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The efficacy of autologous laminectomy bone combined with bone graft extenders in posterolateral lumbar instrumented fusion
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Available online at www.sciencedirect.com
www.elsevier.com/locate/semss
The efficacy of autologous laminectomy bone combined with bone graft extenders in posterolateral lumbar instrumented fusion John T. Awowale, MD, and Seth K. Williams, MDn Department of Orthopedics and Rehabilitation, University of Wisconsin School of Medicine and Public Health, Madison, WI
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Iliac crest autograft has been used successfully for many years in spinal fusion operations. The main advantages to iliac crest autograft are the easy accessibility, the robust combination of osteogenic, osteoinductive, and osteoconductive properties, and the resultant efficacy. However, autograft iliac crest bone graft has fallen out of favor in spinal fusion operations due to the morbidity associated with harvest. Various bone graft substitutes have become commercially available that provide similar fusion rates when compared to iliac crest autograft. None of the bone graft substitutes can match iliac crest bone graft in all 3 osteogenic, osteoinductive, and osteoconductive parameters, but when combined with local autologous laminectomy bone and, therefore, used as a bone graft extender, may very well come close. This article reviews the main categories of bone graft substitutes and extenders and the role of these substances when combined with local autologous laminectomy bone in posterolateral lumbar instrumented fusion operations. & 2016 Elsevier Inc. All rights reserved.
1.
Introduction
A spinal fusion may be defined as bony union between 2 spinal segments after surgical intervention. All spinal fusions involve surgical preparation of the bone surfaces at the fusion site and introduction of material to induce a bone healing response. For a spine fusion to occur, there must be osteogenic cells, an osteoconductive matrix to serve as a scaffold for new bone formation, and osteoinductive cell signaling to influence the formation of bone rather than nonosseous tissues. Iliac crest autograft bone has been used for many years in posterior lumbar spine fusions because of its combination of osteogenic, osteoconductive, and osteoinductive properties. The main drawback to iliac crest autograft harvest is the associated morbidity. The drive to avoid using iliac crest autograft comes from the morbidity associated with harvest, which can be substantial.
In response to the undesirable aspects of iliac crest harvest, over the past several decades, attempts have been made to develop bone graft substitutes. The best studied and most widely used bone graft substitutes are ceramic compounds, demineralized bone matrix (DBM), and bone morphogenetic proteins (BMP). Because these bone graft substitutes do not have the same osteogenic, osteoconductive, and osteoinductive properties as iliac crest autograft bone, they have come to be viewed more as bone graft extenders rather than complete substitutes. Surgeons have increasingly come to rely on these bone graft extenders in combination with local autograft bone from a laminectomy rather than bone from the iliac crest. This combination of local laminectomy autograft bone with a bone graft extender has been shown to have similar fusion rates when compared to autograft iliac crest bone graft (ICBG). Because there are a wide variety of bone graft extenders commercially available for clinical use, it is
n Correspondence to: Department of Orthopedics and Rehabilitation, UWHealth at The American Center, 4602 Eastpark Blvd, Madison, WI 53718. E-mail address: [email protected] (S.K. Williams).
http://dx.doi.org/10.1053/j.semss.2016.12.005 1040-7383/& 2016 Elsevier Inc. All rights reserved.
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important for the surgeon to understand the basic biological responses to the various bone graft substitute categories, and use this knowledge to choose specific bone graft extenders.
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conveys a very small risk of disease transmission, although the risk of disease transmission is close to zero.
2.2.
2. Basic characteristics of bone graft substitutes and extenders The basic science behind the various bone graft substitutes should be understood in order to choose the optimal substance for a particular clinical scenario. Osteoconductivity refers to a material's ability to provide a passive porous scaffold to support bone formation. Examples include ceramics and allograft bone and demineralized bone matrix (DBM). Osteoinductive substances include any material that is able to induce stem cell differentiation of autologous cells into chondroblastic or osteoblastic cell types. Substances in this category include bone morphogenic protein (BMP) and DBM. The final major category of bone graft substitutes are osteogenic substances that contain stem cells with osteogenic potential, which subsequently directly lay down new bone, the classic example being bone marrow aspirate (BMA). In the spine surgery field, the terms “bone graft substitute” and “bone graft extender” are often used when referring to these various materials and are sometimes used interchangeably. However, the difference between these terms should be recognized. A bone graft substitute is a substance or combination of substances that can be used independent of any autologous bone graft to produce a bony fusion. A bone graft extender is largely felt to be a substance that cannot reliably produce a fusion independently, but when added to autologous bone graft, will help induce a spinal fusion.
2.1.
