J Neurosurg Spine 21:867–876, 2014 ©AANS, 2014
Clinical outcomes and fusion rates following anterior lumbar interbody fusion with bone graft substitute i-FACTOR, an anorganic bone matrix/P-15 composite Clinical article Ralph J. Mobbs, B.Sc., M.B.B.S., M.S., F.R.A.C.S.,1,2 Monish Maharaj, M.D., 2 and Prashanth J. Rao, M.D.1,2 1 NeuroSpineClinic, Prince of Wales Private Hospital; and 2Faculty of Medicine, University of New South Wales, Sydney, Australia
Object. Despite limited availability and the morbidity associated with autologous iliac crest bone graft (ICBG), its use in anterior lumbar interbody fusion (ALIF) procedures remains the gold standard to achieve arthrodesis. The search for alternative grafts yielding comparable or superior fusion outcomes with fewer complications continues. In particular, i-FACTOR, a novel bone graft substitute composed of anorganic bone matrix (ABM) with P-15 small peptide, is one example currently used widely in the dental community. Although preclinical studies have documented its usefulness, the role of i-FACTOR in ALIF procedures remains unknown. The authors’ goal was to determine the safety and efficacy of i-FACTOR bone graft composite used in patients who underwent ALIF by evaluating fusion rates and clinical outcomes. Methods. A nonblinded cohort of patients who were all referred to a single surgeon’s practice was prospectively studied. One hundred ten patients with degenerative spinal disease underwent single or multilevel ALIF using the ABM/P-15 bone graft composite with a mean of 24 months (minimum 15 months) of follow-up were enrolled in the study. Patient’s clinical outcomes were assessed using the Oswestry Disability Index for low-back pain, the 12-Item Short Form Health Survey, Odom’s criteria, and a visual analog scale for pain. Fine-cut CT scans were used to evaluate the progression to fusion. Results. All patients who received i-FACTOR demonstrated radiographic evidence of bony induction and early incorporation of bone graft. At a mean of 24 months of follow-up (range 15–43 months), 97.5%, 81%, and 100% of patients, respectively, who had undergone single-, double-, and triple-level surgery exhibited fusion at all treated levels. The clinical outcomes demonstrated a statistically significant (p < 0.05) difference between preoperative and postoperative Oswestry Disability Index, 12-Item Short Form Health Survey, and visual analog scores. Conclusions. The use of i-FACTOR bone graft substitute demonstrates promising results for facilitating successful fusion and improving clinical outcomes in patients who undergo ALIF surgery for degenerative spinal pathologies. (http://thejns.org/doi/abs/10.3171/2014.9.SPINE131151)
A
Key Words • anterior lumbar interbody fusion • i-FACTOR • ABM/P-15 • degenerative disc disease • bone graft substitute
lumbar interbody fusion (ALIF) is performed in patients suffering pain and/or neurological symptoms associated with degenerative disorders of the lumbar spine or posttraumatic instability. The earliest reports of ALIF include those by Capener for the surgical management of spondylolisthesis in 1932, nterior
Abbreviations used in this paper: ABM = anorganic bone matrix; ALIF = anterior lumbar interbody fusion; BMP = bone morphogenetic protein; DDD = degenerative disc disease; ICBG = iliac crest bone graft; ODI = Oswestry Disability Index; rhBMP = recombinant human BMP; SF-12 = 12-Item Short Form Health Survey; VAS = visual analog scale.
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Mercer for the treatment of disc pathology, and performance by Burns in 1933.12,13,34 The objectives of an ALIF procedure are to achieve solid arthrodesis of the degenerative segment, which is critically influenced by bone graft selection.36 Currently, iliac crest bone graft (ICBG) remains the gold standard to achieve lumbar fusion, although patient dissatisfaction stemming from donor site morbidity, lengthier operating times, and finite supply of ICBG support the pursuit for comparable alternatives.35 Graft incorporation and healing for bony fusion inThis article contains some figures that are displayed in color online but in black-and-white in the print edition.
867
868
no DSM, very potent osteoin ductive properties, high fusion rates ++ +++ ++ –
+ – +++ –
+ + ++ ++ ++ + – – – 42.8–100
90‡
79.3–100
44–100
allograft cancellous
DBM
ceramics
rhBMP-2
fresh-frozen freeze-dried
51.9–100 autograft
* DBM = demineralized bone matrix; DSM = donor site morbidity; OC = osteoconduction; OG = osteogenesis; OI = osteoinduction; + = presence of the property; ++ = stronger presence; +++ = strongest presence; – = absence of property. † Cost of grafts are approximate and relative only. ‡ Only one clinical study on the application of demineralized bone matrix to ALIF was conducted.
+++ heterotopic bone formation, early osteolysis, graft subsidence, inflammation
+ cage subsidence
++ graft collapse
lacks strength, only 1 ALIF clinical trial not effective as stand-alone; lack of ALIF clinical trials rare, costly, uncertainty sur rounding appropriate clini cal dosage no DSM; useful as bone extenders no DSM
++ graft collapse
– – –
no DSM; abundant supply; ver- risk of bacterial contamina satility as extender &/or tion, viral transmission, graft host rejection
nil DSM finite supply, increased surgi cal time, blood loss, pain host tissue; natural biological properties – – ++ + +++ + +++ + cancellous bone cortical bone
Complications w/ Graft Disadvantages Advantages Strength OI
Properties
OC OG Type of Graft
Fusion Rate (%) Graft Option
TABLE 1: Summary of bone graft alternatives in ALIF procedures*
volves the processes of hematoma formation, inflammation, vascularization, and the formation and remodeling of bone, all factors that affect overall graft response. The ideal graft should possess the following properties: osteogenicity, osteoinductivity, and osteoconductivity.17,36,50 Only autograft encompasses all 3 properties, and recent ALIF studies with autograft demonstrate arthrodesis rates for single-level noninstrumented fusions ranging between 78.8% and 100%.16,23,37,39 Other interbody fusion studies using autograft supplemented with posterior fixation exhibited fusion rates of 71%–98.6% in either singleor double-level fusions.40,41,48 However, its disadvantages have led to the development and use of graft alternatives including allograft, bone morphogenetic proteins (BMPs), and ceramics (Table 1).14 Allograft is obtained mostly from cadaveric femur or iliac crest, and its use in ALIF procedures has demonstrated fusion rates varying between 60% and 100%.1,6,25,26,30,43 Limitations to its use stem from the possible risk of host rejection and disease transmission from donor to host. Fusion rates for ceramics as a grafting option for spinal procedures have been reported to be greater than 90%; however, very few reports have described their use in ALIF procedures.31,47 Recombinant BMP-2 (rhBMP-2; INFUSE, Medtronic) is widely used in many countries. INFUSE is currently considered the most effective alternative to autograft as it possesses potent osteoinductive properties. INFUSE studies with significant sample sizes have described a high rate of early postsurgical fusion success ranging from 94.5% to 100%.7–9,11,27,44,51 Although they have good osteoinductive properties, BMPs are very expensive. In addition, the literature has demonstrated a high risk of complications, notably ectopic bone formation and bony osteolysis, leading to graft subsidence, and pronounced inflammatory and edematous reactions.4,15,24,32,49 Recently, a novel bone graft substitute, i-FACTOR, an anorganic bone matrix (ABM) with P-15 small peptide (ABM/P-15 composite, Cerapedics Inc.), has been used within the orthopedic community. The ABM provides osteoconductive properties in the form of the calcium phosphate matrix necessary for cellular invasion and migration. The bioactive P-15 peptide represents the biologically active component of the graft. It is a synthetic 15–amino acid residue, which acts as a biomimetic to the cell binding domain of Type I human collagen for osteogenic cells.49 When combined with ABM, it provides the necessary scaffold to initiate cell invasion, binding, and osteogenesis. Attachment of P-15 to osteogenic cells initiates a cascade of intracellular signaling that triggers the synthesis of extracellular matrix and growth factors. This induces cell proliferation and differentiation and subsequent osteogenesis.5,21,28 Although i-FACTOR possesses many of the desired criteria of an ideal bone graft, the lack of published data on its use in spinal fusion in humans makes it a uncommon bone graft choice. Currently, i-FACTOR is still considered an investigational device and has not been approved for use in the US, and clinical use has been permitted in Europe only since 2008, which explains the scarcity of clinical data. Consequently, the literature does not yet include a prospective study demonstrating the clinical efficacy of i-
Cost†
R. J. Mobbs, M. Maharaj, and P. J. Rao
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Clinical outcomes and fusion rates following ALIF with i-FACTOR FACTOR in human ALIF procedures. Thus, the purpose of this study is to prospectively evaluate the radiological and clinical success of ABM/P-15 composite in its use in anterior spondylodesis.
Methods Ethics Approval
Approval was obtained from the South Eastern Sydney Local Health District, New South Wales, Australia.
Patient Recruitment
The study was a consecutive, single-surgeon prospective series, supported through a grant from Cerapedics, Inc. Patients were enrolled between July 2009 and January 2012 by the senior author (R.J.M.), who performed all ALIF procedures. Exclusion criteria were infection, osteoporosis, and cancer. Indications for surgical intervention were as outlined in Radiographic Assessment.
Surgical Technique
All patients underwent an open ALIF using an anterior approach to the lumbosacral spine. A vascular surgeon assisted with the approach to the spine in all procedures. A retroperitoneal exposure of the affected anterior vertebral disc and retraction with a Synframe (Synthes) was performed. Major anterior vessels were mobilized and retracted. The level of pathology was confirmed using radiography prior to disc removal. After initial disc preparation and removal of the cartilaginous endplate with a Cobb elevator, a range of spine curettes and a high-speed drill with a 3-mm round bur were used to even out the endplates to facilitate an even, press-fit of the interbody cage upon insertion. A Synfix intergral fixation (Synthes) stand-alone polyetheretherketone cage was packed with i-FACTOR, inserted, and fixed with 4 divergent screws. Radiography was used to confirm correct placement, and antibiotic irrigation was used prior to closure.
Postoperative Care
In the postoperative period, patients were encouraged to ambulate within 24 hours of surgery. Determinations regarding rehabilitation and the level of physical exercise were based on the recommendation of the treating surgeon.
