may be effective in accomplishing both of
these goals.
Cortical Strut Allografts
Allograft struts can be used to reinforce a deficient proximal
part of the femur in hip arthroplasty or to provide fixation of
a periprosthetic fracture. Although strut grafts wired or cabled
to the proximal part of the femur generally have been success-
ful, the time required for healing is often prolonged. Studies
have shown that the healing of cortical strut grafts to the fe-
mur is enhanced dramatically by the addition of the rhOP-1
device42-44. In one report, fourteen adult dogs underwent a bi-
lateral onlay allograft strut procedure in the midpart of the fe-
mur with use of stainless-steel cables. In each animal, one
femur was treated with 500 mg of rhOP-1 interposed between
Fig. 8-C
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Fig. 8-D Fig. 8-E

Fig. 8-D Excavation of bone with a curet and burr. Fig. 8-E The cavity is packed with a combination of demineralized bone matrix, processed allograft
incorporated with a mixture of BMPs, and a thermoplastic carrier, and the trapdoor is replaced.

the graft and host bone (Fig. 5-A). Radiographs of the struts
treated with rhOP-1 showed rapid formation of new bone and
graft incorporation as early as two weeks after implantation.
By the fourth postoperative week, superior bone-bonding be-
tween the graft and host, increased cortical thickness, and
graft incorporation were evident radiographically in the sites
treated with rhOP-1. The total histologic score for the sites
treated with rhOP-1 was significantly greater (p < 0.0001)
than that for the control sites at each period (Figs. 5-B and 5-
C). This result appears to reflect the superior graft-host incor-
poration and the abundance of new bone formation sur-
rounding the struts in sites treated with rhOP-1. Most
importantly, healing was accelerated significantly.
arthroplasty with porous-surface acetabular and femoral com-
ponents. A centrally located circular defect 2 mm deep and 20
mm wide was created surgically behind the acetabular compo-
nent to mimic loss of bone contact with the implant. All porous
surfaces of the acetabular and femoral components as well as
the created acetabular defects were covered or filled with rh-
BMP-2/alpha-BSM in five dogs and with alpha-BSM alone in
five dogs. The remaining five dogs served as untreated controls.
At the end of the twelve-week study period, radiographs, scan-

Acetabular Defects
In a recent study, use of the rhOP-1 Implant achieved com-
plete healing of acetabular defects in canines45. The percentage
of cancellous bone volume was not significantly different from
that in control hips in which no defect was present. In addi-
tion, bone growth into the porous surface of the acetabular
cup in the rhOP-1-treated defects was comparable with that in
the control group. The rhOP-1-treated defects healed more
completely (37% bone density) than did allograft-treated de-
fects (23%) or empty defects (14%) (p < 0.05) and had a bone
density equivalent to that of the no-defect controls (34%).
Bone ingrowth occurred to a higher degree in the rhOP-1-
treated sites (37% bone ingrowth) than in the allograft-treated
sites (18%) or the empty defects (16%), with the degree of in-
growth in the rhOP-1-treated group equivalent to that in the
controls without defects (30%).

Revision Total Hip Arthroplasty

In a recent study, the combination of alpha-BSM (a carrier) and
a biologically active protein, rhBMP-2, was shown to promote
filling of defects behind acetabular components and bone Fig. 8-F
growth into the porous coatings of total hip replacements46. Fif- Postoperative radiograph showing preservation of the contour of the
teen adult mongrel dogs underwent a unilateral total hip femoral head.
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Fig. 9-A
Preoperative anteroposterior radiograph of the hip of a
nineteen-year-old man with posttraumatic late-stage os-
teonecrosis of the femoral head.
ning electron micrographs, and histologic measurements of
bone ingrowth as a percentage of the defect filled with new bone
were obtained for the three groups. The use of rhBMP-2/alpha-
BSM resulted in extensive bridging of gaps with new bone for-
mation and bone growth into the underlying porous coatings of
the implants and de novo bone formation over the exposed sur-
face of the implant in this weight-bearing canine model. The
combination of uniform bone growth into porous coatings be-
neath a gap, de novo bone formation on the exposed implant
surface, and increased bone density of preexisting adjacent host
Fig. 9-B
Fig. 9-B Photograph showing a large cartilage defect that was discovered intraoperatively. Fig. 9-C The femoral head after débridement and excava-
tion of necrotic cartilage and bone.
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trabecular bone may improve fixation of implants, suggesting a
possible role for BMPs in both primary and revision total hip
arthroplasties.
