guideline update for the performance of fusion procedures
TRANSCRIPT
J Neurosurg Spine 21:106–132, 2014
106
©AANS, 2014
J Neurosurg: Spine / Volume 21 / July 2014
RecommendationsThere is no evidence that conflicts with the previous
recommendations published in the original version of the “Guidelines for the performance of fusion procedures for degenerative disease of the lumbar spine” regarding the use of hydroxyapatite (HA), various calcium-based prep-arations, and recombinant human bone morphogenetic protein–2 (rhBMP-2) as bone graft extenders and substi-tutes for lumbar fusion.48
No prior recommendations regarding the use of rhBMP-7 for lumbar fusions were published in the origi-nal Lumbar Fusion Guidelines.
Guideline update for the performance of fusion procedures for degenerative disease of the lumbar spine. Part 16: Bone graft extenders and substitutes as an adjunct for lumbar fusion
Michael G. Kaiser, M.D.,1 Michael W. Groff, M.D.,2 WilliaM c. Watters iii, M.D.,3 Zoher GhoGaWala, M.D.,4 Praveen v. MuMManeni, M.D.,5 anDreW t. Dailey, M.D.,6 tanvir f. chouDhri, M.D.,7 Jason c. ecK, D.o., M.s.,8 aloK sharan, M.D.,9 Jeffrey c. WanG, M.D.,10 sanJay s. Dhall, M.D.,5 anD Daniel K. resnicK, M.D.11
1Department of Neurosurgery, Columbia University, New York, New York; 2Department of Neurosurgery, Brigham and Women’s Hospital, Boston, Massachusetts; 3Bone and Joint Clinic of Houston, Houston, Texas; 4Alan and Jacqueline Stuart Spine Research Center, Department of Neurosurgery, Lahey Clinic, Burlington, and Tufts University School of Medicine, Boston, Massachusetts; 5Department of Neurological Surgery, University of California, San Francisco, California; 6Department of Neurosurgery, University of Utah, Salt Lake City, Utah; 7Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, New York; 8Center for Sports Medicine and Orthopaedics, Chattanooga, Tennessee; 9Department of Orthopaedic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; 10Department of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California; and 11Department of Neurosurgery, University of Wisconsin, Madison, Wisconsin
In an attempt to enhance the potential to achieve a solid arthrodesis and avoid the morbidity of harvesting au-tologous iliac crest bone (AICB) for a lumbar fusion, numerous alternatives have been investigated. The use of these fusion adjuncts has become routine despite a lack of convincing evidence demonstrating a benefit to justify added costs or potential harm. Potential alternatives to AICB include locally harvested autograft, calcium-phosphate salts, demineralized bone matrix (DBM), and the family of bone morphogenetic proteins (BMPs). In particular, no option has created greater controversy than the BMPs. A significant increase in the number of publications, particularly with respect to the BMPs, has taken place since the release of the original guidelines. Both DBM and the calcium-phosphate salts have demonstrated efficacy as a graft extender or as a substitute for AICB when combined with local autograft. The use of recombinant human BMP-2 (rhBMP-2) as a substitute for AICB, when performing an interbody lumbar fusion, is considered an option since similar outcomes have been observed; however, the potential for het-erotopic bone formation is a concern. The use of rhBMP-2, when combined with calcium phosphates, as a substitute for AICB, or as an extender, when used with local autograft or AICB, is also considered an option as similar fusion rates and clinical outcomes have been observed. Surgeons electing to use BMPs should be aware of a growing body of literature demonstrating unique complications associated with the use of BMPs.(http://thejns.org/doi/abs/10.3171/2014.4.SPINE14325)
Key WorDs • lumbar spine • bone graft • bone substitute • fusion • bone morphogenetic protein • practice guidelines
Abbreviations used in this paper: ACS = absorbable collagen sponge; AICB = autologous iliac crest bone; ALIF = anterior lumbar interbody fusion; b-TCP = b-tricalcium phosphate; BMA = bone marrow aspirate; CHA = coralline hydroxyapatite; CRM = compression-resistant matrix; DBM = demineralized bone matrix; FRA = femoral ring allograft; HA = hydroxyapatite; ICBG = iliac crest bone graft; IDE = investigational device exemption; mJOA = modified Japanese Orthopaedic Association; NRS = numeric rating scale; ODI = Oswestry Disability Index; OP-1 = osteogenic pro-tein–1; PLIF = posterior lumbar interbody fusion; RCT = random-ized controlled trial; rhBMP = recombinant human bone morphoge-netic protein; SF-36 = 36-Item Short Form Health Survey; TLIF = transforaminal lumbar interbody fusion; VAS = visual analog scale.
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Part 16: Bone graft extenders and substitutes
107J Neurosurg: Spine / Volume 21 / July 2014
Demineralized Bone MatrixGrade C (Single Level III and Single Level V Studies)
The use of demineralized bond matrix (DBM) as a bone graft extender is an option for 1- and 2-level instru-mented posterolateral fusions.
Hydroxyapatite/Calcium ExtendersGrade C (Single Level II Study)
The use of b-tricalcium phosphate (b-TCP)/local autograft as a substitute for autologous iliac crest bone (AICB) is an option for single-level instrumented postero-lateral fusion due to comparable fusion rates and clinical outcomes.
Grade C (Single Level II Study)The use of HA with local autograft/bone marrow as-
pirate (BMA) as a substitute for AICB in an option for instrumented posterolateral fusion due to comparable fu-sion rates and clinical outcomes.
Grade C (Multiple Level V Studies)The use of HA can be considered an option as a graft
extender when mixed with AICB for instrumented pos-terolateral fusions.
Grade C (Single Level IV and Multiple Level V Studies)The use of calcium sulfate preparations mixed with
local autograft, as a substitute for AICB, is an option for instrumented posterolateral fusions.
Grade I (Single Level V Study)There is insufficient evidence to recommend for or
against the use of a HA-glass/BMA composite as an au-tograft substitute for posterolateral fusion.
rhBMP-2: Interbody FusionGrade B (Multiple Level II Studies)
The use of rhBMP-2 as a substitute for AICB for ALIF with threaded interbody cages is an option due to similar fusion rates and clinical outcomes.
Grade C (Single Level II Study)The use of rhBMP-2 as a substitute for AICB for
single-level PLIF is an option due to similar fusion rates and clinical outcomes; however, formation of heterotopic bone has been observed.
Grade C (Single Level IV and Multiple Level V Studies)The use of rhBMP-2 as a bone graft extender can be
considered as an option when performing a TLIF proce-dure with a structural interbody graft.
Grade I (Single Level III Study)There is insufficient evidence to make a recommen-
dation regarding the use of rhBMP-2 as a supplement for
stand-alone ALIF procedures using femoral ring allograft (single Level III study) or with a resorbable spacer when performing TLIF procedures (single Level V study).
rhBMP-2: Posterolateral FusionGrade B (Multiple Level II Studies)
The use of rhBMP-2 supplemented with 15% HA/85% b-TCP matrix as a substitute for AICB is an option in single-level posterolateral instrumented fusions given the consistent observation of comparable fusion rate and clinical outcomes.
Grade C (Single Level II and Single Level IV Studies)The use of rhBMP-2 supplemented with graft extend-
ers as an alternative to AICB is an option for single-level, instrumented posterolateral fusions in patients older than 60 years.
Grade C (Single Level III and Single Level V Studies)The use of rhBMP-2 as a graft extender with either
AICB or local bone is an option in patients undergoing either instrumented or noninstrumented posterolateral fu-sions.
Grade IThere is insufficient evidence to formulate a recom-
mendation regarding the use of rhBMP-2/local bone as a substitute for AICB when performing revision postero-lateral fusions (single Level III study) or the use of rh-BMP-2/calcium-based extenders for single level postero-lateral fusions in patients who smoke and elect to undergo surgery for lumbar spondylosis (single Level III study).
rhBMP-2: ComplicationsGrade C (Multiple Level IV and V Studies)
The use of rhBMP-2 as a graft option has been as-sociated with a unique constellation of complications that the surgeon should be aware of when considering the use of this graft extender/substitute.
rhBMP-7Grade C (Single Level II Study)
The use of rhBMP-7 when combined with local auto-graft as an alternative to AICB/local autograft is an option for single-level instrumented fusions based on equivalent clinical and radiographic outcomes. The use of rhBMP-7 has not been approved by the FDA for spinal fusions and currently requires a humanitarian device exemption.
Grade I (Conflicting Level II Studies)No recommendation regarding the use of rhBMP-7/
absorbable collagen sponge (ACS) as a substitute for AICB in posterolateral fusions can be made due to con-flicting evidence from studies of equal strength.
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M. G. Kaiser et al.
108 J Neurosurg: Spine / Volume 21 / July 2014
RationaleThe objective of a lumbar fusion is to create an en-
vironment that will allow bone to form a solid osseous bridge across the involved spinal segments. Autologous iliac crest bone has been considered the gold standard because of its ideal graft characteristics, including osteo-conduction, osteoinduction, and osteogenesis.4,28,39 The harvesting of AICB, however, is commonly associated with increased postoperative pain, which may be under-estimated by the treating surgeon.31,55 Additional draw-backs of AICB include limited supply and increased op-erative time and blood loss.
Allograft bone, one of the original substitutes for AICB, may avoid some of these drawbacks; however, when used alone, it is commonly associated with an in-creased pseudarthrosis rate.28 For this reason, and to avoid the morbidity of harvesting AICB, a great deal of time and expense has been dedicated to investigate and promote extenders and/or substitutes of AICB. Potential candidates include locally harvested autograft, calcium-phosphate salts, such as HA or b-TCP, and DBM. Howev-er, no material has received more attention and generated more controversy than the family of BMPs. There are numerous papers that demonstrate the fusion potential of BMPs;2,7,18,19 however, complications associated with their use have been reported.29,47,50 Whether the benefits of BMPs justify the costs remains to be determined. Pos-sibly more alarming than the potential complications and costs have been questions related to bias and conflict of interest associated with the reporting of results from tri-als investigating the potential of BMPs.9 This escalating controversy prompted the editors of The Spine Journal to dedicate the June 2011 issue to concerns regarding the use of BMPs in spinal fusion surgery.
The objective of this update is to build upon the previous recommendations formulated in the original guidelines publication.48 A review of the recent medical literature was conducted to determine the utility of these materials with respect to their clinical efficacy, fusion potential, and complication risk. It is beyond the scope of the current update to comment on cost utility of these materials or the ethics of investigational reporting.
Search CriteriaA computerized search of the National Library
of Medicine MEDLINE database, utilizing the on-line search engine PubMed, was conducted from 2003 through December 2011 utilizing the following search terms (((“Lumbosacral Region”[MeSH] OR “Lumbar Vertebrae”[MeSH]) AND “Spinal Fusion”[MeSH]) OR “lumbar fusion”[All Fields] OR (“lumbar”[title] AND “fusion”[title])) AND (((“Bone Substitutes”[MeSH] OR “Calcium Phosphates”[MeSH]) OR “Hydroxyapatites” [MeSH]) OR “Bone Morphogenetic Proteins”[MeSH]) AND ((“2003”[PDAT]: “3000”[PDAT]) AND “humans” [MeSH Terms] AND English[lang]). The search was limited to the English language and human subjects and yielded a total of 151 papers. The titles and abstracts of these articles were reviewed and those specifically inves-tigating the fusion potential, clinical efficacy, and poten-
tial complications of bone graft substitutes and extenders were selected. Of these papers a secondary review of the bibliographies was conducted to identify any additional relevant papers. A total of 79 articles were selected and reviewed in detail. Studies supporting similar conclusions of equivalent strength were grouped together. Those pro-viding the best evidence from these compilations were included in the evidentiary tables. A detailed description of high-level studies or a representative of lower-level studies of similar conclusions serve as the scientific foun-dation for this update.
Scientific Foundation
Demineralized Bone Matrix
Since the publication by Urist, the osteoinductive properties of demineralized bone matrix (DBM) have been well recognized and extensively studied as both a substitute and extender of autograft bone.57 Cammisa et al. conducted a multicenter, prospective, controlled trial to investigate the potential of DBM as a graft extender for AICB when performing a posterolateral instrumented lumbar fusion (Table 1).8 One hundred twenty patients with a variety of degenerative disorders were enrolled and underwent up to a 3-level lumbar fusion. An inde-pendent, blinded radiologist, utilizing static and dynamic radiographs, performed fusion assessment at 3, 6, 12, 18, and 24 months. The clinical outcome of these patients was not recorded. All patients served as his/her own con-trol receiving AICB within one intertransverse space and an equal volume of DBM/AICB to the contralateral in-tertransverse space. The follow-up rate at 24 months was 68%. A comparable fusion rate was observed on both sides (52% with DBM/AICB and 54% with AICB). Sev-enty-five percent of patients demonstrated fusion on both sides. Based on these observations the authors concluded that DBM could serve as an effective graft extender, de-creasing the amount of autograft required and potentially reducing the risk and severity of donor site morbidity. Due to the utilization of internal controls, one cannot ex-clude a possible interaction between the investigational and control groups that could affect the outcome. This is therefore considered a case series when determining baseline level of evidence. Additional limitations include a heterogeneous patient population with respect to pre-senting diagnosis and the inclusion of a variety of fusions methods, including various interbody techniques. A large percentage of patients were lost to follow-up at 24 months. In the presence of pedicle screw stabilization, assessment of fusion with plain radiographs may be compromised. Secondary to these limitations, the case series was down-graded to Level V evidence in support of DBM as a graft extender for AICB in posterolateral lumbar fusion.
Schizas et al. conducted a pilot study comparing the clinical and radiographic outcome of patients undergoing 1- and 2-level posterolateral instrumented lumbar fusion using a novel DBM as a graft extender for autograft (Table 1).51 Fifty-nine consecutive patients were divided into the 2 treatment groups; 33 received DBM mixed with autograft/BMA and 26 received only autograft. Fusion assessment
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Part 16: Bone graft extenders and substitutes
109J Neurosurg: Spine / Volume 21 / July 2014
TABL
E 1:
Dem
iner
alize
d bo
ne m
atrix
: sum
mar
y of e
viden
ce*
Auth
ors &
Ye
arLe
vel o
f Ev
idenc
eDe
scrip
tion o
f Stu
dyCo
mmen
ts
Schiz
as et
al.,
20
08III
The o
bjecti
ve of
this
pilot
coho
rt stu
dy w
as to
comp
are t
he cl
inica
l & ra
diogr
aphic
perfo
rman
ce of
a nov
el DB
M as
a gr
aft e
xtend
er fo
r auto
graf
t in 1-
& 2-
level
poste
rolat
instr
umen
ted fu
sions
.
59 co
nsec
utive
pts w
ere d
ivide
d into
the 2
trea
tmen
t gro
ups:
33 re
ceive
d DBM
mixe
d w/ a
uto-
gr
aft/B
MA
(trea
tmen
t) &
26 re
ceive
d only
auto
graf
t (co
ntrol)
. Fus
ion as
sess
ment
was b
linde
d
& de
termi
ned w
/ plai
n rad
iogra
phs.
Valid
ated o
utcom
e mea
sure
s wer
e use
d to d
eterm
ine
cli
nical
status
. At 1
2 mos
after
surg
ery,
the f
usion
rate
for t
he in
terve
ntion
al gr
oup w
as 6
9.7%
& th
at fo
r the
contr
ol gr
oup w
as 76
.9%
(p =
0.57
). Th
ere w
as no
diffe
renc
e in t
he cl
inica
l out-
come
btwn
grou
ps. T
he au
thor
s con
clude
d tha
t DBM
is a
safe
& ef
fectiv
e gra
ft ex
tende
r for
1- &
2-lev
el po
stero
lat fu
sions
.
This
study
is lim
ited b
y the
relat
ively
small
stud
y pop
ulatio
n w/ v
aryin
g
pres
entin
g diag
nose
s. In
adeq
uate
base
line d
emog
raph
ic da
ta ar
e
prov
ided.
The a
utho
rs fa
il to s
tand
ardiz
e the
DBM
/auto
graf
t com
-
posit
e. Du
e to t
hese
limita
tions
this
study
prov
ides L
evel
III ev
i-
dence r
egardin
g the efficacy o
f DBM
to ac
t as a
graft exte
nder.
Camm
isa et
al., 2
004
VTh
e authors co
nducted
a mu
lticenter
prospective co
ntrolled trial to de
termine the e
fficacy o
f DBM
as a
graf
t exte
nder
for p
oster
olat in
strum
ented
lumb
ar fu
sions
. 120
pts w
ere e
nroll
ed w
/ var
y-
ing de
gene
rativ
e diag
nose
s & un
derw
ent u
p to 3
-leve
l lumb
ar fu
sions
. Rad
iogra
phic
asse
ss-
me
nt of
fusio
n was
perfo
rmed
at 3,
6, 12
, 18,
& 24
mos
by in
depe
nden
t blin
ded r
adiol
ogist
s
using
stati
c & dy
nami
c rad
iogra
phs.
No cl
inica
l outc
ome m
easu
res w
ere u
sed.
Each
pt se
rved
as hi
s/her
own c
ontro
l & re
ceive
d equ
al vo
ls of
eithe
r AIC
B or
a DB
M/A
ICB
comp
osite
to th
e
inter
trans
vers
e spa
ces.
The f
ollow
-up r
ate at
24 m
os w
as 6
8%. T
he fu
sion r
ate fo
r the
DBM
/
AICB
comp
osite
side
was
52%
& 5
4% on
the c
ontro
l side
, w/ a
75%
agre
emen
t btw
n the
2
sid
es. B
ased
on th
ese o
bser
vatio
ns th
e aut
hors
conc
luded
that
DBM
can s
erve
as an
effec
tive
gr
aft e
xtend
er, de
crea
sing t
he am
ount
of au
togr
aft r
equir
ed &
poten
tially
redu
cing t
he ri
sk &
seve
rity o
f don
or si
te co
mplic
ation
s.
This stu
dy be
nefits
from
a relative
ly large no
. of pts wh
o were follow
ed
fo
r an e
xtend
ed tim
e; ho
weve
r, this
stud
y is c
onsid
ered
a ca
se se
-
ries s
ince c
ontro
l & tr
eatm
ent c
ohor
ts we
re co
nduc
ted w
/in th
e
same
pt &
ther
efore
poss
ible i
ntera
ction
btwn
the i
nves
tigati
onal
&
contr
ol sites ca
nnot be ex
cluded. A sig
nificant los
s to follow
-up r
ate
(3
2%) w
as en
coun
tered
. A va
riety
of dia
gnos
es w
ere i
nclud
ed &
the
su
rgica
l tech
nique
was
not s
tand
ardiz
ed. T
he us
e of p
lain r
adio-
grap
hs m
ay be
an in
adeq
uate
mean
s of f
usion
asse
ssme
nt in
the
pr
esen
ce of
pedic
le sc
rew
instru
ment
ation
. The
auth
ors f
ailed
to
inc
lude c
linica
l outc
ome d
ata.
Due t
o the
se lim
itatio
ns th
e stu
dy
wa
s dow
ngra
ded t
o Lev
el V
in su
ppor
t of D
BM as
a gr
aft e
xtend
er
fo
r AIC
B in
pts un
derg
oing i
nstru
mente
d pos
terola
t fus
ions.
* AI
CB =
auto
logou
s ilia
c bon
e gra
ft; B
MA
= bo
ne m
arro
w as
pirate
; DBM
= de
mine
raliz
ed bo
ne m
atrix;
pt =
patie
nt.
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M. G. Kaiser et al.
110 J Neurosurg: Spine / Volume 21 / July 2014
was performed 12 months after surgery by a blinded in-dependent observer utilizing plain radiographs. Validated outcome measures, including the Oswestry Disability In-dex (ODI) and visual analog scale (VAS) pain score, were used to determine clinical status. The fusion rate for the in-terventional group was 69.7% and the control group 76.9% (p = 0.57). There was no difference in the clinical outcome between the 2 groups. The authors concluded that DBM is a safe and effective graft extender for single- and 2-level pos-terolateral fusions. The relatively small number of patients, varying diagnoses, inadequate baseline demographic data, and short clinical follow-up all limit the conclusions of this study. The authors failed to standardized the volume and type of autograft used, whether AICB or locally harvested autograft. Due to these limitations the study is considered to provide only Level III evidence in support of DBM as a graft extender.
Calcium Phosphate SaltsThis class of graft extenders and substitutes consists of
calcium phosphate salts of varying composition that pro-vide a lattice framework for in growth of new bone. These materials provide an osteoconductive matrix, having little if any osteoinductive or osteogenic properties. Examples include b-TCP, HA, and coral-based materials (Table 2).
β-Tricalcium Phosphate. Dai and Jiang performed a prospective, randomized, controlled trial to determine the efficacy of b-TCP as a bone graft substitute for AICB in single-level posterolateral instrumented fusions for degen-erative spinal stenosis (Table 2).16 Sixty-two patients were randomized to one of 2 cohorts, receiving either b-TCP (n = 32) or AICB (n = 30), both supplemented with local autograft. An independent observer assessed clinical out-come with validated outcomes measures, including mJOA, 36-Item Short Form Health Survey (SF-36), and VAS for donor site pain, at 6 weeks and 3, 6, 12, 24 and 36 months after surgery. Two independent observers evaluated plain radiographs to assess fusion status at 3, 6, 12, 24, and 36 months after surgery. No patients were lost to follow-up at 36 months. The reported fusion rate for all study partici-pants at 36 months was reported to be 100%, and signifi-cant improvement in the clinical outcome was observed in all patients. No significant differences were observed be-tween the treatment cohort and control group with respect to fusion rate or clinical outcome. A postoperative hemato-ma was reported in 3 patients undergoing harvest of AICB. All patients from the AICB group reported donor site pain after surgery, and only 20% reported no pain at 6 weeks after the operation. In some patients (data not provided) pain was still present 36 months after surgery. The authors concluded that b-TCP, supplemented with local autograft, could serve as an effective substitute for AICB when local bone is insufficient. This was a well-designed and executed trial of a homogeneous group of patients with excellent clinical follow-up over an extended time. There were sev-eral limitations, however, including a failure to describe the randomization process and failure to use a disease-specific outcome measure. The utilization of plain radiographs to determine fusion status may also be considered subopti-mal, particularly in the presence of an instrumented fusion.
Due to these limitations the study is downgraded to Level II evidence in support of utilizing b-TCP/local autograft as a substitute for AICB.
Hydroxyapatite. In 2005, Korovessis et al. conducted a prospective randomized controlled trial (RCT) to deter-mine the fusion potential of coralline hydroxyapatite (CH) in multilevel, instrumented posterolateral lumbar fusions (Table 2).38 Sixty patients were randomized to one of 3 cohorts: bilateral application of AICB, AICB on the left and CH/local bone/BMA on the right, and CH/local bone/BMA bilaterally. Validated outcome measures, including the ODI, VAS, Roland-Morris score, and SF-36, were ob-tained preoperatively and at 6, 12, 24, and 48 months after surgery. Two blinded, independent radiologists evaluated plain radiographs at 3, 6, 12, 24, and 48 months after sur-gery, supplemented with CT imaging at 12 and 24 months, to assess fusion status. Ninety-five percent of patients were available for follow-up at a minimum of 3 years. The fu-sion rate was 100% for all 3 groups at 1 year after sur-gery, based on CT and plain radiographs; however, in the CH/local bone/BMA cohort the fusion was limited to the facet joint and lamina. Reliability of radiographic assess-ment was adequate with an intraobserver and interobserver correlation coefficient (r) of 0.71 and 0.69, respectively. Improvement in all clinical outcome parameters was ob-served; however, no statistical analysis was performed to determine if any intergroup differences existed. The au-thors concluded that CH when combined with local bone/BMA is an appropriate AICB substitute when placed over the lamina and facet; however, this is inappropriate for in-tertransverse fusion. This was a comprehensive study of adequate design; however, the authors fail to provide ad-equate baseline demographic data to determine if pretreat-ment differences existed in the study groups. The authors avoided any limitations of utilizing an internal control by creating 2 additional study cohorts, those receiving only AICB and those receiving CH/local bone/BMA. Differ-ences in clinical outcome are difficult to determine since no statistical analysis was performed. Due to these limita-tions the study is considered to provide Level II evidence in support of the authors’ conclusions.
