Abstract
Background: Previous studies have demonstrated the ability of recombinant human bone morphogenetic protein to achieve a solid fusion in anterior lumbar interbody arthrodesis. The purpose of this study was to compare iliac crest bone graft and recombinant human bone morphogenetic protein-2, combined with a carrier consisting of bovine collagen and ß-tricalcium phosphate-hydroxyapatite to create a compression-resistant matrix, for instrumented single-level posterolateral arthrodesis.
Methods: Four hundred and sixty-three patients with symptomatic single-level lumbosacral degenerative disease with no greater than grade-1 spondylolisthesis were treated with single-level instrumented posterolateral arthrodesis through an open midline approach. Patients were randomly assigned to either the recombinant human bone morphogenetic protein-2 matrix group (239 patients) or the autogenous iliac crest bone-graft group (224 patients). The Oswestry Disability Index, Short Form-36, and back and leg pain scores were determined preoperatively and at 1.5, three, six, twelve, and twenty-four months postoperatively. Radiographs and computed tomography scans were made at six, twelve, and twenty-four months postoperatively to evaluate for fusion.
Results: The mean operative time and mean blood loss in the recombinant human bone morphogenetic protein-2 matrix group (2.5 hours and 343.1 mL, respectively) were significantly less than those in the iliac crest bone-graft group (2.9 hours and 448.6 mL). Both groups showed similar improvements in clinical outcomes and reduced pain. At twenty-four months, 60% of the iliac crest bone-graft group reported donor-site pain. At twenty-four months, fusion was evident in 96% of the patients in the recombinant human bone morphogenetic protein-2 matrix group compared with 89% in the iliac crest bone-graft group (p = 0.014). There was a significant difference (p = 0.011) in the rate of failures because of nonunion (eighteen patients with an iliac crest bone graft compared with six patients with the recombinant human bone morphogenetic protein-2 matrix). Also, the number of patients requiring second surgeries was significantly higher in the iliac crest bone-graft group (thirty-six patients) compared with the recombinant human bone morphogenetic protein-2 matrix group (twenty patients) (p = 0.015).
Conclusions: The use of recombinant human bone morphogenetic protein-2 in instrumented posterolateral lumbar arthrodesis decreases operative time and blood loss and produces earlier and higher fusion rates than does iliac crest bone graft. Clinical outcomes are similar to those with iliac crest bone graft. Thus, the need for harvesting iliac crest bone is eliminated along with the morbidities associated with the harvest procedure.
Level of Evidence: Therapeutic Level I. See Instructions to Authors for a complete description of levels of evidence.
Previous animal studies have demonstrated the ability of recombinant human bone morphogenetic protein-2 (rhBMP-2) to achieve a solid fusion1-3. Recent prospective, randomized clinical studies have demonstrated superior fusion rates and clinical outcomes with the use of rhBMP-2 and a collagen sponge (INFUSE Bone Graft; Medtronic Sofamor Danek, Memphis, Tennessee) in anterior lumbar interbody arthrodesis techniques compared with autograft with use of either cortical bone dowels or threaded interbody cages4,5. Nonhuman primate studies have demonstrated that rhBMP-2 delivered on an absorbable collagen sponge required the use of adjunctive osteoconductive bulking agents to produce successful posterolateral spine fusion6-8. An optimized rhBMP-2 concentration and a compression-resistant carrier developed specifically for posterolateral arthrodesis demonstrated excellent results in nonhuman primates9,10. A randomized human pilot study documented the ability of a 2.0-mg/mL rhBMP-2 concentration combined with biphasic calcium phosphate granules to achieve a successful posterolateral fusion11. Currently, an ongoing, prospective, randomized U.S. Food and Drug Administration (FDA) Investigational Device Exemption study is comparing iliac crest bone graft and rhBMP-2 combined with a compression-resistant carrier, consisting of bovine collagen and ß-tricalcium phosphate-hydroxyapatite (rhBMP-2 matrix), for single-level posterolateral arthrodesis. The purpose of this study was to determine the two-year radiographic results and clinical outcomes with use of rhBMP-2 matrix or iliac crest bone graft from this trial. Adverse events associated with the higher dose of rhBMP-2 used in posterolateral lumbar fusion are also reported.
