The Journal of Bone and Joint Surgery (American) 83:S151-S158 (2001)
© 2001 The Journal of Bone and Joint Surgery, Inc.
Clinical Applications of BMPs in Orthopaedic Surgery |
Osteogenic Protein-1 (Bone Morphogenetic Protein-7) in the Treatment of Tibial Nonunions
A Prospective, Randomized Clinical Trial Comparing rhOP-1 with Fresh Bone Autograft*
Gary E. Friedlaender, MD,
Clayton R. Perry, MD,
J. Dean Cole, MD,
Stephen D. Cook, PhD,
George Cierny, MD,
George F. Muschler, MD,
Gregory A. Zych, DO,
Jason H. Calhoun, MD,
Amy J. LaForte, PhD and
Samuel Yin, PhD
From the Department of Orthopaedics and Rehabilitation, Yale
University School of Medicine, New Haven, Connecticut; U.S. Center
for Sports Medicine, St. Louis, Missouri; Orlando Regional Medical
Center, Orlando, Florida; Department of Orthopaedic Surgery, Tulane
University Medical Center School of Medicine, New Orleans, Louisiana;
Resurgens Orthopaedics, Atlanta, Georgia; Department of Orthopaedic
Surgery, The Cleveland Clinic Foundation, Cleveland, Ohio; Division
of Orthopaedic Surgery, University of Texas Medical Branch at Galveston,
Galveston, Texas; and Stryker Biotech, Hopkinton, Massaschusetts
Gary E. Friedlaender, MD
Department of Orthopaedics and Rehabilitation, Yale University
School of Medicine, P.O. Box 208071, New Haven, CT 06520-8071. E-mail address:
gary.friedlaender{at}yale.edu
Clayton R. Perry, MD
U.S. Center for Sports Medicine, 333 South Kirkwood Road, Suite
200, St. Louis, MO 63122
J. Dean Cole, MD
1118 South Orange Avenue, Suite 205, Orlando, FL 32856-8008.
E-mail address: jdcmdpa@aol.com.
Stephen D. Cook, PhD
Department of Orthopaedic Surgery SL32, Tulane University Medical
Center School of Medicine, 1430 Tulane Avenue, New Orleans, LA
70112-2699. E-mail address: scook2@tulane.edu
George Cierny, MD
Resurgens Orthopaedics, 5671 Peachtree Dunwoody Road NE, Suite
700, Atlanta, GA 30342. E-mail address: osteomyelitis@mindspring.com
George F. Muschler, MD
Department of Orthopaedic Surgery, The Cleveland Clinic Foundation
(A-41), 9500 Euclid Avenue, Cleveland, OH 44195-5029. E-mail
address: muschlg@ccf.org
Georgory A. Zych, DO
Department of Orthopaedics, University of Miami Medical Center,
P.O. Box 106960, Miami, FL 33101. E-mail address: gzych@miami.edu
Jason H. Calhoun, MD
Division of Orthopaedic Surgery, University of Texas Medical
Branch at Galveston, Route G-92, 6.136 McCullough Building, Galveston,
TX 77555-0792. E-mail address: jcalhoun@utmb.edu
Amy J. LaForte, PhD
Samuel Yin, PhD
Stryker Biotech, 35 South Street, Hopkinton, MA 01748. E-mail
address
for A.J. LaForte: laforte.amy@strybio.com. E-mail address
for S. Yin: yin.sam@strybio.com
The sites (and principal investigators at these locations) are
as follows: Cleveland Clinic Foundation, Cleveland, Ohio (George
F. Muschler, M.D.); Barnes Hospital, Washington University Medical
Center, St. Louis, Missouri (Clayton R. Perry, M.D.); Evans Army
Community Hospital, Fort Carson, Colorado (Edward J. Lisecki, M.D.,
and John T. McBride, Jr., M.D.); Henry Ford Hospital, Detroit, Michigan
(J. Tracy Watson, M.D.); Hospital for Joint Disease, Orthopaedic
Institute, New York, New York (Kenneth J. Koval, M.D.); Hospital
of University of Pennsylvania, Philadelphia, Pennsylvania (John
L. Esterhai, M.D.); Memorial Hospitals Association, Modesto, California
(David L. Samani, M.D.); Orlando Regional Medical Center, Orlando,
Florida (J. Dean Cole, M.D.); Presbyterian-St. Luke’s Medical
Center, Denver, Colorado (Ross M. Wilkins, M.D.); St. Joseph’s
Hospital, Atlanta, Georgia (George Cierny, III, M.D.); Stanford
