Despite widespread reports in the literature of successful surgical management of degenerative spinal disorders of the lumbar spine and improvement of pain and quality of life (QoL), relatively few long-term controlled trials have critically evaluated the various devices available to surgeons.1 Indeed, there is a vast array of alternative surgical options and internal fixation devices, as well as bone graft materials and growth factors for the management of spinal conditions, such as degenerative disc disease, spondylolisthesis, and disc herniation. Procedural types and bone grafts for the treatment of these spinal conditions include posterolateral fusion (PLF) and/or posterior lumbar interbody fusion (PLIF)2 with iliac crest or local autograft,3 cadaveric allograft,4 ceramic and other synthetic bone substitutes,5 bone morphogenetic proteins (BMPs),6–8 and bone marrow aspirate (BMA),9 among other options. Although autologous iliac crest bone has long been considered the gold standard bone graft in PLF, harvesting the graft material is associated with significant morbidity such as persistent pain at the donor site, enhanced blood loss, and prolonged hospitalization. Hence, there is much interest in substitute biomaterials to bone autografts.3,10
Actifuse (Baxter Healthcare, Deerfield, IL) is a silicate-substituted calcium phosphate (SiCaP) synthetic bone graft material that combines an optimized osteoconductive scaffold containing Actifuse granules with an aqueous polymer gel to provide a moldable cohesive bone graft for facilitating rapid and sustained bone ingrowth. Infuse (Medtronic, Inc., Memphis, TN), on the contrary, is a bone-inductive agent comprising recombinant human BMP-2 and bovine type I collagen scaffold.
In this multicenter, prospective, randomized study, we investigated vertebral fusion success rates and clinical outcomes following combined PLIF and PLF procedures using either SiCaP or BMP-2 as the bone graft biomaterial in the PLF in adult patients with spinal conditions of degenerative disc disease, spondylolisthesis, or disc herniation.
MATERIALS AND METHODS
The surgery consisted of PLIF and PLF with internal fixation over one or two levels. The trial conducted examined the PLF component of the procedure only. The study design and strict assessment of the PLF was chosen to isolate the biological activity and bone healing potential of the two treatments groups, as achieving a solid, stable intertransverse arthrodesis presents a unique challenge for a bone graft substitute. The PLIF surgery was performed according to the investigating surgeon's preference with the stipulation that autogenous bone (local) only was used in the interbody fusion (no BMP); the PLF surgery was performed according to the study protocol.
Patients were blinded, but surgeons were not blinded to the surgical treatment. The independent radiographic reviewers were also blinded. Randomization to SiCaP or BMP-2 groups was carried out at the time before surgery. Randomization was performed by the Statistics Department at the University of Wollongong. Patients were randomized on a 1:1 basis between SiCaP and BMP-2. Concealment of allocation was achieved by the remote generation of codes that were conveyed to the site in sealed, opaque envelopes, accessed only at the time of operation. Radiographic review was conducted by a validated core laboratory (Medical Metrics, TX).
This was a two-arm, pilot, proof-of-concept study aimed at obtaining estimates of successful fusion from both SiCaP and BMP-2. In addition, the study was designed to provide estimates of variability and feasibility of both therapies in this subject population. The fusion rate for standard historic control (autograft) was estimated conservatively to be approximately 70% at 12 months.11 For patients in the SiCaP group, it was expected that the fusion rate at 12 months would be closer to 86%. On that basis, a sample size of 50 patients in the SiCaP group would have 80% power to detect a success rate of at least 86% with 95% confidence. In order to obtain reasonable estimates for the BMP-2 group for any future research, 50 patients were accrued into this group in a randomized fashion to reduce selection bias. The total sample size for this study was planned to be approximately 100 patients randomized to receive SiCaP or BMP-2 in a 1:1 ratio with 50 patients per group. The primary outcome of fusion success was evaluated at 12 months after treatment, the standard time at which fusion has been observed.
Inclusion criteria were patients with degenerative disc disease, spondylolisthesis, or disc herniation, evidenced by back pain of discogenic/degenerative origin with or without leg pain and corroborative radiographic findings. Patients were also required to have had nonoperative treatment (bed rest/physical therapy/medications and/or spinal injections)-refractory disease for ≥6 months.
The study protocol and informed consent form were reviewed and approved by relevant ethics committees before implementation (EudraCT Number 2009–012672–27 v 2.0, February 18, 2010). This study confirmed to International Conference on Harmonisation-Good Clinical Practice (ICH-GCP) and all applicable regulations and was conducted in accordance with the principles of the Declaration of Helsinki. All eligible patients provided written informed consent before participating in any study-related activities.