Data Collection and Analysis
Radiographic Assessment. Neurological examinations, standing radiography, bone mineral density, bone scan/SPECT CT, and MRI were performed in all patients in the preoperative phase to determine the type and level of pathology. The following 6 indications for ALIF surgery were included in this study: 1) degenerative disc disease (DDD) with back pain and no radiculopathy; 2) DDD with back pain and radiculopathy; 3) spondylolisthesis (degenerative or isthmic); 4) adjacent-segment degeneration; 5) scoliosis; and 6) failed union of a posterior fusion. While ALIF is indicated for a variety of degenerative spinal pathologies, there is no consensus on which specifJ Neurosurg: Spine / Volume 21 / December 2014
ic technique is most favorable to treat these pathologies. In the present study, the surgeon’s training and experience was the fundamental basis for the choice of the anterior approach and implants used. Unrelieved pain and disability despite prolonged conservative management and a multidisciplinary clinic evaluation were prerequisites to having surgery. Fine-cut, high-resolution CT scans were obtained to evaluate fusion after surgery. All patients consented to undergo postoperative standing radiography on Day 1 and CT scanning at 3, 6, and 9–12 months, with additional scans obtained based on individual patient recovery. Scans were used to monitor progression of the incorporation of the graft (Fig. 1). A solid fusion was defined as bridging bone formation between adjacent vertebral bodies as evidenced by bony continuity between the upper and lower endplates, and the absence of radiolucent lines covering greater than 50% of the implant (Fig. 2). All patients had a minimum radiological follow-up period of 15 months. The mean follow-up was 24 months (range 15–43 months). Radiological evaluation of coronal, sagittal, and axial CT scans for fusion was performed by 2 radiologists with experience in evaluation of spinal and musculoskeletal radiology. All radiological data were statistically analyzed using a paired sample t-test.
Clinical Outcome Assessment. Patient clinical outcomes were measured using well-established instruments for spinal procedures: the Oswestry Disability Index (ODI), 12-Item Short Form Health Survey (SF-12), and the 10-point visual analog scale (VAS).18,52 Outcomes were measured pre- and postoperatively at each visit. Patients who had incomplete outcome assessment forms were excluded from statistical analysis; however, more than 95% of patients (105 of 110) completed all follow-up clinical outcome assessments. The pre- and postoperative scores were compared using a 2-tailed, paired sample t-test, and the mean difference between the scores was also determined. A p value < 0.05 was considered significant. All statistical analyses were performed using SPSS software (version 22.0, IBM). At follow-up, patients were also assessed using Odom’s criteria to obtain insight into their quality of life and satisfaction of outcome postsurgery.52 Patients rated their postoperative pain from excellent to poor based on resolution, reduction, or persistence of preoperative symptoms (Table 2). Adverse events were collected by a practice nurse who met with patients separately from the operative surgeon, and were prospectively entered into a custom database.
Results Patient Characteristics
A total of 110 patients were included in the study. All patients satisfied the minimum 15-month radiological and clinical follow-up period. Demographic findings are illustrated in Table 3 with the ALIF indication distribution shown in Fig. 3. The most common indication was DDD with radiculopathy representing almost half of the cohort, followed by those with DDD without radiculopathy. 869
R. J. Mobbs, M. Maharaj, and P. J. Rao
Fig. 1. Images demonstrating progression of interbody fusion in a 45-year-old woman treated for DDD without radiculopathy. A: Radiograph of the L5–S1 level 1 day postsurgery. B: Coronal CT images obtained 1 month postoperatively. C: CT images obtained 5 months postoperatively. D: CT images obtained 12 months postoperatively demonstrating solid fusion.
Radiological Outcomes
The rate of solid arthrodesis was dependent on the specific level operated on and the number of surgically treated levels per patient. In total, surgery was performed at 142 levels in 110 patients. The total observed fusion rate in the cohort was 93.6%. Patients who underwent surgery at 2 levels reported a lower fusion rate of 82% than patients who underwent surgery at 1 level (98%) at the time of radiological follow-up (Table 4). All 3 patients who underwent 3-level surgery reported solid fusion. A high fusion rate of 98% was reported for the L5–S1 level, which was also the most common level operated on, comparatively higher than the other levels (Table 5). It was interesting to note that patients who smoked, had diabetes, or claimed workers’ compensation demonstrated comparably lower fusion rates than those who did not have those factors (Table 6), although only diabetes proved statistically significant (p = 0.004). The mean follow-up time for collection of radiological data was 24 months (range 15–43 months), although evidence of fusion was demonstrated as early as 3 months postsurgery in some patients (Fig. 2). One patient who had undergone a 2-level ALIF had solid fusion at the L5–S1 level at 10 months with a stable nonunion (no movement on flexion/extension radiographs) of the L4–5 ALIF. This case was classified as “not fused” as there was no indication of bone bridging (Fig. 4). All patients undergoing
870
surgery at 3 levels demonstrated evidence of fusion in all 3 levels postsurgery. Of the patient population, 82% of patients undergoing single-level surgery exhibited fusion by 12 months and 98% by 24 months (Table 7). Lower fusion rates were reported in patients who underwent surgery at 2 levels within the same time period, whereas 70% and 81% of patients showed evidence of fusion at 12 and 24 months, respectively. Overall, 86 patients (78.2%) exhibited fusion by 12 months and 102 patients (92.7%) exhibited fusion by 24 months (Fig. 5). Seven of the 104 patients who had radiological follow-up had not exhibited fusion at the time of this study. These patients were observed at a minimum of 15 months after surgery and therefore the fusion rate may increase further as time passes. For patients who did not exhibit fusion at the 12-month mark or who had complications, further clinical follow-up was offered at either 18, 24, or 36 months postoperatively. Patients were offered further CT assessment, as the senior author (R.J.M.) prefers CT analysis over radiography as the primary assessment of arthrodesis. Clinical Outcomes
Postoperative ODI, SF-12, and VAS scores were assessed at a mean of 24 months postsurgery. The clinical results collected demonstrated a statistically significant (p < 0.05) difference between preoperative and postopJ Neurosurg: Spine / Volume 21 / December 2014
Clinical outcomes and fusion rates following ALIF with i-FACTOR
Fig. 2. CT images obtained 4 months postoperatively in a 62-year-old patient who was treated for degenerative spondylolisthesis with radiculopathy at L4–5.
erative scores (Table 8). Patients with incomplete pre- and postoperative clinical outcome data were excluded from the statistical analysis, leaving a total of 105 patients. Improvements were noted across all 3 measures, with statistical significance attained in all. Across patient comorbidities and factors (diabetes, tobacco use, and worker’s compensation), although improvements were observed across cohorts, statistical significance was not attained. Based on Odom’s criteria, 85.3% of 109 patients available for follow-up had excellent to good outcomes (Table 9). Patients with fair to poor outcomes experienced no or minimal symptom relief of their preoperative pain despite adequate decompression and fusion. TABLE 2: Adapted definitions of Odom’s criteria Outcome Criteria
Definition
excellent
all preop symptoms relieved; pain reduced minimal persistence of preoperative symptoms; abnormal findings unchanged or improved definite relief of some preoperative symptoms; other symptoms unchanged or slightly improved symptoms & signs worsened, or unchanged
good fair poor
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Adverse Events and Complications
The overall complications rate (all postoperative complications) was 10%, with 11 complications in total (6 major and 5 minor). Major complications included 4 cases of retrograde ejaculation, a postoperative hematoma, and an incisional hernia that required further surgery. Two patients with retrograde ejaculation recovered within 4 months postsurgery. Minor complications included postoperative deep vein thrombosis and prolonged (> 7 days) postoperative ileus. Notably, there were no reports of wound infection or hardware failure. All complications were associated with the surgical exposure and approach involved with the ALIF procedure. Graft migration was evident on postoperative CT scanning due to the radiodense nature of the i-FACTOR graft material. Despite a minor volume of graft migration in the majority of cases, we did not observe an increased rate of abdominal issues, infection, or retrograde ejaculation in this series as compared with results of similar studies. In the later stages of the study, the anterior hole in the ALIF implant was blocked to stop any graft migration as the material was wholly contained within the implant. One minor complication, unlikely related to i-FACTOR, was vague abdominal pain in a patient in whom a volume of graft had migrated. 871
R. J. Mobbs, M. Maharaj, and P. J. Rao TABLE 3: Patient demographics and characteristics Patient Demographics no. of patients no. of levels age in yrs mean range M/F BMI underweight (30) tobacco use diabetes workers’ compensation follow-up period in mos mean range length of stay in days mean range intraop blood loss in ml mean range total operation time in mins mean range
Value* 110 142 57.6 25–86 48/62 5 70 31 4 19 (17) 10 (9) 22 (20) 24 15–43 4.6 1–19 102 80–700 97 40–195
* Values are the number of patients (%) unless noted otherwise.
Cost Comparator Data
As i-FACTOR is not currently an FDA-approved product in the US, no cost comparison data are available to assess its potential benefits versus existing FDA approved products for similar indications. In the Australian health care system, the Prostheses List provides a fee structure for payment for the use of various medical de-
TABLE 4: Fusion rates of 1-, 2-, and 3-level ALIF proceedures No. of Levels
No of Patients w/ Fusion (%)
1 2 3 total
78/80 (98) 22/27 (82) 3/3 (100) 103/110 (94)
vices including biological materials and bone graft substitutes. i-FACTOR, compared with rh-BMP2 (INFUSE) and rhBMP-7 (OP-1), is significantly less expensive with the added benefit of fewer complications and acceptable/ similar fusion results.