Four hundred and sixty-three patients were treated in this multicenter, prospective, randomized, controlled U.S. Food and Drug Administration-approved Investigational Device Exemption study. There were sixty-three spine surgeons at twenty-nine investigational sites. All sites had institutional review board approval. This clinical trial was registered in (NCT00707265).
The indications for surgery were symptomatic, single-level degenerative disease from L2-L3 to L5-S1 for a duration of at least six months in patients in whom nonoperative care had failed. Radiographic studies confirmed instability (angulation of =5° and/or translation of =4 mm), osteophyte formation, decreased disc height, thickening of ligamentous tissue, disc degeneration or herniation, or facet joint degeneration. Patients were at least eighteen years old, with no greater than grade-1 spondylolisthesis, no previous arthrodesis, and a minimum preoperative score of 30 on the Oswestry Disability Index12. Exclusion criteria included a previous attempt at fusion at the intended surgical level, use of medications that interfere with fusion, osteoporosis confirmed by a bone densitometry scan, autoimmune disease, previous exposure to collagen or any rhBMP, endocrine or metabolic disorders known to affect osteogenesis, a malignant tumor, infection, pregnancy, or the inability to harvest graft because of a previous surgical procurement.
All patients were treated with a single-level instrumented arthrodesis with use of Cotrel-Dubousset Horizon pedicle screws and rods (Medtronic Sofamor Danek). Patients were randomly assigned to either the control group, which received autogenous iliac crest bone graft, or the investigational group, which received rhBMP-2 matrix (AMPLIFY rhBMP-2 Matrix; Medtronic Sofamor Danek). Randomization was centrally generated on a 1:1 basis, stratified by site with use of a fixed block size of 4 and sealed envelopes with sequential numbers. The dose and concentration of rhBMP-2 used was higher (2.0 mg/mL for a total dose of 40 mg) than that of commercially available rhBMP-2 (INFUSE), which is 1.5 mg/mL for a total dose of 12 mg per large kit. Commercially available rhBMP-2 was developed for use in the anterior lumbar spine. The higher dose and concentration of rhBMP-2 used in this study for posterolateral arthrodesis was based on preclinical animal and pilot clinical trials. The posterolateral arthrodesis (an arthrodesis over cortical bone under tension) is a more challenging environment than an anterior interbody arthrodesis, which is under compression. The matrix was a 20-cm3 block of bovine Type-I collagen carrier containing 15% hydroxyapatite and 85% ß-tricalcium phosphate particles. Histological evidence in animals has demonstrated that this composition resorbs at a rate comparable with new bone formation9.
A standard open posterior midline approach was used for both groups. In the iliac crest bone-graft group, bone graft from the iliac crest was obtained through a separate fascial incision. The bone graft was morselized, its volume was measured, and it was placed on the decorticated osseous surface of the transverse processes and pars interarticularis. Any local bone graft obtained from the decompression was discarded in both groups.
The rhBMP-2 was reconstituted according to the manufacturer's instructions with use of sterile water into two 5-mL syringes containing 20 mg of rhBMP-2 and an appropriate buffering agent in each. The matrix (4.7 × 3.8 × 1.1 cm) was cut lengthwise into two equal pieces (1.9 cm in width) of 10 cm3 each with use of a cutting template. The reconstituted rhBMP-2 from each syringe was then uniformly distributed to each piece of the matrix producing a 2 mg/mL concentration of rhBMP-2 in the matrix. The rhBMP-2 matrices were allowed to stand for a minimum of five minutes and were implanted within sixty minutes after preparation. In no instance was the matrix of insufficient length to span the transverse processes of the two vertebrae in a single-level arthrodesis.
