Cervical Corpectomy With Ultra-low-dose rhbmp-2 in High-risk Patients: 5-year Outcomes

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1 Section Editor: Bennie G.P. Lindeque, MD Cervical Corpectomy With Ultra-low-dose rhbmp-2 in High-risk Patients: 5-year Outcomes Sina Pourtaheri, MD; Arash Emami, MD; Ki Hwang, MD; Jesse Allert, MD; Alex Brothers, MD; Kimona Issa, MD; Michael A. Mont, MD Abstract: Twenty-four consecutive patients with cervical spondylosis who were treated with cervical corpectomy and recombinant human bone morphogenetic protein-2 (rhbmp-2) with standalone anterior instrumentation were evaluated. Mean number of levels fused was 2.4. There were significant improvements in visual analog scale neck pain and Oswestry Disability Index scores and cervical lordosis. Cervical corpectomy with a lower dose of rhbmp-2 was found to be safe and efficacious for patients who are at a higher risk for pseudarthrosis. [Orthopedics. 2013; 36(12): ] Recombinant human bone morphogenetic protein-2 (rhbmp-2) has been used successfully when inserted through an anterior approach for lumbar interbody fusion. 1,2 This agent demonstrated safety and efficacy as a bone graft substitute for this application and subsequently gained US Food and Drug Administration approval. 1,2 The motivations for using rhbmp-2 included the high fusion rates and the avoidance of autograft iliac crest donor site harvesting morbidity. 3 It has been reported to be successful in inducing bone growth, with an efficacy The authors are from the Department of Orthopedic Surgery (SP, AE, KH, JA, AB, KI), Seton Hall University of Health and Medical Science, St Joseph s Regional Medical Center, Paterson, New Jersey; and the Department of Orthopedic Surgery (KI, MAM), Sinai Hospital of Baltimore, Baltimore, Maryland. The authors have no relevant financial relationships to disclose. Correspondence should be addressed to: Sina Pourtaheri, MD, Department of Orthopedic Surgery, Seton Hall University of Health and Medical Science, St Joseph s Regional Medical Center, 703 Main St, Paterson, NJ (spourtah@gmail.com). Received: September 13, 2013; Accepted: September 26, 2013; Posted: December 13, doi: / equivalent to, or even greater than, iliac crest autograft. 4,5 In addition, this has marked importance in patients who are at a higher risk for pseudarthrosis, including tobacco smokers and those who have diabetes mellitus. The safety profile of rh- BMP-2 used during lumbar spine fusion has been documented, but the safety and efficacy of its off-label use in the anterior cervical spine has not been widely evaluated Although these studies have reported successful fusion rates using high doses of rhbmp-2 ( mg/ml per level), the high rates of perioperative cervical swelling complications, including airway edema, dysphagia, and visible swelling of the anterior neck, have been concerning. 6,7 These swelling complications typically occurred several days postoperatively. 7 It has been postulated that these adverse effects related to the use of rhbmp-2 may be dose dependent. 12,14 However, no previous study has evaluated the efficacy of ultra-low doses of this agent in cervical cases. The current authors hypothesized that the use of lower doses of rhbmp-2 may have marked advantages in high-risk patients and may be associated with lower complications when performing cervical corpectomies. Therefore, the authors evaluated the clinical and radiographic outcomes of using 0.26 to 0.35 mg/ml of rhbmp-2 in cervical corpectomies in patients who were considered high risk for pseudarthrosis (tobacco smokers and patients with diabetes mellitus). Specifically, the authors evaluated (1) postoperative complications, including cervical swelling, dysphagia, and hematoma formation; (2) length of hospital stay; (3) clinical outcomes measured by visual analog scale (VAS) neck and arm pain scores and Oswestry Disability Index (ODI) scores; and (4) radiographic evaluations, including cervical swelling, graft migration, heterotopic ossification, adjacent segment disease, and cervical lordosis. DECEMBER 2013 Volume 36 Number