The objective of the single-center prospective cohort study conducted by Lee et al. was to determine the efficacy of a HA as a graft extender in instrumented posterolateral fusion (Table 2).41 Thirty-three patients with varying diag-noses underwent either 1- or 2-level circumferential fusion with an HA/AICB mixture or AICB randomly applied to either the right or left intertransverse space. Equal volumes of graft material were used with the control arm receiving twice as much AICB as the investigational side, 6 versus 3 ml, respectively. Radiographs, obtained at 3, 6, and 12 months after surgery, and 3D thin-cut CT scans, obtained at 12 months, were independently reviewed to determine fusion status. Clinical outcome was not objectively re-corded. The fusion status at 12 months was 86.7% in the investigational group and 88.9% in the control group. The volume of fusion was measured with CT and considered significantly greater on the investigational intertransverse space. The authors concluded that HA is a safe and ef-fective graft extender for posterolateral lumbar fusion. A
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Part 16: Bone graft extenders and substitutes
111J Neurosurg: Spine / Volume 21 / July 2014
TABL
E 2:
Cal
cium
pho
spha
te sa
lts: s
umm
ary o
f evid
ence
*
Auth
ors &
Ye
arLe
vel o
f Ev
idenc
eDe
scrip
tion o
f Stu
dyCo
mmen
ts
Dai &
Jian
g,
20
08II
The o
bjective of this sin
gle-center
prospective RCT
was to de
termine the e
fficacy o
f β-TCP
as a
bone
graf
t sub
stitut
e for
AIC
B in
single
-leve
l pos
terola
t instr
umen
ted fu
sions
for d
egen
erati
ve
spina
l sten
osis. 62
pts w
ere r
andomized to o
ne of 2 cohorts
, receiv
ing either β-TCP
(n = 32
) or
AI
CB (n
= 3
0), b
oth su
pplem
ented
w/ lo
cal a
utogr
aft. C
linica
l dat
a wer
e coll
ected
by an
inde
-
pend
ent o
bser
ver a
t 6 w
ks &
3, 6,
12, 2
4, &
36 m
os. V
alida
ted ou
tcome
s mea
sure
s wer
e utili
zed
(m
JOA,
SF-
36, &
VAS
for d
onor
site
pain)
. Fus
ion st
atus w
as as
sess
ed by
2 ind
epen
dent
obse
rver
s eva
luatin
g plai
n rad
iogra
phs a
t 3, 6
, 12,
24, &
36 m
os. T
he 3
6-mo
follo
w-up
rate
was
10
0%. A
ll stu
dy pt
s wer
e con
sider
ed to
have
achie
ved a
solid
arth
rode
sis &
demo
nstra
te
sig
nificant improvem
ent com
pared w
/ their pr
eoperative c
linica
l status
. There was no
difference
in
clinic
al ou
tcome
btwn
the 2
coho
rts. 3
comp
licati
ons (
posto
p hem
atoma
s) we
re as
socia
ted
w/
AIC
B ha
rves
ting,
& do
nor s
ite pa
in wa
s still
reco
rded
in so
me pt
s at th
e 36-
mo fo
llow-
up. T
he
au
thor
s con
clude
d tha
t b-TCP
can b
e used a
s an e
ffective su
bstitu
te for A
ICB wh
en local bone
is ins
ufficien
t.
This
is a r
elativ
ely ho
moge
neou
s, sm
all gr
oup o
f pts
w/ ad
equa
te
inf
orma
tion r
egar
ding b
aseli
ne de
mogr
aphic
s. Th
e foll
ow-u
p
inter
val is
adeq
uate
w/ an
exce
llent
rate
of fo
llow-
up. H
owev
er,
th
e ran
domi
zatio
n pro
cess
was
not d
escr
ibed.
Alth
ough
valid
ated
ou
tcome
mea
sure
s wer
e use
d, th
e aut
hors
faile
d to u
tilize
a
dis
ease-specifi
c instru
ment to me
asure r
esponse to s
urgery. The
me
thod
of fu
sion a
sses
smen
t, par
ticula
rly in
the p
rese
nce o
f an
ins
trume
nted s
pine,
is su
bopti
mal. I
t is no
t clea
r if th
e ass
esso
rs of
clinic
al &
radio
grap
hic da
ta w
ere b
linde
d to t
reatm
ent. D
ue to
thes
e lim
itatio
ns, th
e stu
dy is
down
grad
ed to
Leve
l II ev
idenc
e in
support of β-TCP
/local bone a
s a su
bstitu
te for A
ICB/loc
al bone in
1-
level
instru
mente
d pos
terola
t fus
ions.
Koro
vess
is et
al., 2
005
IITh
is pu
rpos
e of th
is pr
ospe
ctive
RCT
was
to de
termi
ne th
e fus
ion po
tentia
l of C
HA in
mult
ileve
l in-
str
umen
ted po
stero
lat fu
sions
. 60 p
ts we
re ra
ndom
ized i
nto on
e of 3
grou
ps: r
eceiv
ing A
ICB
bilate
rally
, rec
eiving
AIC
B on
the l
eft &
CHA
/loca
l bon
e/BM
A on
the r
ight, &
CHA
/loca
l bon
e/
BMA
bilate
rally
. Vali
dated
outco
mes i
nstru
ments
(ODI
, VAS
, Rola
nd-M
orris
, & S
F-36
) wer
e
obta
ined p
reop
erati
vely
& at
6, 12
, 24,
& 48
mos
after
surg
ery.
Fusio
n ass
essm
ent w
as pe
r-
form
ed w
/ plai
n rad
iogra
phs a
t 3, 6
, 12,
24, &
48 m
os po
stope
rativ
ely, s
upple
mente
d w/ C
T
im
aging
at 12
& 24
mos
. Imag
es w
ere e
valua
ted by
2 ind
epen
dent
radio
logist
s blin
ded t
o the
inter
venti
on. T
he fo
llow-
up ra
te wa
s 95%
at a
minim
um of
3 yr
s. Re
liabil
ity of
radio
grap
hic as
-
sess
ment
of pla
in ra
diogr
aphs
was
perfo
rmed
by re
peati
ng th
e eva
luatio
n afte
r 3 w
ks. T
he
fu
sion r
ate w
as 10
0% fo
r all 3
grou
ps at
1 yr
after
surg
ery,
base
d on C
T &
plain
radio
grap
hs;
ho
weve
r, the
fusio
n obs
erve
d w/ a
pplic
ation
of C
HA/lo
cal b
one/
BMA
was l
imite
d to t
he fa
cet
joi
nt &
lamina
w/o
bridg
ing bo
ne in
the i
ntertr
ansv
erse
spac
e. Th
e intr
a- &
inter
obse
rver
coef-
ficien
t valu
es (r) for fusio
n assessm
ent w
ere 0
.71 & 0.69, respectively. Im
provem
ent in
all clinica
l
outco
me pa
rame
ters w
as ob
serv
ed; h
owev
er, no
stati
stica
l ana
lysis
was p
erfo
rmed
to de
termi
ne
if a
ny in
tergr
oup d
iffere
nces
in cl
inica
l outc
ome o
ccur
red.
The a
utho
rs co
nclud
ed th
at CH
A
wh
en co
mbine
d w/ lo
cal b
one/
BMA
is an
appr
opria
te AI
CB su
bstitu
te wh
en pl
aced
over
the
lam
ina &
face
t but
is ina
ppro
priat
e for
inter
trans
vers
e fus
ion.
This
is a r
elativ
ely sm
all, h
etero
gene
ous p
opula
tion o
f pts
w/ re
spec
t
to pr
eop d
iagno
sis &
no. o
f leve
ls fu
sed.
The p
roce
ss of
rand
om-
iza
tion w
as no
t ade
quate
ly de
scrib
ed. A
lthou
gh th
e aut
hors
state
that
the t
reatm
ent g
roup
s wer
e sim
ilar, a
dequ
ate pr
eop d
emo-
grap
hic da
ta ar
e not
prov
ided,
& th
ey fa
iled t
o dem
onstr
ate
eq
uipois
e btw
n the
trea
tmen
t gro
ups.
The u
se of
an in
terna
l con
-
trol is
subo
ptima
l, sinc
e one
cann
ot ru
le ou
t inter
actio
n btw
n the
2
int
ertra
nsve
rse s
pace
s; ho
weve
r, the
auth
ors c
ontro
lled f
or th
is
lim
itatio
n by c
reati
ng an
isola
ted A
ICB
& CH
A/loc
al bo
ne/B
MA
grou
ps. T
he au
thor
s fail
ed to
perfo
rm ad
equa
te sta
tistic
al an
alysis
of th
e clin
ical re
sults
. Due
to th
ese l
imita
tions
the s
tudy
was
down
-
graded to Le
vel II ev
idence s
upporting the e
fficacy o
f CHA
com-
bin
ed w
/ loca
l bon
e/BM
A as
an A
ICB
subs
titute.
Chan
g et a
l.,
2008
IVTh
e aut
hors
perfo
rmed
a re
trosp
ectiv
e rev
iew of
resu
lts fr
om pt
s und
ergo
ing si
ngle-
segm
ent
po
stero
lat lu
mbar
fusio
n usin
g eith
er lo
cal a
utogr
aft e
xpan
ded w
/ calc
ium su
lfate
or ili
ac cr
est
au
togr
aft. 1
15 pt
s wer
e divi
ded i
nto tr
eatm
ent g
roup
s & ev
aluate
d ove
r 1 yr
. Sim
ilar f
usion
rates
were
obse
rved
, 92.
3% fo
r the
trea
tmen
t gro
up (n
= 6
6) &
92.9
% in
the c
ontro
l (n =
49),
as w
ell
as
clini
cal o
utcom
e, as
deter
mine
d by V
AS sc
ore &
ODI
. The
auth
ors c
onclu
ded t
hat lo
cal a
uto-
gr
aft s
upple
mente
d w/ c
alcium
sulfa
te is
a safe
& ef
fectiv
e alte
rnati
ve to
auto
geno
us ili
ac cr
est
au
togr
aft.
The i
nves
tigato
rs fa
iled t
o des
cribe
how
pts w
ere a
lloca
ted in
to tre
at-
me
nt gr
oups
, whe
ther
the e
valua
tion o
f pts
was b
linde
d, pe
r-
form
ed an
inad
equa
te de
scrip
tion o
f the r
esult
s, ina
dequ
ately
desc
ribed
the s
tatis
tical
analy
sis of
the d
ata,
& ma
de st
ateme
nts
w/
in th
e con
clusio
n tha
t can
not b
e acc
ounte
d for
by th
eir ob
serv
a-
tio
ns. T
his st
udy p
rovid
es Le
vel IV
evide
nce i
n sup
port
of loc
al
au
togr
aft w
/ calc
ium su
lfate
as a
subs
titute
for A
ICB
in sin
gle-
se
gmen
t pos
terola
teral
fusio
ns.
(cont
inued
)
Unauthenticated | Downloaded 02/13/22 06:58 AM UTC
M. G. Kaiser et al.
112 J Neurosurg: Spine / Volume 21 / July 2014
TABL
E 2:
Cal
cium
pho
spha
te sa
lts: s
umm
ary o
f evid
ence
* (co
ntin
ued)
Auth
ors &
Ye
arLe
vel o
f Ev
idenc
eDe
scrip
tion o
f Stu
dyCo
mmen
ts
Lee e
t al.,
2009
VTh
e obje
ctive
of th
is sin
gle-c
enter
pros
pecti
ve co
ntroll
ed co
hort
study
was
to de
termi
ne th
e ef-
ficacy o
f a co
mmercia
lly av
ailable HA
as a graft exte
nder in instrum
ented
poste
rolat fusio
n. 33
pts
w/ v
aryin
g diag
nose
s und
erwe
nt eit
her 1
- or 2
-leve
l circ
umfer
entia
l fusio
n w/ a
n HA/
AICB
mixtu
re or
AIC
B ra
ndom
ly ap
plied
to ei
ther
the r
ight o
r left
poste
rolat
spac
e. Ra
diogr
aphs
, per
-
form
ed at
3, 6,
& 12
mos
after
surg
ery,
& 3D
thin-
cut C
T at
12 m
os, w
ere i
ndep
ende
ntly r
e-
vie
wed t
o dete
rmine
fusio
n sta
tus.
Clini
cal o
utcom
e was
not o
bjecti
vely
reco
rded
. The
fusio
n
statu
s of th
e pos
terola
t spa
ce at
12 m
os w
as 8
6.7%
in th
e inv
estig
ation
al gr
oup &
88.
9% in
the
contr
ol group. Th
e volu
me of fusio
n, me
asured w/ C
T, wa
s consid
ered signific
antly gr
eater
in the
inv
estig
ation
al gr
oup.
The a
utho
rs co
nclud
ed th
at HA
gran
ules a
re a
safe
& ef
fectiv
e gra
ft
ex
tende
r for
poste
rolat
fusio
n.
This
study
is co
nside
red a
case
serie
s sinc
e con
trol &
trea
tmen
t co-
horts
wer
e con
ducte
d w/in
the s
ame p
t, at th
e sam
e lev
el, &
ther
e-
fo
re ca
nnot
be co
nside
red i
ndep
ende
nt va
riable
s. It i
s pos
sible
that
an in
terac
tion o
ccur
red b
twn t
he in
vesti
gatio
nal &
contr
ol sit
es
th
at co
uld ha
ve an
impa
ct on
the o
utcom
e. Th
e outc
omes
of th
e
poste
rolat
fusio
ns m
ay al
so be
alter
ed by
the p
lacem
ent o
f the
interbody gr
aft; therefore, it is diffic
ult to de
termine the true
efficacy o
f HA as a graft exte
nder w/in the p
oster
olat space. T
he
au
thor
s fail
ed to
inclu
de an
objec
tive m
easu
re of
clini
cal o
utcom
e.
Th
e stu
dy po
pulat
ion w
as sm
all &
heter
ogen
eous
w/ r
espe
ct to
pres
entin
g diag
nosis
. This
case
serie
s is t
here
fore
down
grad
ed to
Leve
l V ev
idenc
e in s
uppo
rt of
HA as
a gr
aft e
xtend
er.Ac
hary
a et
al.
, 200
8V
The a
im of this stu
dy was to de
termine the e
fficacy o
f an H
A–bio
active g
lass c
eram
ic comp
osite as
a gra
ft su
bstitu
te fo
r auto
logou
s bon
e in l
umba
r pos
terola
t fus
ions.
24 co
nsec
utive
pts u
nder
go-
ing
poste
rolat
instr
umen
ted lu
mbar
fusio
n wer
e ente
red i
nto th
e stu
dy. T
he le
ft int
ertra
nsve
rse
sp
ace r
eceiv
ed a
stand
ard m
ixtur
e of B
MA/
HA-g
lass c
eram
ic co
mpos
ite &
the r
ight s
ide re
-
ceive
d an e
qual
volum
e of lo
cally
harv
ested
auto
graf
t. The
prim
ary o
utcom
e mea
sure
was
graf
t
cons
olida
tion a
s dem
onstr
ated o
n ante
ropo
sterio
r rad
iogra
phs a
t 12 m
os af
ter su
rger
y, ev
alu-
ate
d by a
n ind
epen
dent
orth
oped
ic su
rgeo
n. At
1 yr
after
surg
ery,
22/24
pts w
ere a
vaila
ble fo
r
evalu
ation. T
he co
ntrol sid
e dem
onstrate
d a fusio
n rate
of 73
%; how
ever, no
definitiv
e fusion
was o
bser
ved o
n the
HA-
glass
/BM
A co
mpos
ite si
de in
any p
t, w/ 7
7% of
pts d
emon
strati
ng
co
mplet
e gra
ft re
sorp
tion.
The s
tudy
was
term
inated
at th
e req
uest
of th
e prin
cipal
inves
tigato
r.
The a
utho
rs co
nclud
ed th
at th
ere w
as no
role
for t
his H
A-gla
ss co
mpos
ite/B
MA
as a
stand
-
alone
graf
t sub
stitut
e in p
oster
olat f
usion
of th
e lum
bar s
pine.
Alth
ough
this
study
attem
pts to
comp
are 2
trea
tmen
t alte
rnati
ves,
a
major
limita
tion i
s the
poten
tial in
terac
tion b
twn t
he co
ntrol
&
int
erve
ntion
al gr
oups
sinc
e both
occu
rred i
n the
same
pt &
ther
e-
fo
re w
ere n
ot ind
epen
dent
of ea
ch ot
her. F
or th
is re
ason
this
study
is co
nside
red a
case
serie
s & no
t a co
mpar
ative
coho
rt stu
dy. T
his
is
a hete
roge
neou
s coh
ort, w
/ res
pect
to pr
eop d
iagno
sis &
no. o
f
levels
fuse
d. A
subo
ptima
l ass
essm
ent o
f fus
ion w
as pe
rform
ed.
Th
e foll
ow-u
p inte
rval
may b
e con
sider
ed br
ief; h
owev
er, 91
% of
enro
lled p
ts we
re av
ailab
le. T
he dr
amati
c diffe
renc
e in f
usion
outco
me is
noted
. Due
to th
ese l
imita
tions
the s
tudy
is do
wngr
ad-
ed
to Le
vel V
evide
nce a
gains
t the u
se of
HA-
glass
/BM
A co
mpos
-
ite as
a fu
sion s
ubsti
tute;
howe
ver, i
t is in
clude
d due
to th
e dra
-
matic
diffe
renc
e in f
usion
rates
.Hs
u et a
l.,
20
05V
The p
urpo
se of
this
pros
pecti
ve co
ntroll
ed co
hort
study
was
to de
termi
ne th
e effe
ctive
ness
of
loc
al ha
rves
ted au
togr
aft &
CHA
as gr
aft e
xtend
ers/s
ubsti
tutes
for A
ICB
w/ in
strum
ented
poste
rolat
fusio
ns. 5
8 pts
were
divid
ed in
to 3 g
roup
s rec
eiving
diffe
rent
graf
t mixt
ure i
n the
righ
t
inter
trans
vers
e spa
ce, A
ICB/
local
bone
(n =
20),
AICB
/CHA
(n =
19),
& CH
A/loc
al bo
ne (n
= 19
).
All p
ts re
ceive
d AIC
B in
the l
eft in
tertra
nsve
rse s
pace
. Fus
ion as
sess
ment
using
radio
grap
hs
wa
s ind
epen
dentl
y per
form
ed by
2 re
viewe
rs at
4, 6,
& 12
mos
after
surg
ery.
If unc
erta
inty e
x-
isted
a CT
was
perfo
rmed
. The
fusio
n rate
s bet
ween
the i
nves
tigati
onal
& co
ntrol
grou
ps at
12
mo
s wer
e 90%
for A
ICB/
local
bone
vs 9
5% co
ntrol,
78.9
% fo
r AIC
B/CH
A vs
84.
2% co
ntrol,
&
57.9% for C
HA/local bone v
s 89.5
% co
ntrol. The on
ly sta
tistically s
ignific
ant diffe
rence in r
e-
po
rted f
usion
rate
was b
twn A
ICB/
local
& CH
A/loc
al. T
he au
thor
s con
clude
d tha
t eith
er lo
cal
bo
ne or
CHA
can s
erve
as a
graf
t exte
nder
w/ A
ICB;
howe
ver, C
HA/lo
cal b
one w
as no
t an a
c-
ce
ptab
le su
bstitu
te fo
r AIC
B w/
instr
umen
ted po
stero
lat fu
sions
.
Ther
e wer
e a re
lative
ly sm
all no
. of p
ts w/
in ea
ch st
udy s
ubgr
oup.
Heter
ogen
eity e
xisted
btwn
stud
y gro
ups w
/ res
pect
to dia
gnos
is
&
surg
ery &
inco
mplet
e dem
ogra
phic
data
are p
rovid
ed. U
se of
the c
ontra
lat in
tertra
nsve
rse s
pace
as a
contr
ol is
subo
ptima
l
since
one c
anno
t rule
out a
n inte
racti
on bt
wn th
e con
trol &
inves
tigati
onal
sides
w/in
the s
ame p
t. The
auth
ors f
ailed
to pe
r-
form
stati
stica
l ana
lysis
btwn
the i
nves
tigati
onal
& co
ntrol
arms
w/
in
each
stud
y sub
grou
p. Du
e to t
hese
limita
tions
the s
tudy
was
down
grad
ed to
Leve
l V ev
idenc
e in s
uppo
rt of
CHA
as a
graf
t
exten
der.
(cont
inued
)
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Part 16: Bone graft extenders and substitutes
113J Neurosurg: Spine / Volume 21 / July 2014
major limitation of the study is the use of the contralat-eral intertransverse space as the control arm in the study subjects. Interaction between treatment and control groups cannot be excluded; therefore, this is considered equivalent to a case series. Additional limitations include the small, heterogeneous population of patients and failure to include an objective assessment of clinical outcome. The study is considered to provide Level V evidence in support of HA acting as a graft extender for AICB.
Chang et al. performed a retrospective comparative study to determine if calcium sulfate mixed with local autograft could serve as an alternative to AICB for sin-gle-segment posterolateral fusions (Table 2).12 One hun-dred fifteen patients were divided between treatment and control groups and were observed for longer than 1 year. Fusion was assessed through static and dynamic radio-graphs as well as reformatted CT images. Outcome was assessed utilizing VAS scores and ODIs. Similar fusion rates (92.3% for the treatment cohort [n = 66] and 92.9% for the control group [n = 49]) and clinical scores were observed between groups. This study benefitted from an accurate assessment of fusion and use of objective out-come measures, but it is limited by the investigators’ failure to describe how patients were allocated to study cohorts, whether the evaluations were blinded, and an in-adequate description of the statistical analysis. Because of these limitations, the study was downgraded to Level IV evidence in support of using a mixture of calcium sul-fate and local autograft as a substitute for AICB.
Acharya et al. conducted a prospective cohort study to determine the efficacy of an HA-bioactive glass ceramic composite as a substitute for autologous bone (Table 2).1 Twenty-four consecutive patients undergoing posterolater-al instrumented lumbar fusion were entered into the study. Each patient served as his or her own control, with the left intertransverse space receiving a standard mixture of BMA and HA-glass ceramic composite and the right side receiving an equal volume of locally harvested autograft. Anteroposterior radiographs obtained 12 months after sur-gery were evaluated by an independent orthopedic surgeon and were used to assess fusion status. The follow-up rate at 1 year after surgery was 91%. A definitive fusion was demonstrated on the control side in 73% of patients; how-ever, there was no clear evidence of a fusion on HA/BMA side for any patient, with 77% of patients demonstrating complete resorption of the HA-bioactive glass/BMA graft. Given the dramatic difference in outcome, the principal in-vestigator terminated the study and the authors concluded that this HA-glass composite/BMA was ineffective as a graft substitute in posterolateral lumbar fusion. Although this study suffers from a relatively small, heterogeneous patient cohort, the outcome assessment was performed in an objective manner with an adequate follow-up rate at the end point of the study. However, the use of an internal control is considered inadequate, as one cannot exclude an interaction between the control and treatment sides. Such an interaction would likely bias in favor of the treatment arm. Despite this inference, this study was considered equivalent to a case series and not a comparative cohort study. Although the observed results demonstrate a sig-nificant difference in fusion potential, the study design and TA
BLE
2: C
alciu
m p
hosp
hate
salts
: sum
mar
y of e
viden
ce* (
cont
inue
d)
Auth
ors &
Ye
arLe
vel o
f Ev
idenc
eDe
scrip
tion o
f Stu
dyCo
mmen
ts
Chen
et al
.,
2005
V
The a
utho
rs pe
rform
ed a
pros
pecti
ve co
ntroll
ed co
hort
study
to de
termi
ne th
e effe
ctive
ness
of
artificia
l calc
ium su
lfate mixed w
/ local auto
graft vs A
ICB for fusion
form
ation in 1- or
2-lev
el
ins
trume
nted p
oster
olat f
usion
s. Bt
wn S
eptem
ber 2
000 &
Sep
tembe
r 200
1, 74
cons
ecut
ive pt
s
were
enro
lled w
/ a m
ean f
ollow
-up o
f 32.
