Next, Louis-Ugbo et al19 tested 2 formulations of the DBM: Grafton DBM Flex and Matrix (Osteotech, Eatontown, NJ), both fiber-based products, for their potential efficacy in a rhesus monkey model, which is difficult to fuse. The posterolateral spine model is quite challenging, as evidenced by the rate of only 21% successful lumbar spine fusions when autogenous iliac crest bone graft is used alone.27 The results show that when combined with local autogenous bone, the Flex form resulted in fusion in 2 of 4 monkeys (50%) and the Matrix in 3 of 4 monkeys (75%) as compared with 21% with autograft alone. This study suggests that the use of Flex or Matrix formulations of the DBM may play a role as a bone graft enhancer (yielding a higher rate of successful fusions than autogenous bone graft alone), not merely an extender.
On the basis of the results of this preclinical work on the Matrix DBM product, the senior author of this article (R.R.B.) retrospectively reviewed his own clinical series of the use of Matrix DBM strips in posterior spinal fusions for AIS (Pahys et al, unpublished data, July 2008). Between 2002 and 2005, 30 patients underwent PSF for AIS at our institution who met the inclusion criteria of a stand alone PSF using pedicle screws or a hook/screw hybrid construct augmented with either allograft cancellous cortical chips (Red Cross) or DBM Matrix strips (Osteotech, Eatontown, NJ) and had a minimum 2-year follow-up. Allograft alone was used in 13 patients during the earlier years of the study and DBM alone was used in 17 in the latter part of the study period. Patients were clinically and radiographically followed at regular intervals to assess fusion using a previously developed radiographic grading system (1 = fusion to 4 = no fusion).28 There were no cases of definitive or probable pseudarthrosis in either the Allograft or DBM group (Figures 1 A–D) as assessed by plain radiographs. No computed tomography scans were done, and the authors acknowledge that there could be pseudarthrosis not detectable radiographically.
Radiographic grading of the fusion mass was evaluated, and all the patients in both groups attained Grade 1 fusion. The timing of achieving fusion was then evaluated. The Allograft group and the DBM group demonstrated a Grade I definitive fusion in an average of 19.5 months (range, 7–36 months) and 13.8 months (range, 5–25 months), respectively (P < 0.05). Using a mixed model ANOVA test, the DBM group demonstrated 63% fusion in 4.23 months compared to 10.57 months in the Allograft group (P < 0.05). Thus, the fusion rate was 60% faster in the DBM group compared to the Allograft group. At 12 months, the average fusion grades for the DBM and Allograft groups were 1.17 and 1.66, respectively (P < 0.05) (Figure 2). This conclusion suggests that both DBM Matrix strips and corticocancellous allograft chips are viable extenders (and possible enhancers) for local bone graft for PSF in the AIS population. However, there appeared to be a faster time to fusion in the DBM matrix strip group.
In addition, the senior author (R.R.B.) explored the in situ posterior spinal fusion of a 7-year-old boy with congenital scoliosis who had been treated with casting and no instrumentation. (It is the senior author's standard practice to explore all noninstrumented in situ fusions at 6 to 12 months for confirmation of a solid fusion or repair of a pseudarthrosis as taught by R. Winter [personal communication]). The posterior spinal fusion had been performed from C6 to T6 with Matrix strips and no autogenous bone graft. At 11 months following original fusion, on exploration, a solid bone mass was seen. Bone biopsies were obtained under an IRB approved protocol. Both specimens consisted of mature bone with no evidence of residual Matrix DBM material evident in either biopsy (Figures 3 A–C).
