2013

Selected

Instructional
Course Lectures
The American Academy of Orthopaedic Surgeons
F REDERICK M. A ZAR
EDITOR, VOL. 58

C OMMITTEE
F REDERICK M. A ZAR
CHAIRMAN

P AUL J. D UWELIUS
K ENNETH A. E GOL
M ARY I. OC ONNOR
P AUL T ORNETTA III
E X -O FFICIO
D EMPSEY S. S PRINGFIELD
DEPUTY EDITOR OF THE JOURNAL OF BONE AND JOINT SURGERY
FOR INSTRUCTIONAL COURSE LECTURES

J AMES D. H ECKMAN
EDITOR-IN-CHIEF,
THE JOURNAL OF BONE AND JOINT SURGERY

Printed with permission of the American Academy of

Orthopaedic Surgeons. This article, as well as other lectures
presented at the Academys Annual Meeting, will be available
in February 2009 in Instructional Course Lectures, Volume 58.
The complete volume can be ordered online at www.aaos.org,
or by calling 800-626-6726 (8 A.M.-5 P.M., Central time).

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The Use of Bone Morphogenetic Protein

in Lumbar Spine Surgery
By Jeffrey A. Rihn, MD, Charley Gates, MD, Steven D. Glassman, MD, Frank M. Phillips, MD,
James D. Schwender, MD, and Todd J. Albert, MD
An Instructional Course Lecture, American Academy of Orthopaedic Surgeons

Lumbar spinal fusion is an integral

component of the surgical management
of degenerative disease, trauma, deformity, tumor, and infection of the spine.
Pseudarthrosis can, in turn, lead to
persistent pain, failure of the instrumentation, and the need for revision
surgery. It is a challenge to obtain a solid
osseous fusion; therefore, both mechanical and biological variables should
be optimized. Mechanical stability is
optimized by using pedicle screws and
rods for rigid fixation until there is
osseous fusion. Internal fixation improves the fusion rates compared with
those associated with lumbar fusion
without instrumentation, but it does
not ensure a 100% fusion rate.
Autogenous bone graft has been
used to optimize the biological environment and is considered the gold
standard for fusion in lumbar spine
surgery; however, pseudarthrosis rates
of up to 55% have been reported even
with use of autogenous bone graft1,2. In
addition, up to 25% of patients have

reported substantial and persistent

morbidity associated with the harvesting of autogenous iliac crest bone3-8.
There is a limited supply of autogenous
iliac crest, and it may not be available for
a patient requiring revision surgery.
Biologics have been used as alternatives to, or enhancements of, autograft in lumbar fusion surgery over the
last decade. One of the most studied and
frequently used biological alternatives to
autograft is bone morphogenetic protein (BMP). In this paper, we review the
types of BMP used in lumbar spine
surgery, the clinical results and complications associated with BMP use, and
their economic impact.
What is BMP?
BMP was discovered by Marshall Urist
in 19659. It is a group of growth factor
proteins within the transforming
growth factor-b (TGF-b) superfamily
of growth factors10. Through molecular
cloning techniques and recombinant
expression, osteoinductive BMP mole-

cules have been identified and have been

produced in mass quantities in their
pure form11,12. More than twenty types
of BMP have been recognized, but only
BMP-2, 4, 6, 7, and 9 have been shown to
have significant osteogenic properties12-17.
BMP molecules seem to induce
bone formation in a stepwise fashion,
with individual BMP molecules functioning at different stages of osteoblastic
differentiation and osteogenesis. There
is probably a synergistic relationship
between the different BMP molecules15.
The BMP molecules combine in vivo to
form heterodimers that are much more
potent osteoinductive agents than the
individual BMP molecules alone18.
Receptors for these heterodimers have
also been discovered19. It has been
postulated that the signaling pathway of
osteoblastic differentiation and osteogenesis is a complex cascade of BMP
expression that consists of substantial
interaction between the different types
of BMP and other signaling molecules
and receptors20.

Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants in
excess of $10,000 from Medtronic and Norton Healthcare. In addition, one or more of the authors or a member of his or her immediate family received, in
any one year, payments or other benefits in excess of $10,000 or a commitment or agreement to provide such benefits from commercial entities
(Medtronic and DePuy Spine). Also, commercial entities (Medtronic and Norton Healthcare) paid or directed in any one year, or agreed to pay or direct,
benefits in excess of $10,000 to a research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which
one or more of the authors, or a member of his or her immediate family, is affiliated or associated.

