SPINE Volume 38, Number 25, pp 2139-2148 ©2013, Lippincotr Williams & Wilkins
RANDOMIZED TRIAL
rhBMP-2 for Posterolateral Instrumented Lumbar Fusion A Multicenter Prospective Randomized Controlled Trial R. John Hurlbert, MD, PhD, FRCSC, FACS,* David Alexander, MD, FRCSC,t Stewart Bailey, MD, FRCSC,+ James Mahood, MD, FRCSC,§ Ed Abraham, MD, FRCSC, 1 Robert McBroom, MD, FRCSC,|| Alain jodoin, MD, FRCSC,** and Charles Fisher, MD, FRCSC, MSctt
Study Design. Multicenter randomized controlled trial. Objective. To evaluate the effect of recombinant human bone morphogenetic protein (rhBMP-2) on radiographical fusion rate and clinical outcome for surgical lumbar arthrodesis compared with iliac crest autograft. Summary of Bacitground Data. In many types of spinal surgery, radiographical fusion is a primary outcome equally important to clinical improvement, ensuring long-term stability and axial support. Biologic induction of bone growth has become a commonly used adjunct in obtaining this objective. We undertook this study to objectify the efficacy of rhBMP-2 compared with traditional iliac crest autograft in instrumented posterolateral lumbar fusion. Methods. Patients undergoing 1- or 2-level instrumented posterolateral lumbar fusion were randomized to receive either autograft or rhBMP-2 for their fusion construct. Clinical and radiographical outcome measures were followed for 2 to 4 years postoperatively. Results. One hundred ninety seven patients were successfully randomized among the 8 participating institutions. Adverse events attributable to the study drug were not significantly different compared with controls. However, the control group experienced From the *University of Calgary Spine Program and Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta; tDivision of Orthopedic Surgery, Dalhousie University, Halifax, Nova Scotia, Canada; ^Division of Orthopedic Surgery, University of Western Ontario, London, Ontario, Canada; §Division of Orthopedic Surgery, University of Alberta, Edmonton, Alberta, Canada; 1 Division of Orthopedic Surgery, Dalhousie University, St. John, New Brunswick, Canada; ||Division of Orthopedic Surgery, Trillium Health Centre, Mississauga, Ontario, Canada; **Division of Orthopedic Surgery, University of Montreal, Montreal, Quebec, Canada; and ttDivision of Orthopedic Surgery, University of British Columbia, Vancouver, British Columbia, Canada. Acknowledgment date: July 8, 2011. First revision date: February 18, 2012. Second revision date: July 28, 2012. Third revision date: November 2, 2012. Fourth revision date: April 12, 2013. Fifth revision date: August 28, 2013. Acceptance date: August 29, 2013. rhBMP-2 is not FDA-approved for this indication. Medtronic Inc. funds were received to support this work. Relevant financial activities outside the submitted work: consultancy. Address correspondence and reprint requests to R. John Hurlbert, MD, PhD, FRCSC, FACS, Department of Clinical Neurosciences, Foothills Hospital, 1403 29th St N.W. Calgary, Alberta, CanadaT2N 2T9; E-mail: jhurlber@ucalgaryca DOI: 10.1097/BRS.0000000000000007 Spine
significantly more graft-site complications as might be expected. 36-ltem Short Form Health Survey, Oswestry Disability Index, and leg/back pain scores were comparable between the 2 groups. After 4 years of foilow-up, radiographical fusion rates remained significantly higher in patients treated with rhBMP-2 (94%) than those who received autograft (59%) (P = 0.007). Conclusion. The use of rhBMP-2 for instrumented posterolateral lumbar surgery significantly improves the chances of radiographical fusion compared with the use of autograft. However, there is no associated improvement in clinical outcome within a 4-year followup period. These results suggest that use of rhBMP-2 should be considered in cases where lumbar arthrodesis is of primary concern. Key words: spine, BMP, osteoinduction, degenerative disease, degenerative disc disease, bone graft, stability, arthrodesis. Level of Evidence: N/A Spine 2013;38:2139-2148
S
urgical arthrodesis is an important outcome for many types of spinal surgery, particularly those aimed at correcting deformity or instability. Success depends on a number of variables including age, smoking status, comorbidities (e.g., osteoporosis), number of levels to be fused, presence or absence of instrumentation, graft-bed preparation, and the graft material used. Despite improved techniques facilitating surgical arthrodesis, nonunion rates of 5% to 15% continue to inflict disability on patients and inflate costs for health care providers.'"' Originally identified in 1965, a number of low molecular weight glycoproteins belonging to the transforming growth factor-beta superfamily have been shown to possess strong osteoinductive properties.'*'^ Recombinant human bone morphogenetic protein-2 (rhBMP-2) has shown consistent results in a number of different animal models'""' and has been found to be successful in promoting fusion in human posterolateral lumbar arthrodesis.'" Despite these encouraging results, class I data from only 284 patients implanted with rhBMP-2 in the setting of posterolateral lumbar fusion has been published.'""'^ The purpose of this study was to assess safety and efficacy of rhBMP-2 compared with iliac crest autograft in promoting www.spinejournal.com
2139
RANDOMIZED TRIAI
radiographical fusion for human posterolateral lumbar spinal arthrodesis and to compare clinical outcome to patients receiving "gold standard" iliac crest autograft.