2 Table 1 Patients Clinical Characteristics Characteristic No. (%) Sex Male 13 (54) Female 11 (46) Medical comorbidity 24 (100) Smoker 17 (70) Diabetes mellitus 9 (38) Peripheral vascular disease 6 (25) Coronary artery disease 8 (33) Cerebral vascular accident 5 (21) Hypercholesteremia 18 (75) Hypertension 19 (79) Materials and Methods A clinical and radiographic review of all cervical corpectomy cases with low-dose rh- BMP-2 performed between August 2007 and December 2009 was conducted. All procedures were performed by an experienced, fellowshiptrained orthopedic spine surgeon (A.E.) at a single institution. The study population consisted of 24 consecutive patients, including 13 men and 11 women. Mean age was 60±9 years, and mean followup was 5 years (range, years). The primary indication for surgery was spondylotic myelopathy. No trauma cases or fractures were included in this study. All medical records, including preoperative history and physical examination, operative notes, hospital discharge summary, appropriate radiographs, and follow-up office visits, were thoroughly reviewed. All patients had a medical risk factor for pseudarthrosis, including 70% being tobacco smokers and 38% having diabetes mellitus (Table 1). Appropriate institutional review board approval was obtained for this study. All anterior fusions were performed through a Smith-Robinson approach. The rh- BMP-2 was prepared at a concentration of 0.26 to 0.35 mg per level (between oneeighth and one-sixth of an extra small sponge [1.4 cc at 1.5 mg/ml]) with local autograft from the corpectomy and demineralized bone matrix (Grafton; BioHorizon, Birmingham, Alabama) in a polyetheretherketone (PEEK) spacer (BENGAL; DePuy, Warsaw, Indiana). The specific dosage of rhbmp-2 used was based on the senior author s experience and review of the literature and was approximately one-third to one-quarter that of previously published reports. 7,15-17 Mean number of levels fused was 2.4±0.58. Eight (33%) patients had an anterior cervical diskectomy and fusion (ACDF) adjacent to the corpectomy level at the index surgery. All patients received a cervical drain and were intubated at the end of the operation. They were given a tapered dose of methylprednisolone postoperatively and discharged once tolerating a diet. A hard collar was worn for 2 weeks, followed by a soft collar for another 2 weeks. Six weeks postoperatively, therapy was initiated. All patients were assessed clinically by the senior author postoperatively at 2 and 6 weeks, 6 months, 1 year, and then annually. During each visit, patients were examined thoroughly, and VAS neck and arm pain and ODI scores were recorded. All complications were recorded. A perioperative swelling complication was defined as one occurring within 6 weeks of the index surgical procedure. These complications involved visible swelling of the surgical site, swallowing dysfunction, and/or breathing difficulties, which then led to any of the following: (1) a delay in discharge during the index surgical hospitalization; (2) otolaryngological consultation as an outpatient; (3) a premature return to the office or to the emergency department after hospital discharge; (4) readmission for observation and medical management of swelling but without surgical intervention; or (5) readmission for incision and drainage of the surgical site for actual or threatened airway compromise. Dysphagia and voice hoarseness were assessed at all clinical visits. Dysphagia was quantified with the clinical notes and telephone questionnaires using the Bazaz dysphagia scale; dysphagia was defined as mild (rare swallowing discomfort for solids), moderate (occasional dysphagia for certain solid foods), or severe (frequent dysphagia for solids and rarely for liquids). 17 Radiographic evaluations were performed preoperatively and during each follow-up visit (Figures 1-2). Adjacent segment degeneration (cranial and caudal to the planned and eventually fused levels) and cervical lordosis was assessed. Adjacent segment degeneration was defined as adjacent segment disease if the patient had symptoms related to it. 18 Also, graft subsidence, graft migration, and heterotopic ossification posterior to the graft and within the spinal canal were evaluated at each visit. Graft subsidence or migration was defined as greater than 2 mm of subsidence or migration on subsequent radiographs. Soft tissue swelling was measured at C2 and C3 two weeks postoperatively. Soft tissue swelling was defined as the distance from the front of the spine to the posterior edge of the trachea. The difference between preoperative and 2-week postoperative values defined the soft tissue swelling. Radiographic fusion was defined as osseous integration of the graft on sequential postoperative radiographs. Flexion/extension radiographs and/or computed tomography scans were obtained if there were concern for pseudarthrosis. All data were recorded on an Excel spreadsheet (Microsoft Corp, Redmond, Washington). Statistical analysis was performed using the Student s t test to compare the pre- and postoperative chang- 932 ORTHOPEDICS Healio.com/Orthopedics