Discussion Despite being the current gold standard, harvested autologous ICBG has many disadvantages both peri- and postoperatively, with donor site pain being the most frequent complication reported with an incidence of 25%– 31%.2,3,29,45,51 Despite the extensive list of associated complications with autograft, including graft collapse, neurological injury, and sacroiliac joint–related complications, the primary reason deterring patients and surgeons from using ICBG harvest is the subjective perception that the harvest is the most painful part of the fusion procedure.16,19,20,22,23,38 The presence of these factors justifies the necessity and use of bone graft substitutes as illustrated in Table 1. While promising results have been observed in both animal and human studies evaluating ABM/P-15 use as a bone graft, our study is the first to investigate its use composite in human ALIF procedures. Overall our data, following a mean 24-month (minimum 15 months) follow-up, demonstrated a fusion rate of 92.7% in the cohort. This is consistent with the prospective trial by Sherman et al.42 in which they used ABM/P-15 in an ovine model (n = 6, fusion rate = 100%) and Lauweryns’ unpublished prospective trial33 utilizing ABM/P-15 in posterior lumbar interbody fusion in humans (autograft 82.2% vs ABM/p-15 97.8%, 12-month follow-up). Lauweryns’ findings, as presented at the 2011 Global Spine Congress in Barcelona, also concluded that in addition to being “statistically superior,” ABM/P-15 achieved solid fusion faster than autologous bone graft with data at 6 months showing a 38.6% difference in fusion. There were no unexpected complications and the complication rate (10%) in our prospective study is comparable to the complication rate of 9.5% in the large retrospective study of BMP in ALIF by Williams et al.53 TABLE 5: Fusion rate per surgically treated level
Fig. 3. Surgical indications for which ALIF was performed. ASD = adjacent-segment disease; R = radiculopathy.
872
Level
No. of Levels Fused (%)
L2–3 L3–4 L4–5 L5–S1 total
3/3 (100) 14/17 (82) 50/59 (85) 62/63 (98) 130/142 (92)
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Clinical outcomes and fusion rates following ALIF with i-FACTOR TABLE 6: Fusion rate according to comorbidities and patient factors Patient Factor (no. of patients)
No. of Patients w/ Fusion
Fusion Rate (%)
tobacco use (19) no tobacco use (91) diabetes (10) no diabetes (100) workers’ compensation (22) non–workers’ compensation (87)*
16 87 7 96 18 83
84.2 95.6 70 96.0 81.8 95.4
TABLE 7: Time period for fusion to occur (months postsurgery), by number of levels operated No. of Patients (fusion rate)
p Value
Months
Single Level
Double Level
Triple Level
0.153
3–6 7–12 13–24 >24 not fused total
34 (43%) 31 (39%) 12 (15%) 1 (1%) 2 78 (98%)
12 (44%) 7 (26%) 3 (11%) 0 5 22 (81%)
1 (33.3%) 1 (33.3%) 1 (33.3%) 0 0 3 (100%)
0.004 0.663
* Workers’ compensation information was not known for 1 patient.
It was interesting to note that patients who smoked, had diabetes, or claimed workers’ compensation demonstrated comparably lower mean fusion rates than those who did not have these factors. This implies that patient morbidities have a negative impact on rates of successful arthrodesis. Patients with diabetes also had reduced clinical improvement in comparison with nondiabetic patients. Clinically, our results also demonstrate favorable findings in response to evaluating i-FACTOR’s suitability for ALIF procedures in humans. The preferred method of evaluating clinical outcome is through validated, patient-based outcome measures such as the ODI, VAS, and SF-12. According to Fairbank and Pynsent’s18 interpretation of ODI scores, this study’s preoperative mean score of 61.02 just falls within the category of crippled
(range 61%–80%), where back pain negatively impacts on all aspects of the patient’s life and intervention is necessary. The mean postoperative ODI score of 28.42 was a significant improvement (p = 0.001), and reduced the disability to moderate, where pain is still experienced but can be managed conservatively. The ODI outcomes observed in the present study (mean improvement 32.6 at the 24-month follow-up) are similar to the results of 15- to 25-point improvement achieved with BMP in the literature, although significant differences in mean follow-up times exist.33,42,44 It is important to recognize that due to the wide range of follow-up periods in our trial (i.e.,15–43 months), direct comparisons cannot be made. The same papers also reported pain scores, albeit with different scales. On a 10-point pain scale, allograft/ ALIF patients improved from a score of 6 to about a score of 4.5 at 6 months after surgery.46 The study conducted by
Fig. 4. CT images obtained 10 months postsurgery in a 73-year-old man who was treated for DDD without radiculopathy. This case was classified as a failed fusion with stable nonunion of the L4–5 ALIF.
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R. J. Mobbs, M. Maharaj, and P. J. Rao TABLE 9: Odom outcomes
Fig. 5. Pie chart showing the overall fusion for patients undergoing 1-, 2-, and 3-level surgery. The values indicate time points in months.
Burkus et al. was analyzed using a 20-point pain scale, and hence, the outcomes cannot be directly compared with the outcomes of our current study, although positive outcomes were maintained at the 6-year follow-up.10 The mean differences were 7.3 and 7.1 for BMP and autograft, respectively, at 6 months postsurgery,9 while a larger improvement from 7.40 preoperatively to 2.65 postoperatively (p = 0.013) was seen in our study. This demonstrates that i-FACTOR is a promising graft substitute to achieve fusion and to assist with the ALIF procedure to reduce pain caused by certain spinal pathologies, without the potential adverse events and complications associated with autograft and BMPs. Although migration of i-FACTOR was seen in patients when not contained, there were no confirmed adverse effects from the graft material located outside the interbody space. Our study used the SF-12 survey to assess clinical outcomes on the basis of increased patient convenience and compliance, demonstrating a mean increase in the score from 68.27 to 92.99 (mean difference 24.72; p = 0.043). The results suggest i-FACTOR use as an adjunct to spinal arthrodesis, significantly improving the quality of life and mental state of patients. Comparisons with other recent studies were not possible due to their implementation of the SF-36. Odom outcomes demonstrated that 85.3% of patients in the current study for whom follow-up was available had excellent to good outcomes. These patients experienced a significant improvement in their quality of life and noted that ALIF using i-FACTOR was an appropriate choice. TABLE 8: Summary of clinical outcome score data within the entire patient cohort Variable
SF-12
ODI
VAS
preop score postop score p value
68.57 ± 14.06 92.99 ± 15.72 0.043*
61.02 ± 21.38 28.42 ± 19.53 0.001*
7.38 ± 1.53 2.65 ± 2.13 0.013*
* Statistically significant.
874
Variable
Excellent
Good
Fair
Poor
1-level 2-level 3-level total
36 13 1 50
33 8 2 43
12 2 0 14
2 0 0 2
It is of paramount importance that evaluation of the success of a graft is made on the basis of both radiological and clinical patient outcome measures, as successful fusion does not always correlate with satisfactory patient outcome. Limitations of our study are the lack of direct control and the potential for respondent bias. Patients who participate in research are more likely to comply with postoperative medications and physiotherapy, thus resulting in better health outcomes. For instance, a few patients declined completing the postoperative outcome data because they were discontent with their outcome. These patients were subsequently excluded from statistical analysis, which may have positively skewed results.
Conclusions
Anterior lumbar interbody fusion using i-FACTOR (ABM/P-15) synthetic bone graft substitute is a useful treatment option for degenerative pathologies of the lumbar spine. The present study demonstrates a high fusion rate and clinical improvements comparable to the published results for ALIF using autograft or BMP. At the same time the use of ABM/P-15 as a graft material avoids the complications specific to those 2 materials. Further studies comparing rate of arthrodesis, clinical outcome, and cost between ABM/P-15 and other graft alternatives are warranted. Disclosure Dr. Mobbs reports receiving clinical or research support for the study described from Cerapedics. Author contributions to the study and manuscript preparation include the following. Conception and design: Mobbs. Acquisition of data: all authors. Analysis and interpretation of data: all authors. Drafting the article: Mobbs. Critically revising the article: all au thors. Reviewed submitted version of manuscript: Mobbs, Rao. Approved the final version of the manuscript on behalf of all authors: Mobbs. Statistical analysis: Mobbs, Maharaj. Administrative/technical/material support: Rao. Study supervision: Mobbs. References 1. Anderson DG, Sayadipour A, Shelby K, Albert TJ, Vaccaro AR, Weinstein MS: Anterior interbody arthrodesis with percutaneous posterior pedicle fixation for degenerative conditions of the lumbar spine. Eur Spine J 20:1323–1330, 2011 2. Banwart JC, Asher MA, Hassanein RS: Iliac crest bone graft harvest donor site morbidity. A statistical evaluation. Spine (Phila Pa 1976) 20:1055–1060, 1995 3. Bednar DA, Al-Tunaib W: Failure of reconstitution of opensection, posterior iliac-wing bone graft donor sites after lumbar spinal fusion. Observations with implications for the etiology of donor site pain. Eur Spine J 14:95–98, 2005