MATERIALS AND METHODS The study was designed and executed as a multicenter prospective randomized controlled clinical trial. It was registered as a Pivotal Clinical Trial with the Health Protection Branch of the Government of Canada under Application File No. 13006 and is published at clinicaltrials.gov (NCT01494454). Eight university affiliated tertiary care centers from across Canada participated in the protocol. Each center received Internal Review Board approval specific to its site. Patients entered into the study were informed of the experimental details and underwent an informed consent process. Patients were randomized 1:1 (iliac crest bone graft [ICBG):rhBMP-2) within a fixed randomization block provided to each participating institution. Surgeons were not blinded to the randomization process for obvious reasons. Patients were not blinded to treatment arm due to open bone graft harvesting (see text hereafter). Sample size determinations were not based on statistical estimations but rather on the study population estimated to be available at the participating institutions within a reasonable time frame. Interim analyses were planned and performed at regular intervals to ensure patient safety and to monitor treatment effect. At the end of recruitment, power calculations proved unnecessary because statistical significance had been achieved in a primary outcome measure (fusion). Inclusion and exclusion criteria are summarized in Table 1. To be considered for the study the patient had to be a candidate for a 1- or 2-level posterolateral instrumented lumbar fusion for the treatment of degenerative disease. The indication for instrumented fusion was based on the presence of symptomatic degenerative disc disease that in the opinion of the treating surgeon, required more than simple decompression. Degenerative disc disease was confirmed with radiographical studies in which one or more of the following were identified; instability (s5° angular motion or >4 mm translation on dynamic radiographs), osteophyte formation, decreased disc height, thickening of ligamentous tissue, disc degeneration or herniation, or facet joint degeneration similar to the criteria used by Boden et al.'" Grade 1 isthmic or degenerative spondylolisthesis were appropriate diagnoses but grade 2 slips and higher were excluded. Preoperative assessment included neurological examination, clinical outcome questionnaires, plain lumbar radiographs (AP, lateral, flexion, extension), and computed tomographic (CT) scan of the lumbar spine. Patients were required to have an Oswestry Disability Index (ODI) score 30 or more. At the time of surgery, patients were randomized at their treating institution into 1 of 2 groups: (1) the control cohort that underwent standard posterolateral instrumentation and fusion with autogenous ICBG; and (2) the investigational or treatment group that underwent similar posterolateral instrumentation but fusion with rhBMP-2 instead of iliac crest. Instrumentation was standardized as either TSRH (Medtronic 2140
www.spinejournal.com
Effect of rhBMP-2 on Lumbar Arthrodesis • Hurlbert et al
TABLE í. ¿g^íg¿¿4]|^5Tii[l!r-5fi" Inclusion
Exclusion
Degenerative disc disease with corresponding back and/ or leg pain necessitating instrumented fusion
Pathology other than degenerative disease (e.g., neoplasm, trauma, infection)
One- or 2-level involvement
Spondylolisthesis more than grade 1
Preoperative Oswestry Disability Index score > 3 0
Previous spinal fusion
Failure of conservative (nonsurgical) care for at least 6 mo
Comorbidities recognized to interfere with surgical outcome (e.g., osteoporosis, steroid administration, alcohol/drug abuse)
Age 2 18 yr
Morbid obesity (>140% ideal body weight)
Able to give informed consent
Titanium alloy allergy Tobacco use at time of surgery Previous exposure to BMP Pregnancy or unknown pregnancy status Presence or prior history of malignancy
BMP indicates bone morphogenetic protein.
Inc., Memphis, TN) or CD Horizon (Medtronic Inc.) fixation systems. In patients who underwent a single-level fusion, each side of the spine was implanted with 10 mL (2.1 mg/mL) of rhBMP-2 on a biphasic calcium phosphate granule (BCP) carrier (60% hydroxyapatite/40% ß-calcium triphosphate/80% porosity—Medtronic Inc., Memphis, TN), resulting in a total rhBMP-2 dose of 42 mg. In patients undergoing 2-level fusions, a third kit was added for a total volume of 30 mL (63 mg). rhBMP-2 was allowed to bind to the BCP carrier for a minimum of 5 minutes to a maximum of 60 minutes before implantation. At the time of bone graft application, ICBG or rhBMP-2/BCP was placed adjacent to the lateral facet joints and overlying the transverse processes of the instrumented segments. ICBG was not used to augment fusion in any of the patients receiving rhBMP-2/BCP; in other words, rhBMP-2/ BCP was used to facilitate arthrodesis as a stand-alone graft material. Local bone acquired through decompression was discarded in both rhBMP-2 and ICBG groups to ensure direct comparison of the 2 techniques. Components of the surgical intervention were not controlled (e.g.., severity of compressive pathology and degree of decompression), allowing each surgeon to decide independently on the basis of individual patient's signs, symptoms, and imaging studies. ICBG was harvested from either the right or left iliac crest and could be performed through the primary midline incision or through a separate paramedian incision. The amount of bone graft harvested from the iliac crest was December 2013
RANDOMIZED TRIAI
not Standardized but instead was left to the discretion of the participating surgeon according to their usual practice; however, enough graft material was required to span the intertransverse space bilaterally through the instrumented levels. Corticocancellous bone was obtained in all cases, involving the outer table and inner cancellous regions; the inner table was not violated. Placement of a drain and method of closure were determined by individual surgeon preference. Inpatient care including pain control, time to mobilization, and time to discharge was left to institutional practice. Similarly, physician preference was used to determine the need for postoperative bracing. The primary outcome measure chosen to test our research hypothesis pertaining to radiographical fusion was plain film radiographs (AP, lateral, flexion, extension) of the lumbar spine corresponding to the established and routine evaluation of postoperative patients in daily practice. Fusion was defined by 3 stringent criteria all of which had to be met: (1) bridging trabecular bone in both fusion masses (left and right intertransverse spaces) and the absence of traversing radiolucent lines; (2) 3 mm or more translation on dynamic (flexion/ extension) films; and (3) less than 5° angulation on dynamic films.'" Two independent blinded radiologists evaluated all radiographical studies for every patient. Thin slice lumbar CT scans with sagittal reconstructions were performed at 6, 12, and 24 months and were incorporated in determining the presence of bridging bone. The primary assessment tool chosen to test our research hypothesis pertaining to clinical outcome was the ODI. Additional clinical assessment tools included the 36-Item Short Form Health Survey (SF-36), analogue back/leg pain scores (0-20), and a detailed neurological examination. These assessments were performed both pre- and postoperatively throughout the course of follow-up. Patients randomized to the ICBG group completed an iliac crest donor site survey at each follow-up visit. Follow-up was scheduled postoperatively at 6 weeks, 3 months, 6 months, 1 year, and 2 years. A smaller cohort of patients was followed for 4 years. Study subjects were followed for adverse events defined as a clinically adverse sign, symptom, syndrome, or illness that occurred or worsened during the operative and postoperative periods ofthe trial, regardless of causality. Grading of severity was planned in accordance with the World Health Organization Toxicity Scale." Grade 3 and 4 toxicity events were considered serious. To meet regulatory requirements "surgical failures" were defined as patients who underwent removal or revision of instrumentation. These patients were subsequently withdrawn from the study protocol and excluded from further analyses. Data were collected prospectively and entered into a central database for analyses. The participating centers were surveyed by external study monitors on a regular basis to ensure protocol and data acquisition compliance. Patient demographics were examined to ensure comparability between both groups. Statistical analyses were performed using the Fisher exact test for proportions and t tests for continuous data. Repeated measure analysis was also performed to Spine
Effect of rhBMP-2 on Lumbar Arthrodesis • Hurlbert et al
assess treatment effect over time. Significance was defined at P < 0.05.
