on Spinal Applications for Recombinant Bone Morphogenetic
Harvinder S. Sandhu, MD(1), Frank P. Cammisa, MD (1),
Stephen E. Heim, MD (2), Edgar G. Dawson, MD(3), Rick B. Delamarter,
MD(3), Eduardo F. Luque, MD(4)
1. New York, 2. Chicago, 3. Los Angeles,
4. Mexico City
An arthrodesis (fusion) of adjacent vertebral segments of
the spinal column is surgically created in nearly 200,000 patients per
year in the United States. Despite recent technical advances, the
incidence of failure of such intervention is still significant.
Furthermore, substantial amounts of autogenous bone graft must be procured
and transplanted from the ileum to the spine to enable consolidation of a
fusion mass with elements of the spinal column. The additional morbidity
associated with this procedure is well known. Finally, secondary attempts
at spinal fusion following initial failure have even a poorer prognosis
and pose greater challenges.
Advances in spinal fixation devices have addressed
some mechanical considerations. However, osteogenesis and skeletal healing
(fusion consolidation) are biologic processes which are facilitated but
not replaced by instrumented fixation. Recently, considerable attention
has been directed toward biologic considerations and, in particular, novel
growth factors that regulate and promote these biologic processes. This
renewed focus has been a consequence of the successful isolation,
purification, and characterization of an entire family of bone
morphogenetic proteins (BMPs), and the demonstration that a singular
molecular species of recombinant human BMP (rhBMP) could induce the entire
cascade of endochondral osteogenesis. Optimism for using such growth
factors as effective bone-graft substitutes increased following a series
of valuable preclinical animal experiments.
Preclinical Studies with
During the past four years several
investigators have demonstrated that rhBMP-2 and rhBMP-7, combined with
appropriate delivery vehicles, can induce successful posterolateral spinal
fusion in rabbits, dogs, and rhesus monkeys without need for autogenous
bone graft. The fusion rate and strength of fusion mass was equal or
superior to the rate and strength of fusions produced with autogenous
graft from the iliac crest. Cook and associates demonstrated that when
using osteogenic protein-1 (OP-1 or rhBMP-7), posterior lumbar
interlaminar fusions in dogs occurred in 12 weeks compared to 26 weeks
when iliac crest bone was used. Sandhu and David, in separate studies,
reported a 100% rate of lumbar intertransverse process fusion in beagles
within six months of implantation of rhBMP-2 compared to 0% and 33% rate
of fusion with autogenous iliac crest. Boden, using a rabbit lumbar
intertransverse process fusion model with a four week postoperative
endpoint, reported a 100%-fusion rate with rhBMP-2 and a 42%-fusion rate
with autogenous graft.
The efficacy of rhBMP-2 for producing anterior
spinal column fusions was also explored. Sandhu et al demonstrated that
implantation of threaded titanium intervertebral “cages” containing
rhBMP-2 without autograft in a sheep anterior lumbar interbody fusion
(ALIF) model consistently resulted in rapid intervertebral osseous fusion
through the fixation device. Similarly, the same investigators showed that
when rhBMP-2 was added to porous tantalum ALIF cages in the same model,
significantly greater bone ingrowth into the porous macrostructure
Data obtained from these lower animal models
prompted further investigation in the higher nonhuman primate model. Boden
et al recently demon-strated the efficacy of rhBMP-2 in a rhesus monkey
ALIF model. Laparoscopic assisted L5-S1 ALIF procedures with threaded,
tapered, titanium cages were performed in seven animals. A type I collagen
sponge carrying a high dose of rhBMP-2, a low dose of rhBMP-2, or no
growth factor was placed into the cage prior to implantation. Animals
implanted with a cage containing rhBMP-2 (high or low dose) all had
successful fusions. The control animals implanted with a cage containing
collagen alone did not fuse. In another recently presented study,
Fishgrund et al reported successful anterior cervical interbody fusions in
a primate model using cadaveric allograft bone dowels filled with rhBMP-2
also carried by a type I collagen sponge. Histologic analysis of the
rhBMP-2 associated cervical fusions revealed complete resorption of the
allograft by six months, an observation not seen when the allograft bone
dowels were filled with autogenous bone graft from the iliac
Clinical Trials with rhBMP-2 - Early
Based upon the promising
results obtained from the preclinical studies, carefully selected and
controlled clinical trials with rhBMP-2 have begun. Each of the studies is
still in progress and formal interpretation and presentation of the data
has not been performed. Some preliminary observations have been made and
are included in the summary below.
A clinical trial has been designed to examine the
dose-response relationship of rhBMP-2 carried on a fibrillar collagen
vehicle in a human skeletal defect site. A controlled defect is made in
the anterior iliac crest during tricortical bone harvest for anterior
cervical discectomy and fusion. The collagen sponge is implanted in the
iliac-crest site in each case. One of three specific doses of rhBMP-2 in
buffered solution are combined with the collagen sponge prior to
implantation. A soak time of 30 to 90 minutes is used during preparation
of the composite device. A sham condition in which the sponge has not been
combined with the rhBMP-2 is also used. CT examination of the iliac crest
site postoperatively and six months later is performed. The amount of de
novo bone formation is quantitatively analyzed. Early observations in this
ongoing study suggest bone formation in the iliac crest site along the
rhBMP-2/collagen implant (Figs. 1a,b). Comparison of bone formation
associated with the different doses of rhBMP-2, including the sham
condition, has not been completed.
A clinical trial examining the use of a
rhBMP-2/collagen sponge composite combined with a threaded titanium
interbody fusion cage for anterior lumbar interbody fusion has been
completed. No autogenous bone graft was used in any patient. A total of
fourteen patients were enrolled. CT images of the fusions were obtained
three and six months following surgery. These images demonstrated de novo
bone formation within the cages bridging adjacent vertebral segments. Bone
formation anterior, posterior, and lateral to the cages was also noted
(Figs. 2a,b and Figs. 3a,b). Formal evaluation of fusion status and
clinical outcome has not yet been completed.
(click on thumbnails to view chart)
A clinical trial examining the use of rhBMP-2 in
posterior lumbar fusion surgery for the treatment of degenerative disease
of the lumbar spine is underway. Evidence of de novo bone formation
attributable to the growth factor is present in follow-up plain
radiographs of the lumbar spine (Fig. 4). Formal evaluation of these cases
and their outcomes is currently in progress.
At this time, evaluations of the
clinical applications of the growth factor rhBMP-2 for the spinal column
are in the earliest stages of study. Early observations suggest that this
growth factor is capable of inducing de novo bone formation in the spinal
environments. Formal examination of these clinical cases, however, is
necessary and pending.
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