Use of BMPs in Soft-Tissue Applications
he repair of articular cartilage is a major challenge. The
T importance of this problem is substantial since both os-
teoarthritis and degenerative disc disease are major causes of
disability among older individuals. Recently, members of the
BMP family of proteins have received much attention as po-
tential anabolic factors for cartilage repair because of their
ability to induce extracellular matrix synthesis and reverse the
effects of catabolic cytokines on articular cartilage in vitro.
Recent studies have shown that many BMPs are endoge-
nously expressed in articular cartilage, including BMP-2, 3, 4,
5, 6, and 7 and cartilage-derived morphogenetic protein-1, 2,
and 3 (CDMP-1, 2, and 3)47. BMP-7 has also been localized in
synovial fluid, synovium, ligaments, tendons, and meniscal
tissue. In cell culture studies48-50, most of these BMPs have been
shown to stimulate chondrocyte differentiation, extracellular
matrix production, and maintenance of the adult chondro-
cytic phenotype. However, to our knowledge, only two BMPs,
rhBMP-2 and rhBMP-7, have been investigated in animal
models of cartilage repair. In most studies of those models51-53,
articular cartilage repair was evaluated in either osteochondral
or chondral defects. We are aware of only one animal study in
which a BMP was used to repair cartilage defects in interverte-
bral discs54.
Articular Cartilage Repair
The earliest studies of cartilage repair with BMPs were per-
formed to evaluate rhOP-1 and rhBMP-2 in osteochondral de-
fect models in the rabbit knee. In one study of eighty-nine
New Zealand White rabbits, rhBMP-2 was delivered in a type-
I collagen sponge to defects created in the trochlear groove51.
Repair of the defects (3 mm in diameter and 3 mm deep) was
Fig. 9-C
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Fig. 9-D Fig. 9-E

Fig. 9-D The defect was filled with rhOP-1, cancellous bone allograft, and autogenous bone marrow. Fig. 9-E Graft material sutured in place over the
filled defect (Graft Jacket; Wright Medical Technology, Arlington, Tennessee).

evaluated at four, eight, twenty-four, and fifty-two weeks post-
implantation. In comparison with control defects, the defects
treated with rhBMP-2 had greatly accelerated formation of new
subchondral bone and improved articular cartilage, with the
formation of a tidemark between the tissues. The rhBMP-2-
treated defects showed better integration of the newly formed
reparative cartilage with the adjacent cartilage, better cellular
morphology, and significantly less type-I collagen when com-
pared with the untreated defects (p < 0.01). At six months, the
thickness of the cartilage was 70% that of the normal adjacent
cartilage, and this thickness was maintained for up to twelve
months. This repair did not require the presence of rhBMP-2
after the initial induction process as evidenced by the fact that
the residence time of the rhBMP-2 in the defect site was four-
teen days. The authors concluded that the repair cartilage was
not identical to normal articular cartilage, but rhBMP-2 stimu-
lated faster repair with more abundant and more hyaline-like
cartilage than that seen in the control defects.

Fig. 9-F Fig. 9-G

Fig. 9-F External fixator placed to distract the joint (arthrodiastasis). This fixation allows hip motion and is left in place for four
months. Fig. 9-G Anteroposterior radiograph made six months postoperatively, showing an intact, spherical femoral head.
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The encouraging results from multiple rabbit studies
provided the impetus to extend the studies on osteochondral
defect repair to larger animal models. The most extensive eval-
uation has been done in dogs, in which 5-mm-diameter, 6-
mm-deep defects in the femoral condyles were treated with
approximately 200 µg of rhOP-1 delivered with bone-derived
type-I collagen particles and carboxymethylcellulose as an ad-
ditive to produce a putty-like formulation52. The repair was
evaluated up to fifty-two weeks postoperatively, but most ani-
mals were killed at sixteen weeks or sooner. Both the subchon-
dral bone and the reparative cartilage in the rhOP-1 treated
sites showed significant improvement compared with those in
the controls at all time-periods (p = 0.0026). The differences
between the rhOP-1-treated and control defects were most
pronounced at the earliest time-points, and in some rhOP-1-
treated samples the repair was so complete that it was difficult
to find the defect site. In the best cases, the defects contained
maturing cartilage that appeared similar to the intact articu-
lar cartilage, had a thickness similar to that of the surrounding
intact cartilage, was minimally degraded at the defect inter-
face, and was generally continuous with the repair cartilage
(Figs. 6-A and 6-B). The control defects were filled primarily
with fibrous tissue or with what appeared to be fibrocartilage.