J Bone Joint Surg Am. 2008;90:2014-25

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Two commercial forms of recombinant BMP have demonstrated

success in preclinical and clinical trials
and are available for clinical use. One is
rhBMP-2 (Infuse; Medtronic Sofamor
Danek, Memphis, Tennessee) and the
other is rhBMP-7 (OP-1; Stryker Biotech, Hopkinton, Massachusetts).
Although both of these types of BMP
have osteogenic properties, only
rhBMP-2 has been shown to induce
osteoblastic differentiation of mesenchymal stem cells17. Currently, the only
United States Food and Drug Administration (FDA)-approved indication for
use of any BMP in the spine is anterior
lumbar interbody fusion with use of
rhBMP-2 within a titanium tapered
cage21. All other uses in the spine are
off-label22-27.
BMP Carriers
To be effective, the BMP must be
maintained at the planned site of fusion
until the cascade of osteoblastic differentiation and osteogenesis is under way.
Because BMP molecules are relatively
soluble, less soluble carriers are used to
maintain the BMP at the planned site of
fusion. Carriers can either have structural, space-occupying properties (synthetic polymers and calcium phosphate
ceramics) or provide little structure or
space maintenance (type-I collagen
sponge). Some of these structural carriers are porous and are composed of
calcium compounds, making them
osteoconductive (e.g., coral). Carriers
with structural integrity are more desirable in posterolateral lumbar fusion
because they maintain a space around
the transverse processes in which the
fusion mass can form. Carriers that are
deformable, such as the type-I collagen
sponge, are more suitable for use within
interbody cages.
Types of BMP carriers include
synthetic polymers, calcium phosphate
ceramics, and type-I collagen28,29.
Synthetic polymers are advantageous
because they are bioinert and can be
manufactured with complete control
over their architecture and rate of
reabsorption. The most common synthetic polymers are polylactic acid and
polyglycolic acid. These polymers are

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also used to make bioabsorbable implants and suture. When used as a BMP
carrier, they are a porous, structural
scaffold, which promotes osseous ingrowth and then is absorbed after the
fusion mass is established.
Calcium phosphate ceramics are
highly crystalline, bioinert materials
that, like synthetic polymers, are reabsorbed over time. The most commonly
used are hydroxyapatite and tricalcium
phosphate29,30. Tricalcium phosphate is
reabsorbed over about six weeks, which
is probably not sufficient time for a
bone fusion mass to develop. The
resorption rate of hydroxyapatite, on the
other hand, is years. Natural coral has
an interconnecting porosity that is
similar to that of bone. It can either be
used in its calcium carbonate form or be
processed (i.e., the carbonate can be
replaced with phosphate) into a form
that contains varying amounts of
hydroxyapatite. The thickness of the
hydroxyapatite determines its rate
of dissolution.
Type-I collagen, the most abundant protein in bone, binds to noncollagenous protein and has a structure
that promotes bone formation. These
properties make it an attractive BMP
carrier. As a BMP carrier, it is usually
manufactured as an absorbable sheet or
sponge from either porcine or bovine
skin or bone. These type-I-collagen
carriers do not provide structural support or maintain space. They can be
combined with calcium phosphate
ceramics to form structural scaffolds
(e.g., Healos [DePuy, Raynham,
Massachusetts] and Mastergraft Matrix
[Medtronic Sofamor Danek]).
The structural support of an
interbody fusion is provided by the
interbody cage, into which BMP carried
on an absorbable type-I collagen sponge
is inserted directly. A posterolateral
lumbar fusion requires a BMP carrier
with a structural capacity to withstand
collapse under the forces of the surrounding paraspinal muscles and provide a space in which the fusion mass
can form. Calcium phosphate ceramic
has been shown to be an effective
structural carrier in this setting30,31.
Alternatively, BMP can be carried on

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an absorbable type-I collagen sponge

that is combined with a bulking agent
(e.g., ceramic, allograft cancellous
chips, or local autograft bone)30-34. This
combination provides structural integrity and resists compression after
placement over the transverse
processes33.
Preclinical Results of BMP
Use in Lumbar Fusion Surgery
Before the use of BMP, a posterior spinal
fusion was done by decorticating the
osseous surfaces of the posterior vertebral elements and then applying an
onlay graft of autogenous or allogenic
bone. Most preclinical studies evaluating the safety and efficacy of rhBMP-7
and rhBMP-2 as substitutes for bone
graft have shown them to be equal or
superior to autogenous iliac crest bone
graft in lumbar fusion surgery.
RhBMP-7 and autograft were
compared with regard to their effect
on the maturation processes of lumbar posterolateral fusions in a canine
model35. Three treatment groups were
compared: autograft alone, autograft
plus rhBMP-7, and rhBMP-7 alone. The
time to fusion, the resistance of the
fusion to motion, and the pathway of
bone formation producing the fusion
were measured. At twelve weeks, fusion
had been achieved at 83% of the posterolateral sites in which autograft plus
rhBMP-7 had been implanted and 72%
of the sites at which rhBMP-7 alone had
been implanted, but only 27% of the
sites treated with autograft alone. Biomechanical testing indicated that the
fusions obtained in both rhBMP-7
treatment groups had substantially less
motion in flexion-extension and in axial
rotation than did those obtained with
the autograft bone alone. Plain and
polarized light microscopic studies
indicated that, in both of the rhBMP-7
treatment groups, bone formation had
occurred by means of intramembranous
ossification whereas, in the group treated
with autograft bone alone, bone had
been produced by means of endochondral bone formation. This may partly
explain the increased prevalence, speed,
and stability of the rhBMP-7-induced
fusions.