Another bone graft extender/enhancer is Healos (DePuy-Spine, Raynham, MA), which is based on a bovine type 1 fibular collagen (70% hydroxyapatite coating and 30% proprietary cross-linked matrix). This composition is reported to closely mimic the early phase of natural bone formation. It is always recommended to be used with bone mineral aspirate as a primary source of osteoprogenitor cells.28
Preclinical studies with Healos have been contradictory. In a posterior spinal fusion rabbit model, Tay et al30 reported that the fusion rate at 8 weeks for Healos with bone mineral aspirate (from the tibia) was better than with autograft. Both the Healos with BMA and the autograft group were better than Healos alone (Table 3). However, a study by Kraiwattanapong et al31 of the Boden posterolateral fusion rabbit model showed no fusion in any animal at 8 weeks in a group with Healos and bone mineral aspirate (from the iliac crest). The difference in these 2 studies may be in the source of BMA cells and their osteoprogenitor capability. In addition, the assessment of fusion is not the same. Further preclinical and clinical study is needed, but what is clear is that Healos needs a source of additional cells to be effective.
In a comparison of 2 noncontrolled clinical studies of Healos, both Grosse et al32 and Kitchel33 found that the fusion rate in patients treated with a one-level posterior lumbar spine fusion and using either autograft or Healos and BMA were similar. However, it is important to point out that in the Kitchel study,33 all patients had an interbody fusion and did not achieve these high levels of fusion with just a posterolateral lumbar spinal fusion. In addition, the number of cases in each group may not be significant. A fusion rate of 84% (21/25) was achieved for the autologous bone grafts and 80% (20/25) for the bone graft substitutes. As reported by McLain et al,34 it is possible to obtain adequate mesenchymal stem cells from direct vertebral body aspiration during pedicle screw placement as compared to iliac crest aspiration.
Another in the group of extenders and enhancers is synthetic bone graft. A common example is beta tricalcium phosphate (β-TCP). There are several generic forms of the product, but the one the senior author (R.R.B.) is most familiar with carries the proprietary name Vitoss (Orthovita, Malvern, PA). Like DBM products, not all generic forms of β-TCP will perform the same, as there are proprietary differences such as porosity that can significantly affect results. The study by Fleming et al14 shows that Vitoss mixed with BMA from iliac crest results in a composite containing a significant number of osteoconductive growth factors and osteogenic precursor bone cells. Epstein35 conducted a prospective study on 40 patients undergoing posterolateral lumbar fusion with 53 levels instrumented with pedicle screws (27 single level, and 13 two level). Vitoss foam strips with bone mineral aspirate from the iliac crest or pedicle plus local bone was used in approximately a 50:50 mix. There was no control group. The results showed a successful fusion for 26 of 27 single-level fusions (with 1 pseudarthrosis) and 11 of 13 two-level fusions (with 2 pseudarthroses) as assessed by dynamic plain radiographs and computed tomography scan. However, postoperative follow-up in this series was only 12 months.
In a randomized study by Lerner et al,36 20 patients using β-TCP (Vitoss) as an extender for local bone graft were compared with 20 patients using iliac crest bone graft. There were no significant differences in the preoperative or follow-up Cobb angles or in the percent correction and maintenance of correction. Follow-up averaged 46 months in the β-TCP group and 48 months in the autograft group. The postoperative visual analog score for iliac crest site showed considerable pain in 14 of 20 patients who experienced a mean of 4.1 (range, 1–8) at discharge, which improved to 4 of 20 patients experiencing pain with a mean of 3.5 (range, 2–5) at last follow-up. No patients underwent reoperation in the iliac crest bone graft group, while 2 patients did in the β-TCP group. One case was a technical failure with only 1 pedicle screw in the lower instrumented level on 1 side, and the other was revision of a pedicle screw, unrelated to the issue being studied.