Clinical data were collected preoperatively and postoperatively at six weeks and at three, six, twelve, and twenty-four months. The outcome instruments used were the Oswestry Disability Index12; the Medical Outcomes Study Short Form-36 (SF-36)13,14; back pain and leg pain scores; and, in the iliac crest bone-graft group, graft site pain scores. Patients were asked to rate the frequency and intensity of the back and leg pain on a scale of 0 to 10. The scores for frequency and intensity were summed to derive a 20-point numerical rating scale for back pain and leg pain. Data on work status, patient satisfaction, adverse events, and neurological examinations were also recorded.
Anteroposterior and lateral flexion-extension radiographs and computed tomography scans with sagittal and coronal reconstructions were used to evaluate the fusion in both groups at six, twelve, and twenty-four months after surgery. Fusion status was determined with use of plain radiographs primarily according to the Investigational Device Exemption protocol-defined analysis. In patients in whom the plain radiographs did not exhibit bridging bone, computed tomography scans were then used to determine the presence of bridging bone. The computed tomography imaging protocol consisted of 1 mm of continuous nonoverlapping axial slices that were made without a bone filter. The window and level settings were set to optimize trabecular bone detail (for example, 2000/350 on scanners from General Electric, Fairfield, Connecticut). Fusion success was defined as the presence of bilateral, continuous trabeculated bone connecting the transverse processes; translation of =3 mm and angulation of <5° on flexion-extension radiographs; and the absence of radiolucent lines through the fusion mass. All parameters must have been met in order to be considered a fusion success. The radiographs and computed tomography scans were evaluated by two independent radiologists who were blinded to which patient group they were evaluating and a third adjudication reviewer was used as needed.
Statistical comparisons were primarily based on the observed and recorded follow-up data. A small number of patients required an additional surgical procedure (removal, revision, or supplemental fixation); their outcomes were recorded as a treatment failure. For other outcome variables, the last observations made before the additional surgical procedures or interventions were carried forward with use of the last observation carried forward technique15 for all future evaluation periods.
The protocol predefined the as-treated analysis as the primary analysis for the study, on the basis of the statistical consideration that intent-to-treat analysis may not be conservative for assessing a noninferiority hypothesis. For comparing patient demographic and preoperative measures, p values were determined from the analysis of variance for continuous variables and from the Fisher exact test for categorical variables. For comparing success or event rates, the Fisher exact test was used to assess a noninferiority hypothesis. To compare continuous outcome measurements such as the Oswestry Disability Index, analysis of covariance was used, with the preoperative score as the covariate. To assess the significance of postoperative improvement in outcome scores from the preoperative status within each treatment group, a paired t test was used. One-sided p values were reported to compare treatment group differences in most clinical outcomes because the study hypotheses defined in the Investigational Device Exemption protocol for those outcomes were one-sided, except for surgery data, adverse events, and additional surgical procedures, as well as for days to return to work, for which two-sided p values were reported.
Source of Funding
This study was sponsored by Medtronic Sofamor Danek.
Of the 463 patients who had surgery, 410 (89%) were available for assessment at two years after surgery; this included 194 in the iliac crest bone-graft group and 216 in the rhBMP-2 matrix group. At all time points, at least 90% of the expected patients were evaluated. Seven patients died because of causes unrelated to surgery. Randomization resulted in a similar distribution of baseline characteristics in the two study groups (Table I). There were two crossovers in the study. They were analyzed on the basis of the treatment received (the so-called as-treated analysis).
The average surgical time for the patients in the iliac crest bone-graft group was significantly longer than that observed in the rhBMP-2 matrix group, with a difference of 0.40 hour (95% confidence interval, 0.23 to 0.57 hour; p < 0.001) (Table II). The average blood loss for the iliac crest bone-graft group was 448.6 mL, which was significantly greater (95% confidence interval for change, 53.76 to 157.24 mL; p < 0.001) than the average blood loss of 343.1 mL observed in the rhBMP-2 matrix group. Decompression was performed in 83% (185) of 224 patients in the iliac crest bone-graft group and in 88% (211) of 239 patients in the rhBMP-2 matrix group (p = 0.087). The average volume of bone graft obtained from the iliac crest in the iliac crest bone-graft group was 36.5 mL (range, 7 to 70 mL). There was no significant difference in the average length of hospital stay between the two groups (95% confidence interval, -0.29 to 0.49 days; p = 0.701). No operation was abandoned because of technical problems, and there was no unanticipated intraoperative complication related to the arthrodesis procedure.