Allograft bone and demineralized bone matrix
The most common human tissue-based graft materials are processed formulations of allograft bone. Allograft bone chips or croutons have been widely used. This substance is largely osteoconductive in nature. Its major disadvantages are a small risk of disease transmission, immunogenic potential, and the relative lack of osteoinductive properties. Demineralized bone matrix (DBM) is a type of processed allograft created by acid treatment of allograft bone. The acid extraction process decalcifies the allograft's mineralized component while retaining the collagenous and noncollagenous components including a small amount of growth factors, including bone morphogenetic proteins (BMPs).1 Commercially available DBM products on the market include InterGros, Optecures, DBXs, and Graftons. These products come in various forms including paste, gel, putty, powder, or moldable strips. Because of this acid processing, DBM has greater osteoinductive properties than allograft bone and is therefore the allograft preparation of choice in spine surgery. However, DBM is primarily osteoconductive and conveys a relatively weak osteoinductive effect when compared to synthetic BMP or autograft bone, which will be discussed later. Advantages with DBM include a combination of osteoconductive and osteoinductive effects. The main disadvantage is its human tissue origin, which limits the supply and
Growth factors/bone morphogenetic proteins
There are several growth factors that guide differentiation of osteoblasts. The most clinically relevant are in the transforming growth factor beta family. Within this family are multiple BMPs. Of the various identified BMPs, the only ones found to positively effect osteogenesis are BMP 2, 4, 6, 7, and 9. Furthermore, the only BMPs currently on the market are recombinant BMP-2 (Infuses) and recombinant BMP-7 (OP1s). BMPs are small proteins that serve as signaling agents for cells, thus making them osteoinductive in nature, but they have also been described as providing an indirect osteogenic effect as they stimulate migration of surrounding native stem cells. Commercially available BMPs are deployed in combination with an osteoconductive scaffold such as DBM, ceramics, or autograft bone. Studies of BMP in combination with autologous bone have shown significantly higher fusion rates as well as biomechanically stronger fusions when compared to fusions with autograft bone alone.2 There are also many studies that show a decreased operative time and decreased blood loss with BMP use versus iliac crest bone graft.3 Disadvantages of BMP include its significantly higher price compared to that of other bone graft substitutes with studies showing posterolateral lumbar fusions incurring a total cost increase on average of $4815 with BMP versus conventional iliac crest bone graft use.4
2.3.
Bone marrow aspirate
Bone marrow aspirate contains native mesenchymal stem cells that can differentiate and proliferate into osteoprogenitor cells.5 However, aspirated bone marrow injected without a stable scaffold shows considerable fluid runoff without a maintained local concentration of mesenchymal cells. To combat the effects of runoff with BMA it is combined with a scaffold typically consisting of collagen, DBM, ceramics, bioactive glass, or different combinations of the 4. The combination of one of these scaffolds with BMA may theoretically be used as a bone graft substitute, providing osteoinductive and osteogenic properties. Advantages include the autologous source and the potential to be true bone graft substitutes. Disadvantages include the small quantity of mesenchymal cells in bone marrow aspirate, which are thought to be 0.001–0.01% of the total nucleated cells in marrow. Enrichment techniques such as centrifugation of the BMA have shown promising spinal fusion results at 3 years.6,7
2.4.
Ceramics
Ceramics are synthetic substances that are purely osteoconductive. This is a category that includes a variety of compounds including different formulations of calcium phosphates and calcium sulfates. The most common chemical formulations of calcium phosphate are β-tricalcium phosphate (β-TCP) and hydroxyapatite. Commercially available preparations include Conduits and MasterGrafts, which
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are composed primarily of β-TCP, as well as ProOsteons and Healoss, which are composed primarily of hydroxyapatite. Commercially available calcium sulfates include Osteosets, BonePlasts, and Calceons. These substances are commercially sold either as an isolated ceramic or as a combination of different ceramics at various ratios. These ceramics and ceramic combinations have various binding, biodegradability, and mechanical properties. The optimal theoretical ceramic characteristic is a stable scaffold for bone formation that resorbs at a rate consistent with fusion development, allowing bone to take its place. Calcium sulfate has the fastest resorption rate and has been shown to fully or almost fully resorb by 6 weeks.8 Hydroxyapatite is a highly stable calcium phosphate that normally occurs in human bone. When used as a bone graft extender it is resorbed over several years, which can make it difficult to identify the fusion mass radiographically as it develops. β-TCP is resorbed over several months, a time frame that is thought to be ideal for bone formation.9 Current products on the market for lumbar spinal fusion are mostly combinations of β-TCP or hydroxyapatite with collagen in different ratios, examples including Vitosss and Healoss. The main advantage of ceramics over allograft bone stems from the lack of dependence on a human source, which simplifies the production process and eliminates the risk of disease transmission and immunogenicity. The primary disadvantage is the absence of any inherent osteoinductive properties.