5 mos
. 39 p
ts un
derw
ent a
1-lev
el fu
sion &
35 a
2-lev
el
fu
sion.
Each
pt re
ceive
d AIC
B to
one s
ide &
a mi
xture
of ca
lcium
sulfa
te/lo
cal a
utogr
aft to
the
oth
er po
stero
lat gu
tter. 2
inde
pend
ent b
linde
d orth
oped
ic su
rgeo
ns ev
aluate
d rad
iogra
phs f
or
br
idging
inter
trans
vers
e bon
e at 3
-mo i
nterv
als fo
r the
1st y
ear &
then
on an
annu
al ba
sis. T
he
proto
col fo
r clinica
l evalua
tion w
as no
t well de
fined, but it a
ppears that OD
Is we
re ob
taine
d in
a r
etros
pecti
ve fa
shion
. The
fusio
n rate
for 1
-leve
l pro
cedu
res w
as 87
.2%
on th
e inv
estig
ation
al
sid
e & 8
9.7%
on th
e con
trol s
ide (p
= 1.
0). F
or 2-
level
proc
edur
es th
e fus
ion ra
te wa
s 82.
9% fo
r
the i
nves
tigati
onal
side &
85.7
% fo
r the
contr
ol sid
e (p =
1.0)
. Clin
ical o
utcom
e was
judg
ed as
exce
llent
or go
od in
78.3%
. The
auth
ors c
onclu
ded t
hat c
alcium
sulfa
te/lo
cal b
one i
s as e
ffecti
ve
as
AIC
B in
achie
ving a
solid
fusio
n for
instr
umen
ted po
stero
lat fu
sions
.
This
is a h
etero
gene
ous s
tudy
popu
lation
w/ r
espe
ct to
pres
entin
g di-
ag
nosis
& th
e aut
hors
fail t
o pro
vide a
dequ
ate ba
selin
e dem
o-
gr
aphic
data
. Sinc
e eac
h pt a
cted a
s his/
her o
wn co
ntrol,
it is
impo
ssibl
e to r
ule ou
t a po
ssibl
e inte
racti
on bt
wn th
e inv
esti-
gatio
nal &
contr
ol sid
es. A
pplic
ation
of gr
aft w
as no
t ran
domi
zed;
ther
efore
bias
cann
ot be
exclu
ded w
/ res
pect
to fu
sion b
ed pr
epa-
ratio
n. Th
e meth
od of
fusio
n ass
essm
ent w
as su
bjecti
ve. T
his
stu
dy is
down
grad
ed to
Leve
l V ev
idenc
e in s
uppo
rt of
calci
um
su
lfate
/loca
l auto
graf
t as a
graf
t sub
stitut
e for
AIC
B.
* AICB
= auto
logous iliac b
one graft; β-TC
P = β-tricalcium
phosphate; BMA = bone marrow aspirate
; CHA
= co
rallin
e hydroxyapatite
; HA = hydroxyapatite
; mJO
A = mo
dified Ja
panese Orth
opaedic
As
socia
tion;
ODI =
Osw
estry
Disa
bility
Inde
x; RC
T =
rand
omize
d con
trolle
d tria
l; SF-
36 =
36-
Item
Shor
t For
m He
alth S
urve
y; VA
S =
visua
l ana
log sc
ore.
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M. G. Kaiser et al.
114 J Neurosurg: Spine / Volume 21 / July 2014
limitations necessitate an assignment of Level V evidence that HA-bioactive glass when combined with BMA cannot serve as a substitute for autologous bone.
A number of lower-quality studies and case series, providing Level IV and V evidence, have also been pub-lished investigating the utility of various calcium-based graft extenders21,22,32 or substitutes for AICB.11,13,15,33,45 These materials were generally mixed with either local autograft or BMA (Table 2). Given the nature of the study design, control groups were poorly designed, historical, or absent; therefore, direct comparisons to AICB are dif-ficult and lack appropriate validity. When compared with previous published results, investigators considered the fusion rates acceptable; however, many of these studies are unable to provide data with respect to the actual clini-cal benefit since baseline demographic data are not pro-vided. Due to these limitations, these studies only dem-onstrate the feasibility of utilizing these calcium-based materials as graft extenders or substitutes.
Bone Morphogenetic ProteinsSince the introduction of BMPs by Marshall Urist in
1965,57 the application of these fusion agents, intended to induce bone formation from surrounding tissue, has dra-matically increased. In 2002, the US FDA granted premar-ket approval for the use of InFUSE (rhBMP-2, Medtronic Sofamor Danek) for single-level ALIF procedures from L-4 to S-1 when used in conjunction with the LT-CAGE Lumbar Tapered Fusion Device (Medtronic Sofamor Danek).58 Under a humanitarian device exemption, the FDA subsequently approved osteogenic protein–1 (OP-1; rhBMP-7, Stryker) for revision posterolateral lumbar spine fusion, where harvesting of autograft was not possible or not expected to achieve solid arthrodesis.60 Although the FDA had granted a similar approval for InFUSE/MAS-TERGRAFT (rhBMP-2, Medtronic Sofamor Danek) for revision of symptomatic, posterolateral lumbar pseudar-throsis, at the request of the sponsor, this device was with-drawn in 2010.59 The use of these agents extends well be-yond the FDA-approved applications, with approximately 85% of primary spine procedures utilizing BMP consid-ered off label.46 Although the off-label use of BMP for spine has met with radiographic and clinical success, con-cern has been raised due to reports of rare but significant neurological or structural complications following the use of BMPs, particularly with interbody fusions.42,50 In addi-tion, whether the routine use of BMPs is cost-effective has yet to be demonstrated. This uncertainty requires a careful evaluation of the literature investigating the various appli-cations of the available BMPs.
rhBMP-2: Interbody Fusion. The utilization of rh-BMP-2 as a substitute for AICB with threaded interbody cages for single-level ALIF procedures has been investi-gated in 2 randomized control trials.5,6
The larger of the 2 trials was previously evaluated in the original Lumbar Fusion Guidelines and was desig-nated as a Level I study.48 These higher-level studies were reevaluated for the purposes of this update since different criteria were used to determine levels of evidence and dif-ferent recommendation grades formulated from the evi-
dence. After reviewing the paper by Burkus et al.,6 several limitations were identified including a failure to perform a power calculation to determine sample size, incomplete description of presenting demographic data (specifically no mention of comorbid medical conditions), and failure to perform an appropriate statistical analysis regarding outcomes between study cohorts (Table 3).
Burkus et al. also performed a prospective RCT in 42 patients to determine fusion progression of rhBMP-2 in a threaded titanium cage compared with AICB for single-level ALIF procedures.5 The investigational cohort (n = 22) received rhBMP-2 and the control arm received AICB (n = 20). Fusion status was determined by 2 independent blinded radiologists evaluating both radiographs and CT images at 2 days and 6, 12, and 24 months after surgery. The fusion rate was 100% in the investigational cohort and 95% in the control group. The patients receiving rhBMP-2 demonstrated a greater average increase in bone density as demonstrated by Hounsfield units. The authors concluded that use of rhBMP-2 is associated with a high fusion rate and is a promising method to facilitate fusion in ALIF pro-cedures. Given the dates of recruitment, these patients may have been included in a previous publication presented by the same authors and reviewed in the original Lumbar Fu-sion Guidelines.6 This study focuses solely on the radio-graphic outcome of these patients without any inclusion of clinical data. The number of patients in each cohort is relatively small and varies with respect to presenting diag-nosis. Although this is an RCT, inadequate baseline demo-graphic data are included and the authors failed to deter-mine appropriate sample size prior to initiating the study. This study therefore provides Level II evidence in support of rhBMP-2 as a substitute for AICB for single-level ALIF procedures with threaded interbody cages (Table 3).
Haid et al. conducted a multicenter prospective ran-domized controled study to investigate the clinical and radiographic outcomes of patients undergoing single-level PLIF utilizing either iliac crest bone graft (ICBG) or rhBMP-2/ACS.29 Sixty-seven patients with single-level degenerative disc disease were randomized. Clinical out-come was assessed utilizing validated outcome measures at 6 weeks and at 3, 6, 12, and 24 months after surgery. Radiographs and CT scans were obtained at 6, 12, and 24 months after surgery. The follow-up rate at all time points was at least 89.6%. At 24 months after surgery the investigational group demonstrated a 92.3% fusion rate while only 77.8% were considered fused in the control group; this difference did not prove to be statistically sig-nificant. Significant clinical improvement was observed in both cohorts, with the investigational group demon-strated superior improvement in the back pain score at 24 months. Although considered to be clinically irrelevant, a significantly greater percentage of patients in the in-vestigational group (71% vs 12%), had heterotopic bone formation posterior to the interbody cage. Sixty percent of controls continued to complain of donor site pain at 24 months. Due to concern regarding the significant increase in heterotopic bone formation, the authors terminated the study but concluded that these results were encouraging. Despite the lack of an observed consequence of this ex-cessive bone formation, the authors elected not to con-
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Part 16: Bone graft extenders and substitutes
115J Neurosurg: Spine / Volume 21 / July 2014
TABL
E 3:
rhBM
P-2 i
n in
terb
ody f
usio
n: su
mm
ary o
f evid
ence
*
Auth
ors &
Ye
arLe
vel o
f Ev
idenc
eDe
scrip
tion o
f Stu
dyCo
mmen
ts
Haid
et al.
,
2004
IITh
is mu
lticen
ter pr
ospe
ctive
rand
omize
d non
blind
ed st
udy w
as in
tende
d to e
valua
te the
clini
cal &
radio
-
graphic
outco
mes a
t 24 m
os of pts u
ndergoing
1-lev
el PL
IF us
ing eithe
r ICB
G or rh
BMP-2/A
CS. 67
pts
w/ 1
-leve
l deg
ener
ative
disc
dise
ase w
ere r
ando
mize
d to s
tudy c
ohor
ts. C
linica
l outc
ome w
as as
-
sess
ed us
ing va
lidate
d outc
ome m
easu
res a
t 6 w
ks &
3, 6,
12, &
24 m
os af
ter su
rger
y. Ra
diogr
aphs
&
CT
scan
s wer
e obta
ined a
t 6, 1
2, &
24 m
os af
ter su
rger
y. Th
e foll
ow-u
p rate
at al
l time
point
s was
at
lea
st 89
.6%. T
he fu
sion r
ates a
t 24 m
os w
ere 9
2.3%
& 77
.8% in
the i
nves
tigati
onal
& co
ntrol
grou
ps,
respectively
; the d
ifference w
as no
t statistica
lly signific
ant. A
signific
antly greater pe
rcenta
ge of pts in
the
inve
stiga
tiona
l gro
up (7
1% vs
12%)
had h
etero
topic
bone
form
ation
poste
rior t
o the
inter
body
cage
.
All clinica
l param
eters improved signific
antly in bo
th stu
dy co
horts co
mpared w/ preop statu
s. The
improvem
ent in
back pa
in score w
as signific
antly greater in the treatm
ent cohort vs c
ontrols at 24 mos.
60
% of
contr
ols co
ntinu
ed to
comp
lain o
f don
or si
te pa
in at
24 m
os. T
he au
thors
conc
luded
that
the
results were e
ncouragin
g regardin
g the us
e of rhB
MP-2 through the po
sterior in
terbody ap
proach;
howe
ver, furthe
r stud
ies incorporating more refined s
urgic
al tec
hniqu
e are required.
This
study
is lim
ited b
y the
nonb
linde
d ass
essm
ent o
f clin
ical
ou
tcome
& re
lative
ly sm
all pt
coho
rts. T
he pr
oces
s of r
an-
do
miza
tion i
s not
adeq
uatel
y des
cribe
d. Th
e stu
dy w
as
ter
mina
ted du
e to c
once
rn re
gard
ing he
teroto
pic bo
ne fo
rma-
tion p
oster
ior to
the i
nterb
ody c
ages
. Alth
ough
this
prov
ed to
be clinically insig
nificant, the s
tudy was no
t restarte
d sinc
e
the u
se of stand-alo
ne PLIF
cages h
ad fallen o
ut of fav
or.
Th
is stu
dy di
d pro
vide L
evel
II evid
ence
in su
ppor
t of
rhBM
P-2 a
s a su
bstitu
te for A
ICB in sin
gle-level P
LIF
w/
thre
aded
cage
s.
Burk
us et
al.,
20
03II
The a
utho
rs co
nduc
ted a
pros
pecti
ve ra
ndom
ized c
ontro
lled t
rial to
deter
mine
fusio
n pote
ntial
of
rhBM
P-2 in a
threaded titanium
cage co
mpared w/ A
ICB for 1-level A
LIF pr
ocedures. B
twn A
ugust
19
98 &
Mar
ch 19
99, 4
5 pts
were
rand
omize
d, w/
42 (9
3%) a
vaila
ble fo
r foll
ow-u
p at 2
4 mos
after
surg
ery.
Ther
e wer
e 22 p
ts in
the i
nves
tigati
onal
coho
rt &
20 in
the c
ontro
l arm
. 2 in
depe
nden
t blin
ded
ra
diolog
ists e
valua
ted bo
th ra
diogr
aphs
& C
T im
ages
at 2
days
& 6,
12, &
24 m
os af
ter su
rger
y.
Ba
sed o
n rad
iogra
ph &
CT
crite
ria, th
e fus
ion ra
te wa
s 100
% in
the i
nves
tigati
onal
coho
rt &
95%
in
the c
ontro
l group. T
he pts receiv
ing rh
BMP-2 d
emonstrate
d a gr
eater
average increase in b
one
density as
demo
nstra
ted by
Hounsfield units; how
ever, the r
ate of follow-up w/ respect to these d
ata is
not consis
tent w
/ the o
verall follow
-up r
ate. T
he au
thors c
onclu
ded that use of rh
BMP-2 is a
ssociated
w/
a hig
h fus
ion ra
te &
is a p
romi
sing m
ethod
to fa
cilita
te fu
sion i
n ALIF
proc
edur
es.
This
study
is lim
ited b
y the
relat
ively
small
pt po
pulat
ion th
at
va
ries w
/ res
pect
to pr
esen
ting d
iagno
sis. T
he au
thor
s fail
to
pr
ovide
adeq
uate
base
line d
emog
raph
ic da
ta. T
he de
scrip
-
tion o
f sta
tistic
al an
alysis
is lim
ited &
no po
wer c
alcula
tions
were
perfo
rmed
to de
termi
ne sa
mple
size.
Due t
o the
se
lim
itatio
ns th
is stu
dy w
as do
wngr
aded
to Le
vel II
evide
nce
that rhBM
P-2 c
an se
rve a
s a su
bstitu
te for A
ICB for 1-level
sta
nd-a
lone A
LIF pr
oced
ure w
/ thre
aded
cage
s.
Burk
us et
al.,
20
02II
The o
bjective of this mu
lticenter
ed pr
ospective ra
ndom
ized trial w
as to co
mpare the efficacy o
f rhB
MP-2
vs
AIC
B fo
r 1-le
vel A
LIF pr
oced
ures
using
tape
red c
ylind
rical
cage
s. 27
9 pts
w/ sy
mptom
atic 1
-leve
l
degenerative d
isease w
ere e
nrolled, randomized in a
1:1 fashio
n to e
ither re
ceive
rhBM
P-2 (n =
143)
or
AIC
B (n
= 13
6). R
adiog
raph
ic ou
tcome
was
inde
pend
ently
asse
ssed
using
stati
c & dy
nami
c rad
io-
gr
aphs
& C
T sc
ans a
t 6, 1
2, &
24 m
os. C
linica
l ass
essm
ent w
as co
nduc
ted at
6 wk
s & 3,
6, 12
, & 24
mos &
inclu
ded w
ork s
tatus
, neu
rolog
ical o
utcom
e, pa
in qu
estio
nnair
es, &
ODI
s. At
24 m
os, th
e
follo
w-up
rate
for b
oth gr
oups
was
>90
%. C
linica
l outc
ome w
as co
mpar
able
btwn
grou
ps. T
he
rhBM
P-2 g
roup de
monstra
ted a fusio
n rate
of 94.5
% at 24
mos while the fusio
n rate
was for 8
8.7%
of
the c
ontro
l gro
up. D
onor
site
pain
was r
epor
ted in
32%
of co
ntrols
at 24
mos
. The
rate
of se
cond
-
ary p
rocedures w
as similar btwn
groups. B
ased on
these r
esults the au
thors c
onclu
ded that rhB
MP-2
wh
en us
ed w
/ a ta
pere
d cag
e is a
n effe
ctive
tech
nique
for A
LIF pr
oced
ures
& av
oids t
he ad
vers
e
effec
ts of
harv
estin
g AIC
B.
This is a w
ell-design
ed clinical trial & be
nefits
from
a large sa
mple
siz
e, va
lidate
d outc
omes
instr
umen
ts, st
anda
rdize
d sur
gical
techn
ique,
comp
rehe
nsive
outco
me an
alysis
, & ex
celle
nt
fol
low-u
p rate
. The
re ar
e num
erou
s lim
itatio
ns in
cludin
g a
fai
lure t
o per
form
powe
r calc
ulatio
n to d
eterm
ine sa
mple
size,
incom
plete
desc
riptio
n of p
rese
nting
demo
grap
hics (
no
me
ntion
of co
morb
id me
dical
factor
s), fa
ilure
to de
scrib
e inc
lu-
sio
n/exc
lusion
crite
ria, &
failu
re to
inde
pend
ently
colle
ct cli
nical
data.
The
autho
rs do
not c
omple
tely d
escri
be th
e dist
ributi
on of
comp
licati
ons b
twn t
reatm
ent &
contr
ol gr
oups
. No s
tatist
ics
we
re pe
rform
ed to
comp
are o
utcom
e btw
n tre
atmen
t & co
ntrol
grou
ps. D
ue to
the n
umer
ous m
inor li
mitat
ions t
he st
udy w
as
down
graded to Le
vel II ev
idence in s
upport of rhBM
P-2 a
s a
su
bstitu
te for
AIC
B w/
1-lev
el AL
IF pr
oced
ures
.
(cont
inued
)
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M. G. Kaiser et al.
116 J Neurosurg: Spine / Volume 21 / July 2014
TABL
E 3:
rhBM
P-2 i
n in
terb
ody f
usio
n: su
mm
ary o
f evid
ence
* (co
ntin
ued)
Auth
ors &
Ye
arLe
vel o
f Ev
idenc
eDe
scrip
tion o
f Stu
dyCo
mmen
ts
Slos
ar et
al.,
20
07III
The o
bjective of this prospective co
hort stu
dy was to de
termine if rhBM
P-2 c
an sa
fely accelerate
al-
log
raft
inter
body
fusio
ns &
redu
ce th
e no.
of no
nunio
ns w
hen c
ompa
red w
/ allo
graf
t alon
e. 75
pts w
/
varying
diagnoses &
undergoin
g 1–3 level fu
sions were e
nrolled; 30 r
eceiv
ed an
FRA
w/ allograft
crouton
s (contr
ol) & 45 r
eceiv
ed an
FRA
supplem
ented
w/ rhB
MP-2 (
investigational); both
groups
re
ceive
d pos
terior
pedic
le sta
biliza
tion w
/o fu
sion.
Fusio
n ass
essm
ent, p
erfo
rmed
at 6,
12, &
24 m
os,
wa
s blin
ded &
perfo
rmed
using
radio
grap
hs &
CT
imag
es. O
bjecti
ve ou
tcome
instr
umen
ts we
re
us
ed to
deter
mine
clini
cal o
utcom
e; ho
weve
r, ass
essm
ent w
as no
t blin
ded.
At 24
mos
after
surg
ery,
the c
ontro
l gro
up fo
llow-
up ra
te wa
s 97%
& th
e inv
estig
ation
al gr
oup r
ate w
as 9
6%. S
tatis
ticall
y sig-
nificant inc
rease in fusion
rate wa
s observed a
t all time p
oints for the investigational group (9
4%,
10
0%, &
100%
) com
pare
d w/ c
ontro
ls (6
6%, 8
4%, &
89%
). Th
e inv
estig
ation
al gr
oup d
emon
strate
d
signifi
cantly b
etter
outco
mes a
t 6 mos, but both groups de
monstra
ted signific
ant im
provem
ent at 12
&
24 m
os co
mpar
ed w
/ bas
eline
. The
auth
ors c
onclu
ded t
hat a
llogr
aft in
terbo
dy fu
sion s
upple
mente
d
w/ rh
BMP-2 s
ignific
antly im
proved the fusion
rate comp
ared w/ allograft alon
e & the m
ore r
apid fusio
n
observed w/ rhB
MP-2 led to more r
apid clinic
al improvem
ent.
The s
tudy
popu
lation
inclu
des p
ts w/
vary
ing di
agno
ses &
the
au
thor
s fail
to de
scrib
e the
distr
ibutio
n of th
ese d
iagno
ses
bt
wn th
e 2 tr
eatm
ent g
roup
s. Th
e pote
ntial
impa
ct of
differ
-
ence
s in t
he ba
selin
e dem
ogra
phic
data
& no
. of le
vels
oper
-
ated b
twn t
he co
horts
cann
ot be
deter
mine
d sinc
e the
auth
ors f
ailed
to pe
rform
stati
stica
l ana
lysis
of th
ese d
ata.
Alth
ough
radio
grap
hic da
ta w
ere i
ndep
ende
ntly r
eview
ed, it
is no
t clea
r if th
e clin
ical a
sses
smen
t was
blind
ed. D
ue to
thes
e lim
itatio
ns th
is stu
dy w
as do
wngr
aded
to Le
vel II
I
w/ re
spect to
rhBM
P-2 a
s a su
pplem
ent to
anter
ior inter
body
fu
sion u
sing f
emor
al rin
g allo
graf
t & pe
dicle
scre
w
sta
biliza
tion.
Mum
mane
ni
et
al.,
20
04
IVTh
is retro
spective c
ohort study was inten
ded to c
ompare the e
fficacy o
f rhB
MP-2 w
/ AICB wh
en placed
in
an in
terbo
dy sp
acer
durin
g a T
LIF pr
oced
ure.
44 pt
s und
erwe
nt th
e TLIF
proc
edur
e btw
n Sep
tem-
be
r 200
2 & D
ecem
ber 2
003.
Follo
w-up
data
wer
e ava
ilable
for 4
0 pts
(90%
). 19
pts r
eceiv
ed A
ICB
in
the inte
rbody s
pace, &
21 pts receiv
ed rh
BMP-2 s
upple
mente
d w/ either AICB (n = 12
) or lo
cal auto
-
graf
t (n =
9). R
adiog
raph
ic ev
aluati
on w
as pe
rform
ed w
/ sta
tic &
dyna
mic r
adiog
raph
s at 6
-wk &
3-m
o
intervals. Clinica
l outc
ome w
as as
sessed at 3-m
o inte
rvals
using
the P
rolo scale
& VAS
for d
onor site
morb
idity.
The
mea
n foll
ow-u
p was
9 mo
s. Th
e fus
ion ra
te in
the A
ICB
grou
p was
95%
. A 10
0%
fusio
n rate
was ob
served in pts receiv
ing rh
BMP-2 w
/ at le
ast 6 mos of follow-up; how
ever, on
ly 76%
of
pts fr
om th
is co
hort
were
avail
able.