Degeneration of the cartilage at the defect interfaces was
noted, with large clusters of chondrocytes observed at the in-
terfaces and fissures separating the intact cartilage from the re-
pair tissue.
In another study, the ability of rhOP-1 to repair chon-
dral defects was evaluated in the sheep knee53. In this study,
10-mm defects were created without damaging the subchon-
dral bone. RhOP-1 dissolved in buffer was delivered to the sy-
novial fluid with an extra-articularly positioned mini-osmotic
pump connected to the joint by polyethylene tubing. Two de-
fects were created in each knee: one on the medial condyle and
the other on the trochlea of the femur. The joints were infused
over a two-week period with either 55 or 170 µg of rhOP-1 or
an acetate buffer control. At three months following the sur-
gery, the defects in the knees treated with rhOP-1 were par-
tially filled with newly formed cartilage, precartilaginous
tissue, and connective tissue at their superior aspect. The car-
tilage formation initially took place at the bottom of the defect
and progressed toward its surface. The control knees had no
signs of cellular growth into the defect area. In the rhOP-1
treated knees, the condylar defects showed a 40% to 62% fill
and the trochlear defects showed a 56% to 81% fill at three
months. At six months, the defects treated with rhOP-1
showed more new cartilage than they had demonstrated at
three months, and this cartilage was well fused to the old carti-
lage and stained positively for type-II collagen. All of these de-
fects showed substantial filling in both the condylar (57% to
71%) and trochlear (74% to 92%) location, but none of the
control defects showed any healing at six months. It is inter-
esting that the repair process continued to progress between
three and six months, even though the rhOP-1 had been deliv-
ered for only the first two weeks and without a scaffolding ma-
terial. It was hypothesized that the continuous presence of
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M U S C U L O S KE L E T A L A P P L I C A T I O N S
rhOP-1 throughout the initial weeks following the surgery
may have attracted sufficient mesenchymal-like cells into the
defect area. Subsequently, the rhOP-1 could have stimulated
these cells to differentiate into chondrocytes, which would
then have produced the appropriate extracellular matrix to fill
the defect.
Intervertebral Disc Repair
The potential for using BMPs to repair intervertebral disc car-
tilage has also been examined. Such studies, which are only in
the early stages, have been conducted only in rabbit models
and only with rhOP-1, to our knowledge. Two disc-defect
models have been developed: a stab model involving a needle
puncture and a lysis model involving injection of chondroi-
tinase ABC to disrupt the extracellular matrix54. In both mod-
els, aqueous rhOP-1 was injected into the disc four weeks after
creation of the defect, and the animals were followed for three
months (Figs. 7-A and 7-B). On radiographs used to quanti-
tate disc space height, the discs that had received rhOP-1 in-
jections demonstrated recovery of disc height over time that
was not significantly different from a normal level at three
months. The control discs showed a reduction of approxi-
mately 40% in height at four weeks, which remained constant
for three months.
A BMP-based therapy for damaged articular or interver-
tebral disc cartilage would appear to have substantial clinical
potential. Although the goal of most investigations is the res-
toration of normal cartilage, the clinical demand for cartilage
repair therapies is so great that any improvement over the re-
sults achieved with current operative procedures might be an
acceptable interim goal. In this regard, the above animal
study54 clearly demonstrated that BMPs can be safely adminis-
tered to the joint or disc tissue. In addition, these studies dem-
onstrated that BMPs can be delivered locally to a focal defect
site on appropriate scaffold materials or can be delivered as in-
jectable formulations into the joint or disc to induce repair.
The latter route of administration might dramatically extend
the therapeutic potential of BMPs for the prevention of os-
teoarthritis and degenerative disc disease.
Use of BMPs in the Treatment of
Osteonecrosis of the Femoral Head
steonecrosis of the femoral head is a relentless process in
O which ischemia and subsequent death of trabecular bone
leads to collapse of the femoral head. It is responsible for ap-
proximately 10% of the total hip replacements performed in
the United States55-57. The use of biological agents to preserve
the femoral head and avoid joint replacement is currently un-
der investigation. Femoral head-preserving procedures uti-
lized to avoid joint replacement include core decompression
and osteotomies, which can be combined with different types
of vascularized and nonvascularized bone-grafting tech-
niques55-58. All of these techniques might utilize BMPs as ad-
junctive agents to aid healing and increase the success rate.