Part II: Bone Grafting in Children With Neuromuscular Deformity
There is a paucity of information regarding bone grafting in patients with neuromuscular deformity. Montgomery et al37 compared 2 groups, 18 patients having autogenous bone grafting versus 12 patients who had freeze dried allograft cancellous and cortical bone as an extender to local autogenous bone. Loss of correction was 46% and 38%, respectively. This study took place before the advent of modern fixation techniques and therefore the failure rate itself is irrelevant, but the comparison between allograft and autograft is important. In the allograft group, anesthesia time decreased from 344 to 281 minutes (P < 0.050), and intraoperative blood loss decreased from an average 2730 to 1740 mL (P < 0.250) as no iliac crest graft was harvested. While the time and amount of blood loss may seem excessive for a degenerative surgery case, it is assumed that the authors were trying to harvest a large amount of ICBG. Yazici and Asher38 reported on the use of freeze-dried allograft for patients with neuromuscular spinal deformities undergoing posterior spinal fusion. In this uncontrolled cohort of 32 patients, the pseudarthrosis rate was 3.1%. There were no deep wound infections; however, there was 1 patient with a delayed wound infection which was presumed to be unrelated to the bone grafting. The level of evidence in these articles is quite poor (level IV) but, in fact, there is no literature of quality published for bone grafting of surgeries in patients with neuromuscular disease.
While confirmed pseudarthrosis may be low in the few published articles, certainly the loss of correction and probable pseudarthrosis rate associated with the loss in correction is of concern. This has led to consideration of the use of BMP in patients with neuromuscular deformity.
BMP-2, under the proprietary name INFUSE (Medtronic Sofamor Danek, Memphis, TN), is indicated for spinal fusion procedures in skeletally mature patients with degenerative disc disease at 1 level from L2 to S1. According to the package insert, it is indicated for use in an anterior interbody cage and is contraindicated in patients with known hypersensitivity, near a resected tumor, in patients who are skeletally immature (<18 years of age), pregnant women, and in those with an active infection. Although these are the indications and contraindications that have been approved by the FDA, it is important to note that this does not necessarily dictate the surgeon's practice. If appropriately justified, the surgeon can use the BMP in other situations.
Mulconrey and Lenke et al (“Safety and efficacy of bone morphogenetic protein [rhBMP-2] in a complex pediatric spinal deformity at a minimum 2-year follow-up.” Presented at International Meeting on Advanced Spine Techniques, July 8–11, 2008, Hong Kong) reported the safety and efficacy of BMP in a series of patients treated for complex pediatric spine deformity and minimum 2-year follow-up. In this retrospective review, Dr. Lenke used BMP in 20 patients with neuromuscular scoliosis, of which 9/20 were revisions for pseudarthroses. Diagnoses included cerebral palsy, muscular dystrophy, myelomeningocele, and Conradi-Hunerman Syndrome. Of the 20, 6 were anterior spinal fusions and 14 were posterior spinal fusions. In the anterior spine fusions, the fusion rate was 100% using 6 mg/level of BMP in a total of 20 vertebral levels. In the posterior group, a total of 118 levels using 5.9 mg/level of BMP had a 94% fusion rate. There was 1 infection but no other complications. One of their conclusions was that a lesser amount of BMP is necessary to develop a posterior spinal fusion in the pediatric population compared to the reported adult concentrations of 20 mg/level.
In patients treated for adolescent idiopathic scoliosis, the authors propose that iliac crest graft may not be needed for obtaining a solid posterior spinal fusion. Local bone graft with an allograft or synthetic extender of local bone graft is recommended. DBM Matrix strips may promote an earlier spinal fusion because of the osteoinductive properties in addition to the osteoconductive properties of all the extenders. It is important to note that these are recommendations for children and cannot be extrapolated to adults. For patients with neuromuscular scoliosis, more study is needed; however, the use of BMP appears to be promising for enhancing the fusion or as a substitute for bone graft.
* Up to 31% of patients have persistent pain at 2 years postsurgery when autogenous iliac crest bone graft is harvested.
* Allograft supplementation of local autograft has been demonstrated in the literature to be as effective as autogenous iliac crest bone grafting in contributing to a successful posterior spinal fusion.
* Both demineralized bone matrix (DBM) and bone morphogenetic protein (BMP) appear to contribute to a successful posterior spinal fusion.
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Keywords:© 2010 Lippincott Williams & Wilkins, Inc.
scoliosis; adolescent idiopathic scoliosis (AIS); bone graft; bone morphogenetic protein (BMP); demineralized bone matrix (DBM)