2.5.
Bioactive glass
Bioactive glass is a group of synthetic silica-based bioactive materials that are osteoconductive in nature and act similarly to ceramics but show various rates of bioactivity and resorption rates based on their chemical composition, specifically the amount of silicone dioxide they contain. One of the commercially available Vitosss formulations is a combination of bioactive glass, collagen, and β-TCP. Compared to ceramics, bioactive glass theoretically promotes local bone turnover by its rate of chemical dissolution, ideally being replaced with native bone. Advantages of bioactive glass are a rapid interaction with surrounding soft tissues, forming a biologically active hydroxyapatite layer at its surface allowing it to rapidly incorporate with bone.10 A disadvantage of degradable bioactive glass is that some studies show they may resorb too quickly to allow for bony fusion.11
3. Autologous bone graft overview: Cortical versus cancellous The primary sources of autograft bone for spinal fusions are the iliac crest and local bone from the laminectomy that is commonly performed along with the fusion. The iliac crest is comprised mainly of cancellous bone, which is an abundant source of osteoblastic stem cells and bone progenitor cells. Due to its osteogenic, osteoconductive, and osteoinductive properties, it has been used with a reasonably high degree of success for many years in spinal fusions and as a consequence is the standard to which other bone graft materials and substitutes are compared. The main disadvantage to iliac
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crest harvest is the increased operative time and the associated morbidity, including pain, blood loss, cutaneous nerve injury, and infection, and there is a limit to the amount of bone that can be harvested.12,13 Cortical bone has fewer osteoblastic stem cells and is less biologically active than cancellous bone for several reasons. Cortical bone is much denser and has less surface area than cancellous bone, which decreases the osteoconductive potential and reduces the accessibility of osteoinductive factors because they are located deep within the osteons. Vascular ingrowth is less robust through the dense cortical bone, and remodeling takes longer compared to cancellous bone. One advantage of cortical bone over cancellous bone is the superior mechanical strength, although this is only applicable when harvested as a structural graft such as with a tricortical iliac crest autograft, and this is generally not applicable to posterolateral lumbar fusions.
4.
Autologous laminectomy bone graft
Bone collected during a laminectomy is predominantly cortical in nature. It is an obvious source of bone graft material, and rather than be discarded, is commonly used as part of a lumbar spine fusion. The main drawback other than the cortical nature of the bone is the limited quantity, which is thought to be approximately 15 cc per level to reliably lead to fusion.14 Laminectomy bone is collected during the decompression by manually collecting the bone fragments as they are removed with a rongeur or a Kerrison punch rongeur in the form of bone chips, or by collecting the shavings that result during the use of a high-speed burr. Microscopic examination of burr shavings showed no evidence of cellular damage, thus implying maintained cellular viability and osteogenic potential.15 Eder et al.16 used tissue culture methods to examine the osteogenic potential of burr shavings and laminectomy bone chips. There was no difference in cellular viability in the 2 groups, but the laminectomy bone chip group had higher osteoblast migration rates and more rapid population doubling times. Defino et al.17 determined that cell proliferation and osteoblastic phenotype development was actually greater in vertebral lamina bone than iliac crest bone. There are several clinical studies evaluating the fusion rate with the use of local autologous laminectomy bone alone. Ohtori et al. randomized patients undergoing a single-level posterior lumbar decompression and fusion to receive local bone graft alone or iliac crest autograft and compared fusion rates. There was no statistical difference, with radiographic fusion rates of 90%.18 Lee et al.19 presented a case series of 182 patients who underwent a single-level posterior lumbar fusion with local laminectomy bone alone, with a 93% fusion rate. A 98% fusion rate was reported in a case series of 92 patients undergoing posterior lumbar 1- to 4-level fusion with local autograft bone alone.20 Herkowitz presented a series of 112 consecutive cases and found higher fusion rates (75%) in patients undergoing 1- to 4-level fusions with iliac crest compared to patients undergoing fusion with local laminectomy bone alone (65%).21 In analyzing the subgroups, there was no difference in fusion rates in patients undergoing
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single-level fusions, and the authors felt this was related to the bone graft volume because many of these patients underwent multi-level laminectomies with just single-level fusions, which therefore provided more local bone graft than is possible with a single-level laminectomy.21 This basic science and clinical evidence supports the principle of using laminectomy bone as part of a posterolateral lumbar spinal fusion, and even used alone in some circumstances such as when performing a multi-level laminectomy and single-level fusion. The data are limited, however, and in practice, this reflects the more common scenario of attempting to extend the osteogenic potential of local autologous laminectomy bone by including a bone graft substitute.