Both SiCaP and BMP-2 devices were placed in the posterolateral gutter (PLG). Transverse processes (TPs) were visualized and decorticated and the device substance was placed in contact with the bleeding decorticated TP bone. The amount of SiCaP used was dependent on the size of the patient, but was typically between 5 and 10 mL. Up to 10 mL of SiCaP per level per side was packed into the decorticated PLGs and was in contact with bleeding decorticated TPs of the operated levels. No addition of BMA or other bone or substitute material was permitted. This range for SiCaP was selected on the basis of previous experience and is supported by a study reporting the safety and efficacy of SiCaP in lumbar fusion surgery.12
For patients receiving BMP-2, one Large II INFUSE kit was used per involved level. Published studies with BMP-2 support its use in conjunction with a bulking agent, Mastergraft granules Fairbank and Pynsent.13 Previous studies have used one large sponge (12 mg rhBMP-2, 1.5 mg/mL) wrapped around 15 cc Mastergraft granules per level, with half a roll in each PLG.12 Therefore, BMP-2 was used with Mastergraft granules (known as INFUSE), and dose selection of BMP-2 was based on the surgeon's previous experience and clinical trial data, in accordance with the study protocol. The BMP-2 INFUSE/absorbable collagen sponge and Mastergraft were prepared as per manufacturer's instructions using a Large II kit of INFUSE Bone Graft (12 mg rhBMP-2 in 8 mL) at 1.5 mg/mL and were applied to the sponge. After 15 minutes, to allow rhBMP-2 binding, the absorbable collagen sponge was cut into two equal segments (2 inch by 3 inch) and up to10 mL Mastergraft granules (15% hydroxyapatite/85% tricalcium phosphate) were used to wrap the absorbable collagen sponge. Each Large II kit of INFUSE produced two 2-inch rolls to be placed in continuity and in contact with bleeding decorticated TPs of the operated levels. No screws or cages were used.
Prolonged use of nonsteroidal anti-inflammatory drugs (NSAIDs) except low-dose aspirin was prohibited for 24 months postoperatively, as was electrical bone growth stimulation of the lumbar spine.
The primary performance endpoint was a composite of grade 4 to 5 fusion and no motion (3 mm or less translational motion and 5° or less angular motion) between the fused vertebral bodies at 12 months. Fusion was deemed to exist if there was evidence of continuous bony connection between the TP of the superior vertebral body and that of the subjacent vertebral body.
The presence and quality of bone formation in PLG were assessed by plain x-rays at 6 weeks and 3, 6, 12, and 24 months with flexion-extension films and computed tomography (CT) scans at 12 and 24 months postoperatively. Radiographs were assessed by independent reviewers who were blinded to treatment. CT scans were graded according to the method of Glassman et al.,14 as summarized in Table 1.
Secondary performance variables were low back and leg pain assessed by visual analog scale (VAS) from 0 (no pain) to 10 (worst pain), and Oswestry Disability Index (ODI),13 general health status and QoL assessed by Medical Outcomes Study 36-Item Short Form Health Survey (SF-36),15 neurological status, and patient satisfaction. Neurological status was based on four measurements such as motor, sensory, reflexes, and straight leg raise; neurological success was defined as maintenance/improvement of neurological function postoperatively versus baseline. Safety was assessed in terms of adverse events (AEs) coded according to Medical Dictionary for Regulatory Activities (MedDRA, https://www.meddra.org/) version 14.0.
All patients underwent postoperative assessments that took place at 6 weeks, and 3, 6, 12, and 24 months after surgery. These postoperative assessments included flexion-extension films and CT scans, monitoring of analgesic medication, assessments for low back and leg pain, with VAS scores, ODI scores, general health status, and QoL scores, assessed by the SF-36,15 neurological status (based on four measurements such as motor, sensory, reflexes, and straight leg raise); neurological success was defined as maintenance/improvement of neurological function postoperatively versus baseline and safety was assessed in terms of AEs.
Analysis populations were defined as the intent-to-treat (ITT) population defined as all patients who were randomized, received treatment, and had sufficient evaluable radiographs for at least one follow-up. In addition, a per-protocol (PP) population was generated, defined as all patients who completed the study without any deviations from the study protocol. In general, descriptive statistics were calculated for each variable assessed. All analyses were performed using SAS software (SAS Institute, NC) version 9.1.3.