RESULTS Target sample size was 100 patients per treatment arm. From August 1999 through April of 2004, of the 207 subjects enrolled, 197 surgical procedures were completed (98 investigational; 99 control). Ten enrolled patients (4 investigational; 6 control) withdrew from the study after randomization but before treatment (Figure 1). Of the 10 withdrawn patients, 4 withdrew for unspecified reasons. Three patients were withdrawn preoperatively because it was discovered after randomization that they did not properly meet the study inclusion/exclusion criteria. One patient randomized to ICBG refused control group surgery. One patient was withdrawn because of nonpermissive insurance coverage. One patient decided preoperatively that they wished to have surgery at a different hospital. These 10 patients were excluded from further analyses. Sixty-three females and 35 males were assigned to receive rhBMP-2, whereas 51 females and 48 males received ICBG (P = 0.084). Twenty percent of the patients treated with rhBMP-2 were working before surgery compared with 24% of ICBG controls (P = 0.608). There were no between-group differences in demographic characteristics (Table 2). All patients received their prescribed treatment. There were a total of 5 intraoperative protocol violations arising from discrepancies in surgical technique. All 5 patients were included in the analyses on an intent-to-treat basis. The surgical deviations included (1) incorrect number of rhBMP-2 kits used; (2) single-level preoperative planning but 2-level instrumented fusion; (3) single-level fusion but 2-level instrumentation; (4) unanticipated unilateral instrumentation; (5) local bone autograft instead of iliac crest. Other protocol violations pertained largely to the missed radiographs at specific follow-up intervals (Table 3). Two patients were lost to follow-up after 6 months in the ICBG group (98% 2-yr follow-up). Allowing for anticipated lag time in accrual, an initial cohort of the study population was followed to 48 months (n = 41 each group). Most surgical procedures were for single rather than 2-level symptomatic disease (88% rhBMP-2 vs. 83% ICBG, P = 0.422). There was no significant difference in operative time (2.5 ± 1.2 hr rhBMP-2 vs. 1.7 ± 1.4 hr ICBG, P = 0.399), blood loss (615 ± 448 mL of rhBMP-2 vs. 643 ± 488 mL of ICBG, P = 0.671), or length of stay between the treatment and control patients (6 ± 3 d rhBMP-2 vs. 7 ± 5 á ICBG, P = 0.514). At the surgeon's discretion, 78% of patients in both groups were treated postoperatively with an external orthosis (P = 0.908). In general, surgery resulted in significant improvements in clinical outcomes irrespective of treatment group (P < 0.001; ODI, SF-36, leg and back pain scores). During the 2-year follow-up period, more than 24-point improvement was noted in the mean ODI for both patients treated with rhBMP-2 and those treated with ICBG (Figure 2). This was sustained throughout for the patients undergoing 4-year follow-up. In www.spinejournal.coin
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RANDOMIZED TRIAL
Effect of rhBMP-2 on Lumbar Arthrodesis • Hurlbert et al
Enrollment Randomized (n = 207)
1 rhBMP-2 (n = 102) • Received allocated intervention (n = 98) • Withdrew before surgery {n = 4)
Iliac crest bone graft (n = 105) • Received allocated intervention (n = 99) • Withdrew before surgery (n = 6)
Protocol not completed (n = 3) • Instrumentation revision (n = 2) • Lost to follow-up (n = 0) • Death (n = 1 )
Protocol not completed (n = 6) • Instrumentation revision (n = 2) • Lost to follow-up (n = 2) • Death (n = 2)
i
1 Analyzed ( n = 93) • Excluded from analysis (n = 0)
Analyzed ( n = 95) • Excluded from analysis (n = 0)
Figure 1. Flow chart of patients assessed and recruited into the study. rhBMP indicates recombinant human bone morphogenetic protein.
addition to total SF-36 scores, both the physical and mental component summaries, as well as all 8 subcomponents improved significantly compared with preoperative scores (Figure 3). Mean leg and back pain scores diminished immedi-
TABLE 2.
JnograpniG^ naracieris TICS OT Tne ^ Lly ^ 1 tliy^iiM
r-
rhBMP-2
ICBG
P
Age (yr)
53
53
0.989
Weight (Ib)
178
172
0.263
Sex (% male)
36
49
0.084
Previous smoking history (%)
30
26
0.636
Two-level surgery (%)
12
17
0.422
Previous back surgery (%)
19
20
1.000
Working before surgery {%)
20
24
0.608
Workman compensation (%)
11
14
0.669
Litigation (%)
5
3
0.498
rhBMP indicates recombinant human bone morphogenetic protein; iCBG, iliac crest bone graft.