To our knowledge, Lieberman et al. were the first to use
BMPs in the treatment of osteonecrosis59. They obtained par-
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tially purified human BMP from Marshall Urist; combined it
with autolyzed, antigen-extracted allogeneic human bone; and
used it with nonvascularized bone graft and a core decom-
pression to treat fifteen patients (seventeen hips). Fourteen of
the seventeen hips had a clinically successful result (no addi-
tional procedure and a Harris hip score of >80 points) at a
mean of fifty-three months (range, twenty-six to ninety-four
months) after treatment. In another study, a prospective ran-
domized multicenter trial, rhBMP-2-soaked collagen carriers
were placed in the femoral head after core decompression in
patients with early-stage (precollapse) osteonecrosis60; how-
ever, the clinical results have not been published.
In a study of a canine femoral head defect model61, one
of us (M.A.M.) and coworkers analyzed the effect on healing
of rhOP-1 used as an adjunct to strut autografting in thirty-
four dogs divided into three groups: (1) a control group in
which a defect was created in the femoral head, (2) a group in
which the defect was supported with strut autograft, and (3) a
group in which the strut autograft was supplemented with
rhOP-1. The healing rate was reported to be 2.3 times faster in
the rhOP-1-treated group than in the strut-autograft and con-
trol groups. The authors concluded that rhOP-1 led to bone
formation and healing of these femoral head defects.
In a clinical study involving a similar method of treat-
ment, one of us (M.A.M.) and coworkers reported on twenty-
one hips in which the necrotic segment was replaced with a
combination of demineralized bone matrix, processed al-
lograft incorporated with a mixture of BMPs, and a thermo-
plastic carrier (Opteform; Exactech, Gainesville, Florida)62
(Figs. 8-A through 8-F). This was done after the dead bone
was evacuated from a window at the femoral head-neck junc-
tion. At a mean of forty-eight months (range, thirty-six to
fifty-five months), 86% of the patients had a clinically success-
ful result as indicated by a Harris hip score of ≥80 points and
no additional surgery. The authors concluded that this tech-
nique can delay the need for total hip arthroplasty and is a
low-morbidity procedure that does not necessitate the pro-
curement of donor bone graft. Recently, this nonvascularized
bone-grafting technique was modified to utilize rhOP-1, bone
marrow, and corticocancellous allograft. Patients treated for
osteonecrosis were evaluated preoperatively and postopera-
tively both clinically and with magnetic resonance imaging
and computed tomography scans to assess bone-healing. Pre-
liminary results were very promising, with only one failure in
the fifteen patients enrolled to date, who were followed for a
mean of six months (range, three to twelve months).
Other applications of BMPs for treatment of osteone-
crosis of the femoral head include combining a nonvascular-
References
1. Urist MR. Bone: formation by autoinduction. Science. 1965;150:893-9.
2. Sampath TK, Reddi AH. Homology of bone-inductive proteins from human,
monkey, bovine, and rat extracellular matrix. Proc Natl Acad Sci USA.
1983;80:6591-5.
3. Cook SD, Wolfe MW, Salkeld SL, Rueger DC. Effect of recombinant human
osteogenic protein-1 on healing of segmental defects in non-human pri-
mates. J Bone Joint Surg Am. 1995;77:734-50.
U S E O F B O N E M O R P H O G E N E T I C P RO T E I N S FOR
M U S C U L O S KE L E T A L A P P L I C A T I O N S
ized bone-grafting technique with arthrodiastasis (external-
fixator-assisted distraction of the joint while the femoral head
heals) with use of rhOP-1, cancellous autograft, and autoge-
nous bone marrow as a grafting substance (Figs. 9-A through
9-G). This technique could allow treatment of hips with late-
stage disease. With use of bone graft and/or graft substitutes
and growth and differentiation factors to reform the femoral
head, arthrodiastasis may permit improved healing of the un-
loaded joint.
Early results of multiple studies indicate that BMPs may
be an effective adjunctive modality for the treatment of os-
teonecrosis of the femoral head. Use of vascular growth factors
in conjunction with osteogenic growth factors may improve
results.
Conclusions
hile early research focused on the evaluation of BMPs
W in bone-defect models, and more specifically on the
treatment of nonunions and on spinal fusions, BMPs have
demonstrated healing capabilities in a variety of models of
musculoskeletal applications, including disc regeneration,
cartilage repair, osteonecrosis, and hip arthroplasty proce-
dures. Newer techniques for delivery of BMPs and other
growth factors may allow development of minimally invasive
techniques with use of arthroscopy or endoscopy for intra-
articular and spinal procedures. These new techniques
would be expected to decrease operative time, operative and
perioperative morbidity, rehabilitative time, and perhaps
overall healing time. The results of research and clinical
studies continue to encourage the hope that surgeons and
patients will be given new tools for the repair of a variety of
musculoskeletal defects. Advanced understanding and future
refinements of BMP mechanisms of action and methods of
delivery may enhance the clinical results.