A total of 103 patients were enrolled and received treatment (SiCaP, n = 51; BMP-2, n = 52); 96 patients completed the study. The PP population comprised 62 patients with evaluable fusion results (SiCaP, n = 35; BMP-2, n = 27; Figure 1) at the primary endpoint of 12-month follow-up. The 41 patients (103–62) were not eligible for inclusion in the PP population for the following reasons: major protocol deviations (n = 21); lost to follow-up (n = 4); missing radiograph images (n = 16). Patients’ baseline demographic characteristics were similar in the two treatment groups (Table 2). Representative series x-rays and CT images of solid fusion are shown in Figures 2A, B and 3A, B, respectively.
The primary diagnosis in the overall population was spondylolisthesis (n = 49; 47.6%), degenerative disc disease (n = 46; 44.7%), stenosis (n = 6; 5.8%), and disc herniation (n = 2; 1.9%). For most patients (n = 74; 71.8%), there was one involved vertebral level; 28 (27.2%) patients had two involved levels and one patient (1.0%) had three involved levels. The most frequently involved levels were L5–S1 in 61 (59.2%) patients and L4–L5 in 59 (57.3%) patients.
Of the 21 protocol deviations, the majority were in the BMP-2 group and were due to the absence of bulking material Mastergraft granules along with the BMP-2/ACS rolls (n = 13). Two patients had an autoimmune disease and two were drug users, one patient received SiCaP granules instead of SiCaP granules with an aqueous polymer gel, one had surgery over three levels, one had hepatic disease, and one had chronic renal failure (Table 3).
Primary and Secondary Performance Endpoints
At 12 months, the ITT analysis (103 patients) demonstrated the primary endpoint of fusion was achieved in 27 of 51 (52.9%) patients of the SiCaP group and 29 of 52 (55.8%) patients of the BMP-2 group (P = 0.8442; Fisher exact test). In the PP population (62 patients), fusion success was achieved in 25 of 35 (71.4%) in the SiCaP group and in 20 of 27 (74.1%) the BMP-2 group (P = 1.00, Figure 4). There was no significant treatment effect for SiCaP versus BMP-2; in either analysis, moreover, none was noted for the effects of age or smoking status.
At 24 months in the ITT analysis, fusion was achieved in 80.4% of patients in both the SiCaP and BMP-2 groups (P = 1.00). In the PP analysis at 24 months, fusions were noted in 78.6% and 84.8% patients in the SiCaP and BMP-2 groups, respectively (P = 0.56, Figure 5).
For both treatment groups, mean VAS scores for back pain were lower than preoperative VAS scores for all subsequent time-points (Figure 6); at 6 months, the SiCaP VAS scores were significantly lower than the BMP group. Table 4 summarizes ODI scores in the two treatment groups throughout the study. In the SiCaP and BMP-2 groups, ODI score and QoL showed steady improvements over time (SF-36 significant at 6 months). At all time-points, the proportion of patients deemed as experiencing neurological success was higher in the SiCaP versus BMP-2 group, although the difference was not significant, except for the 6-month timepoint (Figure 7A, B).
The numbers and frequencies of AEs were similar between the two treatment groups. The most frequently reported AE was pain, followed by wound secretion, pain in an extremity, back pain, nausea, and procedural pain (Table 5). Investigational device-related serious AEs were reported for four of 51 (7.8%) and four of 52 (7.7%) patients in the SiCaP and BMP-2 treatment groups, respectively (two graft dislocations, two surgical failures for both SiCaP and BMP-2, respectively).
In this study, the percentages of patients with successful fusion were very similar in the SiCaP and BMP-2 treatment groups; no significant difference was noted in the ITT or PP populations at 12 and 24 months. The rate of successful fusion was independent of effects of age and smoking status. Pain as assessed by VAS scores demonstrated statistical significance at 6 months only; however, scores were consistently lower in the SiCaP group than in BMP-2 at all time-points. We also noted consistent increases of new bone formation radiographically accompanied by reductions of self-reported pain on VAS in both treatment groups as the study progressed. The safety assessments indicated predictable types of AEs for this surgical population; the occurrence of all types of AEs was generally balanced across the two treatment groups.
Although one may argue that the fusion success rates of the PLF only do not reflect the total procedure (PLF and PLIF), this randomized study provides a direct comparison of the bone healing potential within the two treatment groups.