2142
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ately after surgery to 6 to 8 on a 20-point scale and remained stable throughout the follow-up period (Figure 4). Although mean scores for all clinical outcomes improved as a result of surgery, there were no differences observed between treatment groups. Neurological function improved on the whole compared with preoperative status in both groups throughout all follow-up time points; however, no between-group differences were observed (P > 0.05). There were 10 cases of noninfectious wound complications {e.g., superficial dehiscence, seroma, erythema, persistent discharge), 6 in the rhBMP-2 group, and 4 in the ICBG group (P = 0.519). Eleven cases of wound infection (superficial and deep) were treated in patients receiving rhBMP-2 compared with 5 in control patients (? = 0.119). All were successfully managed with intravenous antibiotics and debridement/ primary closure under general anesthesia. Two of the deep infections encountered in patients treated with rhBMP-2 occurred subsequent to revision surgery. Four patients (n = 2 from each group) underwent revision procedures for symptomatic nonunion within 24 months of their index surgery. As per protocol they were classified as surgical failures and excluded from further analysis beyond the time of their secondary surgery (Figure 1). Additional secondary surgical procedures were performed for repeat December 2013
^SSM
RANDOMIZED TRIAI
Effect of rhBMP-2 on Lumbar Arthrodesis • Hurlbert et al
TABLE 3,
^-««—.
Description
Preoperative
Surgery
ówk
AP radiograph not obtained
0
4
0
0
Eateral radiograph not obtained
4
6
3
Elexion radiograph not obtained
11
N/A
Extension radiograph not obtained
10
Ferguson radiograph not obtained
14
CT/MRI not obtained Imaging performed outside 2-wk window
3 mo 6 mo
1 yr
2yr
4 yr
0
0
0
0
4
N/A
N/A
N/A
N/A
N/A
N/A
9
3
3
1
N/A
N/A
N/A
9
3
2
1
11
8
7
4
1
5
1
2
4
0
0
1
1
1
0
36
1
2
0
12
3
2
0
Missed evaluation
N/A
N/A
0
1
2
2
1
2
Evaluation performed outside 2-wk window
N/A
N/A
21
34
14
4
21
14
Patient forms outside 2-wk window
N/A
0
0
1
1
0
0
0
0
0
Ü
0
1
0
0
0
N/A
5
N/A
N/A
N/A
N/A
N/A
N/A
Inclusion/exclusion not followed
7
0
N/A
N/A
N/A
N/A
N/A
N/A
Incomplete physician form
0
0
2
2
2
1
1
0
Missing physician form
0
0
0
1
0
1
1
0
Weight not obtained
0
N/A
3
1
1
1
3
2
Blood specimen not obtained
0
N/A
N/A
2
N/A
N/A
N/A
N/A
Blood specimen not handled per protocol
2
N/A
N/A
8
N/A
N/A
N/A
N/A
Missing patient form Deviations from surgical technique
CT indicates computed tomography; MRI, magnetic resonance imaging; N/A, not applicable.
decompression (rhBMP-2 n = 2, ICBG n = 3) and adjacent segment degeneration (rhBMP-2 n = 0, ICBG n = 1). During the foilow-up period, 48 patients underwent surgery for unrelated nonspinal conditions (rhBMP-2 n = 26, ICBG n = 22). Gastrointestinal complications consisting primarily of postoperative ileus were more frequent in the ICBG group (26%) compared with patients who received rhBMP-2 (16%), but this difference was not statistically significant (P = 0.147). Graft-site complications of any type (infection, symptomatic hematoma, wound dehiscence) were reported in 12 patients 80 rhBMP-2
12
18
24
30
36
42
48
Time (mo) Figure 2. Mean ODI scores were significantly reduced by surgery in both groups throughout the duration of follow-up (24-mo F < 0.001; 48-mo P < 0.001; repeated measures ANOVA), but did not differ between groups (24-mo P = 0.849; 48-mo P = 0.578; repeated measures ANOVA). ANOVA indicates analysis of variance; ODI, Oswestry Disability Index; rhBMP, recombinant human bone morphogenetic protein; ICBC, iliac crest bone graft. Spine
treated with ICBG, none of which required a second general anesthetic. Throughout the 4-year follow-up period, there were 2 reported instances of nonspinal cancer occurring in each of the control and treatment groups (P = 0.992). Nonspecific or constitutional symptoms were also documented as adverse events. At the conclusion of follow-up, headache was reported by 4 patients treated with rhBMP-2 but not by patients treated with ICBG (P = 0.044). Similarly, there were 4 from the rhBMP-2 group who reported insomnia compared with none reporting the same in the autograft group (P = 0.043). "Other" pain (non-back, non-leg) was reported by 16 patients who received rhBMP-2 and 6 of those Vk'ho received ICBG (P = 0.027). Fusion status was determined by plain radiographs at 6, 12, 24, and 48 months. Adherence to the 3 strictly defined radiographical criteria yielded diagnoses of fusion in 38 of 88 (43%) patients treated with ICBG at 6 months compared with 89 of 93 (96%) patients treated with rhBMP-2 (Figure 5). At subsequent 12- and 24-month assessments, the percentage of patients treated with ICBG demonstrating evidence of bony fusion rose to 57% and 70%, respectively. By 48 months, this trend seemed to have plateaued, remaining stable at 69%. Throughout the duration of the follow-up period, radiographical evidence of fusion remained relatively constant in the rhBMP-2 group at 96%, 98%, and 97% at 6, 12, and 24 months, respectively (P < 0.001), and at 94% at 48 months www.spinejournal.com
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RANDOMIZED TRIAI
Effect of rhBMP-2 on Lumbar Arrhrodesis • Hurlbert et al
Mental Component
Physical Component gjiUU
rhBMP-2 ICBG
S '^ö
• rhBMP-2 •ICBG
80-
u. 60 ro ^^ «r 20-
°
0
6
12
18 24
30
36
0
42 48
6
12
18 24
30
36
42 48
18
30
36
42
Role Physical