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Clinical outcomes and fusion rates following ALIF with i-FACTOR 4. Benglis D, Wang MY, Levi AD: A comprehensive review of the safety profile of bone morphogenetic protein in spine surgery. Neurosurgery 62 (5 Suppl 2):ONS423–ONS431, 2008 5. Bhatnagar RS, Qian JJ, Gough CA: The role in cell binding of a beta-bend within the triple helical region in collagen alpha 1 (I) chain: structural and biological evidence for conformational tautomerism on fiber surface. J Biomol Struct Dyn 14: 547–560, 1997 6. Blumenthal SL, Baker J, Dossett A, Selby DK: The role of anterior lumbar fusion for internal disc disruption. Spine (Phila Pa 1976) 13:566–569, 1988 7. Boden SD, Zdeblick TA, Sandhu HS, Heim SE: The use of rhBMP-2 in interbody fusion cages. Definitive evidence of osteoinduction in humans: a preliminary report. Spine (Phila Pa 1976) 25:376–381, 2000 8. Burkus JK, Dorchak JD, Sanders DL: Radiographic assessment of interbody fusion using recombinant human bone morphogenetic protein type 2. Spine (Phila Pa 1976) 28:372–377, 2003 9. Burkus JK, Gornet MF, Dickman CA, Zdeblick TA: Anterior lumbar interbody fusion using rhBMP-2 with tapered interbody cages. J Spinal Disord Tech 15:337–349, 2002 10. Burkus JK, Gornet MF, Schuler TC, Kleeman TJ, Zdeblick TA: Six-year outcomes of anterior lumbar interbody arthrodesis with use of interbody fusion cages and recombinant human bone morphogenetic protein-2. J Bone Joint Surg Am 91:1181–1189, 2009 11. 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) 27:2396–2408, 2002 12. Burns BH: An operation for spondylolisthesis. Lancet 221: 1233–1239, 1933 13. Capener N: Spondylolisthesis. Br J Surg 19:374–386, 1932 14. Chau AM, Xu LL, Wong JH, Mobbs RJ: Current status of bone graft options for anterior interbody fusion of the cervical and lumbar spine. Neurosurg Rev 37:23–37, 2014 15. Chen Z, Ba G, Shen T, Fu Q: Recombinant human bone morphogenetic protein-2 versus autogenous iliac crest bone graft for lumbar fusion: a meta-analysis of ten randomized controlled trials. Arch Orthop Trauma Surg 132:1725–1740, 2012 16. Cheung KM, Zhang YG, Lu DS, Luk KD, Leong JC: Reduction of disc space distraction after anterior lumbar interbody fusion with autologous iliac crest graft. Spine (Phila Pa 1976) 28:1385–1389, 2003 17. Ehrler DM, Vaccaro AR: The use of allograft bone in lumbar spine surgery. Clin Orthop Relat Res (371):38–45, 2000 18. Fairbank JC, Pynsent PB: The Oswestry Disability Index. Spine (Phila Pa 1976) 25:2940–2952, 2000 19. Fowler BL, Dall BE, Rowe DE: Complications associated with harvesting autogenous iliac bone graft. Am J Orthop 24: 895–903, 1995 20. Greenough CG, Taylor LJ, Fraser RD: Anterior lumbar fusion: results, assessment techniques and prognostic factors. Eur Spine J 3:225–230, 1994 21. Gomar F, Orozco R, Villar JL, Arrizabalaga F: P-15 small peptide bone graft substitute in the treatment of non-unions and delayed union. A pilot clinical trial. Int Orthop 31:93– 99, 2007 22. Heary RF, Schlenk RP, Sacchieri TA, Barone D, Brotea C: Persistent iliac crest donor site pain: independent outcome assessment. Neurosurgery 50:510–517, 2002 23. Ishihara H, Osada R, Kanamori M, Kawaguchi Y, Ohmori K, Kimura T, et al: Minimum 10-year follow-up study of anterior lumbar interbody fusion for isthmic spondylolisthesis. J Spinal Disord 14:91–99, 2001 24. Kanatani M, Sugimoto T, Kaji H, Kobayashi T, Nishiyama K, Fukase M, et al: Stimulatory effect of bone morphogenetic
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protein-2 on osteoclast-like cell formation and bone-resorbing activity. J Bone Miner Res 10:1681–1690, 1995 25. Kim JS, Choi WG, Lee SH: Minimally invasive anterior lumbar interbody fusion followed by percutaneous pedicle screw fixation for isthmic spondylolisthesis: minimum 5-year follow-up. Spine J 10:404–409, 2010 26. Kim JS, Kim DH, Lee SH, Park CK, Hwang JH, Cheh G, et al: Comparison study of the instrumented circumferential fusion with instrumented anterior lumbar interbody fusion as a surgical procedure for adult low-grade isthmic spondylolisthesis. World Neurosurg 73:565–571, 2010 27. Kleeman TJ, Ahn UM, Talbot-Kleeman A: Laparoscopic anterior lumbar interbody fusion with rhBMP-2: a prospective study of clinical and radiographic outcomes. Spine (Phila Pa 1976) 26:2751–2756, 2001 28. Kübler A, Neugebauer J, Oh JH, Scheer M, Zöller JE: Growth and proliferation of human osteoblasts on different bone graft substitutes: an in vitro study. Implant Dent 13:171–179, 2004 29. Kurz LT, Garfin SR, Booth RE Jr: Harvesting autogenous iliac bone grafts. A review of complications and techniques. Spine (Phila Pa 1976) 14:1324–1331, 1989 30. Lee DY, Lee SH, Maeng DH: Two-level anterior lumbar interbody fusion with percutaneous pedicle screw fixation: a minimum 3-year follow-up study. Neurol Med Chir (Tokyo) 50:645–650, 2010 31. Linovitz RJ, Peppers TA: Use of an advanced formulation of beta-tricalcium phosphate as a bone extender in interbody lumbar fusion. Orthopedics 25 (5 Suppl):s585–s589, 2002 32. Mannion RJ, Nowitzke AM, Wood MJ: Promoting fusion in minimally invasive lumbar interbody stabilization with low-dose bone morphogenic protein-2—but what is the cost? Spine J 11:527–533, 2011 33. McAdoo S: Prospective, randomized, controlled trial demonstrates 98% fusion rate at 6-months and 12-months with i-FACTOR™ biologic bone graft and superiority versus autograft in single- and multi-level PLIF spine surgery. Cerapedics. (http:// www.cerapedics.com/intl/news/story6/) [Accessed September 3, 2014] 34. Mercer W: Spondylolisthesis: with a description of a new method of operative treatment and notes of ten cases. Edinburgh Med J 43:545–572, 1936 35. Mobbs RJ, Chung M, Rao PJ: Bone graft substitutes for anterior lumbar interbody fusion. Orthop Surg 5:77–85, 2013 36. Mobbs RJ, Loganathan A, Yeung V, Rao PJ: Indications for anterior lumbar interbody fusion. Orthop Surg 5:153–163, 2013 37. Motosuneya T, Asazuma T, Nobuta M, Masuoka K, Ichimura S, Fujikawa K: Anterior lumbar interbody fusion: changes in area of the dural tube, disc height, and prevalence of cauda equina adhesion in magnetic resonance images. J Spinal Disord Tech 18:18–22, 2005 38. Newman MH, Grinstead GL: Anterior lumbar interbody fusion for internal disc disruption. Spine (Phila Pa 1976) 17: 831–833, 1992 39. Ohtori S, Koshi T, Yamashita M, Takaso M, Yamauchi K, Inoue G, et al: Single-level instrumented posterolateral fusion versus non-instrumented anterior interbody fusion for lumbar spondylolisthesis: a prospective study with a 2-year follow-up. J Orthop Sci 16:352–358, 2011 40. Pavlov PW, Meijers H, van Limbeek J, Jacobs WC, Lemmens JA, Obradov-Rajic M, et al: Good outcome and restoration of lordosis after anterior lumbar interbody fusion with additional posterior fixation. Spine (Phila Pa 1976) 29:1893–1900, 2004 41. Saraph V, Lerch C, Walochnik N, Bach CM, Krismer M, Wimmer C: Comparison of conventional versus minimally invasive extraperitoneal approach for anterior lumbar interbody fusion. Eur Spine J 13:425–431, 2004 42. Sherman BP, Lindley EM, Turner AS, Seim HB III, Benedict J, Burger EL, et al: Evaluation of ABM/P-15 versus autog-
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R. J. Mobbs, M. Maharaj, and P. J. Rao enous bone in an ovine lumbar interbody fusion model. Eur Spine J 19:2156–2163, 2010 43. Shim CS, Lee SH, Jung B, Sivasabaapathi P, Park SH, Shin SW: Fluoroscopically assisted percutaneous translaminar facet screw fixation following anterior lumbar interbody fusion: technical report. Spine (Phila Pa 1976) 30:838–843, 2005 44. Slosar PJ, Josey R, Reynolds J: Accelerating lumbar fusions by combining rhBMP-2 with allograft bone: a prospective analysis of interbody fusion rates and clinical outcomes. Spine J 7:301–307, 2007 45. Summers BN, Eisenstein SM: Donor site pain from the ilium. A complication of lumbar spine fusion. J Bone Joint Surg Br 71:677–680, 1989 46. Thalgott JS, Fogarty ME, Giuffre JM, Christenson SD, Epstein AK, Aprill C: A prospective, randomized, blinded, single-site study to evaluate the clinical and radiographic differences between frozen and freeze-dried allograft when used as part of a circumferential anterior lumbar interbody fusion procedure. Spine (Phila Pa 1976) 34:1251–1256, 2009 47. Thalgott JS, Klezl Z, Timlin M, Giuffre JM: Anterior lumbar interbody fusion with processed sea coral (coralline hydroxyapatite) as part of a circumferential fusion. Spine (Phila Pa 1976) 27:E518—E527, 2002 48. Tiusanen H, Seitsalo S, Osterman K, Soini J: Anterior interbody lumbar fusion in severe low back pain. Clin Orthop Relat Res (324):153–163, 1996 49. US Food and Drug Administration: Summary of Safety and Effectiveness Data. InFUSE™ Bone Graft/LT-CAGE™ Lumbar Tapered Fusion Device. (http://www.accessdata.
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fda.gov/cdrh_docs/pdf/P000058b.pdf) [Accessed September 3, 2014] 50. Vaccaro AR, Chiba K, Heller JG, Patel TC, Thalgott JS, Truumees E, et al: Bone grafting alternatives in spinal surgery. Spine J 2:206–215, 2002 51. Vaidya R, Weir R, Sethi A, Meisterling S, Hakeos W, Wybo CD: Interbody fusion with allograft and rhBMP-2 leads to consistent fusion but early subsidence. J Bone Joint Surg Br 89:342–345, 2007 52. Ware J Jr, Kosinski M, Keller SD: A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med Care 34:220–233, 1996 53. Williams BJ, Smith JS, Fu KM, Hamilton DK, Polly DW Jr, Ames CP, et al: Does bone morphogenetic protein increase the incidence of perioperative complications in spinal fusion? A comparison of 55,862 cases of spinal fusion with and without bone morphogenetic protein. Spine (Phila Pa 1976) 36:1685–1691, 2011
Manuscript submitted December 18, 2013. Accepted September 2, 2014. Please include this information when citing this paper: published online October 17, 2014; DOI: 10.3171/2014.9.SPINE131151. Address correspondence to: Ralph J. Mobbs, B.Sc., M.B.B.S., M.S., F.R.A.C.S., NeuroSpineClinic, Suite 7a, Level 7, Prince of Wales Private Hospital, Randwick, NSW 2031, Australia. email: [email protected].