At 6
mos
after
surg
ery,
58%
of pt
s con
tinue
d to c
ompla
in of
donor site pa
in. The au
thors c
onclu
ded that th
e use of rh
BMP-2 &
local auto
graft is
an ex
cellent op-
tio
n whe
n per
form
ing a
TLIF
proc
edur
e & av
oids A
ICB
dono
r site
mor
bidity
.
This
is a h
etero
gene
ous,
small
coho
rt of
pts th
at va
ried w
/ res
pect
to
diagn
osis
& su
rger
y. It i
s not
clear
how
many
pts u
nder
went
a sup
pleme
ntal p
oster
olat fu
sion.
The n
o. of
pts is
too s
mall t
o
perfo
rm an
y mea
ningfu
l stat
istica
l ana
lysis
to de
termi
ne di
ffer-
en
ces w
/in th
e tre
atmen
t gro
ups.
The r
adiog
raph
ic as
sess
ment
of fus
ion was no
t clea
rly de
fined. C
linica
l outc
ome w
/ respect
to treatm
ent effic
acy w
as no
t conducte
d w/ validated
outco
mes
me
asur
es. T
he fo
llow-
up in
terva
l was
relat
ively
shor
t w/ a
signifi
cant no. of rhB
MP-2 pts n
ot available. The ev
aluation of
bo
th cli
nical
outco
me &
radio
grap
hs w
as no
t blin
ded.
Due t
o
these
limita
tions
the s
tudy i
s dow
ngra
ded t
o Lev
el IV
evide
nce,
supporting the role of rhBM
P-2 a
s a su
pplem
ent to
interbody
fus
ions w
hen p
erfor
ming
a TL
IF.Ge
ibel et al.,
2009
VThis case se
ries d
escribes the clinical & radio
graphic
outco
me of 48
pts u
ndergoing
1- & 2-lev
el PL
IF
& poste
rolat instrum
ented
fusio
ns w/ rhB
MP-2. 37 (77.1%
) underwe
nt a 1
-level procedure & 11
(22.9
%)
un
derw
ent a
2-lev
el pr
oced
ure.
ODIs
were
obtai
ned a
fter s
urge
ry &
CT
imag
es w
ere o
btaine
d to a
sses
s
fusion
. The
aver
age f
ollow
-up w
as 17
mos
. 2 in
depe
nden
t rad
iolog
ists e
valua
ted th
e CT
imag
es &
de-
termined a
fusio
n rate
of 10
0%. P
t satisfa
ction, recorded a
s a willingness to repeat surgery, wa
s
observed in 89
%. The au
thors conclud
ed that rhBM
P-2 c
an se
rve a
s a su
bstitu
te for AICB & effec
tively
& safely a
ccom
plish fusio
n through the P
LIF ap
proach.
This
is a h
etero
gene
ous p
opula
tion o
f pts
w/ re
spec
t to di
agno
-
sis &
surg
ical p
roce
dure
. No p
reop
clini
cal d
ata w
ere
re
cord
ed; th
erefo
re, th
e tre
atmen
t effe
ct of
surg
ery c
anno
t be
de
termi
ned.
Due t
o the
se lim
itatio
ns th
e cas
e ser
ies w
as
down
graded to Le
vel V ev
idence r
egardin
g the efficacy &
safety o
f rhB
MP-2 a
s a su
bstitu
te for A
ICB w/ a PL
IF. (cont
inued
)
Unauthenticated | Downloaded 02/13/22 06:58 AM UTC
Part 16: Bone graft extenders and substitutes
117J Neurosurg: Spine / Volume 21 / July 2014
TABL
E 3:
rhBM
P-2 i
n in
terb
ody f
usio
n: su
mm
ary o
f evid
ence
* (co
ntin
ued)
Auth
ors &
Ye
arLe
vel o
f Ev
idenc
eDe
scrip
tion o
f Stu
dyCo
mmen
ts
Burk
us et
al.,
20
09V
This
repo
rt re
pres
ents
an up
date
of th
e clin
ical &
radio
grap
hic ou
tcome
s of p
ts fro
m 2 s
epar
ate st
udies
undergoin
g stand-alon
e 1-level A
LIF w/ tapered ca
ges &
rhBM
P-2. No
comp
ariso
n w/ th
e contro
l
arm
(pts
rece
iving
auto
logou
s ilia
c cre
st) w
as pe
rform
ed. A
t 6 yr
s afte
r the
inde
x pro
cedu
re, 1
46 pt
s
prov
ided c
linica
l follo
w-up
, & ra
diogr
aphic
evalu
ation
was
perfo
rmed
on 13
0 pts.
A so
lid ar
thro
desis
was identified in 9
8% of pts. Th
ere w
as no
signific
ant diffe
rence in a
ny of the c
linica
l outc
ome m
ea-
sures a
t 6 yrs c
ompared w
/ the v
alues ob
served at 2 yrs a
fter surgery. Sign
ificant im
provem
ent com
-
pare
d w/ p
reop
scor
es w
as m
ainta
ined a
t 6 yr
s afte
r sur
gery.
25 re
vision
surg
eries
wer
e per
form
ed
ov
er th
e 6-y
r foll
ow-u
p per
iod &
7 bt
wn th
e 2- &
6-y
r tim
e poin
ts. T
he au
thor
s con
clude
d tha
t this
techniqu
e was an
effec
tive m
ethod of ob
taining an
ALIF
& main
taining long-te
rm, sign
ificant clinica
l
impr
ovem
ents.
The e
fficacy o
f rhB
MP-2 a
s a su
bstitu
te for a
utolog
ous b
one w
/
tape
red c
ages
in 1-
level
ALIF
was
prev
iously
esta
blish
ed w
/
the p
rior s
tudie
s. Th
e res
ults r
epor
ted in
this
case
serie
s are
limited b
y the signific
ant no. of pts
lost to follow-up, 48%
drop
out r
ate fo
r clin
ical d
ata,
& 55
% fo
r rad
iogra
phic
evalu
-
ation
& th
erefo
re w
as do
wngr
aded
to Le
vel V
evide
nce.
This
case se
ries d
oes n
ot retra
ct or co
ntribu
te sig
nificantly to the
pr
ior st
udies
.
Rihn
et al
.,
2009
49V
The o
bjecti
ve of
this
retro
spec
tive r
eview
of a
case
serie
s was
to de
termi
ne th
e clin
ical &
radio
grap
hic
outco
mes o
f pts undergoin
g 1-level TLIF
w/ rhB
MP-2. 48 of 53 p
ts w/ va
rying
diagnoses o
f lumb
ar
degenerative d
isease w
ere identified o
ver a 2-yr interval. S
tatic & dy
namic radiog
raphs w
ere r
eview
ed
by
an in
depe
nden
t blin
ded s
pine s
urge
on at
an av
erag
e foll
ow-u
p of 1
9.4 m
os. O
dom’
s crit
eria,
pt
sa
tisfac
tion,
& NR
S of
leg &
back
pain
were
obta
ined t
hrou
gh te
lepho
ne in
tervie
w at
an av
erag
e
follo
w-up
of 27
.4 mo
s. Th
e fus
ion ra
te wa
s 95.
8%. 7
1% ac
hieve
d exc
ellen
t or g
ood o
utcom
e, w/
84%
of pts
satisfied w
/ their ou
tcome
. Persis
tent back &
leg p
ain was re
porte
d in 6
0.4% & 41
.7%, respec-
tively
. An o
vera
ll com
plica
tion r
ate of
21.7%
was
repo
rted,
w/ ap
prox
imate
ly 25
% at
tribu
ted to
the u
se
of rhBM
P-2. Th
e authors co
nclud
ed that adequate clinic
al & radio
graphic
outco
mes c
an be
obtaine
d.
This
is a r
etros
pecti
ve re
view
of a c
ase s
eries
of pt
s und
ergo
-
ing a 1-lev
el TL
IF. The study b
enefits fro
m an independent
as
sess
ment
of fu
sion u
sing a
ppro
priat
e rad
iogra
phic
meth
ods.
Valid
ated o
utcom
e mea
sure
s wer
e inc
orpo
rated
to
de
termi
ne re
spon
se to
trea
tmen
t. The
heter
ogen
eous
pt
population
is co
nside
red a
signific
ant limitation, & therefo
re
th
e stu
dy is
down
grad
ed to
Leve
l V ev
idenc
e in s
uppo
rt of
rhBM
P-2 u
sed a
s an a
djunct to
inter
body fusio
n.
Villa
vicen
cio
et
al., 2
005
VTh
is re
trosp
ectiv
e cas
e ser
ies de
scrib
es th
e clin
ical &
radio
grap
hic ou
tcome
s of 7
4 pts
unde
rgoin
g TLIF
w/ allog
raft supplem
ented
w/ rhB
MP-2/AC
S for a va
riety of degenerative d
isorders through a variety
of surgica
l approaches. Pts w
ere d
ivided into
subgroups b
ased on
the n
o. of lev
els fused &
whether
an
open
or m
inima
lly in
vasiv
e app
roac
h was
used
. A si
ngle
indep
ende
nt ra
diolog
ist ev
aluate
d rad
io-
gr
aphs
at 3,
6, 12
, & 24
mos
& C
T im
ages
at 12
& 24
mos
after
surg
ery.
Inde
pend
ent c
linica
l ass
ess-
ment
was p
erfo
rmed
at 12
mos
after
surg
ery u
tilizin
g Mac
Nab c
riter
ia. 9
6% of
pts w
ere a
vaila
ble at
12
mo
s after surgery. There were n
o adverse ev
ents directly re
lated to the u
se of rh
BMP-2. Th
e fusion
rate
for t
he en
tire c
ohor
t was
100%
by 10
mos
after
surg
ery.
Impr
oved
clini
cal o
utcom
e was
obse
rved
in all
grou
ps; h
owev
er, th
ose u
nder
going
mini
mally
inva
sive p
roce
dure
s ten
ded t
o hav
e a be
tter o
ut-
come
. The au
thors c
onclu
ded that rhB
MP-2 is a
safe & effec
tive b
one g
raft exten
der w
hen u
sed in
co
njunc
tion w
/ allo
graf
t for t
he T
LIF pr
oced
ure.
This stu
dy su
ffers from
signific
ant hete
rogeneity w/ respect
to dia
gnos
is &
surg
ical p
roce
dure
. The
no. o
f pts
in ea
ch
su
bgro
up w
as re
lative
ly sm
all, &
inco
mplet
e des
cript
ion of
demo
grap
hic ch
arac
terist
ics is
prov
ided.
Nonv
alida
ted ou
t-
come
mea
sure
s wer
e use
d to a
sses
s clin
ical o
utcom
e. Th
e
study pr
ovide
s only
Level V ev
idence in s
upport of rhBM
P-2
as
a gr
aft e
xtend
er fo
r allo
graf
t for T
LIF pr
oced
ures
.
Lanm
an &
Hopk
ins,
20
04
VTh
is ca
se se
ries d
escr
ibes t
he cl
inica
l & ra
diogr
aphic
resu
lts of
42 pt
s und
ergo
ing th
e TLIF
proc
edur
e
using
rhBM
P-2 &
a bio
resorbable interbody gr
aft. C
linica
l & ra
diographic
follow-up was co
nducted
at
3,
6, &
12 m
os af
ter su
rger
y usin
g the
ODI
, plai
n rad
iogra
phs,
& CT
imag
es. T
he ra
diogr
aphic
follo
w-
up ra
te at 6 m
os was 98%
& at 12
mos was 26
%. P
reop clinical data w
ere o
btain
ed in on
ly 59% of pts
w/
a fo
llow-
up ra
te of
92%
at 6
mos &
36%
at 12
mos
. The
fusio
n rate
was
98%
at 6
mos &
100%
at
12 mos. C
linica
l improvem
ent w
as ob
served at ea
ch study e
nd po
int, although signific
ance was no
t
deter
mine
d. Th
ere w
ere n
o dev
ice-re
lated
comp
licati
ons.
The a
utho
rs co
nclud
e tha
t thes
e res
ults
ind
icate that the c
ombin
ation of rh
BMP-2 w
/ a re
sorbable spacer may be
an ap
propriate alternative for
int
erbo
dy fu
sion &
dese
rves
furth
er in
vesti
gatio
n.
This
is a r
elativ
ely po
orly
cond
ucted
case
serie
s w/ li
ttle in
for-
ma
tion r
egardin
g the efficacy o
f rhB
MP-2 u
sed w
/ a bio-
reso
rbab
le sp
acer.
The
stud
y pop
ulatio
n is s
mall &
varie
s w/
re
spec
t to di
agno
sis, n
o. of
levels
fuse
d, &
op ap
proa
ch. A
n
exce
ssive
no. o
f pts
were
lost
durin
g the
follo
w-up
perio
d to
ma
ke an
y judgm
ents regarding
clinical effic
acy. It is n
ot cle
ar
if t
he ra
diogr
aphic
or cl
inica
l follo
w-up
was
blind
ed. T
he
au
thor
s fail
ed to
perfo
rm an
y sta
tistic
al an
alysis
. This
stud
y
prov
ides o
nly Le
vel V
evide
nce.
* AC
S = absorbable collagen sponge; A
ICB = autolog
ous iliac c
rest bone; A
LIF = ante
rior lum
bar inte
rbody fusion
; FRA
= femo
ral ring
allograft; ICBG
= iliac crest bone graft; NR
S = nume
ric ra
ting
scale
; ODI = Os
westr
y Disa
bility Index; PL
IF = poste
rior lu
mbar inter
body fusio
n; pt = p
atient; r
hBMP-2 =
recomb
inant huma
n morphogenetic p
rotein–2; TL
IF = tra
nsforaminal lu
mbar inter
body fusio
n.
Unauthenticated | Downloaded 02/13/22 06:58 AM UTC
M. G. Kaiser et al.
118 J Neurosurg: Spine / Volume 21 / July 2014
tinue since the use of threaded titanium cages through the PLIF approach had fallen out of favor. The relatively small number of patients (< 50) in each cohort and the lack of a blinded clinical assessment limit conclusions formulated from this study. The study provides Level II evidence in support of using rhBMP-2 with threaded cages through the PLIF approach (Table 3).
Additional studies of lesser quality have explored the potential of rhBMP-2 as a graft extender for lumbar inter-body fusion. Slosar et al. performed a prospective cohort study to determine the impact of rhBMP-2 on fusion rate and clinical outcome following ALIF with femoral ring allograft (FRA).54 Seventy-five patients with varying di-agnoses and undergoing up to a 3-level fusion were en-rolled; 30 control patients (n = 30) received an FRA with allograft croutons and an investigational group (n = 45) received an FRA supplemented with rhBMP-2/ACS. A sta-tistically significant increase in fusion rate was observed at all time points for the investigational group compared with controls. Both groups demonstrated significant clini-cal improvement at 12 and 24 months over baseline, but no significant difference was observed between treatment groups. A heterogeneous patient population with respect to presenting diagnosis and number of levels fused, an inadequate statistical analysis of potentially confounding baseline demographics, and failure to perform an indepen-dent, blinded clinical assessment requires that the study be downgraded to Level III in support of rhBMP-2 as an ad-junct to FRA interbody fusion (Table 3).
Several retrospective cohort studies and case series have investigated the use of rhBMP-2 as a graft extender when performing TLIF with an interbody graft. Rihn et al. performed a retrospective review of 48 patients receiving rhBMP-2 during TLIF procedures and observed a fusion rate of 95.8% at the 2-year follow-up with 71% reporting excellent or good outcomes.49 The complication rate was 21.7% with one-quarter of these complications attributed to the use of rhBMP-2. Villavicencio et al. reviewed the data from 74 patients undergoing either open or minimally invasive TLIF for varying diagnoses using rhBMP-2 and allograft.67 The fusion rate for the entire cohort was 100%; however, a trend toward improved clinical outcome was observed for patients undergoing less invasive procedures. Mummaneni et al. conducted a retrospective cohort study intended to compare the efficacy of rhBMP-2 with AICB for TLIF.44 Forty-four patients underwent a TLIF, with 40 patients (90%) available for a mean follow-up of 9 months. The control arm (n = 19) consisted of patients receiving AICB in an interbody spacer, while the investigational group (n = 21) received rhBMP-2 supplemented with either AICB (n = 12) or local autograft (n = 9). With at least 6 months of follow-up, the fusion rate in the AICB group was 95% and 100% in patients receiving rhBMP-2; however, only 76% of patients receiving rhBMP-2 were available for follow-up. At 6 months after surgery, 58% of patients con-tinued to complain of donor site pain. The authors conclud-ed that rhBMP-2 and local autograft is an excellent graft option and avoids donor site morbidity when performing a TLIF procedure. The relatively small, heterogeneous popu-lation of patients with respect to diagnosis and surgery per-formed limits these studies. Nonvalidated clinical outcome
measures were used, and the method of fusion assessment is questionable given the presence of pedicle screw instru-mentation. In the Mummaneni et al. study, neither the ra-diographic evaluation nor assessment of clinical outcome was performed in an independent, blinded fashion. Due to the baseline study designs and various limitations, these studies provide at best Level IV or V evidence in support of rhBMP-2 as a supplement for interbody fusion through the TLIF approach (Table 3). Additional case series have been published exploring the potential of rhBMP-2 as a graft extender or substitute.7,24,40 Burkus et al. published a long-term clinical and radiographic companion study to their previous published report of patient undergoing single level ALIF procedures with stand-alone tapered cages and rhBMP-2/ACS.7 No significant difference in outcome at 6 years was observed when compared with the previously published data obtained at 2 years after surgery. Geibel et al. reported a 100% fusion rate with an 89% patient satis-faction rate in 48 patients undergoing 1- and 2-level instru-mented PLIF with rhBMP-2 and posterolateral fusion.24 Lanman and Hopkins published the only case series inves-tigating the use of rhBMP-2 in conjunction with a biore-sorbable cage.40 This study was limited by 64% of patients lost to follow-up at 12 months after surgery, compromis-ing any attempt at a meaningful interpretation of the data. Since these studies are all case series with limitations, at best they provide only Level V evidence.
rhBMP-2: Posterolateral Fusion. In 2006, Dimar et al. reported the 24-month radiographic and clinical re-sults of patients enrolled in an FDA investigational device exemption (IDE) study comparing rhBMP-2 combined with a compression-resistant matrix (CRM; bovine type I collagen carrier containing 15% HA and 85% b-TCP) with AICB in instrumented posterolateral fusions (Table 4).19 Ninety-eight of 150 randomized patients were avail-able for review. Clinical outcome, assessed using vali-dated outcomes instruments (SF-36, ODI, and back/leg pain scores), was performed at 6 weeks and 3, 6, 12, and 24 months. Independent assessment of radiographs and CT images was performed at 6, 12, and 24 months. Op-erative parameters, including the surgical time and blood loss, were significantly less in the rhBMP-2/CRM cohort. Both groups demonstrated a significant clinical improve-ment compared with baseline, but not between treatment groups. The rhBMP-2/CRM cohort demonstrated a sta-tistically higher fusion rate, 90.6% compared with 73.3%. At final follow-up, 16% of patients in the AICB cohort continued to complain of donor site pain. The authors concluded that rhBMP-2/CRM demonstrated similar clinical outcomes and improved fusion rates compared with AICB for single-level instrumented posterolateral fusions. Thirty-five percent of patients from the original cohort of randomized patients were lost to follow-up. This study included a heterogeneous patient population with respect to diagnosis. Due to these limitations the study was considered to provide level II evidence in support of rhBMP-2/CRM as a substitute for AICB.
Dimar et al. later reported the 2-year radiographic and clinical outcomes of a multicenter prospective random-ized controlled IDE trial to investigate the use of rhBMP-2
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Part 16: Bone graft extenders and substitutes
119J Neurosurg: Spine / Volume 21 / July 2014
TABL
E 4:
rhBM
P-2 i
n po
ster
olat
eral
fusio
n: su
mm
ary o
f evid
ence
*
Auth
ors &
Ye
arLe
vel o
f Ev
idenc
eDe
scrip
tion o
f Stu
dyCo
mmen
ts
Dima
r et a
l.,
20
09II
The p
urpo
se of
this
study
was
to re
port
the 2
-yr r
adiog
raph
ic &
clinic
al ou
tcome
s of a
mult
icente
r,
prospective, randomized c
ontro
lled IDE
trial to investigate the u
se of rh
BMP-2 m
atrix (bovine
type I co
llagen c
arrier containing 15
% HA & 85% β-TCP
) as a
substitu
te for a
utolog
ous iliac
cr
est fo
r 1-le
vel p
oster
olat in
strum
ented
fusio
ns. W
ell-d
escr
ibed r
adiog
raph
ic cr
iteria
wer
e use
d
to as
sess
fusio
n in a
blind
ed fa
shion
, & va
lidate
d outc
ome m
easu
res w
ere c
omple
ted to
de-
ter
mine
clini
cal o
utcom
e. Cl
inica
l follo
w-up
was
perfo
rmed
at 6
wks &
at 3,
6, 12
, & 24
mos
&
ra
diogr
aphic
follo
w-up
at 6,
12, &
24 m
os. 4
63 pt
s wer
e ran
domi
zed b
twn t
he tr
eatm
ent c
ohor
ts,
w/ a 2-year follow-up ra
te of 89%. T
he co
ntrol group d
emonstrate
d sign
ificantly longer op
times
& blo
od loss. T
he clinical outc
ome m
easures imp
roved s
ignific
antly co
mpared w/ preop sc
ores
in both cohorts
w/ no s
ignific
ant diffe
rence n
oted b
twn treatm
ent groups. 60% of the c
ontro
l
grou
p con
tinue
d to c
ompla
in of
dono
r site
pain
at th
e 24-
mo fo
llow-
up ev
aluati
on. T
he fu
sion
rate, ba
sed o
n CT assessme
nt, de
monstra
ted a sta
tistically s
ignific
ant diffe
rence in fusion
rates
at all tim
es po
ints; the
final fus
ion rate wa
s 96%
in the rhB
MP-2 group &
89% in the c
ontrol group.
Th
ere w
as no
signific
ant diffe
rence in a
dverse ev
ents except that the c
ontro
l group su
ffered 1
7
graft site–rela
ted ev
ents. The au
thors c
onclu
ded that th
e use of rh
BMP-2 m
atrix improved op
para
meter
s, ac
hieve
d a hi
gher
fusio
n rate
& co
mpar
able
clinic
al ou
tcome
s, &
ther
efore
can
eli
mina
te th
e nee
d for
auto
logou
s ilia
c cre
st bo
ne fo
r 1-le
vel p
oster
olat in
strum
ented
fusio
ns.
This
is a w
ell-d
esign
ed tr
ial. T
he au
thor
s fail
ed to
perfo
rm a
powe
r
analy
sis to
deter
mine
samp
le siz
e & fa
iled t
o acc
ount
for p
ts los
t
to fo
llow-
up. It
is no
t clea
r if th
e clin
ical a
sses
smen
t was
blind
ed;
ho
weve
r, give
n tha
t the o
utcom
e mea
sure
s wer
e pt s
elf-a
sses
s-
me
nt ins
trume
nts, th
is fac
t does n
ot detra
ct sig
nificantly from the
ob
serv
ation
s & co
nclus
ions o
f the s
tudy
. Due
to th
ese l
imita
tions
the s
tudy
was
down
grad
ed to
Leve
l II ev
idenc
e to s
uppo
rt th
e use
of rhBM
P-2 a
s a su
bstitu
te for A
ICB in 1-lev
el poste
rolat fusio
ns.