The Oswestry Disability Index scores were similar in both groups over all time intervals and showed significant improvement compared with the preoperative scores (p < 0.001) in both the iliac crest bone-graft and rhBMP-2 matrix groups at all time intervals (Fig. 1). The SF-36 physical component summary scores were similar in both groups at all time intervals and showed significant improvement compared with the preoperative scores (p < 0.001) in both groups (Fig. 2).
The average back pain scores improved significantly from 15.8 preoperatively to 7.8 (95% confidence interval for change, 7.0 to 8.9) at twenty-four months for the iliac crest bone-graft group and from 15.6 to 7.1 (95% confidence interval for change, 7.6 to 9.4), respectively, for the rhBMP-2 group (p < 0.001). Both groups showed similar improvements over all time intervals (Fig. 3), with the average scores at twenty-four months showing no significant difference between the groups (95% confidence interval, -0.51 to 1.91; p = 0.145). Only 3% (seven) of the 239 patients in the rhBMP-2 group and 5% (twelve) of the 224 patients in the iliac crest bone-graft group had no preoperative leg pain. Leg pain scores after surgery in both the iliac crest bone-graft and rhBMP-2 matrix groups improved in a similar manner over all time intervals (Fig. 4). At twenty-four months, the average leg pain score had improved from 14.0 preoperatively in both groups to 6.7 (95% confidence interval for change, 6.13 to 8.47) in the iliac crest bone-graft group and 6.2 (95% confidence interval for change, 6.78 to 8.82) in the rhBMP-2 matrix group (p < 0.001). At twenty-four months, the average difference in leg pain scores between the groups (95% confidence interval, -0.79 to 1.79) was not significant (p = 0.214).
Pain resulting from bone harvest in the iliac crest bone-graft group was measured with use of donor-site pain scores. The mean pain score at discharge was 11.3 and improved to 7.9 at six weeks after surgery and to 6.3 at three months postoperatively. There was minimal improvement at subsequent follow-up periods up to twenty-four months. A large number of patients in the iliac crest bone-graft group (60%; 108 of 180 patients) still had persistent donor-site pain, with a mean pain score of 5.1 at twenty-four months after surgery.
Of the 224 subjects in the iliac crest bone-graft group, 41% (ninety-two) were working before surgery. At twenty-four months, 48% (eighty-nine) of 184 subjects were able to return to work. Of the 239 patients in the rhBMP-2 matrix group, 35% (eighty-three) were working before surgery. At twenty-four months after surgery, 42% (eighty-seven) of 207 subjects were working.
Radiographic assessment showed significant differences between the two groups with regard to protocol-defined fusion success at two time intervals. At six months, 79% (155) of 196 patients in the rhBMP-2 matrix group and 65% (115) of 176 patients in the iliac crest bone-graft group achieved fusion success (p = 0.002). At twelve months, 88% (182) of 208 patients in the rhBMP-2 matrix group had achieved fusion success compared with 83% (151) of 183 patients in the iliac crest bone-graft group (p = 0.107). At twenty-four months, 96% (186) of 194 patients in the rhBMP-2 matrix group had achieved fusion success compared with 89% (151) of 169 patients in the iliac crest bone-graft group (p = 0.014).
Fine-cut computed tomography scans with sagittal and coronal reconstructions showed that 75% of the subjects in the rhBMP-2 matrix group and 56% in the iliac crest bone-graft group had evidence of bilateral bridging bone at six months (p < 0.001). At twelve months, 87% of the subjects in the rhBMP-2 matrix group and 72% in the iliac crest bone-graft group had evidence of bilateral bridging bone (p < 0.001). At twenty-four months, the rate was 95% in the rhBMP-2 group compared with 84% in the iliac crest bone-graft group (p < 0.001).