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One potential complication of

using BMP is leakage of the BMP
resulting in bone formation at remote
sites. The effect of rhBMP-7 intentionally placed into the subarachnoid space
after thecal sac decompression was
studied in a canine model36. An opening
was created in the dura and arachnoid
membranes, and rhBMP-7 was placed
into the subarachnoid space in thirty
dogs. At sixteen weeks, new bone had
developed in the subarachnoid space of
all animals, with spinal stenosis and
compression of the spinal cord. No
neurotoxicity was noted. This result
suggests that bone growth can occur
over exposed dura and that the delivery
and containment of rhBMP-7 are important to minimize this potential
iatrogenic problem.
RhBMP-2 has also been studied
as a bone graft substitute. In a rabbit
model, the posterolateral lumbar fusion
rate was 100% after use of rhBMP-2
on a type-I fibrillar collagen sponge
whereas only 42% of the spines fused
after use of autogenous iliac crest bone
graft37. In a study of beagle dogs evaluated twelve weeks after L4-L5 intertransverse process fusion with either
rhBMP-2 or autograft bone alone, all
dogs treated with rhBMP-2 had a fusion
whereas none of the dogs treated with
autograft bone alone had a fusion38. In
that study, several doses of rhBMP-2
were used, with a fortyfold variation
between the highest and lowest doses.
There were no mechanical, radiographic, or histological differences in
the quality of the fusion masses obtained with the different doses38. This
finding suggests that, above a threshold
dose, the quality of spinal fusion produced with rhBMP-2 does not change
with the dose.
Primates are thought to require
higher doses of BMP to effect similar
outcomes, and in one study concentrations of rhBMP-2 that produced fusions
in canines and rabbits failed to do so in
rhesus monkeys39. One reason for this
finding is that primates are believed
to have lower concentrations of
BMP-responsive cells28.
Another problem encountered in
nonhuman primates that was not seen

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in rabbits and dogs was compression of

the collagen sponge carrier by the large
paraspinal muscles39,40. It is possible that
this excessive compression squeezed the
protein out of the carrier sponge and
prevented the development of an adequate fusion mass39. A subsequent study
showed that a structural ceramic BMP
carrier that is able to resist compression
may be more suitable for posterolateral
fusion in primates: all of fifteen rhesus
monkeys treated with rhBMP-2 in this
structural ceramic carrier had a successful posterolateral fusion40.
The safety of direct contact of
rhBMP-2 with neural tissue was tested
in twenty beagles that underwent an L5
laminectomy41. Half of the dogs had a
puncture wound created in the dura,
and either autogenous bone graft or
rhBMP-2 was randomly applied to the
exposed dura. At twelve weeks, there
was no clinical, radiographic, or histological evidence of neurological abnormalities. The rhBMP-2 had stimulated
bone growth in the laminectomy defect
that was in direct contact with the dural
membrane, and there was no evidence
of abnormal mineralization within the
thecal sac or in the spinal cord itself.
Clinical Results of BMP Use in
Lumbar Fusion Surgery
Anterior Lumbar Interbody Fusion
The use of rhBMP-2 in spinal surgery
was first studied in anterior lumbar
interbody fusion, and this is the only
FDA-approved indication for its use. In
a multicenter, prospective, randomized
study, 279 patients with single-level
degenerative lumbar disc disease underwent anterior lumbar interbody fusion with use of two tapered titanium
threaded fusion cages21. RhBMP-2 on an
absorbable collagen sponge was used in
the cages in 143 patients, and autograft
iliac crest was used in the cages in
136 patients. The dose of rhBMP-2
ranged from 12 to 18 mg (in the form of
a 1.5-mg/mL solution), depending on
the size of the cage that was used. The
mean operative time and blood loss
were less in the rhBMP-2 group. The
autograft group had substantial morbidity at the iliac crest donor site, with
5.9% of the patients experiencing an

