The Journal of Bone and Joint Surgery (American) 83:1219-1230 (2001)
© 2001 The Journal of Bone and Joint Surgery, Inc.
Recombinant Human Bone Morphogenetic Protein-2 Accelerates Healing in a Rabbit Ulnar Osteotomy Model
M. L. Bouxsein, PhD,
T. J. Turek, BS,
C. A. Blake, BS,
D. D’Augusta, BS,
X. Li, MD,
M. Stevens, BS,
H. J. Seeherman, PhD, VMD and
J. M. Wozney, PhD
Investigation performed at Musculoskeletal Sciences, Genetics
Institute/Wyeth-Ayerst Research, Cambridge, Massachusetts
M.L. Bouxsein, PhD
T.J. Turek, BS
C.A. Blake, BS
D. D’Augusta, BS
X. Li, MD
M. Stevens, BS
H.J. Seeherman, PhD, VMD
J.M. Wozney, PhD
Musculoskeletal Sciences, Genetics Institute/Wyeth-Ayerst Research,
87 Cambridge Park Drive, Cambridge, MA 02140. E-mail address for
M.L. Bouxsein: mbouxsein{at}genetics.com
The authors did not receive grants or outside funding in support
of their research or preparation of this manuscript. One or more
of the authors received payments or other benefits or a commitment
or agreement to provide such benefits from a commercial entity (Genetics
Institute). No commercial entity paid or directed, or agreed to
pay or direct, any benefits to any research fund, foundation, educational
institution, or other charitable or nonprofit organization with
which the authors are affiliated or associated.
Read in part at the Annual Meeting of the Orthopaedic Research
Society, Anaheim, California, February 2, 1999.
Background: Approximately 5% to 20% of
fractures have delayed or impaired healing. Therefore, it is desirable
to develop new therapies to enhance fracture-healing that can be
used in conjunction with traditional treatment methods. The purpose
of this study was to evaluate the ability of a single application
of recombinant human bone morphogenetic protein-2 to accelerate
fracture-healing in a rabbit ulnar osteotomy that heals spontaneously.
Methods: Bilateral mid-ulnar osteotomies (approximately
0.5 to 1.0 mm wide) were created in seventy-two skeletally mature
male rabbits. The limbs were assigned to one of three groups: those treated
with an absorbable collagen sponge containing recombinant human
bone morphogenetic protein-2, those treated with an absorbable collagen
sponge containing buffer, and those left untreated. In the first
two groups, an 8 20-mm strip of absorbable collagen sponge containing
either 40 g of recombinant human bone morphogenetic protein-2 or
buffer only was wrapped around the osteotomy site. The rabbits were
killed at two, three, four, or six weeks after surgery. In addition,
twenty-four age-matched rabbits were used to provide data on the
properties of intact limbs. The retention of recombinant human bone
morphogenetic protein-2 at the osteotomy site was determined with
scintigraphic imaging of 125I-labeled
recombinant human bone morphogenetic protein-2. After the rabbits
were killed, the limbs were scanned with peripheral quantitative
computed tomography to assess the area and mineral content of the
mineralized callus. The limbs were then tested to failure in torsion,
and undecalcified specimens were evaluated histologically.
Results: Gamma scintigraphy of 125I-recombinant
human bone morphogenetic protein-2 showed that 73% ± 6% (mean and standard deviation) of the
administered dose was initially retained at the fracture site. Approximately
37% ± 10% of the initial
dose remained at the site one week after surgery, and 8% ± 7% remained after two weeks. The mineralized
callus area was similar in all groups at two weeks, but it was 20% to
60% greater in the ulnae treated with recombinant human
bone morphogenetic protein-2 than in either the ulnae treated with buffer
or the untreated ulnae at three, four, and six weeks (p < 0.05).
Biomechanical properties were similar in all groups at two weeks,
but they were at least 80% greater in the ulnae treated
with recombinant human bone morphogenetic protein-2 at three and
four weeks than in either the ulnae treated with buffer (p < 0.005)
or the untreated ulnae (p < 0.01). By four weeks, the biomechanical
properties of the ulnae treated with recombinant human bone morphogenetic
protein-2 were equivalent to those of the intact ulnae, whereas
the biomechanical properties of both the ulnae treated with buffer
and the untreated ulnae had reached only approximately 45% of those
of the intact ulnae. At six weeks, the biomechanical properties
were similar in all groups and were equivalent to those of the intact
ulnae. The callus geometry and biomechanical properties of the ulnae
treated with buffer were equivalent to those of the untreated ulnae
at all time-points.
Conclusions and Clinical Relevance: These findings
indicate that treatment with an absorbable collagen sponge containing
recombinant human bone morphogenetic protein-2 enhances healing
of a long-bone osteotomy that heals spontaneously. Specifically,
osteotomies treated with recombinant human bone morphogenetic protein-2 healed
33% faster than osteotomies left untreated. The results of
this study provide a rationale for testing the ability of recombinant
human bone morphogenetic protein-2 to accelerate healing in patients
with fractures requiring open surgical management.
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