5. Autologous laminectomy bone graft plus bone graft extenders Ceramic bone graft extenders with local laminectomy bone are reasonably well studied in patients undergoing posterolateral lumbar fusions. Chen et al.22 reported a 91% fusion rate with local laminectomy autograft bone combined with calcium sulfate, though there was no control group. In another study, fusion rates were statistically equal at approximately 85% when calcium sulfate beads with local autograft laminectomy bone were placed on one side of a posterolateral lumbar instrumented fusion and compared to iliac crest autograft bone placed on the contralateral side. One drawback to this study was the placement of all of the laminectomy bone on one side of the spine, which does not typically occur in practice and may have helped the fusion by increasing the amount of autologous bone present.23 Nickoli and Hsu performed a systematic review of ceramic-based bone graft extenders in lumbar spine fusions. Local autologous bone graft used in exclusive combination with ceramic extenders resulted in a fusion rate of 89.8% in 10 studies with 453 total patients. The type of ceramic product used did not appear to affect the fusion rate. Ceramics used in combination with local autograft bone demonstrated the highest fusion rates, and ceramics used with bone marrow aspirate or platelet concentrations had the lowest fusion rates.24 Alsaleh et al. performed a systematic review of osteoconductive bone graft extenders with either bone marrow aspirate or local autograft bone in posterolateral thoracolumbar spine fusions, identifying 13 studies with 768 patients that met inclusion criteria. The risk for bias was determined to be relatively high and there was generally a low methodological quality across all studies. Local autologous bone with a bone graft extender demonstrated similar fusion rates to autograft iliac crest bone graft, and performed better than bone marrow aspirate combined with a bone graft extender. In subgroup analyses the bone graft extender tricalcium phosphate, and a combination of tricalcium phosphate and hyaluronic acid, appeared to perform better than calcium phosphate. There was only one study each with bioactive glass and mineralized collagen.25 Demineralized bone matrix is not extensively studied as a bone graft extender in posterolateral lumbar spine fusions. Kang et al. performed a prospective randomized trial
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comparing DBM with local laminectomy bone to autograft ICBG in single-level lumbar instrumented fusions. Forty-one patients completed follow up, with a fusion rate of 86% in the DBM group and 92% in the ICBG group, which was not a statistically significant difference.26 Cammisa et al. performed posterolateral lumbar instrumented fusions on 120 patients, placing DBM with local autograft bone on one side of the spine and autograft ICBG on the contralateral side. Fusion occurred on the DBM side in 52% of patients and the ICBG side 54% of the time. Though this fusion rate is not particularly impressive, the DBM performed as well as the ICBG.27 Animal studies not only demonstrate robust fusion rates with DBM in most cases but also highlight the sometimesdramatic variability from one commercially available preparation to the next.28,29 Review articles identified just several other lower quality human studies that supported the use of DBM as a bone graft extender when used along with local autologous laminectomy bone.30,31 Bone morphogenetic proteins have been studied on a limited basis with local laminectomy bone in posterolateral lumbar fusions. Singh et al. performed CT scans on 50 patients who underwent a posterolateral lumbar instrumented fusion with either ICBG alone or ICBG with BMP-2 and local autologous laminectomy bone. The BMP with local autograft group had a 97% fusion rate, whereas the ICBG group without BMP had a 77% fusion rate.32 Hamilton et al.33 published a retrospective case series with an 80% fusion rate in patients undergoing noninstrumented posterolateral lumbar fusions using BMP-2 and local autograft bone. Taghavi et al.34 reported a 100% fusion rate in patients undergoing a posterolateral lumbar instrumented fusion with BMP-2 and local autograft bone, compared to a 78% fusion rate with bone marrow aspirate combined with allograft bone. Iliac crest autograft bone with local laminectomy bone was found to have superior CT-confirmed fusion rates compared to BMP-7 with local laminectomy bone in a randomized controlled trial.35 Bone morphogenetic proteins have been more extensively studied in combination with ceramics, the combination being considered a bone graft substitute. Dawson et al. performed a randomized controlled trial comparing BMP-2 combined with a tricalcium phosphate and hydroxyapatite bulking agent to autogenous iliac crest bone graft in posterolateral instrumented fusions. The fusion rate was 95% in the BMP group and 70% in the ICBG group, and the overall success rate was superior (81%) in the BMP group compared to the ICBG group (55%).36 BMP-2 with a ceramic extender demonstrated a superior fusion rate (88%) when compared to iliac crest bone graft (73%) in posterolateral lumbar instrumented fusions in a randomized controlled trial.3 Noshchenko et al. performed a systematic review and meta-analysis of perioperative and long-term clinical outcomes for BMP versus iliac crest autograft and found that BMP-2 appeared to have a lower nonunion rate compared to ICBG. Adverse perioperative events were similar between groups. In total, 50% of patients in the ICBG group were still experiencing graft site harvest pain 2 years after surgery.37 Carragee et al. performed a critical review of BMP-2 trials in spinal surgery and estimated that the incidence of adverse events was 10–50-fold underreported. In posterolateral fusions specifically, the incidence