Physical Function
100-
RANDOMIZED TRIAL
rhBMP-2 for Posterolateral Instrumented Lumbar Fusion A Multicenter Prospective Randomized Controlled Trial R. John Hurlbert, MD, PhD, FRCSC, FACS,* David Alexander, MD, FRCSC,t Stewart Bailey, MD, FRCSC,+ James Mahood, MD, FRCSC,§ Ed Abraham, MD, FRCSC, 1 Robert McBroom, MD, FRCSC,|| Alain jodoin, MD, FRCSC,** and Charles Fisher, MD, FRCSC, MSctt
Study Design. Multicenter randomized controlled trial. Objective. To evaluate the effect of recombinant human bone morphogenetic protein (rhBMP-2) on radiographical fusion rate and clinical outcome for surgical lumbar arthrodesis compared with iliac crest autograft. Summary of Bacitground Data. In many types of spinal surgery, radiographical fusion is a primary outcome equally important to clinical improvement, ensuring long-term stability and axial support. Biologic induction of bone growth has become a commonly used adjunct in obtaining this objective. We undertook this study to objectify the efficacy of rhBMP-2 compared with traditional iliac crest autograft in instrumented posterolateral lumbar fusion. Methods. Patients undergoing 1- or 2-level instrumented posterolateral lumbar fusion were randomized to receive either autograft or rhBMP-2 for their fusion construct. Clinical and radiographical outcome measures were followed for 2 to 4 years postoperatively. Results. One hundred ninety seven patients were successfully randomized among the 8 participating institutions. Adverse events attributable to the study drug were not significantly different compared with controls. However, the control group experienced From the *University of Calgary Spine Program and Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta; tDivision of Orthopedic Surgery, Dalhousie University, Halifax, Nova Scotia, Canada; ^Division of Orthopedic Surgery, University of Western Ontario, London, Ontario, Canada; §Division of Orthopedic Surgery, University of Alberta, Edmonton, Alberta, Canada; 1 Division of Orthopedic Surgery, Dalhousie University, St. John, New Brunswick, Canada; ||Division of Orthopedic Surgery, Trillium Health Centre, Mississauga, Ontario, Canada; **Division of Orthopedic Surgery, University of Montreal, Montreal, Quebec, Canada; and ttDivision of Orthopedic Surgery, University of British Columbia, Vancouver, British Columbia, Canada. Acknowledgment date: July 8, 2011. First revision date: February 18, 2012. Second revision date: July 28, 2012. Third revision date: November 2, 2012. Fourth revision date: April 12, 2013. Fifth revision date: August 28, 2013. Acceptance date: August 29, 2013. rhBMP-2 is not FDA-approved for this indication. Medtronic Inc. funds were received to support this work. Relevant financial activities outside the submitted work: consultancy. Address correspondence and reprint requests to R. John Hurlbert, MD, PhD, FRCSC, FACS, Department of Clinical Neurosciences, Foothills Hospital, 1403 29th St N.W. Calgary, Alberta, CanadaT2N 2T9; E-mail: jhurlber@ucalgaryca DOI: 10.1097/BRS.0000000000000007 Spine
significantly more graft-site complications as might be expected. 36-ltem Short Form Health Survey, Oswestry Disability Index, and leg/back pain scores were comparable between the 2 groups. After 4 years of foilow-up, radiographical fusion rates remained significantly higher in patients treated with rhBMP-2 (94%) than those who received autograft (59%) (P = 0.007). Conclusion. The use of rhBMP-2 for instrumented posterolateral lumbar surgery significantly improves the chances of radiographical fusion compared with the use of autograft. However, there is no associated improvement in clinical outcome within a 4-year followup period. These results suggest that use of rhBMP-2 should be considered in cases where lumbar arthrodesis is of primary concern. Key words: spine, BMP, osteoinduction, degenerative disease, degenerative disc disease, bone graft, stability, arthrodesis. Level of Evidence: N/A Spine 2013;38:2139-2148
S
urgical arthrodesis is an important outcome for many types of spinal surgery, particularly those aimed at correcting deformity or instability. Success depends on a number of variables including age, smoking status, comorbidities (e.g., osteoporosis), number of levels to be fused, presence or absence of instrumentation, graft-bed preparation, and the graft material used. Despite improved techniques facilitating surgical arthrodesis, nonunion rates of 5% to 15% continue to inflict disability on patients and inflate costs for health care providers.'"' Originally identified in 1965, a number of low molecular weight glycoproteins belonging to the transforming growth factor-beta superfamily have been shown to possess strong osteoinductive properties.'*'^ Recombinant human bone morphogenetic protein-2 (rhBMP-2) has shown consistent results in a number of different animal models'""' and has been found to be successful in promoting fusion in human posterolateral lumbar arthrodesis.'" Despite these encouraging results, class I data from only 284 patients implanted with rhBMP-2 in the setting of posterolateral lumbar fusion has been published.'""'^ The purpose of this study was to assess safety and efficacy of rhBMP-2 compared with iliac crest autograft in promoting www.spinejournal.com
2139
RANDOMIZED TRIAI
radiographical fusion for human posterolateral lumbar spinal arthrodesis and to compare clinical outcome to patients receiving "gold standard" iliac crest autograft.