Corresponding author:
Michael A. Mont, MD
Center for Joint Preservation and Reconstruction, Rubin Institute for
Advanced Orthopedics, Sinai Hospital of Baltimore, 2401 West Belvedere
Avenue, Baltimore, MD 21215. E-mail address: rhondamont@aol.com
In support of their research or preparation of this manuscript, one or
more of the authors received grants or outside funding from Stryker Bio-
tech. In addition, one or more of the authors received payments or other
benefits or a commitment or agreement to provide such benefits from a
commercial entity (Stryker Biotech). Also, a commercial entity (Stryker
Biotech) paid or directed, or agreed to pay or direct, benefits to a research
fund, foundation, educational institution, or other charitable or non-
profit organization with which the authors are affiliated or associated.
4. Johnson EE, Urist MR, Finerman GA. Bone morphogenetic protein augmenta-
tion grafting of resistant femoral nonunions. A preliminary report. Clin Orthop.
1988;230:257-65.
5. Johnson EE, Urist MR, Finerman GA. Distal metaphyseal tibial nonunion. De-
formity and bone loss treated by open reduction, internal fixation, and human
bone morphogenetic protein (hBMP). Clin Orthop. 1990;250:234-40.
6. Johnson EE, Urist MR, Finerman GA. Resistant nonunions and partial or
 
THE JOUR NAL OF BONE & JOINT SURGER Y · JBJS.ORG
VO L U M E 86-A · S U P P L E M E N T 2 · 2004
complete segmental defects of long bones. Treatment with implants of a
composite of human bone morphogenetic protein (BMP) and autolyzed,
antigen-extracted, allogeneic (AAA) bone. Clin Orthop. 1992;277:229-37.
7. Johnson EE, Urist MR. One-stage lengthening of femoral nonunion aug-
mented with human bone morphogenetic protein. Clin Orthop.
1998;347:105-16.
8. Johnson EE, Urist MR. Human bone morphogenetic protein allografting for re-
construction of femoral nonunion. Clin Orthop. 2000;371:61-74.
9. Friedlaender GE, Perry CR, Cole JD, Cook SD, Cierny G, Muschler GF, Zych
GA, Calhoun JH, LaForte AJ, Yin S. Osteogenic protein-1 (bone morphoge-
netic protein-7) in the treatment of tibial nonunions. J Bone Joint Surg Am.
2002;Suppl 1(Pt 2):S151-8.
10. Govender M, Csimma C, Genant HK, Valentin-Opran A, Amit Y, Arbel R, Aro
H, Atar D, Bishay M, Borner MG, Chiron P, Choong P, Cinats J, Courtenay B,
Feibel R, Geulette B, Gravel C, Haas N, Raschke M, Hammacher E, van der
Velde D, Hardy P, Holt M, Josten C, Ketterl RL, Lindeque B, Lob G, Mathe-
von H, McCoy G, Marsh D, Miller R, Munting E, Oevre S, Nordsletten L, Pa-
tel A, Pohl A, Rennie W, Reynders P, Rommens PM, Rondia J, Rossouw WC,
Daneel PJ, Ruff S, Ruter A, Santavirta S, Schildhauer TA, Gekle C, Schnett-
ler R, Segal D, Seiler H, Snowdowne RB, Stapert J, Taglang G, Verdonk R,
Vogels L, Weckbach A, Wentzensen A, Wisniewski T; BMP-2 Evaluation in
Surgery for Tibial Trauma (BESTT) Study Group. Recombinant human bone
morphogenetic protein-2 for treatment of open tibial fractures: a prospective,
controlled, randomized study of four hundred and fifty patients. J Bone Joint
Surg Am. 2002;84:2123-34.
11. Giltaij LR, Shimmin A, Friedlaender GE. Osteogenic protein-1 (OP-1) in the re-
pair of bone defects and fractures of long bones: clinical experience. In:
Vukicevic S, Sampath KT, editors. Bone morphogenetic proteins: from labora-
tory to clinical practice. Boston: Birkhauser; 2002. p 193-206.
12. Schemitsch EH, Waddell JP, Wild L. The treatment of long bone nonunion
with rhBMP: results of a prospective pilot study. Presented as a poster ex-
hibit at the Annual Meeting of the American Academy of Orthopaedic Sur-
geons; 2004 Mar 10-14; San Francisco; CA.