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Clinical outcomes and fusion rates following anterior lumbar interbody fusion with bone graft substitute i-FACTOR, an anorganic bone matrix/P-15 composite Clinical article Ralph J. Mobbs, B.Sc., M.B.B.S., M.S., F.R.A.C.S.,1,2 Monish Maharaj, M.D., 2 and Prashanth J. Rao, M.D.1,2 1 NeuroSpineClinic, Prince of Wales Private Hospital; and 2Faculty of Medicine, University of New South Wales, Sydney, Australia
Object. Despite limited availability and the morbidity associated with autologous iliac crest bone graft (ICBG), its use in anterior lumbar interbody fusion (ALIF) procedures remains the gold standard to achieve arthrodesis. The search for alternative grafts yielding comparable or superior fusion outcomes with fewer complications continues. In particular, i-FACTOR, a novel bone graft substitute composed of anorganic bone matrix (ABM) with P-15 small peptide, is one example currently used widely in the dental community. Although preclinical studies have documented its usefulness, the role of i-FACTOR in ALIF procedures remains unknown. The authors’ goal was to determine the safety and efficacy of i-FACTOR bone graft composite used in patients who underwent ALIF by evaluating fusion rates and clinical outcomes. Methods. A nonblinded cohort of patients who were all referred to a single surgeon’s practice was prospectively studied. One hundred ten patients with degenerative spinal disease underwent single or multilevel ALIF using the ABM/P-15 bone graft composite with a mean of 24 months (minimum 15 months) of follow-up were enrolled in the study. Patient’s clinical outcomes were assessed using the Oswestry Disability Index for low-back pain, the 12-Item Short Form Health Survey, Odom’s criteria, and a visual analog scale for pain. Fine-cut CT scans were used to evaluate the progression to fusion. Results. All patients who received i-FACTOR demonstrated radiographic evidence of bony induction and early incorporation of bone graft. At a mean of 24 months of follow-up (range 15–43 months), 97.5%, 81%, and 100% of patients, respectively, who had undergone single-, double-, and triple-level surgery exhibited fusion at all treated levels. The clinical outcomes demonstrated a statistically significant (p < 0.05) difference between preoperative and postoperative Oswestry Disability Index, 12-Item Short Form Health Survey, and visual analog scores. Conclusions. The use of i-FACTOR bone graft substitute demonstrates promising results for facilitating successful fusion and improving clinical outcomes in patients who undergo ALIF surgery for degenerative spinal pathologies. (http://thejns.org/doi/abs/10.3171/2014.9.SPINE131151)
A
Key Words • anterior lumbar interbody fusion • i-FACTOR • ABM/P-15 • degenerative disc disease • bone graft substitute
lumbar interbody fusion (ALIF) is performed in patients suffering pain and/or neurological symptoms associated with degenerative disorders of the lumbar spine or posttraumatic instability. The earliest reports of ALIF include those by Capener for the surgical management of spondylolisthesis in 1932, nterior
Abbreviations used in this paper: ABM = anorganic bone matrix; ALIF = anterior lumbar interbody fusion; BMP = bone morphogenetic protein; DDD = degenerative disc disease; ICBG = iliac crest bone graft; ODI = Oswestry Disability Index; rhBMP = recombinant human BMP; SF-12 = 12-Item Short Form Health Survey; VAS = visual analog scale.
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Mercer for the treatment of disc pathology, and performance by Burns in 1933.12,13,34 The objectives of an ALIF procedure are to achieve solid arthrodesis of the degenerative segment, which is critically influenced by bone graft selection.36 Currently, iliac crest bone graft (ICBG) remains the gold standard to achieve lumbar fusion, although patient dissatisfaction stemming from donor site morbidity, lengthier operating times, and finite supply of ICBG support the pursuit for comparable alternatives.35 Graft incorporation and healing for bony fusion inThis article contains some figures that are displayed in color online but in black-and-white in the print edition.
867
868
no DSM, very potent osteoin ductive properties, high fusion rates ++ +++ ++ –
+ – +++ –
+ + ++ ++ ++ + – – – 42.8–100
90‡
79.3–100
44–100
allograft cancellous
DBM
ceramics
rhBMP-2
fresh-frozen freeze-dried
51.9–100 autograft
* DBM = demineralized bone matrix; DSM = donor site morbidity; OC = osteoconduction; OG = osteogenesis; OI = osteoinduction; + = presence of the property; ++ = stronger presence; +++ = strongest presence; – = absence of property. † Cost of grafts are approximate and relative only. ‡ Only one clinical study on the application of demineralized bone matrix to ALIF was conducted.
+++ heterotopic bone formation, early osteolysis, graft subsidence, inflammation
+ cage subsidence
++ graft collapse
lacks strength, only 1 ALIF clinical trial not effective as stand-alone; lack of ALIF clinical trials rare, costly, uncertainty sur rounding appropriate clini cal dosage no DSM; useful as bone extenders no DSM
++ graft collapse
– – –
no DSM; abundant supply; ver- risk of bacterial contamina satility as extender &/or tion, viral transmission, graft host rejection
nil DSM finite supply, increased surgi cal time, blood loss, pain host tissue; natural biological properties – – ++ + +++ + +++ + cancellous bone cortical bone
Complications w/ Graft Disadvantages Advantages Strength OI
Properties
OC OG Type of Graft
Fusion Rate (%) Graft Option
TABLE 1: Summary of bone graft alternatives in ALIF procedures*
volves the processes of hematoma formation, inflammation, vascularization, and the formation and remodeling of bone, all factors that affect overall graft response. The ideal graft should possess the following properties: osteogenicity, osteoinductivity, and osteoconductivity.17,36,50 Only autograft encompasses all 3 properties, and recent ALIF studies with autograft demonstrate arthrodesis rates for single-level noninstrumented fusions ranging between 78.8% and 100%.16,23,37,39 Other interbody fusion studies using autograft supplemented with posterior fixation exhibited fusion rates of 71%–98.6% in either singleor double-level fusions.40,41,48 However, its disadvantages have led to the development and use of graft alternatives including allograft, bone morphogenetic proteins (BMPs), and ceramics (Table 1).14 Allograft is obtained mostly from cadaveric femur or iliac crest, and its use in ALIF procedures has demonstrated fusion rates varying between 60% and 100%.1,6,25,26,30,43 Limitations to its use stem from the possible risk of host rejection and disease transmission from donor to host. Fusion rates for ceramics as a grafting option for spinal procedures have been reported to be greater than 90%; however, very few reports have described their use in ALIF procedures.31,47 Recombinant BMP-2 (rhBMP-2; INFUSE, Medtronic) is widely used in many countries. INFUSE is currently considered the most effective alternative to autograft as it possesses potent osteoinductive properties. INFUSE studies with significant sample sizes have described a high rate of early postsurgical fusion success ranging from 94.5% to 100%.7–9,11,27,44,51 Although they have good osteoinductive properties, BMPs are very expensive. In addition, the literature has demonstrated a high risk of complications, notably ectopic bone formation and bony osteolysis, leading to graft subsidence, and pronounced inflammatory and edematous reactions.4,15,24,32,49 Recently, a novel bone graft substitute, i-FACTOR, an anorganic bone matrix (ABM) with P-15 small peptide (ABM/P-15 composite, Cerapedics Inc.), has been used within the orthopedic community. The ABM provides osteoconductive properties in the form of the calcium phosphate matrix necessary for cellular invasion and migration. The bioactive P-15 peptide represents the biologically active component of the graft. It is a synthetic 15–amino acid residue, which acts as a biomimetic to the cell binding domain of Type I human collagen for osteogenic cells.49 When combined with ABM, it provides the necessary scaffold to initiate cell invasion, binding, and osteogenesis. Attachment of P-15 to osteogenic cells initiates a cascade of intracellular signaling that triggers the synthesis of extracellular matrix and growth factors. This induces cell proliferation and differentiation and subsequent osteogenesis.5,21,28 Although i-FACTOR possesses many of the desired criteria of an ideal bone graft, the lack of published data on its use in spinal fusion in humans makes it a uncommon bone graft choice. Currently, i-FACTOR is still considered an investigational device and has not been approved for use in the US, and clinical use has been permitted in Europe only since 2008, which explains the scarcity of clinical data. Consequently, the literature does not yet include a prospective study demonstrating the clinical efficacy of i-
Cost†
R. J. Mobbs, M. Maharaj, and P. J. Rao
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Clinical outcomes and fusion rates following ALIF with i-FACTOR FACTOR in human ALIF procedures. Thus, the purpose of this study is to prospectively evaluate the radiological and clinical success of ABM/P-15 composite in its use in anterior spondylodesis.
Methods Ethics Approval
Approval was obtained from the South Eastern Sydney Local Health District, New South Wales, Australia.
Patient Recruitment
The study was a consecutive, single-surgeon prospective series, supported through a grant from Cerapedics, Inc. Patients were enrolled between July 2009 and January 2012 by the senior author (R.J.M.), who performed all ALIF procedures. Exclusion criteria were infection, osteoporosis, and cancer. Indications for surgical intervention were as outlined in Radiographic Assessment.
Surgical Technique
All patients underwent an open ALIF using an anterior approach to the lumbosacral spine. A vascular surgeon assisted with the approach to the spine in all procedures. A retroperitoneal exposure of the affected anterior vertebral disc and retraction with a Synframe (Synthes) was performed. Major anterior vessels were mobilized and retracted. The level of pathology was confirmed using radiography prior to disc removal. After initial disc preparation and removal of the cartilaginous endplate with a Cobb elevator, a range of spine curettes and a high-speed drill with a 3-mm round bur were used to even out the endplates to facilitate an even, press-fit of the interbody cage upon insertion. A Synfix intergral fixation (Synthes) stand-alone polyetheretherketone cage was packed with i-FACTOR, inserted, and fixed with 4 divergent screws. Radiography was used to confirm correct placement, and antibiotic irrigation was used prior to closure.
Postoperative Care
In the postoperative period, patients were encouraged to ambulate within 24 hours of surgery. Determinations regarding rehabilitation and the level of physical exercise were based on the recommendation of the treating surgeon.