Daws
on et
al., 2
009
IITh
e pur
pose
of th
is mu
lticen
ter pr
ospe
ctive
rand
omize
d con
trolle
d tria
l was
to in
vesti
gate
the u
se
of rhBM
P-2 o
n an A
CS re
inforced w
/ 15%
HA/85% TCP
ceramic g
ranules
as a repla
ceme
nt for
ilia
c cre
st au
togr
aft in
poste
rolat
instr
umen
ted fu
sions
. Well
-des
cribe
d rad
iogra
phic
crite
ria w
ere
us
ed to
asse
ss fu
sion i
n a bl
inded
fash
ion, &
valid
ated o
utcom
e mea
sure
s wer
e com
pleted
to
de
termi
ne cl
inica
l outc
ome.
Over
all su
cces
s was
deter
mine
d by c
ombin
ing th
e res
ults o
f thes
e
meas
ures
. Clin
ical fo
llow-
up w
as pe
rform
ed at
3, 6,
12, &
24 m
os &
radio
grap
hic fo
llow-
up at
6,
12
, & 24
mos
. 50 p
ts we
re ra
ndom
ized t
o the
coho
rts w
/ a 24
-mo f
ollow
-up r
ate of
88%
in th
e
treatm
ent g
roup
& 8
6% in
the c
ontro
l gro
up. Im
prov
emen
ts we
re ob
serv
ed in
all c
linica
l outc
ome
me
asur
es in
both
grou
ps w
/ a tr
end t
owar
d sup
erior
impr
ovem
ent in
the e
xper
imen
tal g
roup
. At
each tim
e poin
t, there was a tre
nd for m
ore s
uccessful fu
sion in the treatment group, w
/ final
fu
sion r
ates o
f 95%
in th
e inv
estig
ation
al gr
oup &
70%
in th
e con
trol g
roup
. No d
iffere
nce i
n the
radio
graphic
or clinical fo
llow-up pr
oved to be
statistically signific
ant. T
he au
thors c
onclu
ded
that the c
ombin
ation of rh
BMP-2 &
HA/TC
P ma
y be a
n effe
ctive alter
native to a
utolog
ous b
one
gr
aft fo
r 1-le
vel p
oster
olat in
strum
ented
fusio
ns.
This
is a w
ell-d
esign
ed st
udy b
ut wa
s dow
ngra
ded t
o Lev
el II e
vi-
de
nce d
ue to
the r
elativ
ely sm
all pt
coho
rts (<
50 pt
s/coh
ort),
in-
co
mplet
e des
cript
ion of
base
line p
t dem
ogra
phic
data
, failu
re to
desc
ribe i
f the c
linica
l ass
essm
ent w
as bl
inded
, & an
over
all ou
t-
come
mea
sure
that
has n
ot be
en va
lidate
d.
(cont
inued
)
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M. G. Kaiser et al.
120 J Neurosurg: Spine / Volume 21 / July 2014
TABL
E 4:
rhBM
P-2 i
n po
ster
olat
eral
fusio
n: su
mm
ary o
f evid
ence
* (co
ntin
ued)
Auth
ors &
Ye
arLe
vel o
f Ev
idenc
eDe
scrip
tion o
f Stu
dyCo
mmen
ts
Glassm
an et
al.
, 200
8II
The p
urpo
se of
this
pros
pecti
ve R
CT w
as to
comp
are t
he cl
inica
l & ra
diogr
aphic
outco
mes o
f
paten
ts >6
0 yrs un
dergoin
g instru
mente
d poster
olat fusion
s w/ either rh
BMP-2/AC
S or AICB.
Va
rious
bone
graf
t exte
nder
s wer
e app
lied a
t the d
iscre
tion o
f the s
urge
on in
both
coho
rts. V
al-
ida
ted ou
tcome
mea
sure
s (SF
-36,
ODI, &
NRS
for b
ack &
leg p
ain) w
ere a
dmini
stere
d. 2-
yr
follow-up da
ta were c
ollected
in 94%
of the p
ts (49 in the rh
BMP-2 c
ohort &
51 in the A
ICB
group). Baseline NRS
leg p
ain was re
porte
d w/ greate
r frequency in the r
hBMP-2/AC
S cohort
(p =
0.03
1); ho
weve
r, the
re w
ere n
o oth
er di
ffere
nces
in ba
selin
e dem
ogra
phics
. The
re w
as a
statis
ticall
y gre
ater n
o. of
comp
licati
ons i
n the
AIC
B co
hort
(20 v
s 8, p
= 0.
014),
alth
ough
none
of
the c
omplications were d
irectly a
ttribu
ted to either the h
arvest of AICB
or the u
se of rh
BMP-2/
ACS. Statistically s
ignific
ant im
provem
ent w
as ob
served in all clinica
l outc
ome m
easures in b
oth
cohorts
comp
ared w/ baseline, although no
ne of the d
ifferences btwn
the c
ohorts wa
s sign
ifi-
ca
nt. C
T im
ages
wer
e obt
ained
in 9
9 pts
at 24
mos
after
surg
ery (
93%
follo
w-up
rate)
. The
fusio
n rate
in the r
hBMP-2/AC
S cohort wa
s 86.3%
& 70
.8% in the A
ICB group. Th
e average CT
grade w
as signific
antly higher in the r
hBMP-2/AC
S group (4.3
vs 3.8 [p =
0.03]). Revision su
r-
gery for n
onunion
was re
quired in 1
pt in the r
hBMP-2 c
ohort &
5 in the A
ICB group. An
estim
ation of total cost over the 2 yrs w
as no
t sign
ificantly different btwn
the 2
groups ($
42,574
for the AICB cohort & $40,1
31 for the rh
BMP-2/AC
S cohort). T
he au
thors c
onclu
ded that th
e
study pr
ovide
d Level I evid
ence su
pporting the us
e of rhB
MP-2/AC
S as an
AICB repla
ceme
nt
fo
r lumb
ar fu
sion i
n the
olde
r pt.
This
is a h
etero
gene
ous p
opula
tion o
f pts
w/ re
spec
t to th
e pre
sent-
ing di
agno
sis, le
vel o
f invo
lveme
nt, &
no. o
f leve
ls inc
luded
in th
e
surg
ery.
No po
wer a
nalys
is wa
s per
form
ed to
deter
mine
samp
le
siz
e. Th
e sur
gical
proc
edur
e was
not s
tand
ardiz
ed, w
/ bon
e gra
ft
ex
tende
rs ad
ded t
o both
grou
ps at
the d
iscre
tion o
f the s
urge
on.
It i
s not
clear
if th
e “gr
ading
” sch
eme o
f fus
ion as
sess
ment
has
be
en va
lidate
d. No
stati
stics
wer
e per
form
ed w
/ res
pect
to ra
te of
fusio
n. Du
e to t
hese
limita
tions
the s
tudy
was
down
grad
ed to
Level II ev
idence in s
upport of rhBM
P-2 a
s a su
bstitu
te for A
ICB
when
supp
lemen
ted w
/ a gr
aft e
xtend
er fo
r pos
terola
t instr
umen
t-
ed fu
sions
in pt
s >60
yrs.
Dima
r et a
l.,
20
06II
The p
urpo
se of
this
pros
pecti
ve ra
ndom
ized n
onbli
nded
repo
rt wa
s to p
rese
nt the
24-m
o rad
iogra
phic
&
clinic
al re
sults
of pt
s enr
olled
in an
FDA
IDE
study
unde
rgoin
g 1-le
vel in
strum
ented
poste
rolat
fusion
w/ either rh
BMP-2/C
RM or AICB. 98
of 15
0 pts, a follow
-up rate
of 65
%, w
ere a
vailable
at
24
mos
after
surg
ery.
Clini
cal a
sses
smen
t w/ v
alida
ted ou
tcome
s ins
trume
nts (S
F-36
, ODI
, & ba
ck/
leg
pain
scor
es) w
as pe
rform
ed at
6 wk
s & 3,
6, 12
, & 24
mos
. A bl
inded
radio
logist
& 2
ortho
pedic
surg
eons
inde
pend
ently
evalu
ated r
adiog
raph
s & C
T im
ages
at 6,
12, &
24 m
os. T
he su
rgica
l time
& blo
od loss were s
ignific
antly less in the rhB
MP-2/CRM
cohort. Sign
ificant im
provem
ents in all
cli
nical
outco
me m
easu
res c
ompa
red w
/ bas
eline
value
s wer
e obs
erve
d in b
oth gr
oups
, but
no
difference ex
isted btwn
groups. A
signific
antly higher fusio
n rate
was ob
served in the rhB
MP-2/
CR
M co
hort
(90.6
% vs
73.3%
). 16%
of pt
s in t
he A
ICB
coho
rt co
ntinu
ed to
comp
lain o
f don
or si
te
pain at 24 mos. The au
thors conclud
ed that rhBM
P-2/C
RM de
monstrated
similar clinical re
sults &
im
prov
ed fu
sion r
ates a
s AIC
B for
1-lev
el ins
trume
nted p
oster
olat fu
sions
.
The h
etero
gene
ous p
t pop
ulatio
n w/ r
espe
ct to
diagn
osis
limits
this
study & the s
ignific
ant lo
ss to follow-up at the 2
-yr study en
d poin
t.
Valid
ated c
linica
l outc
omes
wer
e utili
zed &
an ef
fectiv
e meth
od
of
fusio
n ass
essm
ent w
as pe
rform
ed in
a bli
nded
fash
ion. D
ue to
the s
ignific
ant lo
ss to follow-up the s
tudy is do
wngraded to Le
vel
II e
vidence in su
pport of rhB
MP-2/CR
M as a substitu
te for A
ICB in
1-
level
poste
rolat
instr
umen
ted fu
sions
.
(cont
inued
)
Unauthenticated | Downloaded 02/13/22 06:58 AM UTC
Part 16: Bone graft extenders and substitutes
121J Neurosurg: Spine / Volume 21 / July 2014
TABL
E 4:
rhBM
P-2 i
n po
ster
olat
eral
fusio
n: su
mm
ary o
f evid
ence
* (co
ntin
ued)
Auth
ors &
Ye
arLe
vel o
f Ev
idenc
eDe
scrip
tion o
f Stu
dyCo
mmen
ts
Tagh
avi e
t
al., 2
010
IIITh
e obje
ctive of this retro
spective c
omparative s
tudy was to de
termine the e
fficacy o
f rhB
MP-2/
local
bone
to ei
ther
allog
raft
or au
togr
aft in
revis
ion in
strum
ented
poste
rolat
fusio
ns. 6
2 pts
w/
varying
initia
l diag
noses w
ere includ
ed w/ m
inimu
m follow-up of 2 yrs. Pts w
ere d
ivided into
3
groups: G
roup 1 (n = 24
) receiv
ed rh
BMP-2, Group 2
(n = 18
) BMA/allograft, & Group 3 (n = 20
)
auto
graf
t. All r
eceiv
ed su
pplem
enta
l loca
l bon
e. Fu
sion a
sses
smen
t, thr
ough
stati
c & dy
nami
c
radio
grap
hs, w
as pe
rform
ed by
3 bli
nded
inde
pend
ent r
eview
ers w
/ a di
agno
sis of
nonu
nion
based o
n either su
rgica
l exploration if revis
ion was pe
rform
ed or
radio
graphic
findin
gs. C
linica
l
outco
me was de
termined through VAS
scores. G
roup 1 demo
nstra
ted a fusio
n rate
of 10
0%,
Group 2
demo
nstra
ted a 77.8%
fusio
n rate
, & Group 3 had a
100%
fusio
n rate
. Pts undergoin
g
multil
evel
proc
edur
es w
/ BM
A/all
ogra
ft de
mons
trated
a sta
tistic
ally l
ower
fusio
n rate
. No d
iffer-
ence in VAS
scores was ob
served. T
he au
thors c
onclu
ded that rhB
MP-2 c
ould be an
appropri-
ate al
terna
tive t
o AIC
B in
revis
ion po
stero
lat fu
sion.
Alth
ough
an ad
equa
te de
scrip
tion o
f bas
eline
demo
grap
hics i
s
prov
ided w
/ app
ropr
iate s
tatis
tical
analy
sis. th
ere r
emain
s the
pos-
sibilit
y of s
electi
on bi
as du
e to t
he po
tentia
l diffe
renc
es in
pres
entin
g diag
nose
s tha
t the a
uthor
s do n
ot de
scrib
e. Th
e auth
ors
inc
luded
an ad
equa
te as
sess
ment
of fu
sion w
/ acc
epta
ble ra
dio-
gr
aphic
crite
ria &
inco
rpor
ated v
alida
ted ou
tcome
mea
sure
s. Du
e
to th
e retr
ospe
ctive
natur
e of th
e stu
dy de
sign,
but la
ck of
sig-
nificant lim
itations, th
e study is co
nside
red L
evel III ev
idence in
support of rhB
MP-2/loc
al bone as
an alter
native to A
ICB for revi-
sio
n pos
terola
t fus
ions.
Sing
h et a
l.,
20
06III
This is a p
rospective c
ase-ma
tched co
hort stu
dy to de
termine if rhBM
P-2 e
nhances fusion
rate w/in
a s
horte
r tim
e inte
rval
for pt
s und
ergo
ing in
strum
ented
poste
rolat
fusio
n usin
g AIC
B. 52
pts
presenting w
/ sten
osis & spondylolisthesis
were e
valua
ted: 41 receiv
ed rh
BMP-2/A
ICB/loc
al bone
&
11 re
ceive
d AIC
B/loc
al bo
ne. F
usion
asse
ssme
nt wa
s per
forme
d w/ r
eform
atted
CT
imag
es &
evalu
ated i
n a bl
inded
, inde
pend
ent m
anne
r by 2
surg
eons
& 1
radio
logist
. 2 pt
s wer
e los
t to
follow
-up a
t the 2
-yr tim
e poin
t. The fusio
n rate
s in the rh
BMP-2 &
AICB cohorts were 9
7% & 77
%,
respectively
. Pts receiving rh
BMP-2 w
ere judged to fuse faster & de
monstrate mo
re robust fus
ions.
Fusio
n rate
& qu
ality of fus
ion proved to be
statistically su
perior in
the rhB
MP-2 co
hort. No c
ompli-
cation w
as attrib
uted to the us
e of rhB
MP-2. The au
thors conclud
ed that rhBM
P-2 m
ay se
rve a
s a
sa
fe &
effec
tive s
upple
ment
to AI
CB fo
r pos
terola
t instr
umen
ted fu
sion.
Limita
tions
of th
is stu
dy in
clude
the p
otenti
al for
selec
tion b
ias si
nce a
n
inade
quate
desc
riptio
n of b
aseli
ne de
mogr
aphic
s is p
rovid
ed &
the
autho
rs failed
to ev
aluate
these d
ata for sign
ificant diffe
rences, e.g.,
it i
s not
know
n if th
e no.
of lev
els fu
sed w
as co
mpar
able
btwn
tre
atmen
t gro
ups.
The n
o. of
pts w
/in th
e con
trol g
roup
is re
lative
ly
sm
all. It
is no
t clea
r whe
ther t
he su
rgica
l tech
nique
was
stan
dard
-
ized b
etwee
n coh
orts,
w/ n
o men
tion r
egar
ding t
he am
ount
of AI
CB
us
ed. T
he va
lue of
the o
utcom
e par
amete
rs, in
parti
cular
the s
ub-
jec
tive a
sses
smen
t of fu
sion q
uality
, is of
limite
d valu
e & ha
s not
been
show
n to i
mpac
t clin
ical o
utcom
e. Du
e to t
hese
limita
tions
the st
udy w
as do
wngr
aded
to Le
vel II
I evid
ence
in su
ppor
t of
rhBM
P-2 a
s a graft exte
nder for A
ICB in ins
trume
nted p
osterola
t
fusion
s.
(cont
inued
)
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M. G. Kaiser et al.
122 J Neurosurg: Spine / Volume 21 / July 2014
TABL
E 4:
rhBM
P-2 i
n po
ster
olat
eral
fusio
n: su
mm
ary o
f evid
ence
* (co
ntin
ued)
Auth
ors &
Ye
arLe
vel o
f Ev
idenc
eDe
scrip
tion o
f Stu
dyCo
mmen
tsGlassm
an et
al.
, 200
727III
The o
bjecti
ve of
this
retro
spec
tive r
eview
of da
ta co
llecte
d dur
ing a
pros
pecti
ve, r
ando
mize
d, unblinded trial was to de
termine the influence o
f smo
king o
n fusion
rate & outco
me of pts receiv
ing
either A
ICB or rh
BMP-2 for single-lev
el poste
rolateral fus
ions. All pts we
re ev
aluate
d at a minimu
m of
2 yrs
after
surg
ery.
Clini
cal o
utcom
e was
mea
sure
d utili
zing v
alida
ted ou
tcome
s ins
trume
nts
(ODI
, SF-
36, b
ack &
leg p
ain sc
ores
) at 6
wks
& 3,
6, 12
, & 24
mos
after
surg
ery.
An in
depe
nden
t, bli
nded
asse
ssme
nt of
fusion
statu
s was
perfo
rmed
w/ s
tatic
& dy
nami
c rad
iogra
phs &
CT
imag
-ing
at 6,
12, &
24 m
os af
ter su
rger
y. Th
e rec
ords
of 14
8 pts
were
revie
wed,
42 sm
oker
s & 10
6 no
nsmo
kers.
The
smok
ers w
ere e
quall
y dist
ribute
d btw
n the
2 co
horts
, w/ 5
5 non
smok
ers i
n the
rhBM
P-2 c
ohort &
51 in the A
ICB group. Fusio
n rate
at 24
mos ba
sed o
n radiog
raphs w
as 10
0%
in the
rhBM
P-2 n
onsm
okers, 95.2%
in the rhB
MP-2 sm
okers, 94.1%
in the A
ICB nonsmo
kers, &
76.2%
in the A
ICB sm
okers. A sig
nificant difference was ob
served btwn
all smo
kers (85.7
%) &
all no
nsmo
kers
(97.2%
) as w
ell as
btwn
smok
ers &
nons
moke
rs re
ceivi
ng A
ICB.
Sim
ilar r
ates o
f fus
ion w
ere d
eterm
ined w
/ CT
imag
ing. C
linica
l outc
ome w
as im
prov
ed in
all p
aram
eters
in all
4 cohorts, w
/o a s
ignific
ant diffe
rence in the de
gree of im
provem
ent btwn g
roups. When c
onsid
ered
colle
ctive
ly, th
e non
smok
ers c
onsis
tently
demo
nstra
ted be
tter O
DI &
SF-
36 sc
ores
. The
autho
rs conclud
ed that rhBM
P-2/C
RM may en
hance fusion
rate in cig
arette s
mokers undergoin
g sing
le-lev
el fus
ion &
that
smok
ing is
detrim
ental
to cl
inica
l outc
ome r
egar
dless
of fu
sion s
tatus
.
The r
etros
pecti
ve na
ture o
f this
study
does
limit i
nfere
nces
form
u-lat
ed fr
om th
e res
ults d
espit
e the
fact
that
the d
ata w
ere c
ollec
ted
durin
g a pr
ospe
ctive
RCT
. Sinc
e pts
were
not r
ando
mize
d w/ r
e-spect to
smoking
statu
s, the b
enefit of th
e randomization p
rocess
is nullifi
ed. G
iven the study d
esign
, this report provide
s Level III
evide
nce r
egardin
g the im
pact of rhBM
P-2/CR
M on fusio
n rate
in
smok
ers &
the i
mpac
t of s
mokin
g on c
linica
l outc
ome.
Lee e
t al.,
2009
IVThe o
bjective of this retrospective c
omparative s
tudy w
as to de
termine the e
fficacy o
f rhB
MP-2 in pts
>65 y
rs un
derg
oing a
n ins
trume
nted p
oster
olat fu
sion.
127 p
ts w/
lumb
ar de
gene
rativ
e dise
ase
were divid
ed into 3 g
roups: pts
>65 yrs receiv
ed bo
th rhBM
P-2 &
allog
raft (Group A
, n = 34), p
ts <65 y
rs receive
d rhB
MP-2 & allog
raft (Group B
, n = 52), &
pts >
65 yrs receiv
ed au
tograft (Group
C, n
= 41).
Fusio
n ass
essm
ent w
as pe
rform
ed by
an in
depe
nden
t blin
ded r
adiol
ogist
using
stati
c &
dyna
mic r
adiog
raph
s, su
pplem
ented
w/ C
T wh
en fu
sion w
as qu
estio
nable
. Kirk
aldy-W
illis &
VAS
sc
ores
wer
e use
d to d
eterm
ine cl
inica
l outc
ome.
The a
vera
ge fo
llow-
up w
as ~3
6 mos
, alth
ough
VA
S scores were o
btaine
d up to 2
4 mos after su
rgery. The fusion
rates
were 8
2.4% in Group A,
94.2%
in Group B, &
78.1%
in Group C. A
t 2 yrs, Group B
demo
nstrated
a sta
tistically s
uperior
VAS score c
ompared w
/ Group A. C
linica
l outc
ome w
as no
t statistica
lly different btw
n the 3
groups. The au
thors conclud
ed that rhBM
P-2/a
llograft yields eq
uivale
nt outco
mes to A
ICB in pts
>6
5 yrs,
but is
not a
ble to
over
come
all n
egati
ve co
morb
iditie
s ass
ociat
ed w
/ age
.
Ther
e are
limite
d bas
eline
demo
grap
hic da
ta pr
ovide
d, w/
an in
ad-
eq
uate
desc
riptio
n of c
omor
biditie
s tha
t wou
ld af
fect fu
sion
po
tentia
l. App
aren
t diffe
renc
es ex
ist w
/ res
pect
to se
vera
l of th
ese
co
morb
iditie
s, e.g
., no.
of lev
els fu
sed,
& the
autho
rs fai
l to de
ter-
mine if the
se differences were s
ignific
ant. T
he ex
istence of se
lection
bia
s the
refor
e can
not b
e exc
luded
. The
surg
ical te
chniq
ue is
not d
e-
sc
ribed
. An a
dequ
ate as
sess
ment
of fus
ion w
as pe
rform
ed, a
l-
thoug
h the
autho
rs inc
lude t
ime t
o fus
ion, w
hich i
s of q
uesti
onab
le
sig
nificance. Du
e to these lim
itations the s
tudy w
as do
wngraded
to Level IV
evide
nce in s
upport of rhBM
P-2/a
llograft as a
substitu
te
for
AIC
B in
pts >
65 yr
s und
ergo
ing 1-
level,
instr
umen
ted, p
oster
olat
fus
ions.
Hami
lton e
t
al., 2
008
VTh
e auth
ors p
erfor
med a
retro
spec
tive r
eview
of pt
s und
ergo
ing no
ninstr
umen
ted po
stero
lat fu
sion
using
local harveste
d auto
graft supple
mente
d w/ rhB
MP-2/ACS
. 47 o
f 55 p
ts, median
age 6
8.2
ye
ars,
were
evalu
ated.
Fusio
n ass
essm
ent w
as in
depe
nden
tly pe
rform
ed us
ing ra
diogr
aphs
& C
T
sc
ans a
t var
ious t
ime p
oints
up to
36 m
os af
ter su
rger
y. An
inde
pend
ent c
linica
l eva
luatio
n usin
g
valid
ated i
nstru
ments
was
perfo
rmed
at le
ast 2
9 mos
& up
to 36
mos
after
surg
ery.
The f
usion
rate wa
s 80%
. Greate
r than 8
5% of pts d
emonstrate
d an imp
roved c
linica
l outc
ome &
pain relief.
The a
uthors c
onclu
ded that th
e use or rh
BMP-2 a
s a su
pplem
ent to
nonin
strum
ented
poste
rolat
fus
ions l
eads
to im
prov
ed pa
in &
a com
para
ble fu
sion r
ate in
elde
rly pt
s.
This
case
serie
s con
tains
a he
terog
eneo
us st
udy p
opula
tion w
/
respect to
fusio
n justification &
no. of le
vels inv
olved. A
lthough the
cli
nical
outco
me w
as pe
rform
ed by
an in
depe
nden
t ass
esso
r, pts
were
requ
ired t
o “re
call”
their
pre-
& po
stop p
ain &
healt
h sta
tus.