13. McQueen MM, Hajducka C, Court-Brown CM. A comparison of rhBMP-7 (Os-
sigraft) and autogenous graft for treatment of metaphyseal defects after os-
teotomy of the distal radius. Read at the Annual Meeting of the Orthopaedic
Trauma Association; 2003 Oct 9-11; Salt Lake City, UT.
14. McKee MD, Schemitsch EH, Waddell JP, Kreder HJ, Stephen DJG, Leigh-
ton RK, Buckley RE, Powell JN, Wild LM, Blachut PA, O’Brien PJ, Pirani S,
McCormack RG. The effect of human recombinant bone morphogenic pro-
tein (rhBMP-7) on the healing of open tibial shaft fractures: results of a
multi-center, prospective, randomized clinical trial. Read at the Annual
Meeting of the Orthopaedic Trauma Association; 2002 Oct 11-13; Toronto,
Ontario, Canada.
15. Einhorn TA, Majeska RJ, Mohaideen A, Kagel EM, Bouxsein ML, Turek TJ,
Wozney JM. A single percutaneous injection of recombinant human bone
morphogenetic protein-2 accelerates fracture repair. J Bone Joint Surg Am.
2003;85:1425-35.
16. Edwards RB 3rd, Seeherman HJ, Bogdanske JJ, Devitt J, Vanderby R Jr, Mar-
kel MD. Percutaneous injection of recombinant human bone morphogenetic
protein-2 in a calcium phosphate paste accelerates healing of a canine tibial
osteotomy. J Bone Joint Surg Am. 2004;86:1425-38.
17. Lieberman JR, Daluiski A, Stevenson S, Wu L, McAllister P, Lee YP, Kabo
JM, Finerman GA, Berk AJ, Witte ON. The effect of regional gene therapy
with bone morphogenetic protein-2-producing bone-marrow cells on the repair
of segmental femoral defects in rats. J Bone Joint Surg Am. 1991;81:905-17.
18. Abe N, Lee YP, Sato M, Zhang X, Wu J, Mitani K, Lieberman JR. Enhance-
ment of bone repair with a helper-dependent adenoviral transfer of bone mor-
phogenetic protein-2. Biochem Biophys Res Commun. 2002;297:523-7.
19. Zlotolow DA, Vaccaro AR, Salamon ML, Albert TJ. The role of human bone
morphogenetic proteins in spinal fusion. J Am Acad Orthop Surg. 2000;8:3-9.
20. Lewandrowski KU, Ozuna RM, Pedlow FX, Hecht AC. Advances in the biol-
ogy of spinal fusion: growth factors and gene therapy. Curr Opin Orthop.
2000;11:167-75.
21. Burkus JK, Gornet MF, Dickman CA, Zdeblick TA. Anterior lumbar interbody
fusion using rhBMP-2 with tapered interbody cages. J Spinal Disord Tech.
2002;15:337-49.
22. Fischgrund JS, Patel TC, Vaccaro AR, Truumees E, Herkowitz HN, Albert T,
Hilibrand A, Phillips F, Wetzel T, McCulloch J. Two-year follow-up on patients
in a pilot safety and efficacy study of OP-1 putty (rhBMP-7) in posterolateral
fusion as a replacement for iliac crest autograft. Presented as a poster ex-
hibit at the Annual Meeting of the Spine Society of Europe; 2004 Jun 1-4;
Porto, Portugal.
U S E O F B O N E M O R P H O G E N E T I C P RO T E I N S FOR
M U S C U L O S KE L E T A L A P P L I C A T I O N S
23. Damien CJ, Grob D, Boden SD, Benedict JJ. Purified bovine BMP extract and
collagen for spine arthrodesis: preclinical safety and efficacy. Spine.
2002;27(16 Suppl 1):S50-8.
24. Govender PV, Rampersaud YR, Rickards L, Fehlings MG. Use of osteogenic
protein-1 in spinal fusion: literature review and preliminary results in a pro-
spective series of high-risk cases. Neurosurg Focus. 2002;13:1-6.
25. Brady OH, Garbuz DS, Masri BA, Duncan CP. The treatment of periprosthetic
fractures of the femur using cortical onlay allograft struts. Orthop Clin North
Am. 1999;30:249-57.
26. Emerson RH Jr, Malinin TI, Cuellar AD, Head WC, Peters PC. Cortical strut
allografts in the reconstruction of the femur in revision total hip arthroplasty.
A basic science and clinical study. Clin Orthop. 1992;285:35-44.