MATERIALS AND METHODS The study was designed and executed as a multicenter prospective randomized controlled clinical trial. It was registered as a Pivotal Clinical Trial with the Health Protection Branch of the Government of Canada under Application File No. 13006 and is published at clinicaltrials.gov (NCT01494454). Eight university affiliated tertiary care centers from across Canada participated in the protocol. Each center received Internal Review Board approval specific to its site. Patients entered into the study were informed of the experimental details and underwent an informed consent process. Patients were randomized 1:1 (iliac crest bone graft [ICBG):rhBMP-2) within a fixed randomization block provided to each participating institution. Surgeons were not blinded to the randomization process for obvious reasons. Patients were not blinded to treatment arm due to open bone graft harvesting (see text hereafter). Sample size determinations were not based on statistical estimations but rather on the study population estimated to be available at the participating institutions within a reasonable time frame. Interim analyses were planned and performed at regular intervals to ensure patient safety and to monitor treatment effect. At the end of recruitment, power calculations proved unnecessary because statistical significance had been achieved in a primary outcome measure (fusion). Inclusion and exclusion criteria are summarized in Table 1. To be considered for the study the patient had to be a candidate for a 1- or 2-level posterolateral instrumented lumbar fusion for the treatment of degenerative disease. The indication for instrumented fusion was based on the presence of symptomatic degenerative disc disease that in the opinion of the treating surgeon, required more than simple decompression. Degenerative disc disease was confirmed with radiographical studies in which one or more of the following were identified; instability (s5° angular motion or >4 mm translation on dynamic radiographs), osteophyte formation, decreased disc height, thickening of ligamentous tissue, disc degeneration or herniation, or facet joint degeneration similar to the criteria used by Boden et al.'" Grade 1 isthmic or degenerative spondylolisthesis were appropriate diagnoses but grade 2 slips and higher were excluded. Preoperative assessment included neurological examination, clinical outcome questionnaires, plain lumbar radiographs (AP, lateral, flexion, extension), and computed tomographic (CT) scan of the lumbar spine. Patients were required to have an Oswestry Disability Index (ODI) score 30 or more. At the time of surgery, patients were randomized at their treating institution into 1 of 2 groups: (1) the control cohort that underwent standard posterolateral instrumentation and fusion with autogenous ICBG; and (2) the investigational or treatment group that underwent similar posterolateral instrumentation but fusion with rhBMP-2 instead of iliac crest. Instrumentation was standardized as either TSRH (Medtronic 2140
www.spinejournal.com
Effect of rhBMP-2 on Lumbar Arthrodesis • Hurlbert et al
TABLE í. ¿g^íg¿¿4]|^5Tii[l!r-5fi" Inclusion
Exclusion
Degenerative disc disease with corresponding back and/ or leg pain necessitating instrumented fusion
Pathology other than degenerative disease (e.g., neoplasm, trauma, infection)
One- or 2-level involvement
Spondylolisthesis more than grade 1
Preoperative Oswestry Disability Index score > 3 0
Previous spinal fusion
Failure of conservative (nonsurgical) care for at least 6 mo
Comorbidities recognized to interfere with surgical outcome (e.g., osteoporosis, steroid administration, alcohol/drug abuse)
Age 2 18 yr
Morbid obesity (>140% ideal body weight)
Able to give informed consent
Titanium alloy allergy Tobacco use at time of surgery Previous exposure to BMP Pregnancy or unknown pregnancy status Presence or prior history of malignancy
BMP indicates bone morphogenetic protein.
Inc., Memphis, TN) or CD Horizon (Medtronic Inc.) fixation systems. In patients who underwent a single-level fusion, each side of the spine was implanted with 10 mL (2.1 mg/mL) of rhBMP-2 on a biphasic calcium phosphate granule (BCP) carrier (60% hydroxyapatite/40% ß-calcium triphosphate/80% porosity—Medtronic Inc., Memphis, TN), resulting in a total rhBMP-2 dose of 42 mg. In patients undergoing 2-level fusions, a third kit was added for a total volume of 30 mL (63 mg). rhBMP-2 was allowed to bind to the BCP carrier for a minimum of 5 minutes to a maximum of 60 minutes before implantation. At the time of bone graft application, ICBG or rhBMP-2/BCP was placed adjacent to the lateral facet joints and overlying the transverse processes of the instrumented segments. ICBG was not used to augment fusion in any of the patients receiving rhBMP-2/BCP; in other words, rhBMP-2/ BCP was used to facilitate arthrodesis as a stand-alone graft material. Local bone acquired through decompression was discarded in both rhBMP-2 and ICBG groups to ensure direct comparison of the 2 techniques. Components of the surgical intervention were not controlled (e.g.., severity of compressive pathology and degree of decompression), allowing each surgeon to decide independently on the basis of individual patient's signs, symptoms, and imaging studies. ICBG was harvested from either the right or left iliac crest and could be performed through the primary midline incision or through a separate paramedian incision. The amount of bone graft harvested from the iliac crest was December 2013
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not Standardized but instead was left to the discretion of the participating surgeon according to their usual practice; however, enough graft material was required to span the intertransverse space bilaterally through the instrumented levels. Corticocancellous bone was obtained in all cases, involving the outer table and inner cancellous regions; the inner table was not violated. Placement of a drain and method of closure were determined by individual surgeon preference. Inpatient care including pain control, time to mobilization, and time to discharge was left to institutional practice. Similarly, physician preference was used to determine the need for postoperative bracing. The primary outcome measure chosen to test our research hypothesis pertaining to radiographical fusion was plain film radiographs (AP, lateral, flexion, extension) of the lumbar spine corresponding to the established and routine evaluation of postoperative patients in daily practice. Fusion was defined by 3 stringent criteria all of which had to be met: (1) bridging trabecular bone in both fusion masses (left and right intertransverse spaces) and the absence of traversing radiolucent lines; (2) 3 mm or more translation on dynamic (flexion/ extension) films; and (3) less than 5° angulation on dynamic films.'" Two independent blinded radiologists evaluated all radiographical studies for every patient. Thin slice lumbar CT scans with sagittal reconstructions were performed at 6, 12, and 24 months and were incorporated in determining the presence of bridging bone. The primary assessment tool chosen to test our research hypothesis pertaining to clinical outcome was the ODI. Additional clinical assessment tools included the 36-Item Short Form Health Survey (SF-36), analogue back/leg pain scores (0-20), and a detailed neurological examination. These assessments were performed both pre- and postoperatively throughout the course of follow-up. Patients randomized to the ICBG group completed an iliac crest donor site survey at each follow-up visit. Follow-up was scheduled postoperatively at 6 weeks, 3 months, 6 months, 1 year, and 2 years. A smaller cohort of patients was followed for 4 years. Study subjects were followed for adverse events defined as a clinically adverse sign, symptom, syndrome, or illness that occurred or worsened during the operative and postoperative periods ofthe trial, regardless of causality. Grading of severity was planned in accordance with the World Health Organization Toxicity Scale." Grade 3 and 4 toxicity events were considered serious. To meet regulatory requirements "surgical failures" were defined as patients who underwent removal or revision of instrumentation. These patients were subsequently withdrawn from the study protocol and excluded from further analyses. Data were collected prospectively and entered into a central database for analyses. The participating centers were surveyed by external study monitors on a regular basis to ensure protocol and data acquisition compliance. Patient demographics were examined to ensure comparability between both groups. Statistical analyses were performed using the Fisher exact test for proportions and t tests for continuous data. Repeated measure analysis was also performed to Spine
Effect of rhBMP-2 on Lumbar Arthrodesis • Hurlbert et al
assess treatment effect over time. Significance was defined at P < 0.05.