3 1A 1B 1C Figure 1: Preoperative radiograph of severe stenosis and kyphosis (A). Radiograph 2 weeks after C6 corpectomy (B). Radiograph 6 months postoperatively showing osseous integration and maintained correction of cervical lordosis (C). 2A 2B 2C Figure 2: Preoperative radiograph of multilevel degenerative changes with stenosis (A). Radiograph 2 weeks after C4 corpectomy and C5-C6 diskectomy and fusion (B). Radiograph 6 months postoperatively showing osseous integration and maintenance of cervical lordosis (C). es in VAS neck and arm pain and ODI scores. STATA version 11.0 statistical software (STATACorp, College Station, Texas) was used to perform the analyses. A P value less than.05 was considered significant. Results No airway or cervical swelling complications occurred, and no patient required outpatient otolaryngological consultation for swallowing issues. At 2-week follow-up, 14 (58%) patients reported hoarseness, which resolved in all but 2 patients, and 12 (50%) patients reported dysphagia (8 mild, 3 moderate, and 1 severe). Nine (38%) patients continued to have dysphagia at 6 weeks (8 mild, 1 moderate). Five (21%) patients reported dysphagia at 6 months (5 mild). Four (17%) patients reported dysphagia at latest follow-up (mean, 4.5 years). Mean hospital stay was 1.1±0.34 days. No patient had a prolonged hospital stay (longer than 48 hours) due to either dysphagia or visible neck swelling. No patient was readmitted for either medical management or surgical irrigation and debridement of anterior neck swelling. There were significant improvements in VAS neck and arm pain and ODI scores from preoperatively to final followup. Mean VAS neck and arm pain scores improved from preoperative values of 7.5±12.5 and 5.3±2.4 points, respectively, to postoperative values of 2.0±1.2 (P=.0001) and 0.92±0.72 (P=.0001) points, respectively. In addition, mean ODI score improved from a preoperative value of 28.8±5.4 points to a postoperative value of 13.4±5.0 points (P=.0001) (Table 2). On radiographic evaluation, mean swelling anterior to the C2 and C3 vertebral bodies 2 weeks postoperatively was 4.8 and 8.8 mm, respectively. No graft migration was observed. Four (17%) patients developed heterotopic ossification posterior to the graft that was not clinically significant. Also, 4 (17%) patients developed postoperative adjacent segment degeneration and 4 (17%) developed subsidence (Table 3). Only 1 of the patients with adjacent segment degeneration was symptomatic, and it was addressed with a 1-level anterior cervical fusion without ODI rhbmp-2; symptoms resolved with no dysphagia at 6-week and 2-year follow-up. None of the cases of subsidence was symptomatic. Mean lordosis improved from a preoperative value of 4.5±12.5 points to a postoperative value of 11.2±10 points (P=.0001) (Table 4). All patients fused within 6 months postoperatively. Pseudarthrosis was not seen after a mean 5-year follow-up. Characteristic Table 2 Clinical Summary Mean (Range) Age, y 60 (43-77) LOS, d 1.1 (1-2) VAS neck pain Preop 7.5 (4-10) Postop 2 (0-5).0001 VAS arm pain Preop 5.3 (0-9) Postop 0.92 (0-2).0001 Preop 28.8 (19-40) Postop 13.4 (4-23).0001 Abbreviations: LOS, length of stay; ODI, Oswestry Disability Index; Postop, postoperative; Preop, preoperative; VAS, visual analog scale. Discussion The purported advantages of using rhbmp-2 in cervical corpectomy are the high fusion rates and the avoidance of autograft harvesting site morbidity. 2 Also, it has marked clinical importance in high-risk patients, P DECEMBER 2013 Volume 36 Number

4 Table 3 Patients Radiographic Characteristics Characteristic No. (%) ASD 4 (17) Subsidence 4 (17) Migration 0 (0) Resorption at 2 wk 10 (42) HO in spinal canal 0 (0) HO posterior to graft 6 (25) Abbreviations: ASD, adjacent segment disease; HO, heterotopic ossification. such as tobacco smokers and those with diabetic mellitus, who are at an increased risk for pseudarthrosis. However, the traditional dose of rhbmp-2 ( mg/ml per level) in anterior cervical fusions has been associated with increased complications, such as cervical swelling, hematoma formation, airway edema, and dysphagia. 7,15-17 Thus, the authors hypothesized that ultra-low doses of rhbmp-2 might still provide clinical advantage in high-risk patients who undergo cervical corpectomy and also may be associated with lower complications. In the current study of 24 consecutive cervical corpectomies with rh- BMP-2, a 100% fusion rate at 6 months was maintained at a mean 5-year follow-up, with no cervical swelling, hematoma formation, or increase in length of stay. Patients had acceptable levels of dysphagia for a cervical corpectomy (17% at 2-year follow-up). 