Copyright © 2009 by The Journal of Bone and Joint Surgery, Inc.
Commentary & Perspective
Commentary & Perspective by
James D. Kang, MD*,
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Posted July 2009
The authors of this study prospectively randomized patients
who were undergoing a posterolateral fusion with instrumentation into two groups:
those who received an iliac crest bone graft, and those who received bone
morphogenetic protein-2 (BMP-2) with a ceramic bulking agent (15%
hydroxyapatite and 85% tricalcium phosphate ceramic granules). They observed a
higher, but not significantly higher, fusion rate in the BMP group as compared
with that in the control group (95% compared with 70%, respectively, at two
years; p = 0.174) and a trend toward better clinical outcome measures in the
BMP group. The study, which was funded and sponsored by Medtronics (Memphis,
Tennessee), suggests that BMP-2 is
effective in promoting bone formation for spinal arthrodesis. BMP-2 has become
a very successful product for its manufacturer, with total annual sales nearing
$763 million1. Although the United States Food and Drug
Administration approval for the use of BMP-2 in the spine is limited to
anterior lumbar arthrodesis with a titanium tapered cage, the majority of BMP-2
use by clinicians is "off-label," during posterior lumbar fusion surgery. The
current study seems to support continued clinical use of BMP-2 in posterior
lumbar spine surgery.
There are several issues that should be put into perspective
when considering the widespread use of BMP-2 in spinal fusion surgery. The
proponents of using BMPs or other bone graft substitutes point to the major
morbidity associated with iliac crest bone-graft harvest, citing risks of wound
infections, hematomas, neuromas, and chronic hip pain. There is no doubt that
such complications do indeed occur with bone-graft harvest; however, it is of
interest that in every prospective randomized clinical study comparing BMP-2
with that of iliac crest bone-graft harvest, the overall patient-based outcomes
never show a statistical difference between the two groups as measured with use
of the Oswestry Disability Index or the Short Form-36 (SF-36)2,3. If
harvesting iliac crest bone graft causes such painful morbidity that severely affects
patients' lives, the outcome measures should support this premise. Therefore,
one must wonder whether the pain associated with the bone-graft site is really
a major adverse factor.
Another important consideration is the cost of BMP-2. At nearly
$4,500 per kit of BMP-2, the cost of using this agent adds a substantial burden
to the overall cost of lumbar fusion surgery. Carreon et al.4 did a
cost analysis of BMP-2 and concluded that BMP-2 is cost-effective when compared
with the costs of revising the greater number of nonunions and complications that
are associated with iliac crest bone-grafting. The net effect of such a
conclusion should result in an overall dollar savings for providing care for
spine patients, and perhaps fewer overall operative procedures because of fewer
complications. However, Martin et al.5 showed that, despite
technological advancements in spinal surgery in the 1990s, the overall cost of
spine care in the U.S. and the total number of revision spinal operations being
done have increased substantially over the ensuing decade. It is also quite
possible that the number of fusion surgeries has increased due to the relative
"ease" of doing a fusion operation with BMP-2.
It is of interest to review a study by Boden et al. in 20026,
as it is similar to the current study. Boden et al. reported on the results of
a pilot study (also sponsored by Medtronics) in which patients were prospectively
randomized into three groups: posterolateral fusion with instrumentation and iliac
crest bone graft; fusion with instrumentation and BMP-2 with the addition of
15% hydroxyapatite and 85% tricalcium phosphate ceramic bulking agent; and
fusion with only BMP-2 with the addition of 15% hydroxyapatite and 85%
tricalcium phosphate ceramic bulking agent and without instrumentation. The
study showed that the best patient-based outcomes occurred in patients who underwent
posterior lumbar fusion with BMP-2 (and ceramic bulking agent) alone without
spinal instrumentation. Both of the BMP-2 groups (with and without
instrumentation) achieved a fusion rate of 100%. The small number of patients
in this study (n = 25) precluded a definitive conclusion that instrumentation
was not necessary if BMP-2 was utilized, but the study confirmed the
effectiveness of BMP-2 in achieving a solid arthrodesis. If this study had been
moved into a pivotal trial with larger number of patients, it might have been
possible to demonstrate more conclusively that BMP-2 can replace not only iliac
crest bone graft but perhaps also spinal instrumentation (for single-level
lumbar fusion). Unfortunately, this larger-scale study was never done. The
question raised by Boden's study (i.e., Do we need spinal instrumentation for
single-level fusions if BMP-2 is used?) has yet to be definitively answered. If
BMP-2 can truly obviate the need for spinal instrumentation, then its cost
would be better justified.