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adverse event related to graft harvest

and 32% of the patients reporting
discomfort at the graft site after two
years. Two years after the surgery, plain
radiographs and computed tomography
scans were used to evaluate the osseous
fusion. The rhBMP-2 group was reported to have a 94.5% fusion rate
compared with an 88.7% fusion rate in
the autograft group. Both groups had
similar improvements in clinical outcome measures through the duration
of the study.
Two different prospective multicenter studies were performed to compare rhBMP-2 and autogenous iliac
crest used in threaded allograft cortical
dials for single-level anterior lumbar
interbody fusion22,23. Plain radiographs
and computed tomography scans were
used to evaluate the fusion. In the first
study, all twenty-four patients in the
rhBMP-2 group and only 68% of the
twenty-two in the autograft group had a
solid osseous fusion at two years after
the surgery22. At the time of final followup, the patients in the rhBMP-2 group
had a better neurological status and less
back and lower-limb pain than the
patients in the autograft group. No
adverse events were associated with the
use of rhBMP-2. In the second study,
131 patients had a single-level anterior
lumbar interbody fusion with threaded
allograft dials; seventy-nine received
rhBMP-2, and fifty-two received autograft23. The authors reported a 100%
fusion rate in the rhBMP-2 group at one
and two years and an 89% fusion rate at
one year and an 81.5% fusion rate at
two years in the autograft group. Eighteen percent of the patients in the
rhBMP-2 group had transient vertebral
osteolysis; all of these cases resolved by
two years and had no effect on the
clinical outcome.
Posterolateral Lumbar Fusion
The use of rhBMP-2 was compared with
the use of autograft iliac crest bone in
posterolateral lumbar fusion in two
prospective, randomized, multicenter,
FDA-regulated investigational device
exemption clinical studies. Part of the
first FDA-regulated study was a prospective, randomized clinical pilot study

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Fig. 1

Axial (A), coronal (B), and sagittal (C) computed tomography images acquired twelve months after an L4-L5 posterolateral fusion with use of rhBMP-2.
RhBMP-2 was delivered as a dose of 20 mg per side on a compression-resistant matrix consisting of hydroxyapatite and tricalcium phosphate/collagen.
These computed tomography images demonstrate a solid bilateral fusion.

comparing posterolateral lumbar spine

fusion in three groups of patients32. Five
patients were treated with autograft
with pedicle screw fixation; eleven
patients, with rhBMP-2 with pedicle
screw fixation; and nine patients, with
rhBMP-2 without pedicle screw fixation. All patients had single-level
degenerative disc disease with no greater
than Grade-I spondylolisthesis. The
dose of rhBMP-2 was 20 mg per side
of the spine (in a 2-mg/mL solution),
which was larger than the dose used in
the anterior lumbar interbody fusion
procedures21-23, carried on calcium
phosphate ceramic granules. At an
average of seventeen months postoperatively, only 40% of the spines in the
autograft group were fused whereas
100% of those in the groups that had
received rhBMP-2 (both with and
without pedicle screw fixation) were
fused; also, clinical improvement was
seen earlier in the rhBMP-2 groups.
The patients treated with rhBMP-2
without pedicle screws had the greatest
improvement in the Oswestry Disability Index at the time of final
follow-up.
In the second ongoing prospective, randomized, FDA-regulated study,
rhBMP-2 at a dose of 20 mg per side (in
a 2-mg/mL solution) on a compression-

resistant matrix (hydroxyapatite and

tricalcium phosphate/collagen) carrier
was compared with autograft iliac crest
for use in a single-level posterolateral
lumbar fusion42. The patients in the
study had degenerative lumbar disc
disease with no greater than Grade-I
spondylolisthesis and a failure of at least
six months of conservative treatment.
The rhBMP-2 group had a significantly
higher mean fusion grade than the
autograft group at both six months (p <
0.0001) and twelve months (p < 0.0023)
(Fig. 1). In a later report of the two-year
results of this study43, which included
forty-five patients in the autograft group
and fifty-three in the rhBMP-2 group,
there was a shorter operative time and
less blood loss in the rhBMP-2 group.
There were no differences in clinical
outcomes. The fusion rates were 73% in
the autograft group and 91% in the
rhBMP-2 group (p = 0.051). Complication rates were similar, and most
complications were secondary to gastrointestinal, traumatic, or cardiac
events.
A separate publication involving
the same data presented a comparison
of patients who smoked and those who
did not44. At two years after the surgery,
solid lumbar fusion was obtained in
100% of the fifty-five nonsmokers and