RESULTS Target sample size was 100 patients per treatment arm. From August 1999 through April of 2004, of the 207 subjects enrolled, 197 surgical procedures were completed (98 investigational; 99 control). Ten enrolled patients (4 investigational; 6 control) withdrew from the study after randomization but before treatment (Figure 1). Of the 10 withdrawn patients, 4 withdrew for unspecified reasons. Three patients were withdrawn preoperatively because it was discovered after randomization that they did not properly meet the study inclusion/exclusion criteria. One patient randomized to ICBG refused control group surgery. One patient was withdrawn because of nonpermissive insurance coverage. One patient decided preoperatively that they wished to have surgery at a different hospital. These 10 patients were excluded from further analyses. Sixty-three females and 35 males were assigned to receive rhBMP-2, whereas 51 females and 48 males received ICBG (P = 0.084). Twenty percent of the patients treated with rhBMP-2 were working before surgery compared with 24% of ICBG controls (P = 0.608). There were no between-group differences in demographic characteristics (Table 2). All patients received their prescribed treatment. There were a total of 5 intraoperative protocol violations arising from discrepancies in surgical technique. All 5 patients were included in the analyses on an intent-to-treat basis. The surgical deviations included (1) incorrect number of rhBMP-2 kits used; (2) single-level preoperative planning but 2-level instrumented fusion; (3) single-level fusion but 2-level instrumentation; (4) unanticipated unilateral instrumentation; (5) local bone autograft instead of iliac crest. Other protocol violations pertained largely to the missed radiographs at specific follow-up intervals (Table 3). Two patients were lost to follow-up after 6 months in the ICBG group (98% 2-yr follow-up). Allowing for anticipated lag time in accrual, an initial cohort of the study population was followed to 48 months (n = 41 each group). Most surgical procedures were for single rather than 2-level symptomatic disease (88% rhBMP-2 vs. 83% ICBG, P = 0.422). There was no significant difference in operative time (2.5 ± 1.2 hr rhBMP-2 vs. 1.7 ± 1.4 hr ICBG, P = 0.399), blood loss (615 ± 448 mL of rhBMP-2 vs. 643 ± 488 mL of ICBG, P = 0.671), or length of stay between the treatment and control patients (6 ± 3 d rhBMP-2 vs. 7 ± 5 á ICBG, P = 0.514). At the surgeon's discretion, 78% of patients in both groups were treated postoperatively with an external orthosis (P = 0.908). In general, surgery resulted in significant improvements in clinical outcomes irrespective of treatment group (P < 0.001; ODI, SF-36, leg and back pain scores). During the 2-year follow-up period, more than 24-point improvement was noted in the mean ODI for both patients treated with rhBMP-2 and those treated with ICBG (Figure 2). This was sustained throughout for the patients undergoing 4-year follow-up. In www.spinejournal.coin
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Effect of rhBMP-2 on Lumbar Arthrodesis • Hurlbert et al
Enrollment Randomized (n = 207)
1 rhBMP-2 (n = 102) • Received allocated intervention (n = 98) • Withdrew before surgery {n = 4)
Iliac crest bone graft (n = 105) • Received allocated intervention (n = 99) • Withdrew before surgery (n = 6)
Protocol not completed (n = 3) • Instrumentation revision (n = 2) • Lost to follow-up (n = 0) • Death (n = 1 )
Protocol not completed (n = 6) • Instrumentation revision (n = 2) • Lost to follow-up (n = 2) • Death (n = 2)
i
1 Analyzed ( n = 93) • Excluded from analysis (n = 0)
Analyzed ( n = 95) • Excluded from analysis (n = 0)
Figure 1. Flow chart of patients assessed and recruited into the study. rhBMP indicates recombinant human bone morphogenetic protein.
addition to total SF-36 scores, both the physical and mental component summaries, as well as all 8 subcomponents improved significantly compared with preoperative scores (Figure 3). Mean leg and back pain scores diminished immedi-
TABLE 2.
JnograpniG^ naracieris TICS OT Tne ^ Lly ^ 1 tliy^iiM
r-
rhBMP-2
ICBG
P
Age (yr)
53
53
0.989
Weight (Ib)
178
172
0.263
Sex (% male)
36
49
0.084
Previous smoking history (%)
30
26
0.636
Two-level surgery (%)
12
17
0.422
Previous back surgery (%)
19
20
1.000
Working before surgery {%)
20
24
0.608
Workman compensation (%)
11
14
0.669
Litigation (%)
5
3
0.498
rhBMP indicates recombinant human bone morphogenetic protein; iCBG, iliac crest bone graft.