Th
e description
of clinical re
sults is diffic
ult to inter
pret. CT evalu
-
ation
was
only
perfo
rmed
in 8
5% of
stud
y pts.
Due
to th
ese l
imita
-
tions
, the c
ase s
eries
is do
wngr
aded
to Le
vel V
evide
nce t
hat
rhBM
P-2 is a
n effe
ctive bo
ne gr
aft exte
nder.
* AC
S = absorbable collagen s
ponge; AICB
= au
tolog
ous iliac c
rest bone; β-TCP
= β-trica
lcium
phosphate
; BMA = bone marrow aspirate
; CRM
= co
mpression
-resis
tant ma
trix; HA
= hy
droxyapatite
; IDE = investigational devic
e exemp
tion; NR
S = n
umeric rating s
cale; ODI = Os
westr
y Disa
bility Index; pt = p
atient; R
CT = random
ized c
ontro
lled trial; rhB
MP-2 =
recomb
inant huma
n bone m
orphoge-
netic pr
otein–
2; SF
-36 =
36-Item Sh
ort Form He
alth S
urvey; VA
S = vis
ual analog
scale
.
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Part 16: Bone graft extenders and substitutes
123J Neurosurg: Spine / Volume 21 / July 2014
matrix as a substitute for AICB for single-level postero-lateral instrumented fusion (Table 4).20 Fusion assessment was performed in a blinded fashion, and clinical status was evaluated through validated outcome measures. Clinical follow-up was performed at 6 weeks and at 3, 6, 12, and 24 months and radiographic follow-up at 6, 12, and 24 months. Four hundred sixty-three patients were randomized, with a 2-year follow-up rate of 89%. Significantly longer op-erative times and greater blood loss was observed in the control group. There was no statistical difference in clini-cal outcome between groups, although both demonstrated significant improvement compared with baseline scores. Donor site pain was reported in 60% of the control group at final follow-up. Based on CT imaging, the interventional group demonstrated a statistically superior fusion rate at 6 months (79% with rhBMP-2 and 65% with AICB [p = 0.002]) and at 24 months [96% with rhBMP-2 and 89% with AICB [p = 0.014]). The overall rate of adverse events was statistically similar; however, 17 graft-related compli-cations were recorded in the control group. The authors concluded that the use of rhBMP-2 matrix improved op-erative parameters, led to a higher fusion rate, and achieved comparable clinical outcomes to AICB and therefore can be considered an acceptable substitute for single-level pos-terolateral instrumented fusion. This was a well-designed and well-executed study. It is not clear if the clinical as-sessment was blinded; however, utilization of patient self-assessment questionnaires decreases the likelihood of bias with reporting. The authors did not perform an appropriate power analysis to determine sample size and failed to pro-vide information regarding patients lost to follow-up. Due to these limitations the study was downgraded to Level II evidence in support of rhBMP-2 matrix as a substitute for AICB.
Dawson et al. conducted a multicenter prospective RCT to investigate if rhBMP-2/ACS supplemented with an HA/TCP extender could serve as an appropriate sub-stitute for AICB in instrumented posterolateral fusions (Table 4).17 Fifty patients were randomized; clinical fol-low-up was performed at 3, 6, 12, and 24 months, and radiographic follow-up at 6, 12, and 24 months. At 24 months, the follow-up rate was 88% in the treatment group and 86% in the control group. Both groups demonstrated improvements in all clinical outcome measures with the rhBMP-2 cohort demonstrating a trend toward better out-comes. The fusion rate was higher at all time points in the rhBMP-2 cohort, with final fusion rates of 95% in the investigational group and 70% in the control group. No difference in the radiographic or clinical outcome proved to be statistically significant. The authors concluded that the combination of rhBMP-2 and HA/TCP could be an effective alternative to AICB for single-level posterolat-eral instrumented fusions. The relatively small numbers of patients (< 50 patients per treatment arm), failure to provide adequate baseline demographic data, and utiliza-tion of a nonvalidated composite score to assess overall success are limitations of the study. The study was there-fore considered to provide Level II evidence in support of rhBMP-2/ACS and HA/TCP as a graft substitute for instrumented posterolateral fusions.
Glassman et al. conducted a prospective RCT to com-
pare the clinical and radiographic outcomes of 106 pa-tients older than 60 years of age undergoing instrumented posterolateral fusions with either rhBMP-2/ACS or AICB (Table 4).26 The method of grafting was not standardized, with various graft extenders added at the discretion of the surgeon. Clinical outcome was determined with validated outcome measures, including SF-36, ODI, and numeric rat-ing scale (NRS) for back and leg pain. Computed tomog-raphy scans were used to assess fusion. At 24 months after surgery the clinical and radiographic follow-up was 94% and 93%, respectively. At baseline, the patients in the rh-BMP-2 cohort reported leg pain with greater frequency (p = 0.031); there were no other differences in baseline demo-graphics. The complication rate was significantly greater in the AICB cohort (20 vs 8, p = 0.014), although none of the complications were directly attributed to either the harvest of AICB or the use of rhBMP-2/ACS. Both cohorts dem-onstrated a statistically significant clinical improvement over baseline; however, there was no difference in clini-cal outcome between treatment groups. An 86.3% fusion rate was observed in the rhBMP-2/ACS cohort, compared with 70.8% in the AICB group. The authors provided a CT “grade” for the observed fusion with the rhBMP-2 cohort demonstrating a significantly higher score (4.3 vs 3.8 [p = 0.03]). Nonunion requiring revision was reported in 1 pa-tient in the rhBMP-2 cohort and 5 in the AICB group. An estimation of total cost over 2 years was calculated, and the difference between the 2 groups was not significantly dif-ferent ($42,574 for the AICB cohort and $40,131 for the rh-BMP-2/ACS cohort). The authors concluded that the study provided Level I evidence supporting the use of rhBMP-2/ACS as an AICB replacement for lumbar fusion in the older patient. This study suffers from several limitations, including a heterogeneous patient cohort with respect to presenting diagnosis, failure to account for patients lost to follow-up, lack of a standard surgical protocol, question-able “grading” scheme to assess fusion, failure to deter-mine sample size through a power analysis, and failure to perform an adequate statistical analysis. Due to these limi-tations the study was downgraded to Level II evidence in support of rhBMP-2 for patients older than 60 years of age undergoing posterolateral lumbar fusions.
Singh et al. published a prospective cohort study to compare outcome of patients receiving a mixture of rhBMP-2/local bone/AICB (n = 41) to those receiv-ing only local bone/AICB (n = 11).53 Fusion assessment was performed in an independent, blinded manner with reformatted CT images. The fusion rate with rhBMP-2 was 97% while the control cohort demonstrated a fusion rate of 77%. Those receiving rhBMP-2 were thought to achieve fusion faster and demonstrate a more robust fu-sion. However, this study failed to provided an adequate description of baseline demographics (for example, the number of levels fused in each group). This is a small and heterogeneous population of patients; it is not clear if the surgical procedure was standardized between cohorts, and no objective clinical outcomes were reported. The study was therefore downgraded to Level III evidence in support of utilizing rhBMP-2 as an extender.
Hamilton et al. published a retrospective case se-ries of patients undergoing noninstrumented posterolat-
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M. G. Kaiser et al.
124 J Neurosurg: Spine / Volume 21 / July 2014
eral fusions utilizing local autograft supplemented with rhBMP-2.30 An 80% fusion rate was observed; 85% of patients were felt to demonstrate clinical improvement. This study provides only Level V evidence in support of rhBMP-2 as an extender with local bone for noninstru-mented fusions due to the heterogeneous patient popula-tion, failure to collect clinical outcomes in a prospective manner, and a radiographic follow-up rate of only 85%.
Taghavi et al. performed a retrospective cohort study to determine the efficacy of rhBMP-2/local bone to either allograft combined with bone marrow aspirate or autograft, in revision instrumented, posterolateral fusions. Sixty-two patients with varying diagnoses were included with a mini-mum follow-up of 2 years.56 Patients were divided into 3 groups: Group 1 (n = 24) received rhBMP-2, Group 2 (n = 18) received BMA/allograft, and Group 3 (n = 20) received autograft. The exact source of autograft bone for Group 3 was not clearly defined. All 3 cohorts received supplemen-tal local bone. Static and dynamic radiographs were used to assess fusion and were reviewed by 3 blinded indepen-dent reviewers with a diagnosis of nonunion based on either surgical exploration if revision performed or radiographic findings. Clinical outcome was determined through VAS scores. A fusion rate of 100% was observed for Groups 1 and 3; however, Group 2 demonstrated a 77.8% fusion rate. Patients undergoing multilevel procedures with BMA/al-lograft demonstrated a statistically lower fusion rate. No difference in VAS scores was observed. The authors con-cluded that rhBMP-2 could be an appropriate alternative to AICB in revision posterolateral fusion. Although this study was well executed with appropriate follow-up, vali-dated outcome measures, and appropriate assessment of fusion, due to the retrospective nature of the study design it provides Level III evidence. As this was the only study identified to investigate the use of rhBMP-2 in revision sur-gery, evidence is insufficient to formulate a recommenda-tion. Additional studies of similar or lesser quality, such as retrospective reviews or case series, promoting the use of rhBMP-2 for various clinical scenarios, such as in patients who use tobacco, have been published.3,25,27,36 Due to an in-sufficient number of such studies no formal recommenda-tions could be constructed regarding the use of rhBMP-2 under the specific clinical circumstances.
rhBMP-2: Complications. Between 2003 and 2007, the annual number of procedures utilizing BMPs increased by 4.3-fold (from 23,900 to 103,194 cases), with spinal fu-sions accounting for almost 93% of these cases.46 Although it is difficult to deny a positive impact on fusion rate, sur-geons must be aware of the potential risks and complica-tions related to the use of BMPs, particularly since the ma-jority of procedures would be considered off label.
Rihn et al. performed a single-center retrospective co-hort study to specifically identify complications associated with the use of rhBMP-2 for single-level TLIF procedures and to determine if these complications differed compared with the use of AICB.50 Between January of 2004 and May of 2007, 130 patients underwent a single-level TLIF using either AICB or rhBMP-2 (Table 5). One hundred nineteen patients were available for review, 33 receiving AICB and 86 receiving rhBMP-2, with an average radiographic fol-
low-up of 19.1 months and an average clinical follow-up of 27.6 months. A combination of plain radiographs and CT images were used to assess fusion status. Those patients receiving AICB demonstrated a 96.5% fusion rate, and the fusion rate in the rhBMP-2 cohort was 97% (p = 0.09). The overall complication rate was higher in the autograft cohort (45.5% vs 29.1%), but the difference was not significant. Donor site morbidity was the most common complication associated with AICB, and postoperative radiculitis was more often observed in the rhBMP-2 cohort (14% vs 3% [p = 0.08]). A significant decrease in radiculitis was observed after 2006 (20.4% to 5.4% [p = 0.047]), following the uti-lization of a hydrogel sealant intended to shield the exiting root. Additional complications thought to be related to the use of rhBMP-2 included osteolysis and heterotopic bone formation. The authors concluded that the TLIF proce-dure, regardless of graft, is associated with a relatively high complication rate (33.6% for the entire cohort). Although rhBMP-2 eliminates donor site morbidity, the surgeon should be aware of additional complications, such as radic-ulitis, osteolysis, and heterotopic bone formation, that may be associated with its use. The authors failed to disclose if the assessment, clinical or radiographic, was performed in a blinded fashion. No validated outcome measures were used, and the fusion criteria were not adequately described. This study provides Level IV evidence supporting the use of rhBMP-2; however, more importantly, it highlights sev-eral of the more common complications thought to be as-sociated with the interbody application of rhBMP-2.
Pradhan et al. observed an increased rate of graft re-sorption, fracture, or collapse in patients undergoing stand-alone ALIF with femoral ring allograft.47 Lewandrowski et al. observed osteolysis of the vertebral endplate follow-ing minimally invasive TLIF and speculated that endplate violation during interbody decortication may have been a contributing factor.42 Although not specific for lumbar pro-cedures, Vaidya et al. observed a higher incidence of graft subsidence when rhBMP-2 was used with an allograft inter-body spacer.66 Joseph and Rampersaud observed a greater incidence of heterotopic bone formation following the use of rhBMP-2 for minimal access interbody lumbar fusion, but no clinical sequelae associated with this excessive bone formation were identified.34 Mindea et al. observed a high-er incidence of postoperative radiculitis of a nonstructural cause associated with the use of rhBMP-2 during minimal access TLIF procedures.43 Garrett et al. reported on the formation of painful postoperative seromas following the use of rhBMP-2 during posterolateral fusions.23 Finally, Carragee et al. identified a higher incidence of retrograde ejaculation in patients receiving rhBMP-2 during ALIF procedures.10 There have been a number of additional ret-rospective reviews and case series that have corroborated the findings from these reports.3,14,37,52
Although a direct cause and effect relationship be-tween the use of rhBMP-2 and these complications can-not be formulated based on these studies, the potential association should not be ignored. The surgeon should carefully consider the off-label utilization of rhBMP-2, or any osteobiologic, and make sure that the patient has been adequately informed regarding these risks.
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Part 16: Bone graft extenders and substitutes
125J Neurosurg: Spine / Volume 21 / July 2014
rhBMP-7: Posterolateral Fusion. Osteogenic pro-tein–1, also known as rhBMP-7, is another member of the transforming growth factor–b superfamily and plays a key role in osteoblast differentiation. Compared with rhBMP-2, there have been relatively few clinical stud-ies investigating rhBMP-7 as an agent of spinal fusion, with the majority, if not all, focusing on posterolateral fu-sion techniques. The FDA has not approved the use of rhBMP-7 for spinal fusions. Currently, its use requires a humanitarian device exemption. There were no recom-mendations pertaining to the use of rhBMP-7 in the origi-nal guidelines publication (Table 6).48
Delawi et al. published a prospective multicenter RCT comparing the efficacy of local autograft supple-mented with either rhBMP-7 or AICB in single-level in-strumented posterolateral fusions for isthmic or degen-erative spondylolisthesis.18 Clinical and fusion assessment was performed at 6 weeks, and 3, 6, and 12 months after surgery. Fusion assessment through CT imaging was per-formed in a blinded fashion. Validated clinical measures (ODI and VAS) were used to determine response to sur-gery. The follow-up rate at 12 months was 89%. There was no statistical difference in the fusion rate between the groups (63% in the rhBMP-7 group and 67% in the AICB cohort). Both groups demonstrated clinical improvement compared with baseline scores, but there was no statisti-cal difference regarding clinical outcome between groups. At 12 months after surgery, 64% of AICB patients com-plained of at least “mild” donor site pain (2.7 ± 2.8 VAS). No specific adverse event was related to AICB harvesting or use of rhBMP-7. The authors concluded that rhBMP-7 is an effective alternative to AICB for supplementing lo-cal autograft for single-level posterolateral fusions. The small sample size (< 50 patients), incomplete statistical analysis, and potential impact of differences in baseline characteristics requires that the study be downgraded to Level II evidence in support of utilizing rhBMP-7/local autograft as a substitute for AICB/local autograft in sin-gle-level instrumented posterolateral fusions.
In 2008, Vaccaro et al. conducted a multicenter pro-spective RCT to further investigate the safety and effi-cacy of rhBMP-7/ACS and to demonstrate noninferiority as a replacement for AICB for noninstrumented, single-level posterolateral fusion.62 Three hundred thirty-five patients were randomized in a 2:1 fashion, but only 293 were treated (208 patients received rhBMP-7/ACS and 87 received AICB). Independent blinded clinical and radio-graphic evaluations were performed at 6 weeks and at 3, 6, 12, 24, and longer than 36 months utilizing validated outcome measures, including ODI, SF-36, and VAS, and radiographs. Fusion assessment after 36 months was sup-plemented with CT scans. The primary overall success was reported as a composite measure, intended for FDA submission, and required a 20% improvement in ODI, ab-sence of treatment-emergent adverse events related to the device, absence of a decline in neurological status, and ra-diographic successful fusion. At 24 months with a follow-up rate of 87%, the investigational group did not achieve statistical equivalence with respect to the overall success rate compared with controls (38.7% compared with 49.4% [p = 0.33]). The investigational group demonstrated a TA
BLE
5: C
ompl
icat
ions
and
the u
se o
f rhB
MP-2
: sum
mar
y of e
viden
ce*
Auth
ors &
Ye
arLe
vel o
f Ev
idenc
eDe
scrip
tion o
f Stu
dyCo
mmen
ts
Rihn
et al
.,
2009
50IV
This
retro
spec
tive c
ohor
t stu
dy w
as in
tende
d to e
valua
te th
e com
plica
tions
asso
ciated
w/ 1
-leve
l TLIF
proc
e-
dures &
deter
mine if comp
lications d
iffered b
twn p
ts receiving AICB or rh
BMP-2. 119 o
f 130 pts w
ere a
vail-
able for follow
-up, 33 re
ceiving au
tograft &
86 r
hBMP-2. After
2006, a hy
drogel seala
nt wa
s used in 3
7 pts to
shield the ne
rve r
oot from exposure to the r
hBMP-2. Fusio
n assessm
ent, through a comb
ination o
f radio-
grap
hs &
CT
scan
s, wa
s per
form
ed on
aver
age a
t 19.1
mos
& cl
inica
l follo
w-up
at 27
.6 mo
s afte
r sur
gery.
The fusion
rate for the au
tolog
ous c
ohort w
as 96.5%
& it wa
s 97%
for the rh
BMP-2 c
ohort (
p = 0.09). A
highe
r com
plica
tion r
ate w
as ob
serv
ed in
the a
utogr
aft c
ohor
t (45
.5% vs
29.1%
), bu
t the d
iffere
nce w
as no
t
signifi
cant. Donor site mo
rbidity wa
s the most com
mon c
omplication in the au
tolog
ous c
ohort. P
ostop
radi-
culitis w
as more c
ommo
nly ob
served in the r
hBMP-2 c
ohort (1
4% vs
3% [p = 0.08]); ho
wever, this
incid
ence
sig
nificantly d
ecreased after
the a
pplication of the h
ydrogel sealan
t (20.4%
to 5.4%
[p = 0.047]). Ad
dition
al
comp
lications thought to be re
lated to the u
se of rh
BMP-2 includ
ed os
teoly
sis & he
teroto
pic bo
ne form
ation.
Th
e aut
hors
conc
luded
that
the T
LIF pr
oced
ure,
rega
rdles
s of g
raft,
is as
socia
ted w
/ a re
lative
ly hig
h com
-
plication r
ate (33.6%
for the en
tire c
ohort), & although rh
BMP-2 e
limina
tes do
nor site morbid
ity, additio
nal
co
mplic
ation
s suc
h as r
adicu
litis,
oste
olysis
, & he
teroto
pic bo
ne fo
rmati
on ar
e ass
ociat
ed w
/ its u
se.
The s
tudy
is lim
ited d
ue to
its re
trosp
ectiv
e des
ign &
failu
re
to
desc
ribe i
f the a
sses
smen
t of c
ompli
catio
ns &
fusio
n
statu
s was
perfo
rmed
in a
blind
ed fa
shion
. No v
alida
ted
ou
tcome
instr
umen
ts we
re us
ed. T
he cr
iteria
for f
usion
asse
ssme
nt we
re no
t ade
quate
ly de
scrib
ed, &
it is
not
cle
ar if
simila
r meth
ods w
ere p
erfo
rmed
equa
lly fo
r both
study
grou
ps. T
his re
trosp
ectiv
e coh
ort s
tudy
is do
wn-
gr
aded
from
Leve
l III to
Leve
l IV w
/ res
pect
to th
e com
pli-
cations as
socia
ted w/ th
e use of rh
BMP-2 in T
LIF
pr
oced
ures
.
* AICB
= au
tolog
ous iliac c
rest bone; pt = pa
tient; rh
BMP-2 =
recomb
inant huma
n bone m
orphogenetic p
rotein–2; TL
IF = transfo
raminal lu
mbar inter
body fusio
n.
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M. G. Kaiser et al.
126 J Neurosurg: Spine / Volume 21 / July 2014
TABL
E 6:
rhBM
P-7 i
n po
ster
olat
eral
fusio
n: su
mm
ary o
f evid
ence
*
Auth
ors &
Ye
arLe
vel o
f Ev
idenc
eDe
scrip
tion
Comm
ents
Delaw
i et a
l.,
20
10II
The o
bjecti
ve of
this
pilot,
pros
pecti
ve, r
ando
mize
d, co
ntroll
ed m
ultice
nter t
rial w
as to
comp
are t
he
efficacy o
f rhB
MP-7 w
/ AICB, bo
th supplem
ented
w/ lo
cal bone, in 1-lev
el ins
trume
nted p
oster
olat
fus
ions f
or is
thmic
or de
gene
rativ
e spo
ndylo
listhe
sis. C
linica
l & fu
sion a
sses
smen
ts we
re pe
rform
ed
at
6 wks
& 3,
6, &
12 m
os af
ter su
rger
y. Fu
sion a
sses
smen
t thro
ugh C
T im
aging
was
perfo
rmed
in a b
linde
d fas
hion.
Valid
ated c
linica
l mea
sure
s (OD
I & V
AS) w
ere u
sed t
o dete
rmine
resp
onse
to
su
rger
y. Th
e foll
ow-u
p rate
at 12
mos
was
89%
. The
re w
as no
stati
stica
l diffe
renc
e in t
he fu
sion
rate btwn
the g
roups (63% in the r
hBMP-7 g
roup & 67
% in the A
ICB cohort). B
oth gr
oups de
m-
on
strate
d clin
ical im
prov
emen
t com
pare
d w/ b
aseli
ne sc
ores
, but
ther
e was
no st
atisti
cal d
iffere
nce
re
gard
ing cl
inica
l outc
ome b
twn g
roup
s. At
12 m
os af
ter su
rger
y, 64
% of
AIC
B pts
comp
laine
d of a
t
least “m
ild” d
onor site pain (2.7 ± 2.8 V
AS). No
specific
adverse e
vent wa
s rela
ted to AICB harvest-
ing
or us
e of rhB
MP-7. Th
e authors co
nclud
ed that rhBM
P-7 is a
n effe
ctive alter
native to A
ICB
when
supp
lemen
ting l
ocal
auto
graf
t for 1
-leve
l pos
terola
t fus
ions &
avoid
s the
mor
bidity
asso
ciated
w/ A
ICB
harv
estin
g.
This
study
popu
lation
is re
lative
ly sm
all (<
50 pt
s), bu
t rep
rese
nts
a h
omog
eneo
us gr
oup o
f pts.
The
rand
omiza
tion p
roto
col is
adeq
uatel
y des
cribe
d & th
e tre
ating
surg
eon w
as bl
inded
as
be
st as
poss
ible r
egar
ding i
nterv
entio
n. De
spite
rand
omiza
-
tion t
here
was
a dif
feren
ce bt
wn gr
oups
w/ r
espe
ct to
the s
pinal
se
gmen
t und
ergo
ing fu
sion.