95% of the twenty-one smokers in the

rhBMP-2 group. In the autograft group,
solid fusion was achieved in 94% of the
fifty-one nonsmokers and 76% of the
twenty-one smokers. Despite the improved rate of solid fusion in the
smokers who had received rhBMP-2,
the values for the clinical outcome
measures for the smokers were decreased compared with the values for
the nonsmokers. The authors concluded that rhBMP-2 can enhance
the fusion rate in smokers who undergo
single-level posterolateral lumbar
fusion.
In another study, a group of fortyone patients who had had a posterolateral lumbar fusion with rhBMP-2
(12 mg in the form of a 1.5-mg/mL
solution) on a collagen sponge placed
along with autograft iliac crest was
compared with a group of eleven age
and sex-matched patients who had
been treated with autograft iliac crest
alone45. The rhBMP-2/autograft group
had an increased rate of fusion of
97% (sixty-eight of seventy operatively treated levels) compared with
the autograft group, which had a
fusion rate of 77% (seventeen of twentytwo operatively treated levels) (p <
0.05). Although the combination of
rhBMP-2 and autograft iliac crest pro-

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Fig. 2-A

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Fig. 2-B

Figs. 2-A through 2-L Images demonstrating the transforaminal lumbar interbody fusion procedure with use of
rhBMP-2 in a forty-year-old man who presented with low-back pain and right lower-limb pain that were equal in severity.
An extensive course of nonoperative treatment had failed. Figs. 2-A and 2-B Anteroposterior and lateral radiographs
demonstrating substantial disc degeneration at the L4-L5 level.

vided the highest reported fusion rate

following posterolateral lumbar arthrodesis, to our knowledge, it does
not eliminate the substantial potential
for morbidity at the iliac crest harvest
site.
In a retrospective study, ninetyone patients who had been treated, at a
single institution, with a posterolateral
lumbar spine fusion with use of rhBMP-2
(12 mg in the form of a 1.5-mg/mL
solution) on a collagen sponge that was
wrapped around local bone and bonegraft extender were compared with a
group of thirty-five patients who had
undergone single-level posterolateral
lumbar fusion with use of autogenous
iliac bone graft27. In the rhBMP-2 group,
forty-eight patients had a primary singlelevel fusion, twenty-seven had a primary
multilevel fusion, and sixteen patients
had revision fusion surgery because of
nonunion. At the time of follow-up, at a
minimum of two years, the nonunion
rates in these three groups were 4.2%,

0%, and 25%, respectively. The autograft group had a nonunion rate of
11.4%. Within the rhBMP-2 group, a
subgroup of patients who were identified as smokers had no nonunions. The
men in the rhBMP-2 group had a
significantly higher nonunion rate than
the women (11.1% and 3.4%, respectively; p = 0.036). The authors of the
study concluded that use of the lower
dose of rhBMP-2 (compared with that
used in prior studies), applied with local
bone and bone graft extender, results in
a fusion rate similar to that following
use of autograft iliac crest in posterolateral lumbar fusion. It also appeared
that rhBMP-2 may increase fusion rates
in smokers.
Several investigators have evaluated the clinical efficacy of rhBMP-7
(OP-1), particularly in posterolateral
lumbar fusion46-50. These early studies
did not show the fusion rate following
use of OP-1 combined with autograft to
be superior to that achieved with auto-

graft alone, but there were no documented complications related to the use
of OP-1. A larger multicenter, prospective, randomized, FDA-approved investigational device exemption clinical
study was performed to evaluate the use
of OP-1 putty as a replacement for iliac
crest autograft in single-level posterolateral lumbar fusion in patients with
symptomatic lumbar stenosis and
Grade-I or II degenerative spondylolisthesis48-51. Twenty-four patients were
randomized to receive OP-1 putty and
twelve, to receive iliac crest autograft.
The OP-1 putty (3.5 mg per side of the
spine) was placed between the transverse processes at the level of interest.
No local autograft bone or instrumentation was used. At one year48, two
years49, and four years50 postoperatively,
the OP-1 and iliac crest autograft groups
had similar fusion rates (approximately
50%) and clinical outcomes. No adverse
effects had resulted from the use of
the OP-151.

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Fig. 2-C

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Fig. 2-D

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Fig. 2-E

Fig. 2-C T2-weighted midsagittal magnetic resonance image showing substantial L4-L5 disc degeneration with vertebral end-plate changes. Figs. 2-D
and 2-E Parasagittal T1-weighted magnetic resonance images showing evidence of a right-sided foraminal disc herniation that is causing substantial
compression of the L4 nerve root. An L4-L5 transforaminal lumbar interbody fusion was performed from the right side, with use of rhBMP-2 and local
autograft bone.