This leads to another critical issue concerning industry-supported
clinical trials. There is no doubt that the costs associated with doing
prospective clinical trials can be prohibitive for noncommercial funding
bodies. Industry-sponsored clinical trials can be valuable in this regard, and they
help clinicians study important clinical questions. Obviously, the results of
the current study support efforts by Medtronics to promote the effectiveness of
BMP-2. Although the authors of this study are outstanding surgeons and
clinicians, the possibility of clinical bias must be considered when
interpreting the relevance of this study. In a perfect world, this study would
have more credence if it were funded by a public or university source.
Despite the concerns mentioned above, a careful analysis of
the data permits several conclusions to be made with respect to use of BMP-2 in
surgery of the lumbar spine. BMP-2 has been shown to be efficacious in spinal
fusion surgery and has yielded results that are comparable with those obtained
with use of iliac crest autograft. However, whether BMP-2 should definitively
replace the "gold standard" (iliac crest bone graft) is still debatable. Governmental
and insurance agencies that closely scrutinize the clinical data will note that
patient-based outcomes have not really been significantly improved with the use
of BMP-2 (i.e., slightly higher fusion rates did not collectively result in
improved outcomes). In this era of escalating medical costs, it seems prudent
for all spine surgeons to carefully review not only the effectiveness but the
cost-effectiveness of expensive biological agents. Finally, it should be remembered
that use of BMP-2 should not obviate the need for meticulous surgical
technique. Complete soft-tissue dissection to expose the intricate osseous
anatomy of the posterolateral spine, along with careful decortication to
optimize the fusion bed, will more likely lead to a solid arthrodesis
regardless of whether BMP-2 or iliac crest bone graft is used.
*The author did not receive any outside funding or grants in support of his research for or preparation of this work. Neither he nor a member of his immediate family received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity.
References
1. Mroz T, Yamashita T, Lieberman I. The on and off-label use of rhBMP-2 Infuse in Medicare and non-Medicare patients. The Spine Journal. 2008;8:41S-42S.
2. Papakostidis C, Kontakis G, Bhandari M, Giannoudis PV. Efficacy of autologous iliac crest bone graft and bone morphogenetic proteins for posterolateral fusion of lumbar spine: a meta-analysis of the results. Spine. 2008;33:E680-E692.
3. Dimar JR, Glassman SD, Burkus KJ, Carreon LY. Clinical outcomes and fusion success at 2 years of single-level instrumented posterolateral fusions with recombinant human bone morphogenetic protein-2/compression resistant matrix versus iliac crest bone graft. Spine. 2006;31:2534-40.
4. Carreon LY, Glassman SD, Djurasovic M, Campbell MJ, Puno RM, Johnson JR, Dimar JR 2nd: RhBMP-2 versus iliac crest bone graft for lumbar spine fusion in patients over 60 years of age: a cost-utility study. Spine. 2009;34:238-43.
5. Martin BI, Mirza SK, Comstock BA, Gray DT, Kreuter W, Deyo RA. Are lumbar spine reoperation rates falling with greater use of fusion surgery and new surgical technology? Spine. 2007;32:2119-26.
6. Boden SD, Kang J, Sandhu H, Heller JG. Use of recombinant human bone morphogenetic protein-2 to achieve posterolateral lumbar spine fusion in humans: a prospective, randomized clinical pilot trial. Spine. 2002;27:2662-73.
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