Data Collection and Analysis
Radiographic Assessment. Neurological examinations, standing radiography, bone mineral density, bone scan/SPECT CT, and MRI were performed in all patients in the preoperative phase to determine the type and level of pathology. The following 6 indications for ALIF surgery were included in this study: 1) degenerative disc disease (DDD) with back pain and no radiculopathy; 2) DDD with back pain and radiculopathy; 3) spondylolisthesis (degenerative or isthmic); 4) adjacent-segment degeneration; 5) scoliosis; and 6) failed union of a posterior fusion. While ALIF is indicated for a variety of degenerative spinal pathologies, there is no consensus on which specifJ Neurosurg: Spine / Volume 21 / December 2014
ic technique is most favorable to treat these pathologies. In the present study, the surgeon’s training and experience was the fundamental basis for the choice of the anterior approach and implants used. Unrelieved pain and disability despite prolonged conservative management and a multidisciplinary clinic evaluation were prerequisites to having surgery. Fine-cut, high-resolution CT scans were obtained to evaluate fusion after surgery. All patients consented to undergo postoperative standing radiography on Day 1 and CT scanning at 3, 6, and 9–12 months, with additional scans obtained based on individual patient recovery. Scans were used to monitor progression of the incorporation of the graft (Fig. 1). A solid fusion was defined as bridging bone formation between adjacent vertebral bodies as evidenced by bony continuity between the upper and lower endplates, and the absence of radiolucent lines covering greater than 50% of the implant (Fig. 2). All patients had a minimum radiological follow-up period of 15 months. The mean follow-up was 24 months (range 15–43 months). Radiological evaluation of coronal, sagittal, and axial CT scans for fusion was performed by 2 radiologists with experience in evaluation of spinal and musculoskeletal radiology. All radiological data were statistically analyzed using a paired sample t-test.
Clinical Outcome Assessment. Patient clinical outcomes were measured using well-established instruments for spinal procedures: the Oswestry Disability Index (ODI), 12-Item Short Form Health Survey (SF-12), and the 10-point visual analog scale (VAS).18,52 Outcomes were measured pre- and postoperatively at each visit. Patients who had incomplete outcome assessment forms were excluded from statistical analysis; however, more than 95% of patients (105 of 110) completed all follow-up clinical outcome assessments. The pre- and postoperative scores were compared using a 2-tailed, paired sample t-test, and the mean difference between the scores was also determined. A p value < 0.05 was considered significant. All statistical analyses were performed using SPSS software (version 22.0, IBM). At follow-up, patients were also assessed using Odom’s criteria to obtain insight into their quality of life and satisfaction of outcome postsurgery.52 Patients rated their postoperative pain from excellent to poor based on resolution, reduction, or persistence of preoperative symptoms (Table 2). Adverse events were collected by a practice nurse who met with patients separately from the operative surgeon, and were prospectively entered into a custom database.
Results Patient Characteristics
A total of 110 patients were included in the study. All patients satisfied the minimum 15-month radiological and clinical follow-up period. Demographic findings are illustrated in Table 3 with the ALIF indication distribution shown in Fig. 3. The most common indication was DDD with radiculopathy representing almost half of the cohort, followed by those with DDD without radiculopathy. 869
R. J. Mobbs, M. Maharaj, and P. J. Rao
Fig. 1. Images demonstrating progression of interbody fusion in a 45-year-old woman treated for DDD without radiculopathy. A: Radiograph of the L5–S1 level 1 day postsurgery. B: Coronal CT images obtained 1 month postoperatively. C: CT images obtained 5 months postoperatively. D: CT images obtained 12 months postoperatively demonstrating solid fusion.
Radiological Outcomes
The rate of solid arthrodesis was dependent on the specific level operated on and the number of surgically treated levels per patient. In total, surgery was performed at 142 levels in 110 patients. The total observed fusion rate in the cohort was 93.6%. Patients who underwent surgery at 2 levels reported a lower fusion rate of 82% than patients who underwent surgery at 1 level (98%) at the time of radiological follow-up (Table 4). All 3 patients who underwent 3-level surgery reported solid fusion. A high fusion rate of 98% was reported for the L5–S1 level, which was also the most common level operated on, comparatively higher than the other levels (Table 5). It was interesting to note that patients who smoked, had diabetes, or claimed workers’ compensation demonstrated comparably lower fusion rates than those who did not have those factors (Table 6), although only diabetes proved statistically significant (p = 0.004). The mean follow-up time for collection of radiological data was 24 months (range 15–43 months), although evidence of fusion was demonstrated as early as 3 months postsurgery in some patients (Fig. 2). One patient who had undergone a 2-level ALIF had solid fusion at the L5–S1 level at 10 months with a stable nonunion (no movement on flexion/extension radiographs) of the L4–5 ALIF. This case was classified as “not fused” as there was no indication of bone bridging (Fig. 4). All patients undergoing
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surgery at 3 levels demonstrated evidence of fusion in all 3 levels postsurgery. Of the patient population, 82% of patients undergoing single-level surgery exhibited fusion by 12 months and 98% by 24 months (Table 7). Lower fusion rates were reported in patients who underwent surgery at 2 levels within the same time period, whereas 70% and 81% of patients showed evidence of fusion at 12 and 24 months, respectively. Overall, 86 patients (78.2%) exhibited fusion by 12 months and 102 patients (92.7%) exhibited fusion by 24 months (Fig. 5). Seven of the 104 patients who had radiological follow-up had not exhibited fusion at the time of this study. These patients were observed at a minimum of 15 months after surgery and therefore the fusion rate may increase further as time passes. For patients who did not exhibit fusion at the 12-month mark or who had complications, further clinical follow-up was offered at either 18, 24, or 36 months postoperatively. Patients were offered further CT assessment, as the senior author (R.J.M.) prefers CT analysis over radiography as the primary assessment of arthrodesis. Clinical Outcomes
Postoperative ODI, SF-12, and VAS scores were assessed at a mean of 24 months postsurgery. The clinical results collected demonstrated a statistically significant (p < 0.05) difference between preoperative and postopJ Neurosurg: Spine / Volume 21 / December 2014
Clinical outcomes and fusion rates following ALIF with i-FACTOR
Fig. 2. CT images obtained 4 months postoperatively in a 62-year-old patient who was treated for degenerative spondylolisthesis with radiculopathy at L4–5.
erative scores (Table 8). Patients with incomplete pre- and postoperative clinical outcome data were excluded from the statistical analysis, leaving a total of 105 patients. Improvements were noted across all 3 measures, with statistical significance attained in all. Across patient comorbidities and factors (diabetes, tobacco use, and worker’s compensation), although improvements were observed across cohorts, statistical significance was not attained. Based on Odom’s criteria, 85.3% of 109 patients available for follow-up had excellent to good outcomes (Table 9). Patients with fair to poor outcomes experienced no or minimal symptom relief of their preoperative pain despite adequate decompression and fusion. TABLE 2: Adapted definitions of Odom’s criteria Outcome Criteria
Definition
excellent
all preop symptoms relieved; pain reduced minimal persistence of preoperative symptoms; abnormal findings unchanged or improved definite relief of some preoperative symptoms; other symptoms unchanged or slightly improved symptoms & signs worsened, or unchanged
good fair poor
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Adverse Events and Complications
The overall complications rate (all postoperative complications) was 10%, with 11 complications in total (6 major and 5 minor). Major complications included 4 cases of retrograde ejaculation, a postoperative hematoma, and an incisional hernia that required further surgery. Two patients with retrograde ejaculation recovered within 4 months postsurgery. Minor complications included postoperative deep vein thrombosis and prolonged (> 7 days) postoperative ileus. Notably, there were no reports of wound infection or hardware failure. All complications were associated with the surgical exposure and approach involved with the ALIF procedure. Graft migration was evident on postoperative CT scanning due to the radiodense nature of the i-FACTOR graft material. Despite a minor volume of graft migration in the majority of cases, we did not observe an increased rate of abdominal issues, infection, or retrograde ejaculation in this series as compared with results of similar studies. In the later stages of the study, the anterior hole in the ALIF implant was blocked to stop any graft migration as the material was wholly contained within the implant. One minor complication, unlikely related to i-FACTOR, was vague abdominal pain in a patient in whom a volume of graft had migrated. 871
R. J. Mobbs, M. Maharaj, and P. J. Rao TABLE 3: Patient demographics and characteristics Patient Demographics no. of patients no. of levels age in yrs mean range M/F BMI underweight (30) tobacco use diabetes workers’ compensation follow-up period in mos mean range length of stay in days mean range intraop blood loss in ml mean range total operation time in mins mean range
Value* 110 142 57.6 25–86 48/62 5 70 31 4 19 (17) 10 (9) 22 (20) 24 15–43 4.6 1–19 102 80–700 97 40–195
* Values are the number of patients (%) unless noted otherwise.
Cost Comparator Data
As i-FACTOR is not currently an FDA-approved product in the US, no cost comparison data are available to assess its potential benefits versus existing FDA approved products for similar indications. In the Australian health care system, the Prostheses List provides a fee structure for payment for the use of various medical de-
TABLE 4: Fusion rates of 1-, 2-, and 3-level ALIF proceedures No. of Levels
No of Patients w/ Fusion (%)
1 2 3 total
78/80 (98) 22/27 (82) 3/3 (100) 103/110 (94)
vices including biological materials and bone graft substitutes. i-FACTOR, compared with rh-BMP2 (INFUSE) and rhBMP-7 (OP-1), is significantly less expensive with the added benefit of fewer complications and acceptable/ similar fusion results.