Alth
ough
stati
stics
wer
e ad-
equately d
escribe
d, it is d
ifficult to d
eterm
ine the s
ignific
ance
due to the sm
all sa
mple siz
e & no
confidence inte
rvals
were
ap
plied
. The
small
samp
le siz
e, inc
omple
te sta
tistic
al an
alysis
,
& po
tentia
l impa
ct of
differ
ence
s in b
aseli
ne ch
arac
terist
ics
re
quire
that
the s
tudy
be do
wngr
aded
to Le
vel II
evide
nce i
n
support of rhB
MP-7 a
s a su
bstitu
te for A
ICB to supplem
ent
loc
al au
togr
aft in
1-lev
el ins
trume
nted p
oster
olat f
usion
s.Va
ccar
o et a
l.,
2008
62II
The p
urpo
se of
the p
rosp
ectiv
e ran
domi
zed c
ontro
lled m
ultice
nter s
tudy w
as to
deter
mine
the s
afety
&
efficacy o
f rhB
MP-7/AC
S & to demo
nstrate nonin
feriority as
a repla
ceme
nt for AICB for un
instru
-
mente
d, 1-
level
poste
rolat
fusio
n. 33
5 pts
were
rand
omize
d, bu
t only
293 w
ere t
reate
d. 20
8 pts
re-
ceive
d rhB
MP-7 & 87 co
ntrol pts
receive
d AICB. Independent blinded c
linica
l & radio
graphic
evalu
-
ation
s wer
e per
forme
d at 6
wks
& at
3, 6,
12, 2
4, &
>36 m
os af
ter su
rger
y usin
g vali
dated
outco
me
me
asur
es &
radio
grap
hs. F
usion
asse
ssme
nt af
ter 36
mos
was
supp
lemen
ted w
/ CT
scan
s. At
the
24
-mo e
nd po
int th
e inv
estig
ation
al gr
oup d
id no
t ach
ieve s
tatist
ical e
quiva
lence
w/ r
espe
ct to
the
overall su
ccess rate
comp
ared w/ controls (38.7
% vs
49.4%
[p = 0.3
3]). The investigational group
de
mons
trated
a low
er fu
sion r
ate (6
1.7%
vs 83
.1%). N
oninf
erior
ity of
the o
vera
ll suc
cess
was
dem-
onstrate
d after 36 m
os (47.2
% in the investigational group &
46.8%
in the c
ontrol cohort [p
= 0.0
25]).
CT
evalu
ation
demo
nstra
ted a
statis
ticall
y gre
ater p
erce
ntage
of pt
s in t
he co
ntrol
arm
demo
nstra
ting
bridg
ing bo
ne ac
ross the inte
rtransverse sp
ace (83% vs
56% [p = 0.0
01]). There w
as no
t a statistically
sig
nificant difference in the rate
of treatment-rela
ted se
rious ad
verse
events btw
n the investigational
& control groups (85.6
% & 84
.7%, respectively [p = 0
.863]). Do
nor site pa
in wa
s reported
in 44
% of
co
ntrols
at 12
mos
& 35
% af
ter 36
mos
, w/ V
AS sc
ores
of 1.
6 at 1
2 mos
& 1.
1 afte
r 36 m
os. O
p tim
e
& blo
od loss were s
ignific
antly less in the investigational cohort. No s
ignific
ant im
munolog
ical re
ac-
tion rela
ted to the a
pplication of rh
BMP-7 w
as recorded. The au
thors conclud
ed that rhBM
P-7/c
olla-
gen c
omposite is a
safe & effec
tive a
lternative to IC
BG.
This
is a w
ell-d
esign
ed la
rge p
rosp
ectiv
e ran
domi
zed t
rial b
ut
se
vera
l limi
tatio
ns ex
ist. A
lthou
gh th
e aut
hors
perfo
rmed
a
powe
r calc
ulation to d
eterm
ine sa
mple siz
e, the b
enefits of ran-
domi
zatio
ns w
ere c
ompr
omise
d sinc
e 13%
of pt
s wer
e not
treate
d & th
e aut
hors
faile
d to d
escr
ibe th
ese p
ts. T
he fo
llow-
up ra
te at
24 m
os w
as 87
% of
pts t
reate
d (76
% of
pts r
ando
m-
ize
d), d
ropp
ing to
69%
(60%
of ra
ndom
ized p
ts) af
ter 3
6 mos
.
The a
ssessm
ent of overall s
uccess was modifie
d after 3
6 mos
co
mpar
ed w
/ the 2
4-mo
evalu
ation
. Due
to th
ese l
imita
tions
,
this stu
dy pr
ovide
s Level II e
vidence that at 24 mos, rhB
MP-7
did
not a
chiev
e a no
ninfer
ior ou
tcome
to A
ICB,
as m
easu
red
by the a
priori overall s
uccess criteria de
fined by
the a
uthors,
at
24 m
os co
mpar
ed w
/ AIC
B. T
he re
sults
wer
e com
para
ble
af
ter 3
6 mos
; how
ever,
this
conc
lusion
is co
mpro
mise
d due
to
the s
ignific
ant dropout rate.
(cont
inued
)
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Part 16: Bone graft extenders and substitutes
127J Neurosurg: Spine / Volume 21 / July 2014
TABL
E 6:
rhBM
P-7 i
n po
ster
olat
eral
fusio
n: su
mm
ary o
f evid
ence
* (co
ntin
ued)
Auth
ors &
Ye
arLe
vel o
f Ev
idenc
eDe
scrip
tion
Comm
ents
Kana
yama
et
al.
, 200
6II
The o
bjecti
ve of
this
pros
pecti
ve R
CT w
as to
comp
are t
he cl
inica
l & ra
diogr
aphic
outco
mes o
f pts
unde
r-
going
1-lev
el po
stero
lat in
strum
ented
fusio
ns fo
r deg
ener
ative
spon
dylol
isthe
sis. 2
0 pts
were
rand
om-
ize
d into
2 groups, rhB
MP-7/collagen (n =
10) &
local auto
graft/H
A/TC
P (n = 1
0). Static & dynamic
ra
diogr
aphs
& C
T im
ages
wer
e obta
ined a
t 3 &
6 wk
s as w
ell as
at 3,
6, &
12 m
os to
asse
ss fu
sion
sta
tus. V
alida
ted cl
inica
l outc
ome m
easu
res (
ODI)
were
obtai
ned a
t 3, 6
, 9, &
12 m
os af
ter su
rger
y. Al
l
pts w
ho de
mons
trated
radio
grap
hic fu
sion u
nder
went
remo
val o
f instr
umen
tation
, reg
ardle
ss of
clini
cal
sta
tus. The follow-up rate at 1 y
r was 90
%. B
oth co
horts de
monstrated
signific
ant im
provem
ent in
the
OD
I scores a
t 3 mos after su
rgery; howe
ver, n
o sign
ificant diffe
rence w
as ob
served btwn
the g
roups.
It is n
ot cle
ar if the
signific
ance of clinical im
provem
ent w
as main
tained a
fter this
time p
oint. T
he
fus
ion rate based o
n radiog
raphic assessme
nt wa
s 78%
in the rhB
MP-7 cohort & 90% in the c
ontrol
group. Those p
ts conside
red fused (7 in the rhB
MP-7/collagen c
ohort &
9 controls
) underwe
nt surgica
l
explo
ration a
t an a
verage of 15
.3 mo
s after the index p
rocedure. S
olid a
rthrodesis
was identified in
57% of rh
BMP-7 p
ts explo
red (calcu
lated fusio
n rate
for all p
atients receiving rh
BMP-7/c
ollagen =
44
%) &
in 78
% of
the c
ontro
l gro
up (c
alcula
ted fu
sion r
ate fo
r enti
re co
ntrol
grou
p = 70
%). N
o stat
isti-
cal analys
is regarding
fusio
n rate
was pe
rform
ed. The au
thors conclud
ed that rhBM
P-7 w
as ca
pable
of ind
ucing
new bone grow
th howe
ver the fusio
n rate
was no
t encouragin
g & they su
ggested
modific
a-
tio
ns in
eithe
r sur
gical
techn
ique o
r car
rier m
ay be
requ
ired.
This is a s
mall p
t popula
tion, but it be
nefits
from
the h
omoge-
neou
s diag
nosis
. The
auth
ors f
ail to
desc
ribe t
he ra
ndom
iza-
tio
n sch
eme.
It is n
ot cle
ar if
the r
adiog
raph
ic as
sess
ment
was p
erfo
rmed
in a
blind
ed fa
shion
. The
auth
ors p
rovid
e
curs
ory b
aseli
ne de
mogr
aphic
data
. No p
ower
calcu
lation
was
perfo
rmed to de
termine sa
mple siz
e & a superficia
l description
of sta
tistic
al an
alysis
was
perfo
rmed
. The
intra
op de
termi
na-
tio
n of f
usion
statu
s is g
ener
ally c
onsid
ered
the “
gold
stand
ard”
for f
usion
asse
ssme
nt &
a clea
r adv
anta
ge in
this
study
. Due
to lim
itatio
ns th
is stu
dy w
as do
wngr
aded
to Le
vel II
evide
nce,
not supporting the u
se of rh
BMP-7 for 1-
level ins
trume
nted
po
stero
lat fu
sions
in de
gene
rativ
e spo
ndylo
listh
esis.
Vacc
aro e
t al.,
20
04
IITh
e pur
pose
of th
e pro
spec
tive r
ando
mize
d con
trolle
d mult
icente
r pilo
t stu
dy w
as to
deter
mine
the
safety &
efficacy o
f rhB
MP-7/A
CS as
a repla
ceme
nt for A
ICB for u
ninstrum
ented
poste
rolat fusio
n.
36
pts w
/ deg
ener
ative
spon
dylol
isthe
sis w
ere r
ando
mize
d & fo
llowe
d at 6
wks
& 3,
6, &
12 m
os
af
ter su
rger
y. Sa
fety w
as de
termi
ned b
y com
parin
g the
natur
e & fr
eque
ncy o
f adv
erse
even
ts.
Ra
diogr
aphs
wer
e ana
lyzed
by in
depe
nden
t rad
iolog
ists,
blind
ed to
the i
nterv
entio
n, &
valid
ated
outco
mes instru
ments
were u
sed to d
eterm
ine clinical effic
acy. Th
e follow
-up r
ate at 12
mos was
79
% fo
r the
inve
stiga
tiona
l gro
up &
83%
for t
he co
ntrols
. The
rate
of ad
vers
e eve
nts di
d not
differ
btwn
groups & no
specific
adverse e
vent wa
s rela
ted to the r
hBMP-7. Th
e fusion
rate for the
rhBM
P-7 c
ohort w
as 74
% & for the co
ntrol group 6
0% (p
= 0.675). T
he clinical success ra
te wa
s
86% for the rh
BMP-7 c
ohort &
73% for the co
ntrol group (
p = 0.39). Th
e authors co
nclud
ed that
rhBM
P-7 h
as an
accepta
ble sa
fety p
rofile
, & the c
omparable
results to AICB jus
tify furth
er investiga-
tion to d
efine the e
fficacy o
f rhB
MP-7 a
s a bo
ne gr
aft substitute.
This
is a w
ell-d
esign
ed pi
lot st
udy b
ut is
limite
d by t
he sm
all
sa
mple
size (
<50 p
ts) &
pts l
ost to
follo
w-up
at th
e stu
dy en
d
point
. No p
ower
calcu
lation
was
perfo
rmed
to de
termi
ne th
e
samp
le siz
e. Th
e 1-y
r end
point
may
also
be co
nside
red t
oo
br
ief fo
r fus
ion pr
oced
ures
. The
mea
sure
of ov
erall
clini
cal s
uc-
ce
ss w
as a
nonv
alida
ted co
mpos
ite sc
ore o
f both
fusio
n & cl
ini-
ca
l mea
sure
s. Du
e to t
hese
limita
tions
the s
tudy
was
down
-
graded to Le
vel II, finding
that the u
se of rh
BMP-7 a
s a bo
ne
gr
aft s
ubsti
tute i
n unin
strum
ented
poste
rolat
fusio
ns is
safe
&
effec
tive.
Vacc
aro e
t al.,
20
05II
The p
urpo
se of
this
study
was
to re
port
the l
ong-
term
follo
w-up
data
from
the p
revio
usly
repo
rted
pilot stu
dy de
scribed ab
ove. Pts w
ere follow
ed up
to 24
mos after
surgery u
sing the sa
me clinical &
ra
diogr
aphic
outco
me m
easu
res a
s pre
vious
ly re
porte
d. Th
e clin
ical &
radio
grap
hic ra
tes of
follo
w-
up
wer
e 86%
& 8
3%, r
espe
ctive
ly. T
he fu
sion r
ates f
or th
e con
trol &
inve
stiga
tiona
l coh
ort w
ere
40
% &
55%
, res
pecti
vely.
Clin
ical s
ucce
ss, w
/ res
pect
to th
e vali
dated
outco
mes i
nstru
ment,
was
85%
in th
e inv
estig
ation
al co
hort
& 64
% in
the c
ontro
l gro
up. N
o lon
g-ter
m ad
vers
e eve
nts w
ere
specific
ally rela
ted to the u
se of rh
BMP-7. Th
e authors co
nclud
ed that safety &
efficacy o
f rhB
MP-7
is
comp
arab
le to
AICB
for a
t leas
t 24 m
os af
ter su
rger
y.
The i
nitial
stud
y (fro
m 20
04) w
as do
wngr
aded
to Le
vel II
evide
nce
du
e to l
imita
tions
outlin
ed in
the c
omme
nts. A
t the 2
4-mo
time
period n
o additio
nal sign
ificant limitations were identified;
ther
efore
the s
tudy
main
taine
d a Le
vel II
desig
natio
n sup
port-
ing rh
BMP-7 a
s a bo
ne gr
aft substitute.
(cont
inued
)
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M. G. Kaiser et al.
128 J Neurosurg: Spine / Volume 21 / July 2014
TABL
E 6:
rhBM
P-7 i
n po
ster
olat
eral
fusio
n: su
mm
ary o
f evid
ence
* (co
ntin
ued)
Auth
ors &
Ye
arLe
vel o
f Ev
idenc
eDe
scrip
tion
Comm
ents
Vacc
aro e
t al.,
20
0865
III
The p
urpo
se of
this
study
was
to re
port
the lo
ng-te
rm fo
llow-
up da
ta fro
m the
prev
iously
repo
rted p
ilot
stu
dy de
scribed ab
ove. Pts w
ere follow
ed up
to 48
mos after su
rgery u
sing the sa
me clinical & radio
-
grap
hic ou
tcome
mea
sure
s as p
revio
usly
repo
rted.
The c
linica
l & ra
diogr
aphic
rates
of fo
llow-
up w
ere
69
% &
61%
, res
pecti
vely.
The
fusio
n rate
s for
the c
ontro
l & in
vesti
gatio
nal c
ohor
t wer
e 50%
& 68
.8%,
re
spec
tively
. Clin
ical s
ucce
ss, w
/ res
pect
to the
valid
ated o
utcom
es in
strum
ent, w
as 73
.7% in
the i
n-
ve
stiga
tiona
l coh
ort &
57.1%
in th
e con
trol g
roup
. The
over
all su
cces
s was
62.5%
in th
e inv
estig
ation
al
cohort & 33.3%
in the c
ontrol group. N
o long-term adverse
events we
re sp
ecific
ally rela
ted to the u
se
of rhBM
P-7. The a
uthors c
onclu
ded that safe
ty & efficacy o
f rhB
MP-7 is comp
arable to AICB
for at
lea
st 48
mos
after
surg
ery.
The i
nitial
stud
y (fro
m 20
04) w
as do
wngr
aded
to Le
vel II
evide
nce
du
e to l
imita
tions
outlin
ed in
the c
omme
nts. F
urth
er lim
itatio
ns
we
re identified du
ring the follow-up pe
riod that sign
ificantly lim
it
conc
lusion
s dra
wn fr
om th
is stu
dy, in
parti
cular
the l
arge
no. o
f
pts lost to follow-up. D
ue to this sig
nificant lim
itation this
follow-
up re
port provide
s only
Level III evid
ence su
pporting r
hBMP-7
as
a bo
ne gr
aft s
ubsti
tute.
Vacc
aro e
t al.,
20
03IV
The p
urpose of this pilot stu
dy was to de
termine the s
afety of rhBM
P-7 c
ombin
ed w/ auto
graft fo
r
poste
rolat
unins
trume
nted f
usion
s in p
ts w/
symp
tomati
c deg
ener
ative
spon
dylol
isthe
sis. 1
2 pts
un-
derwent a 1-
level fusio
n receiv
ing rh
BMP-7 m
ixed w
/ AICB. Independent radiog
raphic assessme
nt
of
dyna
mic r
adiog
raph
s was
perfo
rmed
at 6
wks &
3, 6,
9, &
12 m
os, &
valid
ated o
utcom
es in
stru-
ments
, ODI
scor
es, w
ere u
sed t
o ass
ess c
linica
l outc
ome a
t 6 &
12 m
os. R
esult
s wer
e com
pare
d
w/ a
histor
ical c
ohor
t of p
ts wh
o only
rece
ived A
ICB.
75%
of pt
s ach
ieved
clini
cal s
ucce
ss &
55%
attaine
d a so
lid fusio
n. Th
ere w
ere n
o adverse ev
ents specific
ally a
ssociated w/ th
e use of
rhBM
P-7. Th
e authors co
nclud
ed that rhBM
P-7 d
emonstrate
d an a
cceptable
safety p
rofile
when
us
ed as
an ad
junct
to AI
CB.
The s
mall p
t pop
ulatio
n, co
mpar
ed w
/ a hi
storic
al co
hort,
&
re
lative
ly sh
ort fo
llow-
up fo
r a fu
sion p
roce
dure
limit t
his co
hort
stu
dy. T
he study d
esign
is diffic
ult to ca
tegorize b
ut falls btwn
a pro
spec
tive c
ase s
eries
& re
trosp
ectiv
e coh
ort s
tudy
. It w
as
ini
tially
cons
idere
d a Le
vel II
I stu
dy bu
t due
to th
e lim
itatio
ns
wa
s dow
ngra
ded t
o Lev
el IV
evide
nce s
uppo
rting
the s
afety
&
efficacy o
f rhB
MP-7 a
s a bo
ne gr
aft exte
nder for u
ninstrum
ent-
ed
1-lev
el po
stero
lat fu
sions
in pt
s w/ s
ympto
matic
spon
dylo-
listh
esis.
* AC
S = a
bsorbable
collagen s
ponge; AICB
= autolog
ous iliac c
rest bone; H
A = h
ydroxyapatite; IC
BG = ilia
c crest bone graft; O
DI = Os
westr
y Disa
bility Index; pt = p
atient; R
CT = random
ized c
ontro
lled
trial; rh
BMP-7 =
recomb
inant huma
n bone m
orphogenetic p
rotein–7; TC
P = tricalcium
phosphate
; VAS
= visual analo
g scale.
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Part 16: Bone graft extenders and substitutes
129J Neurosurg: Spine / Volume 21 / July 2014
lower fusion rate (61.7% vs 83.1%). Noninferiority of the overall success was demonstrated after 36 months (47.2% in the investigational group and 46.8% in the control co-hort [p = 0.025]). Computed tomography evaluation dem-onstrated a statistically greater percentage of patients in the control arm demonstrating bridging bone across the intertransverse space (83% vs 56% [p = 0.001]). However, at 36 months after surgery, only 69% of the original 293 patients were available for evaluation. There was no sig-nificant difference in the rate of treatment-related serious adverse events between the investigational and control groups, 85.6% and 84.7% respectively (p = 0.863). No sig-nificant immunological reaction related to the application of rhBMP-7 was recorded. The authors concluded that rh-BMP-7/collagen composite is a safe and effective alterna-tive to ICBG. This was a well-designed and executed trial; however, limitations exist. The randomization process was compromised as 13% of those originally randomized were not treated, and no data are provided regarding these pa-tients or those lost at final follow-up. The method of fu-sion assessment was altered at the final follow-up, with the addition of CT images, and a significant number of patients not available for evaluation (> 30%). Due to these limitations the study was downgraded to Level II evidence that rhBMP-7/ACS is noninferior to AICB for noninstru-mented posterolateral lumbar fusion.
Kanayama et al. conducted a prospective RCT to com-pare the clinical and radiographic outcomes in 20 patients with degenerative spondylolisthesis receiving either rh-BMP-7/ACS (n = 10) or local autograft/HA/TCP (n = 10) for single-level posterolateral instrumented fusions.35 Fu-sion status was assessed using plain radiographs and CT images at 3 and 6 weeks as well as at 3, 6, and 12 months after surgery. Validated clinical outcome measures (ODI) were obtained at 3, 6, 9, and 12 months after surgery. Re-gardless of clinical status, all patients underwent a second surgery to remove their instrumentation if a solid arthrod-esis was diagnosed based on radiographic imaging, on av-erage 15.3 months following the index procedure. At 1 year after surgery the follow-up rate was 90%. The ODI scores significantly improved at 3 months in both cohorts; how-ever, it is difficult to determine if the significance of this improvement was maintained beyond 3 months. The fu-sion rate based on radiographic assessment was 78% in the rhBMP-7 cohort; however, only 57% of these patients dem-onstrated a solid arthrodesis during direct surgical explora-tion. The radiographic fusion rate of the control group was 90%, with 78% of controls demonstrating a fusion at the time of implant removal. No statistical analysis regarding fusion rate was performed. The authors concluded that uti-lization of rhBMP-7 was feasible, but the observed fusion rate was not encouraging, suggesting that modifications of the surgical technique or carrier were required. The study cohort was small yet homogeneous with respect to surgical procedure and presenting diagnosis. It is not clear if the ra-diographic assessment was performed in a blinded fashion; however, confirmation of fusion through direct operative exploration is considered the gold standard for fusion as-sessment. Limitations of the study design include failure to describe the randomization scheme or perform a power calculation to determine sample size. The authors failed
to perform an adequate statistical analysis; this may be a secondary consequence of the small sample size. Despite the randomized nature of this study, the study was down-graded to Level II evidence suggesting that rhBMP-7 is an inadequate substitute for AICB in instrumented posterolat-eral fusion.
Vaccaro et al. published 3 separate studies over a 4-year period reporting the radiographic and clinical results from a prospective randomized controlled multicenter clinical pilot study investigating the efficacy and safety of OP-1 compared with AICB in noninstrumented posterolateral lumbar fusions.61,64,65 The original pilot study, published in 2004, randomized 36 patients with degenerative spondy-lolisthesis to receive either rhBMP-7/ACS or AICB.64 The initial study followed patients at 6 weeks and at 3, 6, and 12 months after the index procedure. An independent blinded radiologist evaluated plain radiographs to assess fusion and validated outcome measures; ODI and SF-36, were used to assess clinical status. At 12 months after surgery, the follow-up rate was 79% for the rhBMP-7 cohort and 83% for the control group. No short-term adverse events directly related to the use of rhBMP-7 were reported. At 12 months after surgery, the fusion and clinical success rates were 74% and 86%, respectively, for the rhBMP-7 co-hort and 60% and 73%, respectively, in the control group, with no statistically significant difference between groups. From this initial study the authors concluded that rhBMP-7 has an acceptable safety profile and comparable results to AICB to justify further investigation. This initial study was limited by the lack of a power calculation, a small sample size (< 50 patients), and significant loss to follow-up within the interventional group. A nonvalidated overall clinical outcome composite score is included that is difficult to ob-jectify. Given these limitations, and those inherent with a pilot study, the initial publication is downgraded to Level II evidence in support of an acceptable safety profile and comparable efficacy of rhBMP-7 to AICB.
The same authors published 2 follow-up studies in 2005 and 2008 to report the 2- and 4-year outcomes from the same study population.61,65 As the initial report provid-ed Level II evidence, the subsequent reports were started at this level and downgraded further if additional limitations were identified. At the 24-month follow-up end point, the follow-up rate for the investigational and control groups were 86% and 83%, respectively.61 Radiographic fusion occurred in 55% of patients receiving OP-1 and 40% of AICB patients. Clinical success was recorded in 85% of OP-1 patients and 64% of control patients. No additional limitations were identified in this study; therefore, a Level II designation is maintained. However, at 48 months only 69% and 61% were available for clinical and radiographic evaluations, respectively.65 The fusion and clinical success rates were reported as 68.8% and 73.7% in the rh-BMP-7 group and 50% and 57.1% in the control cohort. Due to the small number of patients available at 48 months, formal statistical analysis was not performed. The authors con-cluded that rhBMP-7 had an acceptable safety profile and comparable results to AICB. Due to the additional attrition of patients at the 48-month follow-up time point, this study was downgraded to Level III evidence in support of com-parable efficacy between rhBMP-7 and AICB.