In a prospective randomized
study, OP-1 putty (3.5 mg per side, in
nine patients) was compared with a
mixture of local autograft and calcium
phosphate ceramic granules (in ten
patients) for a single-level posterolateral
lumbar fusion with internal fixation in
patients with spinal stenosis and degenerative spondylolisthesis. At one year
postoperatively, radiographic evidence
of fusion was present in seven of the
nine patients who had received OP-1
and nine of the ten patients who had
received the autograft-ceramic mixture51. In sixteen patients, the hardware
was removed and the fusion mass was
explored. In that group, only four of the
seven patients treated with OP-1 and
seven of the nine treated with the
autograft-ceramic mixture had a solid
fusion. The authors concluded that,
although OP-1 does stimulate new
bone formation at the site of a posterolateral fusion, the rate of solid fusion
is low.

Transforaminal Lumbar
Interbody Fusion
This procedure, first described by
Harms and Rolinger52 in 1982, allows an
anterior interbody fusion and a posterolateral fusion to be achieved through
a single posterior approach. An interbody cage with bone graft is placed into
a distracted disc space through a posterolateral transforaminal approach,
and a standard posterolateral fusion
with pedicle screw stabilization is
done. To eliminate the need for iliac
crest autograft and the morbidity
associated with its harvest, off-label
use of rhBMP-2 in transforaminal
lumbar interbody fusion has become
increasingly popular (Figs. 2-A through
2-L).
In a preliminary study of transforaminal lumbar interbody fusions,
with an average duration of follow-up of
nine months, the fusion rate associated
with use of rhBMP-2 and autograft (in
twenty-one patients) was compared

with the fusion rate associated with use

of iliac crest autograft alone (in nineteen
patients)24. Of the twenty-one patients
who were treated with rhBMP-2 and
autograft, twelve received iliac crest
autograft and nine received autograft
obtained locally from the laminectomy.
In this group, the autograft was
packed posterior to the rhBMP-2-filled
cage. The mean time to fusion was six
months in the autograft group, four
months in the rhBMP-2/iliac crest autograft group, and three months in the
rhBMP-2/local bone group. One
patient in the autograft group and one
patient in the rhBMP-2/local bone
group had a pseudarthrosis. No patient
in the rhBMP-2/iliac crest autograft
group had a pseudarthrosis or symptomatic foraminal bone formation.
The authors concluded that rhBMP-2
is a safe and effective alternative to
iliac crest autograft for use in transforaminal lumbar interbody fusion
and that it leads to more rapid

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Fig. 2-F

Intraoperative photograph demonstrating the approach for the transforaminal lumbar interbody fusion. The inferior articulating facet, the

IN

fusion while eliminating harvest-site

morbidity.
The use of rhBMP-2 in both
minimally invasive and open transforaminal lumbar interbody fusion procedures was reported in seventy-four
patients followed for an average of
twenty months26. The study included
single-level and multilevel transforaminal lumbar interbody fusions, many of
which were performed in the setting of
previous lumbar surgery. The BMP-2
was applied on an absorbable collagen
sponge and was combined with autogenous local bone and/or allograft bone.
All patients in the study had a solid
fusion within ten months after the
surgery, with a mean time to fusion of
4.1 months. There were no complications or allergic reactions that the
authors attributed specifically to the
use of the rhBMP-2. Two patients,
however, were noted to have persistent,
postoperative radiculitis. No ectopic
bone formation was observed.

pars interarticularis, and a portion of the lamina of the L4 vertebral

body were removed with use of an osteotome and a Kerrison rongeur.
The locations of the L4 and L5 pedicles are defined by the black circles.
The solid black arrow points to the exiting L4 nerve root, and the open
arrow points to the thecal sac. The triangle highlights the area through
which the transforaminal lumbar interbody fusion is performed. Its
borders are formed by the exiting nerve root, the thecal sac, and the
inferior aspect of the disc space of interest. The anulus is incised and
the disc space is prepared through this triangle.

Fig. 2-G

After the disc space is prepared, the BMP-soaked collagen sponge is

packed into the interbody cage, and the cage is inserted into the
anterior two-thirds of the disc space to maximize lordosis and minimize
the risk of exposing the nerve root to BMP.