Discussion Despite being the current gold standard, harvested autologous ICBG has many disadvantages both peri- and postoperatively, with donor site pain being the most frequent complication reported with an incidence of 25%– 31%.2,3,29,45,51 Despite the extensive list of associated complications with autograft, including graft collapse, neurological injury, and sacroiliac joint–related complications, the primary reason deterring patients and surgeons from using ICBG harvest is the subjective perception that the harvest is the most painful part of the fusion procedure.16,19,20,22,23,38 The presence of these factors justifies the necessity and use of bone graft substitutes as illustrated in Table 1. While promising results have been observed in both animal and human studies evaluating ABM/P-15 use as a bone graft, our study is the first to investigate its use composite in human ALIF procedures. Overall our data, following a mean 24-month (minimum 15 months) follow-up, demonstrated a fusion rate of 92.7% in the cohort. This is consistent with the prospective trial by Sherman et al.42 in which they used ABM/P-15 in an ovine model (n = 6, fusion rate = 100%) and Lauweryns’ unpublished prospective trial33 utilizing ABM/P-15 in posterior lumbar interbody fusion in humans (autograft 82.2% vs ABM/p-15 97.8%, 12-month follow-up). Lauweryns’ findings, as presented at the 2011 Global Spine Congress in Barcelona, also concluded that in addition to being “statistically superior,” ABM/P-15 achieved solid fusion faster than autologous bone graft with data at 6 months showing a 38.6% difference in fusion. There were no unexpected complications and the complication rate (10%) in our prospective study is comparable to the complication rate of 9.5% in the large retrospective study of BMP in ALIF by Williams et al.53 TABLE 5: Fusion rate per surgically treated level
Fig. 3. Surgical indications for which ALIF was performed. ASD = adjacent-segment disease; R = radiculopathy.
872
Level
No. of Levels Fused (%)
L2–3 L3–4 L4–5 L5–S1 total
3/3 (100) 14/17 (82) 50/59 (85) 62/63 (98) 130/142 (92)
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Clinical outcomes and fusion rates following ALIF with i-FACTOR TABLE 6: Fusion rate according to comorbidities and patient factors Patient Factor (no. of patients)
No. of Patients w/ Fusion
Fusion Rate (%)
tobacco use (19) no tobacco use (91) diabetes (10) no diabetes (100) workers’ compensation (22) non–workers’ compensation (87)*
16 87 7 96 18 83
84.2 95.6 70 96.0 81.8 95.4
TABLE 7: Time period for fusion to occur (months postsurgery), by number of levels operated No. of Patients (fusion rate)
p Value
Months
Single Level
Double Level
Triple Level
0.153
3–6 7–12 13–24 >24 not fused total
34 (43%) 31 (39%) 12 (15%) 1 (1%) 2 78 (98%)
12 (44%) 7 (26%) 3 (11%) 0 5 22 (81%)
1 (33.3%) 1 (33.3%) 1 (33.3%) 0 0 3 (100%)
0.004 0.663
* Workers’ compensation information was not known for 1 patient.
It was interesting to note that patients who smoked, had diabetes, or claimed workers’ compensation demonstrated comparably lower mean fusion rates than those who did not have these factors. This implies that patient morbidities have a negative impact on rates of successful arthrodesis. Patients with diabetes also had reduced clinical improvement in comparison with nondiabetic patients. Clinically, our results also demonstrate favorable findings in response to evaluating i-FACTOR’s suitability for ALIF procedures in humans. The preferred method of evaluating clinical outcome is through validated, patient-based outcome measures such as the ODI, VAS, and SF-12. According to Fairbank and Pynsent’s18 interpretation of ODI scores, this study’s preoperative mean score of 61.02 just falls within the category of crippled
(range 61%–80%), where back pain negatively impacts on all aspects of the patient’s life and intervention is necessary. The mean postoperative ODI score of 28.42 was a significant improvement (p = 0.001), and reduced the disability to moderate, where pain is still experienced but can be managed conservatively. The ODI outcomes observed in the present study (mean improvement 32.6 at the 24-month follow-up) are similar to the results of 15- to 25-point improvement achieved with BMP in the literature, although significant differences in mean follow-up times exist.33,42,44 It is important to recognize that due to the wide range of follow-up periods in our trial (i.e.,15–43 months), direct comparisons cannot be made. The same papers also reported pain scores, albeit with different scales. On a 10-point pain scale, allograft/ ALIF patients improved from a score of 6 to about a score of 4.5 at 6 months after surgery.46 The study conducted by
Fig. 4. CT images obtained 10 months postsurgery in a 73-year-old man who was treated for DDD without radiculopathy. This case was classified as a failed fusion with stable nonunion of the L4–5 ALIF.
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R. J. Mobbs, M. Maharaj, and P. J. Rao TABLE 9: Odom outcomes
Fig. 5. Pie chart showing the overall fusion for patients undergoing 1-, 2-, and 3-level surgery. The values indicate time points in months.
Burkus et al. was analyzed using a 20-point pain scale, and hence, the outcomes cannot be directly compared with the outcomes of our current study, although positive outcomes were maintained at the 6-year follow-up.10 The mean differences were 7.3 and 7.1 for BMP and autograft, respectively, at 6 months postsurgery,9 while a larger improvement from 7.40 preoperatively to 2.65 postoperatively (p = 0.013) was seen in our study. This demonstrates that i-FACTOR is a promising graft substitute to achieve fusion and to assist with the ALIF procedure to reduce pain caused by certain spinal pathologies, without the potential adverse events and complications associated with autograft and BMPs. Although migration of i-FACTOR was seen in patients when not contained, there were no confirmed adverse effects from the graft material located outside the interbody space. Our study used the SF-12 survey to assess clinical outcomes on the basis of increased patient convenience and compliance, demonstrating a mean increase in the score from 68.27 to 92.99 (mean difference 24.72; p = 0.043). The results suggest i-FACTOR use as an adjunct to spinal arthrodesis, significantly improving the quality of life and mental state of patients. Comparisons with other recent studies were not possible due to their implementation of the SF-36. Odom outcomes demonstrated that 85.3% of patients in the current study for whom follow-up was available had excellent to good outcomes. These patients experienced a significant improvement in their quality of life and noted that ALIF using i-FACTOR was an appropriate choice. TABLE 8: Summary of clinical outcome score data within the entire patient cohort Variable
SF-12
ODI
VAS
preop score postop score p value
68.57 ± 14.06 92.99 ± 15.72 0.043*
61.02 ± 21.38 28.42 ± 19.53 0.001*
7.38 ± 1.53 2.65 ± 2.13 0.013*
* Statistically significant.
874
Variable
Excellent
Good
Fair
Poor
1-level 2-level 3-level total
36 13 1 50
33 8 2 43
12 2 0 14
2 0 0 2
It is of paramount importance that evaluation of the success of a graft is made on the basis of both radiological and clinical patient outcome measures, as successful fusion does not always correlate with satisfactory patient outcome. Limitations of our study are the lack of direct control and the potential for respondent bias. Patients who participate in research are more likely to comply with postoperative medications and physiotherapy, thus resulting in better health outcomes. For instance, a few patients declined completing the postoperative outcome data because they were discontent with their outcome. These patients were subsequently excluded from statistical analysis, which may have positively skewed results.
Conclusions
Anterior lumbar interbody fusion using i-FACTOR (ABM/P-15) synthetic bone graft substitute is a useful treatment option for degenerative pathologies of the lumbar spine. The present study demonstrates a high fusion rate and clinical improvements comparable to the published results for ALIF using autograft or BMP. At the same time the use of ABM/P-15 as a graft material avoids the complications specific to those 2 materials. Further studies comparing rate of arthrodesis, clinical outcome, and cost between ABM/P-15 and other graft alternatives are warranted. Disclosure Dr. Mobbs reports receiving clinical or research support for the study described from Cerapedics. Author contributions to the study and manuscript preparation include the following. Conception and design: Mobbs. Acquisition of data: all authors. Analysis and interpretation of data: all authors. Drafting the article: Mobbs. Critically revising the article: all au thors. Reviewed submitted version of manuscript: Mobbs, Rao. Approved the final version of the manuscript on behalf of all authors: Mobbs. Statistical analysis: Mobbs, Maharaj. Administrative/technical/material support: Rao. Study supervision: Mobbs. References 1. Anderson DG, Sayadipour A, Shelby K, Albert TJ, Vaccaro AR, Weinstein MS: Anterior interbody arthrodesis with percutaneous posterior pedicle fixation for degenerative conditions of the lumbar spine. Eur Spine J 20:1323–1330, 2011 2. Banwart JC, Asher MA, Hassanein RS: Iliac crest bone graft harvest donor site morbidity. A statistical evaluation. Spine (Phila Pa 1976) 20:1055–1060, 1995 3. Bednar DA, Al-Tunaib W: Failure of reconstitution of opensection, posterior iliac-wing bone graft donor sites after lumbar spinal fusion. Observations with implications for the etiology of donor site pain. Eur Spine J 14:95–98, 2005