University Medical Center, Stanford, California (George E. Sims,
M.D.); Texas Tech University Health Sciences Center, Lubbock, Texas
(Andrew F. Brooker, M.D.); Tulane University Medical Center, New
Orleans, Louisiana (Stephen D. Cook, Ph.D.); University of California,
San Diego Medical Center, San Diego, California (Wayne H. Akeson,
M.D.); University of Miami School of Medicine, Miami, Florida (Gregory
A. Zych, D.O.), University of Texas Medical Branch at Galveston,
Galveston, Texas (Jason H. Calhoun, M.D.); and Valley Lutheran Hospital,
Mesa, Arizona (Dennis Armstrong, M.D.).
In support of their research or preparation of this manuscript,
one or more of the authors received grants or outside funding from
Stryker Biotech. In addition, one or more of the authors received
payments or other benefits or a commitment or agreement to provide
such benefits from a commercial entity (Stryker Biotech). 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.
Background: The role of bone morphogenetic proteins
(BMPs) in osseous repair has been demonstrated in numerous animal
models. Recombinant human osteogenic protein-1 (rhOP-1 or BMP-7)
has now been produced and was evaluated in a clinical trial conducted
under a Food and Drug Administration approved Investigational Device
Exemption to establish both the safety and efficacy of this BMP in
the treatment of tibial nonunions. The study also compared the clinical
and radiographic results with this osteogenic molecule and those
achieved with fresh autogenous bone.
Materials and Methods: One hundred and twenty-two
patients (with 124 tibial nonunions) were enrolled in a controlled,
prospective, randomized, partially blinded, multi-center clinical
trial between February, 1992, and August, 1996, and were followed
at frequent intervals over 24 months. Each patient was treated by insertion
of an intramedullary rod, accompanied by rhOP-1 in a type I collagen
carrier or by fresh bone autograft. Assessment criteria included
the severity of pain at the fracture site, the ability to walk with full
weight-bearing, the need for surgical re-treatment of the nonunion
during the course of this study, plain radiographic evaluation of
healing, and physician satisfaction with the clinical course. In addition,
adverse events were recorded, and sera were screened for antibodies
to OP-1 and type-I collagen at each outpatient visit.
Results: At 9 months following the operative procedures (the
primary end-point of this study), 81% of the OP-1-treated
nonunions (n = 63) and 85% of those receiving
autogenous bone (n = 61) were judged by clinical criteria
to have been treated successfully (p = 0.524). By radiographic
criteria, at this same time point, 75% of those in the
OP-1-treated group and 84% of the autograft-treated patients
had healed fractures (p = 0.218). These clinical results
continued at similar levels of success throughout 2 years of observation,
and there was no statistically significant difference in outcome
between the two groups of patients at this point (p = 0.939).
All patients experienced adverse events. Forty-four percent of patients
in each treatment group had serious events, none of which were related
to their bone grafts. More than 20% of patients treated
with autografts had chronic donor site pain following the procedure.
Conclusions: rhOP-1 (BMP-7), implanted with a type
I collagen carrier, was a safe and effective treatment for tibial nonunions.
This molecule provided clinical and radiographic results comparable
with those achieved with bone autograft, without donor site morbidity.
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