SiCaP is a novel, synthetic, porous bone graft that provides trabecular structure similar to that of cancellous bone.16 The osseous struts are macroporous and microporous with high levels of interconnectivity, accelerating osteointegration. Incorporation of silicate ions into the calcium phosphate structure as in SiCaP appears to enhance the early in vivo bioactivity of this bone substitute material by altering the bone-forming and resorbing cellular activity. Thus, angiogenesis and vascularization of the SiCaP matrix and transport of nutrients to host bone are facilitated, which allows rapid bone ingrowth and greater volume of ossification with subsequent remodeling of the graft to mature bone.16
Although BMP-2, the comparator bone graft substitute in this study, has not gained FDA approval for use in PLF, this osteoinductive agent has been demonstrated to be highly efficacious at inducing bone ingrowth in humans6–8 and is used extensively off label for this surgical procedure. For instance, in patients undergoing posterolateral lumbar spine fusion procedures, equivalent bone fusion success was achieved using BMP-2 compared with control patients receiving iliac crest bone graft.17 Furthermore, in patients with pain of lumbar disc degeneration who had failed ≥6 months’ nonoperative treatment, a successful spine arthrodesis was demonstrated in all recipients of BMP-2 bone grafts irrespective of the presence or absence of internal instrumentation.6 Similar results were obtained in a pilot clinical trial comparing BMP-7 putty versus autogenous iliac crest bone graft for one-level uninstrumented PLF8 and in a study evaluating BMP-7 versus local autograft in PLF with pedicle screw instrumentation.5
Therefore, in the present study, BMP-2 was selected as comparator bone graft substitute material and demonstration of equivalent safety and efficacy associated with SiCaP compared with BMP-2 would be considered encouraging study endpoints. Indeed, historical data suggest that PLF using iliac bone autograft with or without pedicle screw fixation, considered the gold standard surgical procedure for short lumbar fusions, achieves successful fusion in approximately 75% to 84% of cases,18,19 and a meta-analysis of trials comparing autologous iliac crest bone graft versus BMP-7 in PLF suggested equivalent efficacy in promoting fusion.20 Our finding of a similar rate of fusion success for SiCaP as for BMP-2, therefore, suggests that SiCaP may be as useful as iliac crest bone graft for PLF3,10 without the limitations of obtaining sufficient graft quantity and risk of infection that is associated with iliac crest. Furthermore, SiCaP provides an alternative bone graft substitute to BMP-2, circumventing the concerns that have been associated with the safety profile of BMP-2 in spinal fusion surgery.21
The study was underpowered due to the number of patients who could not be included in the PP population. This was in part due to the numbers of protocol deviations, mostly arising from the omission of bulking agent to the BMP-2 material.
The success of lumbar fusion and magnitude of clinical improvement is also dependent on patient baseline characteristics. A recent study compared the clinical outcomes following interbody fusion surgery and demonstrated that by stratifying patients into severity of initial diagnosis, the results could be correlated with success of clinical outcomes.22 This should be considered when drawing conclusions between treatment groups, and furthermore, the results in this study should be treated with caution when making comparisons with other fusion techniques.
SiCaP synthetic bone graft has demonstrated prior success in various other surgical settings. For instance, in a randomized trial comparing lumbar single-level stand-alone extreme lateral interbody fusion (XLIF) using SiCaP or BMP-2 in patients with degenerative disc disease, complete long-term solid fusion was achieved in all patients at 36 months.23 When spinal arthrodesis was attempted using SiCaP alone as graft material in patients with degenerative and traumatic conditions affecting all spinal regions (cervical, thoracic, lumbar), combined fusion rates of 86% of patients and 90% of levels were observed.24 Unlike rhBMPs, SiCaP is not contraindicated in skeletally immature individuals. Therefore, in patients with adolescent idiopathic scoliosis, corrective posterior instrumentation with fusion using SiCaP enriched with BMA was performed and accomplished durable curve correction in all patients (100% fused).16 Meanwhile, in children with benign bone lesions of the lower extremity curettage and filling of the defect with SiCaP led to uneventful healing with full weight bearing within a few weeks postoperatively.25
In conclusion, SiCaP bone graft substitute was safe and well tolerated in this group of patients with conditions of degenerative disc disease, spondylolisthesis, and/or herniated disc, who underwent PLF and PLIF. SiCaP provided fusion rates similar to those observed in patients receiving BMP-2 bone graft material. On the basis of historical control data, SiCaP may be as useful as iliac crest bone autograft in the context of spine fusion surgery, with less risk of unwanted donor site morbidity associated with that commonly performed procedure.
Dr. Laila Guzadhur and Dr. Ryan Russell of Niche Science & Technology, Ltd. provided medical writing and editorial support during development of the manuscript and this service was paid for by Baxter Healthcare.
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Keywords:Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
bone graft; bone morphogenetic protein (BMP)-2; degenerative disc disease; degenerative spinal disorders; posterior lumbar interbody fusion (PLIF); posterolateral lumbar fusion (PLF); prospective randomized study; silicated calcium phosphate (SiCaP); spinal disease; spondylolisthesis