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Clinical outcomes and fusion rates following ALIF with i-FACTOR 4. Benglis D, Wang MY, Levi AD: A comprehensive review of the safety profile of bone morphogenetic protein in spine surgery. Neurosurgery 62 (5 Suppl 2):ONS423–ONS431, 2008 5. Bhatnagar RS, Qian JJ, Gough CA: The role in cell binding of a beta-bend within the triple helical region in collagen alpha 1 (I) chain: structural and biological evidence for conformational tautomerism on fiber surface. J Biomol Struct Dyn 14: 547–560, 1997 6. Blumenthal SL, Baker J, Dossett A, Selby DK: The role of anterior lumbar fusion for internal disc disruption. Spine (Phila Pa 1976) 13:566–569, 1988 7. Boden SD, Zdeblick TA, Sandhu HS, Heim SE: The use of rhBMP-2 in interbody fusion cages. Definitive evidence of osteoinduction in humans: a preliminary report. Spine (Phila Pa 1976) 25:376–381, 2000 8. Burkus JK, Dorchak JD, Sanders DL: Radiographic assessment of interbody fusion using recombinant human bone morphogenetic protein type 2. Spine (Phila Pa 1976) 28:372–377, 2003 9. Burkus JK, Gornet MF, Dickman CA, Zdeblick TA: Anterior lumbar interbody fusion using rhBMP-2 with tapered interbody cages. J Spinal Disord Tech 15:337–349, 2002 10. Burkus JK, Gornet MF, Schuler TC, Kleeman TJ, Zdeblick TA: Six-year outcomes of anterior lumbar interbody arthrodesis with use of interbody fusion cages and recombinant human bone morphogenetic protein-2. J Bone Joint Surg Am 91:1181–1189, 2009 11. 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) 27:2396–2408, 2002 12. Burns BH: An operation for spondylolisthesis. Lancet 221: 1233–1239, 1933 13. Capener N: Spondylolisthesis. Br J Surg 19:374–386, 1932 14. Chau AM, Xu LL, Wong JH, Mobbs RJ: Current status of bone graft options for anterior interbody fusion of the cervical and lumbar spine. Neurosurg Rev 37:23–37, 2014 15. Chen Z, Ba G, Shen T, Fu Q: Recombinant human bone morphogenetic protein-2 versus autogenous iliac crest bone graft for lumbar fusion: a meta-analysis of ten randomized controlled trials. Arch Orthop Trauma Surg 132:1725–1740, 2012 16. Cheung KM, Zhang YG, Lu DS, Luk KD, Leong JC: Reduction of disc space distraction after anterior lumbar interbody fusion with autologous iliac crest graft. Spine (Phila Pa 1976) 28:1385–1389, 2003 17. Ehrler DM, Vaccaro AR: The use of allograft bone in lumbar spine surgery. Clin Orthop Relat Res (371):38–45, 2000 18. Fairbank JC, Pynsent PB: The Oswestry Disability Index. Spine (Phila Pa 1976) 25:2940–2952, 2000 19. Fowler BL, Dall BE, Rowe DE: Complications associated with harvesting autogenous iliac bone graft. Am J Orthop 24: 895–903, 1995 20. Greenough CG, Taylor LJ, Fraser RD: Anterior lumbar fusion: results, assessment techniques and prognostic factors. Eur Spine J 3:225–230, 1994 21. Gomar F, Orozco R, Villar JL, Arrizabalaga F: P-15 small peptide bone graft substitute in the treatment of non-unions and delayed union. A pilot clinical trial. Int Orthop 31:93– 99, 2007 22. Heary RF, Schlenk RP, Sacchieri TA, Barone D, Brotea C: Persistent iliac crest donor site pain: independent outcome assessment. Neurosurgery 50:510–517, 2002 23. Ishihara H, Osada R, Kanamori M, Kawaguchi Y, Ohmori K, Kimura T, et al: Minimum 10-year follow-up study of anterior lumbar interbody fusion for isthmic spondylolisthesis. J Spinal Disord 14:91–99, 2001 24. Kanatani M, Sugimoto T, Kaji H, Kobayashi T, Nishiyama K, Fukase M, et al: Stimulatory effect of bone morphogenetic
J Neurosurg: Spine / Volume 21 / December 2014
protein-2 on osteoclast-like cell formation and bone-resorbing activity. J Bone Miner Res 10:1681–1690, 1995 25. Kim JS, Choi WG, Lee SH: Minimally invasive anterior lumbar interbody fusion followed by percutaneous pedicle screw fixation for isthmic spondylolisthesis: minimum 5-year follow-up. Spine J 10:404–409, 2010 26. Kim JS, Kim DH, Lee SH, Park CK, Hwang JH, Cheh G, et al: Comparison study of the instrumented circumferential fusion with instrumented anterior lumbar interbody fusion as a surgical procedure for adult low-grade isthmic spondylolisthesis. World Neurosurg 73:565–571, 2010 27. Kleeman TJ, Ahn UM, Talbot-Kleeman A: Laparoscopic anterior lumbar interbody fusion with rhBMP-2: a prospective study of clinical and radiographic outcomes. Spine (Phila Pa 1976) 26:2751–2756, 2001 28. Kübler A, Neugebauer J, Oh JH, Scheer M, Zöller JE: Growth and proliferation of human osteoblasts on different bone graft substitutes: an in vitro study. Implant Dent 13:171–179, 2004 29. Kurz LT, Garfin SR, Booth RE Jr: Harvesting autogenous iliac bone grafts. A review of complications and techniques. Spine (Phila Pa 1976) 14:1324–1331, 1989 30. Lee DY, Lee SH, Maeng DH: Two-level anterior lumbar interbody fusion with percutaneous pedicle screw fixation: a minimum 3-year follow-up study. Neurol Med Chir (Tokyo) 50:645–650, 2010 31. Linovitz RJ, Peppers TA: Use of an advanced formulation of beta-tricalcium phosphate as a bone extender in interbody lumbar fusion. Orthopedics 25 (5 Suppl):s585–s589, 2002 32. Mannion RJ, Nowitzke AM, Wood MJ: Promoting fusion in minimally invasive lumbar interbody stabilization with low-dose bone morphogenic protein-2—but what is the cost? Spine J 11:527–533, 2011 33. McAdoo S: Prospective, randomized, controlled trial demonstrates 98% fusion rate at 6-months and 12-months with i-FACTOR™ biologic bone graft and superiority versus autograft in single- and multi-level PLIF spine surgery. Cerapedics. (http:// www.cerapedics.com/intl/news/story6/) [Accessed September 3, 2014] 34. Mercer W: Spondylolisthesis: with a description of a new method of operative treatment and notes of ten cases. Edinburgh Med J 43:545–572, 1936 35. Mobbs RJ, Chung M, Rao PJ: Bone graft substitutes for anterior lumbar interbody fusion. Orthop Surg 5:77–85, 2013 36. Mobbs RJ, Loganathan A, Yeung V, Rao PJ: Indications for anterior lumbar interbody fusion. Orthop Surg 5:153–163, 2013 37. Motosuneya T, Asazuma T, Nobuta M, Masuoka K, Ichimura S, Fujikawa K: Anterior lumbar interbody fusion: changes in area of the dural tube, disc height, and prevalence of cauda equina adhesion in magnetic resonance images. J Spinal Disord Tech 18:18–22, 2005 38. Newman MH, Grinstead GL: Anterior lumbar interbody fusion for internal disc disruption. Spine (Phila Pa 1976) 17: 831–833, 1992 39. Ohtori S, Koshi T, Yamashita M, Takaso M, Yamauchi K, Inoue G, et al: Single-level instrumented posterolateral fusion versus non-instrumented anterior interbody fusion for lumbar spondylolisthesis: a prospective study with a 2-year follow-up. J Orthop Sci 16:352–358, 2011 40. Pavlov PW, Meijers H, van Limbeek J, Jacobs WC, Lemmens JA, Obradov-Rajic M, et al: Good outcome and restoration of lordosis after anterior lumbar interbody fusion with additional posterior fixation. Spine (Phila Pa 1976) 29:1893–1900, 2004 41. Saraph V, Lerch C, Walochnik N, Bach CM, Krismer M, Wimmer C: Comparison of conventional versus minimally invasive extraperitoneal approach for anterior lumbar interbody fusion. Eur Spine J 13:425–431, 2004 42. Sherman BP, Lindley EM, Turner AS, Seim HB III, Benedict J, Burger EL, et al: Evaluation of ABM/P-15 versus autog-
875
R. J. Mobbs, M. Maharaj, and P. J. Rao enous bone in an ovine lumbar interbody fusion model. Eur Spine J 19:2156–2163, 2010 43. Shim CS, Lee SH, Jung B, Sivasabaapathi P, Park SH, Shin SW: Fluoroscopically assisted percutaneous translaminar facet screw fixation following anterior lumbar interbody fusion: technical report. Spine (Phila Pa 1976) 30:838–843, 2005 44. Slosar PJ, Josey R, Reynolds J: Accelerating lumbar fusions by combining rhBMP-2 with allograft bone: a prospective analysis of interbody fusion rates and clinical outcomes. Spine J 7:301–307, 2007 45. Summers BN, Eisenstein SM: Donor site pain from the ilium. A complication of lumbar spine fusion. J Bone Joint Surg Br 71:677–680, 1989 46. Thalgott JS, Fogarty ME, Giuffre JM, Christenson SD, Epstein AK, Aprill C: A prospective, randomized, blinded, single-site study to evaluate the clinical and radiographic differences between frozen and freeze-dried allograft when used as part of a circumferential anterior lumbar interbody fusion procedure. Spine (Phila Pa 1976) 34:1251–1256, 2009 47. Thalgott JS, Klezl Z, Timlin M, Giuffre JM: Anterior lumbar interbody fusion with processed sea coral (coralline hydroxyapatite) as part of a circumferential fusion. Spine (Phila Pa 1976) 27:E518—E527, 2002 48. Tiusanen H, Seitsalo S, Osterman K, Soini J: Anterior interbody lumbar fusion in severe low back pain. Clin Orthop Relat Res (324):153–163, 1996 49. US Food and Drug Administration: Summary of Safety and Effectiveness Data. InFUSE™ Bone Graft/LT-CAGE™ Lumbar Tapered Fusion Device. (http://www.accessdata.
876
fda.gov/cdrh_docs/pdf/P000058b.pdf) [Accessed September 3, 2014] 50. Vaccaro AR, Chiba K, Heller JG, Patel TC, Thalgott JS, Truumees E, et al: Bone grafting alternatives in spinal surgery. Spine J 2:206–215, 2002 51. Vaidya R, Weir R, Sethi A, Meisterling S, Hakeos W, Wybo CD: Interbody fusion with allograft and rhBMP-2 leads to consistent fusion but early subsidence. J Bone Joint Surg Br 89:342–345, 2007 52. Ware J Jr, Kosinski M, Keller SD: A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med Care 34:220–233, 1996 53. Williams BJ, Smith JS, Fu KM, Hamilton DK, Polly DW Jr, Ames CP, et al: Does bone morphogenetic protein increase the incidence of perioperative complications in spinal fusion? A comparison of 55,862 cases of spinal fusion with and without bone morphogenetic protein. Spine (Phila Pa 1976) 36:1685–1691, 2011
Manuscript submitted December 18, 2013. Accepted September 2, 2014. Please include this information when citing this paper: published online October 17, 2014; DOI: 10.3171/2014.9.SPINE131151. Address correspondence to: Ralph J. Mobbs, B.Sc., M.B.B.S., M.S., F.R.A.C.S., NeuroSpineClinic, Suite 7a, Level 7, Prince of Wales Private Hospital, Randwick, NSW 2031, Australia. email: [email protected].
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