Analysis of adverse events showed no significant differences between the study groups for all event categories (Table III), with the significant exception of seventeen graft site-related events in the iliac crest bone-graft group (p < 0.001). No adverse event that was specifically attributed to the use of rhBMP-2 matrix in the study group was identified. No heterotopic ossification in the surrounding soft tissue was noted. Operative adverse events occurred in 8% (twenty) of 239 patients in the rhBMP-2 matrix group and 9% (twenty) of 224 patients in the iliac crest bone-graft group; the difference was not significant. No significant difference between the groups was demonstrated with respect to serious adverse events, such as death, neurological injury, and cardiovascular events.
The rate of second surgery was similar in the groups (Table IV). The number of patients requiring a second surgery following the index surgery was significantly higher in the iliac crest bone-graft group (thirty-six patients) compared with the rhBMP-2 matrix group (twenty patients) (p = 0.015). The most common second-surgery classification in both groups was nonelective removal of the device, with an incidence of 4% (ten) of 239 patients in the rhBMP-2 matrix group and 10% (twenty-three) of 224 patients in the iliac crest bone-graft group. There was no surgical intervention related to recurrent stenosis or inadequate decompression in any patient.
A guiding principle for the surgical treatment of painful or unstable lumbosacral degenerative spinal disease remains the ability to achieve a solid fusion. Although the use of autologous iliac crest bone graft is the current standard, the morbidity associated with graft harvest has led surgeons to seek viable alternatives, such as allografts, ceramics, and various types of autologous growth factors16-20. These graft substitutes have exhibited great variability in achieving fusion, and they present their own unique problems, including limited availability and the potential for rejection or immunologic reaction17,18,21.
Bone morphogenetic proteins are naturally occurring proteins that stimulate bone healing by means of a cascade mechanism that results in the differentiation of primitive mesenchymal cells and preosteoblasts into osteoblasts that promote bone formation and, ultimately, healing22,23. As part of an ongoing FDA-regulated Investigational Device Exemption study, a new rhBMP-2 formulation was evaluated for use in a single-level posterolateral arthrodesis combined with pedicle screw and rod instrumentation. Aside from the use of a higher concentration of rhBMP-2 (2.0 mg/mL compared with 1.5 mg/mL) than in previous clinical studies, a carrier that provided substantial resistance to muscle compression in the lateral gutters that also has a high binding affinity for rhBMP-2 and a suitable resorption profile was designed by combining ß-tricalcium phosphate and hydroxyapatite granules with a collagen matrix.
Although local bone graft is rarely discarded in clinical practice, the quality and quantity of local bone grafts are highly variable. In this study, local bone graft was discarded in both treatment groups to allow for a direct comparison of the fusion rates of the rhBMP-2 matrix and the iliac crest bone graft without local bone graft as a confounding variable.
Perioperative measures indicated that operative time and blood loss were significantly less in the rhBMP-2 matrix group than in the iliac crest bone-graft group although the length of hospital stay was the same for both groups. Because of the nature of adverse event reporting in FDA-regulated trials, most patients experienced an adverse event over the two-year course of the study. There were no differences in adverse event rates between the study groups, except for iliac crest bone graft-related complications, which occurred in seventeen (7%) of the control patients.
In both groups, most of the improvement in the Oswestry Disability Index scores and SF-36 physical component summary scores occurred within the first three months after surgery. This improvement was maintained through the follow-up periods up to twenty-four months. The improvement in the physical component summary scores at twenty-four months in both groups was well above the 5.41-point threshold in the literature for clinically important improvement24. The decrease in Oswestry Disability Index scores at twenty-four months in both groups was >25 points, which is also above that necessary to demonstrate treatment efficacy25,26.
Most of the improvement in back pain and leg pain scores was noted within the first six weeks after surgery and was maintained throughout the entire follow-up period of twenty-four months. The average decrease in back pain of 8.4 points in the rhBMP-2 matrix group and 8.1 points in the iliac crest bone-graft group indicates a clinically substantial diminution in back pain after surgery. The average decrease in leg pain of 7.3 points in the rhBMP-2 matrix group and 6.6 points in the iliac crest bone-graft group indicates a clinically substantial diminution in leg pain after surgery. More importantly, two years after surgery, more than half of the patients in the iliac crest bone-graft group still reported pain from the donor graft site.