Safety of BMP in Lumbar

Spine Surgery
Few documented adverse events can be
attributed to BMP. Nonetheless, certain
complications and safety issues related
to use of BMP in the lumbar spine are
concerns. Adverse reactions with
repeat BMP exposure include postoperative radiculitis, vertebral osteolysis
and edema, and neurocompressive
ectopic bone formation (i.e., bone formation in the central canal or intervertebral foramen).
As a foreign protein, BMP has the
potential to stimulate the formation of
antibodies. Antibodies to BMP can, on
reexposure, lead to a hyperinflammatory response with local (e.g., wound)
problems and systemic consequences
(e.g., anaphylaxis), but there is no
clinical evidence to suggest that reexposure to BMP can have detrimental
effects53. The use of BMP, particularly in
transforaminal lumbar interbody fusion
and posterior lumbar interbody fusion,
has been associated with severe postoperative radiculitis, which can start
days after the surgery without neural
compression. The cause is thought to be
a BMP-related pro-inflammatory reac-

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Fig. 2-H

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Fig. 2-I

Fig. 2-H A BMP-soaked collagen sponge is rolled around local autograft bone and placed posterolaterally, bridging the transverse processes. Some
surgeons avoid placing BMP posterolaterally on the side of the transforaminal lumbar interbody fusion to avoid nerve root irritation and postoperative
radiculitis. Fig. 2-I Lateral radiograph made following a transforaminal lumbar interbody fusion procedure. Note that the interbody cage (marked by
metallic beads) is located in the anterior two-thirds of the disc space.

tion and/or ectopic bone formation in

the vicinity of the nerve root sleeve and
the intervertebral foramen. Postoperative nerve injury (i.e., a new or increased
neurological deficit) was reported in
20.7% and 14.3% of patients who had

Fig. 2-J

undergone one and two-level minimally

invasive transforaminal lumbar interbody fusion with rhBMP-2, respectively 26. The authors stated that none of
the complications were specifically attributed to rhBMP-2. Two of the pa-

Fig. 2-K

tients in their study had persistent

postoperative radiculitis that was still
present at the time of the latest followup. In another study, with a retrospective design, radiculitis that lasted more
than six months developed in nine of

Fig. 2-L

Axial (Fig. 2-J), coronal (Fig. 2-K), and sagittal (Fig. 2-L) computed tomography scans demonstrating a solid interbody fusion twelve
months following the transforaminal lumbar interbody fusion performed with rhBMP-2.

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Fig. 3

Axial (A) and coronal (B) computed tomography scans demonstrating ectopic bone formation in the intervertebral foramen (white arrows) following a
transforaminal lumbar interbody fusion performed with rhBMP-2.

thirty-nine patients who had had a

transforaminal lumbar interbody fusion
with use of rhBMP-2 and only one of
twenty-nine patients who had had the
fusion with use of iliac crest autograft54.
The average duration of the postoperative radiculitis in the rhBMP-2
group was 13.4 months. There is anecdotal evidence that the use of a
sealant, such as DuraSeal Xact Sealant
System (Confluent Surgical, Waltham,
Massachusetts), to minimize the
amount of rhBMP-2 in the vicinity of
the nerve root may decrease the prevalence of postoperative radiculitis.
Clinical studies are needed to further
explore this issue.
Ectopic bone formation can potentially occur in the anterior epidural
space and near the nerve root, along the
track of insertion of BMP, when an
interbody fusion is performed from a
posterolateral or transforaminal approach (Fig. 3)55. Although the risks of
ectopic bone formation developing with
BMP use remain unknown, hematoma
seems to be a carrier and excessive

bleeding can disperse the BMP. Hemostatic agents, such as Gelfoam (Pfizer,
New York, NY), have also been implicated as carriers. An early study of the
use of BMP in posterior lumbar interbody fusion demonstrated a high rate of
substantial ectopic bone formation in
the spinal canal55. No clinical symptoms,
however, developed secondary to this
ectopic bone formation55. Clinical
studies of the use of BMP in transforaminal lumbar interbody fusion have
not revealed problems with ectopic bone
formation24-26. Placement of the rhBMP2 anterior to and within the interbody
cage in the anterior column, but not in
the middle column near the anulotomy,
is thought to minimize the risk of
ectopic bone formation in the spinal
canal and/or intervertebral foramen
following a transforaminal lumbar
interbody fusion.
Vertebral osteolysis and vertebral edema have been observed after
use of BMP in an interbody fusion23,56.
The pathophysiology and relevance of
the vertebral osteolysis are unknown. It

has been reported to occur in 8% to

18% of cases23,56. It seems to resolve
spontaneously, but patients may have
pain while it is present (Fig. 4). It
may be due, at least in part, to a
violation of the vertebral body end
plate during preparation of the disc
space.
Economics of BMP Use in
Spine Surgery
There have been several economic
evaluations comparing the cost of
BMP use with the cost of traditional
autogenous iliac crest bone-grafting57-59.
Most investigators have concluded
that BMPs will prove to be cost-neutral.
The costs associated with the use of
BMPs are largely offset by the prevention of the pain and complications
associated with the harvest of autogenous iliac crest bone graft. Ultimately,
the largest long-term cost offset may be
associated with a reduced number of
fusion failures and the reduced need
for revision57. An economic model
based on clinical trial data, peer-