17 Although the safety of rh- BMP-2 use during lumbar spine fusion has been documented, the safety and efficacy of its off-label use in the anterior cervical spine has not been widely evaluated. Previous studies of rhbmp-2 in ACDF reported a higher incidence of dysphagia and airway complications compared with patients who did not receive rhbmp-2. However, these complications may be dose dependent. Smucker et al 7 evaluated outcomes of ADCF in 69 patients who had received rhbmp-2 (1.5 mg/ml) compared with 165 patients who had not. They reported that the rhbmp-2 group had 27.5% clinically significant swelling events (P<.0001) compared Table 4 Radiographic Details Variable Mean (Range) P C2, mm a 3.6 (2 to 5) Preop Postop 8.3 (2 to 24).0002 C3, mm a 4.7 (2.3 to 7.4) Preop Postop 14.1 (5 to 31).0001 Swelling, mm b C2 4.8 (0 to 20) C3 8.8 (0 to 25) No. of corpectomy levels 1.04 (1 to 1.5) No. of fused levels 0.4 (2 to 4) Lordosis, deg Preop 4.5 (-20 to 30) Postop 11.2 (-4 to 31).0001 Improvement 6.8 (0 to 17) Abbreviations: deg, degrees; Postop, postoperative; Preop, preoperative. a Distance from the anterior vertebral body to the trachea. b Amount of swelling anterior to the vertebral body. with 3.6% without rhbmp-2. In the rhbmp-2 group, complications included 3 irrigation and debridements for neck swelling, 1 tracheostomy, 1 gastric tube placement, 2 reintubations, and 5 readmissions. Tobacco smoking, history of prior anterior cervical fusion, and surgical variables (plating, operations that included or were proximal to C4-C5, number of levels fused, and 3 or more levels fused) were associated with higher complication rates. Tumialan et al, 14 in their study of 200 patients who underwent single- or multilevel ACDF with titanium plate fixation and PEEK spacer, lowered the initial rhbmp-2 dosage of 2.1 mg/ml to 0.7 mg/ml per level. At a mean 16-month follow-up, they reported good to excellent clinical outcomes in 165 (85%) patients, with all (100%) patients achieving solid radiographic fusion on radiographic evaluation. However, 14 (7%) patients experienced clinically important dysphagia and 4 (2%) required repeat surgery for hematoma or seroma. The patients in the current study received doses of rh- BMP-2 equivalent to one-third to one-quarter that of the lowest previously evaluated doses. No studies have evaluated such doses of rhbmp-2 during anterior cervical surgery. The current authors found dysphagia rates (50%, 38%, 21%, and 16.5% at 2 and 6 weeks, 6 months, and 2 years postoperatively, respectively) similar to those of other studies that did not use rhbmp-2. Bazaz et al 17 prospectively evaluated 221 patients undergoing anterior cervical surgery and reported dysphagia rates of 50%, 32%, 18%, and 13% at 1-, 2-, and 6-month and 1-year follow-up, respectively. A second arm of Bazaz et al s 17 study of 97 single-level cervical corpectomies standalone (no hybrid constructs) had dysphagia rates similar to those of the overall patient cohort: 54%, 20.2%, and 15.1% at 1-, 2-, and 6-month follow-up, respectively. 19 Riley et al, 19 in a meta-analysis of 15 prospective studies on anterior cervical surgery and postoperative dysphagia (without rhbmp-2), found that the incidence of dysphagia ranged from 13% to 21% at 1-year follow-up. The current study had rates of 934 ORTHOPEDICS Healio.com/Orthopedics

5 dysphagia in the early postoperative period and in the long term similar to cervical corpectomies without rhbmp-2. In the current study, no perioperative airway or cervical swelling complications were encountered, and no patient had a prolonged hospital stay (longer than 48 hours) due to dysphagia or visible neck swelling. One explanation for these outcomes might be the good rhbmp-2 containment methods practiced in the study. The ultralow-dose rhbmp-2 was packed in the center of the PEEK cage and insulated with allograft and autograft, which may have prevented spread to surrounding soft tissues. In a retrospective study of 20 patients who underwent ACDF with bioabsorbable interbody spacers containing rhbmp-2, no rhbmp-2 related complications were noted. 20 The dose per level of rhbmp-2 used was not specified, but, similar to the current study, the rhbmp-2 sponge had been contained within the bioabsorbable spacer. 