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M. G. Kaiser et al.
130 J Neurosurg: Spine / Volume 21 / July 2014
In 2003, Vaccaro et al. conducted a pilot study to de-termine the safety of rhBMP-7 combined with AICB for posterolateral uninstrumented fusions in patients with symptomatic degenerative spondylolisthesis.63 Seventy-five percent of patients achieved clinical success and 55% at-tained a solid fusion. There were no adverse events spe-cifically associated with the use of rhBMP-7. The authors concluded that rhBMP-7 demonstrated an acceptable safe-ty profile when used as an adjunct to AICB. The small pa-tient population, comparison with a historical cohort, and relatively short follow-up for a fusion procedure limit the study. Due to these limitations the study is downgraded to Level IV evidence. As this was the only study investigating this specific application of rhBMP-7, there is insufficient evidence to formulate a recommendation.
SummaryA wide variety of bone graft extenders and substitutes
are currently available. Enhanced fusion rates and the ability to avoid complications associated with iliac crest harvesting are the intended benefits of their use. Many, if not all, of these extenders and substitutes evaluated in this review have demonstrated a positive effect on fusion rate with clinical outcomes comparable to AICB. Convincing evidence exists that calcium-based composites cannot be considered substitutes for AICB due to inferior fusion rates. These materials, along with allograft-derived grafts (DBM), function primarily as extenders, requiring some form of autograft to achieve adequate fusion rates. There has been little if any risk associated with the use of these extenders.
Bone morphogenetic proteins have dramatically al-tered the landscape of spinal fusion surgery. These pow-erful osteoinductive agents have demonstrated excellent potential as substitutes for AICB with both interbody and posterolateral fusions. The vast majority of investigations have evaluated the effect of rhBMP-2. Although rhBMP-2 has shown a positive effect on fusion rate, complications have been reported related to its use. As a result, careful consideration is required when utilizing these products.
Despite the beneficial effect on fusion, the current literature has also not adequately addressed the issue of whether these improved fusion rates justify the cost, es-pecially for treatment of routine degenerative lumbar dis-ease. Although it is likely that certain patient populations would benefit from the addition of BMPs when perform-ing spinal fusion surgery, the current literature has failed to adequately identify such patient populations.
Key Issues for Future InvestigationThere has already been an extensive amount of re-
search investigating the potential impact of these graft extenders and substitutes. Further investigations should focus on improving study design to validate the conclu-sions formulated from previous publications and a com-prehensive evaluation of risks and complications will be necessary to properly inform our patients. Identification of patient populations at risk for pseudarthrosis would also better define patient populations where the benefits of utilizing BMPs justify the risks. Potentially more rel-
evant than defining the clinical impact of these materi-als is to determine their cost utility. Comprehensive cost analyses, not simply a superficial quantification of upfront costs, will ultimately be required. Such an endeavor will require the concerted effort of a multidisciplinary panel of experts from the clinical, epidemiological, and admin-istrative disciplines.
Acknowledgments
We would like to acknowledge the AANS/CNS Joint Guide-lines Committee (JGC) for their review, comments, and sugges-tions; Laura Mitchell, CNS Guidelines Project Manager, for her organizational assistance; and Linda O’Dwyer, medical librarian, for assistance with the literature searches. We would also like to acknowledge the following individual JGC members for their con-tributions throughout the review process: Timothy Ryken, M.D.; Kevin Cockroft, M.D.; Sepideh Amin-Hanjani, M.D.; Steven N. Kalkanis, M.D.; John O’Toole, M.D., M.S.; Steven Casha, M.D., Ph.D.; Aaron Filler, M.D., Ph.D., F.R.C.S.; Daniel Hoh, M.D.; Steven Hwang, M.D.; Todd McCall, M.D.; Jeffrey J. Olson, M.D.; Julie Pilitsis, M.D., Ph.D.; Joshua Rosenow, M.D.; and Christopher Winfree, M.D.
Disclosure
Administrative costs of this project were funded by the Con-gress of Neurological Surgeons and the Joint Section on Disorders of the Spine and Peripheral Nerves of the American Association of Neurological Surgeons and Congress of Neurological Surgeons. No author received payment or honorarium for time devoted to this project. Dr. Ghogawala receives grants from the Patient Centered Outcomes Research Institute (PCORI) and the National Institutes of Health (NIH). Dr. Groff is a consultant for DePuy Spine and EBI Spine. Dr. Mummaneni owns stock in Spinicity and receives hono-raria from DePuy Spine and Globus and royalties from DePuy Spine, Quality Medical Publishers, and Thieme Publishing. Dr. Wang owns stock in Bone Biologics, AxioMed, Amedica, CoreSpine, Expand-ing Orthopedics, Pioneer, Syndicom, VG Innovations, PearlDiver, Flexuspine, Axis, FzioMed, Benvenue, Promethean, Nexgen, Elec-troCore, and Surgitech and holds patents with and receives royalties from Biomet, Stryker, SeaSpine, Aesculap, Osprey, Amedica, Syn-thes, and Alphatec. The authors report no other potential conflicts of interest concerning the materials or methods used in this study or the findings specified in this paper.
Author contributions to the study and manuscript preparation include the following. Acquisition of data: all authors. Analysis and interpretation of data: all authors. Drafting the article: Kaiser. Criti-cally revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Kaiser. Study supervision: Kaiser.
References
1. Acharya NK, Kumar RJ, Varma HK, Menon VK: Hydroxyap-atite-bioactive glass ceramic composite as stand-alone graft substitute for posterolateral fusion of lumbar spine: a prospec-tive, matched, and controlled study. J Spinal Disord Tech 21:106–111, 2008
2. Agarwal R, Williams K, Umscheid CA, Welch WC: Osteoin-ductive bone graft substitutes for lumbar fusion: a systematic review. Clinical article. J Neurosurg Spine 11:729–740, 2009
3. Balseiro S, Nottmeier EW: Vertebral osteolysis originating from subchondral cyst end plate defects in transforaminal lumbar interbody fusion using rhBMP-2. Report of two cases. Spine J 10:e6–e10, 2010
4. Banwart JC, Asher MA, Hassanein RS: Iliac crest bone graft harvest donor site morbidity. A statistical evaluation. Spine (Phila Pa 1976) 20:1055–1060, 1995
Unauthenticated | Downloaded 02/13/22 06:58 AM UTC
Part 16: Bone graft extenders and substitutes
131J Neurosurg: Spine / Volume 21 / July 2014
5. Burkus JK, Dorchak JD, Sanders DL: Radiographic assess-ment of interbody fusion using recombinant human bone mor-phogenetic protein type 2. Spine (Phila Pa 1976) 28:372–377, 2003
6. Burkus JK, Gornet MF, Dickman CA, Zdeblick TA: Anterior lumbar interbody fusion using rhBMP-2 with tapered inter-body cages. J Spinal Disord Tech 15:337–349, 2002
7. Burkus JK, Gornet MF, Schuler TC, Kleeman TJ, Zdeblick TA: Six-year outcomes of anterior lumbar interbody arthrod-esis with use of interbody fusion cages and recombinant hu-man bone morphogenetic protein-2. J Bone Joint Surg Am 91:1181–1189, 2009
8. Cammisa FP Jr, Lowery G, Garfin SR, Geisler FH, Klara PM, McGuire RA, et al: Two-year fusion rate equivalency between Grafton DBM gel and autograft in posterolateral spine fusion: a prospective controlled trial employing a side-by-side compari-son in the same patient. Spine (Phila Pa 1976) 29:660–666, 2004
9. Carragee EJ, Ghanayem AJ, Weiner BK, Rothman DJ, Bono CM: A challenge to integrity in spine publications: years of living dangerously with the promotion of bone growth factors. Spine J 11:463–468, 2011
10. Carragee EJ, Mitsunaga KA, Hurwitz EL, Scuderi GJ: Retro-grade ejaculation after anterior lumbar interbody fusion using rhBMP-2: a cohort controlled study. Spine J 11:511–516, 2011
11. Carter JD, Swearingen AB, Chaput CD, Rahm MD: Clinical and radiographic assessment of transforaminal lumbar inter-body fusion using HEALOS collagen-hydroxyapatite sponge with autologous bone marrow aspirate. Spine J 9:434–438, 2009
12. Chang CH, Lin MZ, Chen YJ, Hsu HC, Chen HT: Local au-togenous bone mixed with bone expander: an optimal option of bone graft in single-segment posterolateral lumbar fusion. Surg Neurol 70 Suppl 1:S47–S49, 2008
13. Chen CL, Liu CL, Sun SS, Han PY, Lee CS, Lo WH: Postero-lateral lumbar spinal fusion with autogenous bone chips from laminectomy extended with OsteoSet. J Chin Med Assoc 69:581–584, 2006
14. Chen NF, Smith ZA, Stiner E, Armin S, Sheikh H, Khoo LT: Symptomatic ectopic bone formation after off-label use of recombinant human bone morphogenetic protein-2 in trans-foraminal lumbar interbody fusion. Report of 4 cases. J Neu-rosurg Spine 12:40–46, 2010
15. Chen WJ, Tsai TT, Chen LH, Niu CC, Lai PL, Fu TS, et al: The fusion rate of calcium sulfate with local autograft bone compared with autologous iliac bone graft for instrumented short-segment spinal fusion. Spine (Phila Pa 1976) 30:2293–2297, 2005
16. Dai LY, Jiang LS: Single-level instrumented posterolateral fu-sion of lumbar spine with beta-tricalcium phosphate versus autograft: a prospective, randomized study with 3-year fol-low-up. Spine (Phila Pa 1976) 33:1299–1304, 2008
17. Dawson E, Bae HW, Burkus JK, Stambough JL, Glassman SD: Recombinant human bone morphogenetic protein-2 on an absorbable collagen sponge with an osteoconductive bulk-ing agent in posterolateral arthrodesis with instrumentation. A prospective randomized trial. J Bone Joint Surg Am 91:1604–1613, 2009
18. Delawi D, Dhert WJ, Rillardon L, Gay E, Prestamburgo D, Garcia-Fernandez C, et al: A prospective, randomized, con-trolled, multicenter study of osteogenic protein-1 in instru-mented posterolateral fusions: report on safety and feasibility. Spine (Phila Pa 1976) 35:1185–1191, 2010
19. Dimar JR, Glassman SD, Burkus KJ, Carreon LY: Clinical outcomes and fusion success at 2 years of single-level instru-mented posterolateral fusions with recombinant human bone morphogenetic protein-2/compression resistant matrix versus iliac crest bone graft. Spine (Phila Pa 1976) 31:2534–2540, 2006
20. Dimar JR II, Glassman SD, Burkus JK, Pryor PW, Hardacker JW, Carreon LY: Clinical and radiographic analysis of an op-timized rhBMP-2 formulation as an autograft replacement in posterolateral lumbar spine arthrodesis. J Bone Joint Surg Am 91:1377–1386, 2009
21. Epstein NE: Beta tricalcium phosphate: observation of use in 100 posterolateral lumbar instrumented fusions. Spine J 9:630–638, 2009
22. Epstein NE: Efficacy of different bone volume expanders for augmenting lumbar fusions. Surg Neurol 69:16–19, 2008
23. Garrett MP, Kakarla UK, Porter RW, Sonntag VKH: Forma-tion of painful seroma and edema after the use of recombinant human bone morphogenetic protein-2 in posterolateral lum-bar spine fusions. Neurosurgery 66:1044–1049, 2010
24. Geibel PT, Boyd DL, Slabisak V: The use of recombinant hu-man bone morphogenic protein in posterior interbody fusions of the lumbar spine: a clinical series. J Spinal Disord Tech 22:315–320, 2009
25. Glassman SD, Carreon L, Djurasovic M, Campbell MJ, Puno RM, Johnson JR, et al: Posterolateral lumbar spine fusion with INFUSE bone graft. Spine J 7:44–49, 2007
26. Glassman SD, Carreon LY, Djurasovic M, Campbell MJ, Puno RM, Johnson JR, et al: RhBMP-2 versus iliac crest bone graft for lumbar spine fusion: a randomized, controlled trial in pa-tients over sixty years of age. Spine (Phila Pa 1976) 33:2843–2849, 2008
27. Glassman SD, Dimar JR III, Burkus K, Hardacker JW, Pryor PW, Boden SD, et al: The efficacy of rhBMP-2 for posterolat-eral lumbar fusion in smokers. Spine (Phila Pa 1976) 32:1693–1698, 2007
28. Goldberg VM, Stevenson S: Natural history of autografts and allografts. Clin Orthop Relat Res (225):7–16, 1987
29. Haid RW Jr, Branch CL Jr, Alexander JT, Burkus JK: Poste-rior lumbar interbody fusion using recombinant human bone morphogenetic protein type 2 with cylindrical interbody cag-es. Spine J 4:527–539, 2004
30. Hamilton DK, Jones-Quaidoo SM, Sansur C, Shaffrey CI, Osk-ouian R, Jane JA Sr: Outcomes of bone morphogenetic pro-tein-2 in mature adults: posterolateral non-instrument-assisted lumbar decompression and fusion. Surg Neurol 69:457–462, 2008
31. Heary RF, Schlenk RP, Sacchieri TA, Barone D, Brotea C: Persistent iliac crest donor site pain: independent outcome as-sessment. Neurosurgery 50:510–517, 2002
32. Hsu CJ, Chou WY, Teng HP, Chang WN, Chou YJ: Coralline hydroxyapatite and laminectomy-derived bone as adjuvant graft material for lumbar posterolateral fusion. J Neurosurg Spine 3:271–275, 2005
33. Jenis LG, Banco RJ: Efficacy of silicate-substituted calcium phosphate ceramic in posterolateral instrumented lumbar fu-sion. Spine (Phila Pa 1976) 35:E1058–E1063, 2010
34. Joseph V, Rampersaud YR: Heterotopic bone formation with the use of rhBMP2 in posterior minimal access interbody fu-sion: a CT analysis. Spine (Phila Pa 1976) 32:2885–2890, 2007
35. Kanayama M, Hashimoto T, Shigenobu K, Yamane S, Bauer TW, Togawa D: A prospective randomized study of postero-lateral lumbar fusion using osteogenic protein-1 (OP-1) versus local autograft with ceramic bone substitute: emphasis of sur-gical exploration and histologic assessment. Spine (Phila Pa 1976) 31:1067–1074, 2006
36. Katayama Y, Matsuyama Y, Yoshihara H, Sakai Y, Nakamura H, Imagama S, et al: Clinical and radiographic outcomes of posterolateral lumbar spine fusion in humans using recombi-nant human bone morphogenetic protein-2: an average five-year follow-up study. Int Orthop 33:1061–1067, 2009
37. Knox JB, Dai JM III, Orchowski J: Osteolysis in transforami-nal lumbar interbody fusion with bone morphogenetic pro-tein-2. Spine (Phila Pa 1976) 36:672–676, 2011
Unauthenticated | Downloaded 02/13/22 06:58 AM UTC
M. G. Kaiser et al.
132 J Neurosurg: Spine / Volume 21 / July 2014
38. Korovessis P, Koureas G, Zacharatos S, Papazisis Z, Lambiris E: Correlative radiological, self-assessment and clinical anal-ysis of evolution in instrumented dorsal and lateral fusion for degenerative lumbar spine disease. Autograft versus coralline hydroxyapatite. Eur Spine J 14:630–638, 2005
39. Kurz LT, Garfin SR, Booth RE Jr: Harvesting autogenous iliac bone grafts. A review of complications and techniques. Spine (Phila Pa 1976) 14:1324–1331, 1989
40. Lanman TH, Hopkins TJ: Lumbar interbody fusion after treatment with recombinant human bone morphogenetic pro-tein-2 added to poly(L-lactide-co-D,L-lactide) bioresorbable implants. Neurosurg Focus 16(3):E9, 2004
41. Lee JH, Hwang CJ, Song BW, Koo KH, Chang BS, Lee CK: A prospective consecutive study of instrumented posterolateral lumbar fusion using synthetic hydroxyapatite (Bongros-HA) as a bone graft extender. J Biomed Mater Res A 90:804–810, 2009
42. Lewandrowski KU, Nanson C, Calderon R: Vertebral osteoly-sis after posterior interbody lumbar fusion with recombinant human bone morphogenetic protein 2: a report of five cases. Spine J 7:609–614, 2007
43. Mindea SA, Shih P, Song JK: Recombinant human bone mor-phogenetic protein-2-induced radiculitis in elective minimally invasive transforaminal lumbar interbody fusions: a series re-view. Spine (Phila Pa 1976) 34:1480–1485, 2009
44. Mummaneni PV, Pan J, Haid RW, Rodts GE: Contribution of recombinant human bone morphogenetic protein-2 to the rapid creation of interbody fusion when used in transforaminal lum-bar interbody fusion: a preliminary report. J Neurosurg Spine 1:19–23, 2004
45. Neen D, Noyes D, Shaw M, Gwilym S, Fairlie N, Birch N: Healos and bone marrow aspirate used for lumbar spine fu-sion: a case controlled study comparing healos with autograft. Spine (Phila Pa 1976) 31:E636–E640, 2006
46. Ong KL, Villarraga ML, Lau E, Carreon LY, Kurtz SM, Glassman SD: Off-label use of bone morphogenetic proteins in the United States using administrative data. Spine (Phila Pa 1976) 35:1794–1800, 2010
47. Pradhan BB, Bae HW, Dawson EG, Patel VV, Delamarter RB: Graft resorption with the use of bone morphogenetic protein: lessons from anterior lumbar interbody fusion using femoral ring allografts and recombinant human bone morphogenetic protein-2. Spine (Phila Pa 1976) 31:E277–E284, 2006
48. Resnick DK, Choudhri TF, Dailey AT, Groff MW, Khoo L, Matz PG, et al: Guidelines for the performance of fusion pro-cedures for degenerative disease of the lumbar spine. Part 16: bone graft extenders and substitutes. J Neurosurg Spine 2: 733–736, 2005
49. Rihn JA, Makda J, Hong J, Patel R, Hilibrand AS, Anderson DG, et al: The use of RhBMP-2 in single-level transforaminal lumbar interbody fusion: a clinical and radiographic analysis. Eur Spine J 18:1629–1636, 2009
50. Rihn JA, Patel R, Makda J, Hong J, Anderson DG, Vaccaro AR, et al: Complications associated with single-level trans-foraminal lumbar interbody fusion. Spine J 9:623–629, 2009
51. Schizas C, Triantafyllopoulos D, Kosmopoulos V, Tzinier-is N, Stafylas K: Posterolateral lumbar spine fusion using a novel demineralized bone matrix: a controlled case pilot study. Arch Orthop Trauma Surg 128:621–625, 2008
52. Shah RK, Moncayo VM, Smitson RD, Pierre-Jerome C, Terk MR: Recombinant human bone morphogenetic protein 2-in-duced heterotopic ossification of the retroperitoneum, psoas muscle, pelvis and abdominal wall following lumbar spinal fusion. Skeletal Radiol 39:501–504, 2010
53. Singh K, Smucker JD, Gill S, Boden SD: Use of recombinant human bone morphogenetic protein-2 as an adjunct in pos-terolateral lumbar spine fusion: a prospective CT-scan analy-sis at one and two years. J Spinal Disord Tech 19:416–423, 2006 (Erratum in J Spinal Disord Tech 20:185, 2007)
54. Slosar PJ, Josey R, Reynolds J: Accelerating lumbar fusions by combining rhBMP-2 with allograft bone: a prospective analy-sis of interbody fusion rates and clinical outcomes. Spine J 7: 301–307, 2007
55. Summers BN, Eisenstein SM: Donor site pain from the ilium. A complication of lumbar spine fusion. J Bone Joint Surg Br 71:677–680, 1989
56. Taghavi CE, Lee KB, Keorochana G, Tzeng ST, Yoo JH, Wang JC: Bone morphogenetic protein-2 and bone marrow aspirate with allograft as alternatives to autograft in instrumented revi-sion posterolateral lumbar spinal fusion: a minimum two-year follow-up study. Spine (Phila Pa 1976) 35:1144–1150, 2010
57. Urist MR: Bone: formation by autoinduction. Science 150:893–899, 1965
58. US Food and Drug Administration: InFUSE™ Bone Graft/LT-CAGE™ Lumbar Tapered Fusion Device - P000058. http://www.fda.gov/MedicalDevices/ProductsandMedical Procedures/DeviceApprovalsandClearances/Recently-Ap provedDevices/ucm083423.htm) [Accessed April 21, 2014]
59. US Food and Drug Administration: Listing of CDRH Hu-manitarian Device Exemptions. (http://www.fda.gov/Medical Devices/ProductsandMedicalProcedures/DeviceApprovals andClearances/HDEApprovals/ucm161827.htm) [Accessed April 21, 2014]
60. US Food and Drug Administration: OP-1 Putty - H0200008. (http://www.fda.gov/MedicalDevices/ProductsandMedical rocedures/DeviceApprovalsandClearances/Recently-App rovedDevices/ucm081181.htm) [Accessed April 21, 2014]
61. Vaccaro AR, Anderson DG, Patel T, Fischgrund J, Truumees E, Herkowitz HN, et al: Comparison of OP-1 Putty (rhBMP-7) to iliac crest autograft for posterolateral lumbar arthrodesis: a minimum 2-year follow-up pilot study. Spine (Phila Pa 1976) 30:2709–2716, 2005
62. Vaccaro AR, Lawrence JP, Patel T, Katz LD, Anderson DG, Fis-chgrund JS, et al: The safety and efficacy of OP-1 (rhBMP-7) as a replacement for iliac crest autograft in posterolateral lumbar arthrodesis: a long-term (>4 years) pivotal study. Spine (Phila Pa 1976) 33:2850–2862, 2008
63. Vaccaro AR, Patel T, Fischgrund J, Anderson DG, Truumees E, Herkowitz H, et al: A pilot safety and efficacy study of OP-1 putty (rhBMP-7) as an adjunct to iliac crest autograft in posterolateral lumbar fusions. Eur Spine J 12:495–500, 2003
64. Vaccaro AR, Patel T, Fischgrund J, Anderson DG, Truumees E, Herkowitz HN, et al: A pilot study evaluating the safety and ef-ficacy of OP-1 Putty (rhBMP-7) as a replacement for iliac crest autograft in posterolateral lumbar arthrodesis for degenerative spondylolisthesis. Spine (Phila Pa 1976) 29:1885–1892, 2004
65. Vaccaro AR, Whang PG, Patel T, Phillips FM, Anderson DG, Albert TJ, et al: The safety and efficacy of OP-1 (rhBMP-7) as a replacement for iliac crest autograft for posterolateral lum-bar arthrodesis: minimum 4-year follow-up of a pilot study. Spine J 8:457–465, 2008
66. Vaidya R, Weir R, Sethi A, Meisterling S, Hakeos W, Wybo CD: Interbody fusion with allograft and rhBMP-2 leads to consistent fusion but early subsidence. J Bone Joint Surg Br 89:342–345, 2007
67. Villavicencio AT, Burneikiene S, Nelson EL, Bulsara KR, Fa-vors M, Thramann J: Safety of transforaminal lumbar inter-body fusion and intervertebral recombinant human bone mor-phogenetic protein-2. J Neurosurg Spine 3:436–443, 2005
Manuscript submitted March 27, 2014.Accepted April 9, 2014.Please include this information when citing this paper: DOI:
10.3171/2014.4.SPINE14325.Address correspondence to: Michael G. Kaiser, M.D., Columbia
University, Neurological Surgery, The Neurological Institute, 710 W. 168th St., New York, NY 10032. email: [email protected].
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