27. Head WC, Malinin TI, Mallory TH, Emerson RH Jr. Onlay cortical allografting
for the femur. Orthop Clin North Am. 1998;29:307-12.
28. Etienne G, Ragland PS, Mont MA. Use of cancellous bone chips and dem-
ineralized bone matrix in the treatment of acetabular osteolysis: preliminary
2-year follow-up. Orthopedics. 2004;27(1 Suppl):s123-6.
29. Gazdag AR, Lane JM, Glaser D, Forster RA. Alternatives to autogenous bone
graft: efficacy and indications. J Am Acad Orthop Surg. 1995;3:1-8.
30. Pelker R, Friedlander GE, Markham TC. Biomechanical properties of bone al-
lografts. Clin Orthop. 1983;174:54-7.
31. Schwarz N, Schlag G, Thurnher M, Eschberger J, Dinges HP, Redl H. Fresh
autogeneic, frozen allogeneic, and decalcified allogeneic bone grafts in dogs.
J Bone Joint Surg Br. 1991;73:787-90.
32. Hooten JP Jr, Engh CA, Heekin RD, Vinh TN. Structural bulk allografts in ace-
tabular reconstruction. Analysis of two grafts retrieved at post-mortem. J
Bone Joint Surg Br. 1996;78:270-5.
33. Burchardt H. The biology of bone graft repair. Clin Orthop. 1983;174:28-42.
34. Enneking WF, Burchardt H, Puhl JJ, Piotrowski G. Physical and biological as-
pects of repair in dog cortical-bone transplants. J Bone Joint Surg Am.
1975;57:237-52.
35. Celeste AJ, Iannazzi JA, Taylor RC, Hewick RM, Rosen V, Wang EA, Wozney
JM. Identification of transforming growth factor beta family members present
in bone-inductive protein purified from bovine bone. Proc Natl Acad Sci USA.
1990;87:9843-7.
36. Collier JP, Bauer TW, Bloebaum RD, Bobyn JD, Cook SD, Galante JO,
Harris WH, Head WC, Jasty MJ, Mayor MB, Sumner DR, Whiteside LA.
Results of implant retrieval from postmortem specimens in patients with
well-functioning, long term total hip replacement. Clin Orthop. 1992;274:
97-112.
37. Garellick G, Malchau H, Herberts P. Survival of hip replacements. A compari-
son of a randomized trial and a registry. Clin Orthop. 2000;375:157-67.
38. Maloney WJ, Jasty M, Harris WH, Galante JO, Callaghan JJ. Endosteal ero-
sion in association with stable uncemented femoral components. J Bone
Joint Surg Am. 1990;72:1025-34.
39. Soballe K, Hansen ES, Brockstedt-Rasmussen H, Pedersen CM, Bunger C.
Bone graft incorporation around titanium-alloy- and hydroxyapatite-coated im-
plants in dogs. Clin Orthop. 1992;274:282-93.
40. Greis PE, Kang JD, Silvaggio V, Rubash HE. A long-term study on defect fill-
ing and bone ingrowth using a canine fiber metal total hip model. Clin Orthop.
1992;274:47-59.
41. Jasty M, Rubash HE, Paiement GD, Bragdon CR, Parr J, Harris WH. Porous-
coated uncemented components in experimental total hip arthroplasty in
dogs. Effect of plasma-sprayed calcium phosphate coatings on bone in-
growth. Clin Orthop. 1992;280:300-9.
42. Jensen TB, Overgaard S, Lind M, Rahbek O, Bunger C, Soballe K. Osteo-
genic protein 1 device increases bone formation and bone graft resorption
around cementless implants. Acta Orthop Scand. 2002;73:31-9.
43. Lind M, Overgaard S, Jensen TB, Song Y, Goodman SB, Bunger C, Soballe
K. Effect of osteogenic protein 1/collagen composite combined with im-
pacted allograft around hydroxyapatite-coated titanium alloy implants is mod-
erate. J Biomed Mater Res. 2001;55:89-95.
44. Lind M, Overgaard S, Song Y, Goodman SB, Bunger C, Soballe K. Osteo-
genic protein 1 device stimulates bone healing to hydroxyapatite-coated and
titanium implants. J Arthroplasty. 2000;15:339-46.
45. Cook SD, Barrack RL, Patron LP, Salkeld SL. Osteoinductive agents in recon-
structive hip surgery: a look forward. Clin Orthop. 2003;417:195-202.
46. Bragdon CR, Doherty AM, Rubash HE, Jasty M, Li XJ, Seeherman H, Harris
WH. The efficacy of BMP-2 to induce bone ingrowth in a total hip replacement
model. Clin Orthop. 2003;417:50-61.