20 There are several limitations to this study, including the small sample size and lack of a comparison cohort. Also, the retrospective design of the study could have introduced potential biases. Reliability of plain radiographs to assess fusion at 6-month follow-up may be poor. Also, unmeasured confounding factors may have influenced the findings. Patient satisfaction and broader quality of life measures were not evaluated. Nevertheless, the authors believe that the results are valuable because, to their knowledge, this is the first study to evaluate the outcomes of cervical corpectomy using a lower dosage of rhbmp-2. Conclusion The authors found that, compared with previously published reports of higher doses, ultra-low-dose rhbmp-2 ( mg/ml per level) was safe and associated with fewer complications during cervical corpectomy. These low doses led to good clinical and radiographic results in patients who were considered at high risk for pseudarthrosis. The authors consider this a pilot study for future larger, multicenter studies. Prospective, randomized studies with longer follow-up may be necessary to better define the optimal dose of rh- BMP-2 during anterior cervical surgery. References 1. Burkus JK, Transfeldt EE, Kitchel SH, Watkins RG, Balderston RA. Clinical and radiographic outcomes of anterior lumbar interbody fusion using recombinant human bone morphogenetic protein-2. Spine (Phila Pa 1976). 2002; 27(21): Burkus JK, Gornet MF, Dickman CA, Zdeblick TA. Anterior lumbar interbody fusion using rhbmp-2 with tapered interbody cages. J Spinal Disord Tech. 2002; 15: Vaidya R, Sethi A, Bartol S, Jacobson M, Coe C, Craig JG. Complications in the use of rh- BMP-2 in PEEK cages for interbody spinal fusions. J Spinal Disord Tech. 2008; 21: Cheng H, Jiang W, Phillips, FM, et al. Osteogenic activity of fourteen types of human bone morphogenetic proteins. J Bone Joint Surg Am. 2003; 85: Mummaneni PV, Pan J, Haid RW, Rodts GE. Contribution of recombinant human bone protein-2 to the rapid creation of interbody fusion: a preliminary report. J Neurosurg Spine. 2004; 1(1): Shields LB, Raque GH, Glassman SD, et al. Adverse effects associated with high-dose recombinant human bone morphogenetic protein-2 use in anterior cervical fusion. Spine (Phila Pa 1976). 2006; 31: Smucker JD, Rhee JM, Singh K, Yoon ST, Heller JG. Increased swelling complications associated with off-label usage of rhbmp-2 in the anterior cervical spine. Spine (Phila Pa 1976). 2006; 31(24): Lu DC, Tumialan LM, Chou D. Multilevel anterior cervical discectomy and fusion with and without rhbmp-2: a comparison of dysphagia rates and outcomes in 150 patients. J Neurosurg Spine. 2013; 18(1): Hodges SD, Eck JC, Newton D. Retrospective study of posterior cervical fusions with rhbmp-2. Orthopedics. 2012; 35(6):e895- e Shen HX, Buchowski JM, Yeom JS, Liu G, Lin N, Riew KD. Pseudarthrosis in multilevel anterior cervical fusion with rhbmp-2 and allograft: analysis of one hundred twentyseven cases with minimum twoyear follow-up. Spine (Phila Pa 1976). 2010; 35(7): Tumialan LM, Rodts GE. Adverse swelling associated with use of rhbmp-2 in anterior cervical discectomy and fusion. Spine J. 2007; 7(4): Dickerman RD, Reynolds AS, Morgan BC, Tompkins J, Cattorini J, Bennett M. rhbmp-2 can be used safely in the cervical spine: dose and containment are the keys! Spine J. 2007; 7(4): Mesfin A, Buchowski JM, Zebala LP, et al. High-dose rh- BMP-2 for adults: major and minor complications: a study of 502 spine cases. J Bone Joint Surg Am. 2013; 95(17): Tumialan LM, Pan J, Rodts GE, Mummanemi PV. The safety and efficacy of anterior cervical discectomy and fusion with polyetheretherketone spacer and recombinant human bone morphogenetic protein-2: a review of 200 patients. J Neurosurg Spine. 2008; 8(6): Chen AY, Frankowski R, Bishop-Leone J, et al. The development and validation of a dysphagia-specific quality-of-life questionnaire for patients with head and neck cancer: the M. D. Anderson dysphagia inventory. Arch Otolaryngol Head Neck Surg. 2001; 127(7): Buttermann GR. Prospective nonrandomized comparison of an allograft with bone morphogenic protein versus an iliac-crest autograft in anterior cervical discectomy and fusion. Spine J. 2008; 8(3): Bazaz R, Lee MJ, Yoo JU. Incidence of dysphagia after anterior cervical spine surgery. Spine (Phila Pa 1976). 2002; 27(22): Carrier CS, Bono CM, Lebl DR. Evidence-based analysis of adjacent segment degeneration and disease after ACDF: a systematic review. Spine J Riley LH III, Vaccaro AR, Dettori JR, Hashimoto R. Postoperative dysphagia in anterior cervical spine surgery. Spine (Phila Pa 1976). 2010; 35(9 Suppl):S76-S Lanman TH, Hopkins TJ. Early findings in a pilot study of anterior cervical interbody fusion in which recombinant human bone morphogenetic protein-2 was used with poly (L-lactideco-D,L-lactide) bioabsorbable implants. Neurosurgical Focus. 2004; 16(3):E6. DECEMBER 2013 Volume 36 Number