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Fig. 4

Coronal computed tomography scan (A) and sagittal T1-weighted magnetic resonance image (B) demonstrating vertebral
osteolysis six months following a transforaminal lumbar interbody fusion performed with use of rhBMP-2. Although this finding is
often associated with increased back pain and radiculitis, it seems as though the vertebral body reaction to BMP is a self-limiting
process that does not affect the clinical outcome or the rate of fusion.

reviewed literature, and clinical expert

opinion suggested that, over a two-year
period after the surgery, the upfront
cost of BMP is likely to be offset to a
substantial extent by more efficient
use of other medical resources, including a decreased length of hospital stay
and decreased use of pain clinics and
rehabilitation services58.
In an economic prospective,
randomized, controlled trial, fifty patients, over sixty years old, who were
treated with lumbar spine surgery with
rhBMP-2 were compared with fifty-two
patients, over sixty years old, who
were treated with lumbar spine surgery
with iliac crest bone graft, with or
without graft extender59. All costs during the first three months after the
surgery (the perioperative Medicare
global billing period) were recorded. A
research nurse followed all patients
throughout their hospital stay and posthospitalization recovery to identify any

adverse events or additional outpatient

medical care. The total payer expenditure
for the three months averaged $33,860 in
the rhBMP-2 group and $37,227 in the
iliac crest bone-graft group. In the
rhBMP-2 group, the mean operative
time was twenty-two minutes shorter,
the mean length of stay in the hospital
was almost a day shorter, and inpatient
rehabilitation was utilized less frequently.
Overview
The use of BMPs in lumbar fusion
surgery has increased over the last
several years. Both rhBMP-2 and
rhBMP-7 are members of the TGF-b
superfamily and have been used with
success in both preclinical and clinical
trials. The only FDA-approved indication for BMP in the spine is anterior
lumbar interbody fusion with use of
rhBMP-2 in a titanium tapered cage.
Off-label uses of BMPs are becoming increasingly popular as enthu-

siasm for them grows and indications

for their clinical application expand.
Several randomized trials are currently
being performed to study the use of
BMPs in both posterolateral lumbar
fusion and transforaminal lumbar interbody fusion. These studies have
produced promising early results.
Important concerns regarding the clinical application of BMP include safety
and cost. Finally, the large upfront
cost of BMPs appears to be offset by
the prevention of complications
associated with iliac crest harvest, including a longer operative time, more
blood loss, and longer inpatient and
rehabilitation stays. Ultimately, if
use of BMPs is able to reduce the number
of fusion failures, then they will prove
to be cost-sparing in the long run.
Jeffrey A. Rihn, MD
Todd J. Albert, MD
Department of Orthopaedic Surgery,

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LU M B A R S P I N E S U R G E RY

The Rothman Institute, Thomas Jefferson

University Hospital, 925 Chestnut Street,
5th Floor, Philadelphia, PA 19107.
E-mail address for J.A. Rihn:
jrihno16@yahoo.com

University of Louisville School of Medicine,

Kenton D. Leatherman Spine Center,
210 East Gray Street,
Suite 900, Louisville, KY 40202

Charley Gates, MD
Department of Orthopaedic Surgery,
University of Pittsburgh Medical Center,
3471 Fifth Avenue,
Suite 1010, Pittsburgh,
PA 15213

Frank M. Phillips, MD
Department of Orthopaedic Surgery,
Rush University Medical Center,
1725 West Harrison Street,
Suite 1063, Chicago,
IL 60612

Steven D. Glassman, MD
Department of Orthopaedic Surgery,

James D. Schwender, MD
Department of Orthopaedic Surgery,

IN

University of Minnesota,
2450 Riverside Avenue, SR 200,
Minneapolis,
MN 55454
Printed with permission of the American
Academy of Orthopaedic Surgeons. This
article, as well as other lectures presented
at the Academys Annual Meeting, will
be available in February 2009 in
Instructional Course Lectures, Volume 58.
The complete volume can be ordered
online at www.aaos.org, or by calling
800-626-6726 (8 A.M.-5 P.M., Central
time).

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