 
THE JOUR NAL OF BONE & JOINT SURGER Y · JBJS.ORG
VO L U M E 86-A · S U P P L E M E N T 2 · 2004
47. Chubinskaya S, Kuettner KE. Regulation of osteogenic proteins by chondro-
cytes. Int J Biochem Cell Biol. 2003;35:1323-40.
48. Blunk T, Sieminski AL, Appel B, Croft C, Courter DL, Chieh JJ, Goepferich A,
Khurana JS, Gooch KJ. Bone morphogenetic protein 9: a potent modulator of
cartilage development in vitro. Growth Factors. 2003;21:71-7.
49. Boskey AL, Paschalis EP, Binderman I, Doty SB. BMP-6 accelerates both
chondrogenesis and mineral maturation in differentiating chick limb-bud mes-
enchymal cell cultures. J Cell Biochem. 2002;84:509-19.
50. Grunder T, Gassmaier C, Fritz J, Stoop R, Hortschonsky P, Mollenhauer J,
Aicher WK. Bone morphogenetic protein (BMP)-2 enchances the expression
of type II collagen and aggrecan in chondrocytes embedded in alginate
beads. Osteoarthritis Cartilage. 2004;12:559-67.
51. Sellers RS, Peluso D, Morris EA. The effect of recombinant human bone mor-
phogenetic protein-2 (rhBMP-2) on the healing of full-thickness defects of ar-
ticular cartilage. J Bone Joint Surg Am. 1997;79:1452-63.
52. Cook SD, Patron LP, Salkeld SL, Rueger DC. Repair of articular cartilage de-
fects with osteogenic protein-1 (BMP-7) in dogs. J Bone Joint Surg Am.
2003;85 Suppl 3:116-23.
53. Jelic M, Pecina M, Haspl M, Kos J, Taylor K, Maticic D, McCartney J, Yin S,
Rueger D, Vukicevic S. Regeneration of articular cartilage chondral defects
by osteogenic protein-1 (bone morphogenetic protein-7) in sheep. Growth Fac-
tors. 2001;19:101-13.
54. Masuda K, Imai Y, Okuma M, Nakagawa K, Akeda K, Muehleman C, Thonar
E, Andersson G, An H. Osteogenic protein-1 injection into a degenerated disc
induced a significant regeneration of the intervertebral disc in the rabbit an-
U S E O F B O N E M O R P H O G E N E T I C P RO T E I N S FOR
M U S C U L O S KE L E T A L A P P L I C A T I O N S
nular puncture model. Read at the Annual Meeting of the North American
Spine Society; 2004 Oct 26-30; Chicago, Illinois.
55. Mont MA, Hungerford DS. Non-traumatic avascular necrosis of the femoral
head. J Bone Joint Surg Am. 1995;77:459-74.
56. Mont MA, Jones LC, Einhorn TA, Hungerford DS, Reddi AH. Osteonecrosis of
the femoral head. Potential treatment with growth and differentiation factors.
Clin Orthop. 1998;355(Suppl):S314-35.
57. Lieberman JR, Berry DJ, Mont MA, Aaron RK, Callaghan JJ, Rajadhyaksha
AD, Urbaniak JR. Osteonecrosis of the hip: management in the 21st century.
Instr Course Lect. 2003;52:337-55.
58. Mont MA, Einhorn TA, Sponseller PD, Hungerford DS. The trapdoor proce-
dure using autogenous cortical and cancellous bone grafts for osteonecrosis
of the femoral head. J Bone Joint Surg Br. 1998;80:56-62.
59. Lieberman JR, Comduaha A, Urist MR. Treatment of osteonecrosis of the
femoral head with core decompression and human BMP. Unpublished data.
60. Stevens K, Tao C, Lee SU, Salem N, Vandevenne J, Cheng C, Neumann G,
Valentin-Opran A, Lang P. Subchondral fractures in osteonecrosis of the fem-
oral head: comparison of radiography, CT, and MR imaging. AJR Am J Roent-
genol. 2003;180:363-8.
61. Mont MA, Jones LC, Elias JJ, Inoue N, Yoon TR, Chao EY, Hungerford DS.
Strut-autografting with and without osteogenic protein-1: a preliminary study
of a canine femoral head defect model. J Bone Joint Surg Am.
2001;83:1013-22.
62. Mont MA, Etienne G, Ragland PS. Outcome of nonvascularized bone grafting
for osteonecrosis of the femoral head. Clin Orthop. 2003;417:84-92.