When fusion success was determined with use of the Investigational Device Exemption protocol-defined criteria as specified in the methodology, the rhBMP-2 matrix group had significantly higher rates of fusion success compared with the iliac crest bone-graft group at six and twenty-four months postoperatively. With use of thin-cut computed tomography scans only, bilateral bridging bone was reported by the independent radiologists significantly more often in the rhBMP-2 matrix group than in the iliac crest bone-graft group at all three time points. Although it may be beneficial to know the effectiveness of rhBMP-2 in achieving a successful posterior fusion for specific pathological conditions, it is beyond the scope of this study.
At the twenty-four-month follow-up period, the iliac crest bone-graft group had twice as many patients with established nonunion and twice as many nonelective surgical procedures to remove instrumentation compared with the rhBMP-2 group. The possible reasons for the higher number of patients undergoing removal of the instrumentation in the iliac crest bone-graft group included the potential for surgeon bias (that is, the surgeon expected a higher fusion rate in the rhBMP-2 matrix group and, therefore, was quicker to explore the patients who received iliac crest bone graft), a quantitatively higher rate of nonunion in the iliac crest bone-graft group that resulted in persistent pain, and uncertainty as to whether pain was originating from the fusion or from residual pain at the iliac crest bone-graft donor site. Finally, there were no adverse events directly attributable to the use of rhBMP-2 matrix.
In conclusion, in posterolateral lumbar arthrodesis, rhBMP-2 matrix decreases operative time and blood loss and has earlier, higher fusion rates and similar clinical outcomes as iliac crest bone graft, and its use can eliminate the need for harvesting iliac crest bone in this procedure. 
Note: The authors thank the following Principal Investigators for their valuable contribution to this study: David J. Abraham, MD, The Reading Neck & Spine Center, Wyomissing, PA; Avi Bernstein, MD, Lutheran Spine Center, Park Ridge, IL; Miroslav Bobek, MD, Medford Neurological & Spine Clinic, Medford, OR; Gregory Carlson, MD, Orthopaedic Specialty Institute, Orange, CA; Alan M. Levine, MD, Sinai Hospital Cancer Institute, Baltimore, MD; Curtis A. Dickman, MD, Barrow Neurosurgical Associates, Phoenix, AZ; Jeffrey Fischgrund, MD, Southfield, MI; Ernest M. Found, MD, University of Iowa Hospitals & Clinics, Iowa City, IA; Leon Grobler, MD, Sun City, AZ; Brent Alford, MD, Fort Worth Brain & Spine Institute, L.L.P., Fort Worth, TX; Gregory Helm, MD, PhD, UVA Department of Neurosurgery, Charlottesville, VA; Randall Hendricks, MD, Central States Orthopedic Specialists, Tulsa, OK; Richard A. Hynes, MD, Brevard Orthopaedic Clinic, Inc., Melbourne, FL; William C. Lauerman, MD, Georgetown University Hospital Department of Orthopaedic Spine Surgery, Washington, DC; Lynn M. Nelson, MD, Des Moines Orthopaedic Surgeons, West Des Moines, IA; Michael Neuwirth, MD, Beth Israel Medical Center, New York, NY; Richard S. Rabinowitz, MD, Barrington Orthopedic Specialists, Hoffman Estates, IL; William Richardson, MD, Duke University Medical Center, Durham, NC; Michael E. Russell II, MD, Tyler, TX; Paul Sawin, MD, Florida Neurological Consultants, Winter Park, FL; Meic Schmidt, MD, Salt Lake City, UT; Arnold M. Schwartz, MD, Melville, NY; John Small, MD, Florida Orthopaedic Institute, Tampa, FL; Joseph B. Stachniak, MD, Richardson, TX; Jeffrey C. Wang, MD, UCLA Orthopedic Hospital, Santa Monica, CA; and David A. Wiles, MD, East Tennessee Brain & Spine, Johnson City, TN.
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