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ately after surgery to 6 to 8 on a 20-point scale and remained stable throughout the follow-up period (Figure 4). Although mean scores for all clinical outcomes improved as a result of surgery, there were no differences observed between treatment groups. Neurological function improved on the whole compared with preoperative status in both groups throughout all follow-up time points; however, no between-group differences were observed (P > 0.05). There were 10 cases of noninfectious wound complications {e.g., superficial dehiscence, seroma, erythema, persistent discharge), 6 in the rhBMP-2 group, and 4 in the ICBG group (P = 0.519). Eleven cases of wound infection (superficial and deep) were treated in patients receiving rhBMP-2 compared with 5 in control patients (? = 0.119). All were successfully managed with intravenous antibiotics and debridement/ primary closure under general anesthesia. Two of the deep infections encountered in patients treated with rhBMP-2 occurred subsequent to revision surgery. Four patients (n = 2 from each group) underwent revision procedures for symptomatic nonunion within 24 months of their index surgery. As per protocol they were classified as surgical failures and excluded from further analysis beyond the time of their secondary surgery (Figure 1). Additional secondary surgical procedures were performed for repeat December 2013
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Effect of rhBMP-2 on Lumbar Arthrodesis • Hurlbert et al
TABLE 3,
^-««—.
Description
Preoperative
Surgery
ówk
AP radiograph not obtained
0
4
0
0
Eateral radiograph not obtained
4
6
3
Elexion radiograph not obtained
11
N/A
Extension radiograph not obtained
10
Ferguson radiograph not obtained
14
CT/MRI not obtained Imaging performed outside 2-wk window
3 mo 6 mo
1 yr
2yr
4 yr
0
0
0
0
4
N/A
N/A
N/A
N/A
N/A
N/A
9
3
3
1
N/A
N/A
N/A
9
3
2
1
11
8
7
4
1
5
1
2
4
0
0
1
1
1
0
36
1
2
0
12
3
2
0
Missed evaluation
N/A
N/A
0
1
2
2
1
2
Evaluation performed outside 2-wk window
N/A
N/A
21
34
14
4
21
14
Patient forms outside 2-wk window
N/A
0
0
1
1
0
0
0
0
0
Ü
0
1
0
0
0
N/A
5
N/A
N/A
N/A
N/A
N/A
N/A
Inclusion/exclusion not followed
7
0
N/A
N/A
N/A
N/A
N/A
N/A
Incomplete physician form
0
0
2
2
2
1
1
0
Missing physician form
0
0
0
1
0
1
1
0
Weight not obtained
0
N/A
3
1
1
1
3
2
Blood specimen not obtained
0
N/A
N/A
2
N/A
N/A
N/A
N/A
Blood specimen not handled per protocol
2
N/A
N/A
8
N/A
N/A
N/A
N/A
Missing patient form Deviations from surgical technique
CT indicates computed tomography; MRI, magnetic resonance imaging; N/A, not applicable.
decompression (rhBMP-2 n = 2, ICBG n = 3) and adjacent segment degeneration (rhBMP-2 n = 0, ICBG n = 1). During the foilow-up period, 48 patients underwent surgery for unrelated nonspinal conditions (rhBMP-2 n = 26, ICBG n = 22). Gastrointestinal complications consisting primarily of postoperative ileus were more frequent in the ICBG group (26%) compared with patients who received rhBMP-2 (16%), but this difference was not statistically significant (P = 0.147). Graft-site complications of any type (infection, symptomatic hematoma, wound dehiscence) were reported in 12 patients 80 rhBMP-2
12
18
24
30
36
42
48
Time (mo) Figure 2. Mean ODI scores were significantly reduced by surgery in both groups throughout the duration of follow-up (24-mo F < 0.001; 48-mo P < 0.001; repeated measures ANOVA), but did not differ between groups (24-mo P = 0.849; 48-mo P = 0.578; repeated measures ANOVA). ANOVA indicates analysis of variance; ODI, Oswestry Disability Index; rhBMP, recombinant human bone morphogenetic protein; ICBC, iliac crest bone graft. Spine
treated with ICBG, none of which required a second general anesthetic. Throughout the 4-year follow-up period, there were 2 reported instances of nonspinal cancer occurring in each of the control and treatment groups (P = 0.992). Nonspecific or constitutional symptoms were also documented as adverse events. At the conclusion of follow-up, headache was reported by 4 patients treated with rhBMP-2 but not by patients treated with ICBG (P = 0.044). Similarly, there were 4 from the rhBMP-2 group who reported insomnia compared with none reporting the same in the autograft group (P = 0.043). "Other" pain (non-back, non-leg) was reported by 16 patients who received rhBMP-2 and 6 of those Vk'ho received ICBG (P = 0.027). Fusion status was determined by plain radiographs at 6, 12, 24, and 48 months. Adherence to the 3 strictly defined radiographical criteria yielded diagnoses of fusion in 38 of 88 (43%) patients treated with ICBG at 6 months compared with 89 of 93 (96%) patients treated with rhBMP-2 (Figure 5). At subsequent 12- and 24-month assessments, the percentage of patients treated with ICBG demonstrating evidence of bony fusion rose to 57% and 70%, respectively. By 48 months, this trend seemed to have plateaued, remaining stable at 69%. Throughout the duration of the follow-up period, radiographical evidence of fusion remained relatively constant in the rhBMP-2 group at 96%, 98%, and 97% at 6, 12, and 24 months, respectively (P < 0.001), and at 94% at 48 months www.spinejournal.com
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Effect of rhBMP-2 on Lumbar Arrhrodesis • Hurlbert et al
Mental Component
Physical Component gjiUU
rhBMP-2 ICBG
S '^ö
• rhBMP-2 •ICBG
80-
u. 60 ro ^^ «r 20-
°
0
6
12
18 24
30
36
0
42 48
6
12
18 24
30
36
42 48
18
30
36
42
Role Physical
Physical Function
100-