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of adverse effects associated with BMP-2 use were equivalent to or greater than the use of iliac crest autograft, with 15–20% of patients experiencing early back and leg pain.38 The American Association of Neurological Surgeons and the Congress of Neurological Surgeons Joint Guidelines Committee evaluated bone graft extenders and substitutes in lumbar fusions, and published updated guidelines in 2014. Both DBM and calcium phosphates were independently found to be efficacious as bone graft extenders when combined with local laminectomy bone. BMP-2 was efficacious as a bone graft substitute when combined with calcium phosphates and as a bone graft extender when combined with local laminectomy bone.39
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Conclusion
Autograft iliac crest bone graft has been used successfully for many years in posterolateral lumbar instrumented fusion surgery. Over the past decade, there has been a trend toward using local laminectomy bone along with a bone graft extender rather than ICBG. This is mainly to minimize the morbidity associated with ICBG harvest rather than an attempt to improve the fusion rate. Local autologous laminectomy bone has been shown to have osteogenic potential and is an effective adjunct in inducing spinal fusion, but in most cases it is not available in sufficient quantity to be used alone. Three main classes of bone graft extenders have been shown to be effective when used along with local autologous laminectomy bone, which are DBM, ceramics, and BMP. However, there are limitations to the conclusions that can be drawn from the available studies, especially with demineralized bone matrix products. The studies have not been able to establish a particular ceramic or DBM product that is superior to the others, nor have they established particular circumstances when one should be used instead of the other. BMP-2 is an effective bone graft extender and appears to be superior to BMP-7, but there has been recent focus on the adverse effects of BMP, which were likely underreported in the most commonly cited studies. Other classes of bone graft extenders such as bioactive glass and bone marrow aspirate, are not well enough studied to draw conclusions about their efficacy. BMP with ceramics, and bone marrow aspirate with ceramics, show the greatest potential as a true bone graft substitute, though there are not enough data to justify their routine use for posterolateral lumbar fusions. Local laminectomy bone is usually available during posterolateral lumbar fusion surgeries, thus producing a need for a bone graft extender rather than a bone graft substitute, and BMP, DBM, and ceramics are all reasonable considerations under these circumstances. It is up to the surgeon to choose an osteoinductive, osteoconductive, or combination bone graft extender for each individual patient depending on the clinical circumstances.
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20. Hirunyachote P, Adulkasem W. Posterolateral fusion with autogenous laminospinous process bone graft. J Med Assoc Thai. 2002;85:1105–1112. 21. Sengupta DK, Truumees E, Patel CK, et al. Outcome of local bone versus autogenous iliac crest bone graft in the instrumented posterolateral fusion of the lumbar spine. Spine (Phila Pa 1976). 2006;31:985–991. 22. Chen CL, Liu CL, Sun SS, Han PY, Lee CS, Lo WH. Posterolateral lumbar spinal fusion with autogenous bone chips from laminectomy extended with OsteoSet. J Chin Med Assoc. 2006;69:581–584. 23. Chen WJ, Tsai TT, Chen LH, et al. The fusion rate of calcium sulfate with local autograft bone compared with autologous iliac bone graft for instrumented short-segment spinal fusion. Spine (Phila Pa 1976). 2005;30:2293–2297. 24. Nickoli MS, Hsu WK. Ceramic-based bone grafts as a bone grafts extender for lumbar spine arthrodesis: a systematic review. Global Spine J. 2014;4:211–216. 25. Alsaleh KA, Tougas CA, Roffey DM, Wai EK. Osteoconductive bone graft extenders in posterolateral thoracolumbar spinal fusion: a systematic review. Spine (Phila Pa 1976). 2012;37: E993–E1000. 26. Kang J, An H, Hilibrand A, Yoon ST, Kavanagh E, Boden S. Grafton and local bone have comparable outcomes to iliac crest bone in instrumented single-level lumbar fusions. Spine (Phila Pa 1976). 2012;37:1083–1091. 27. Cammisa FP Jr., Lowery G, Garfin SR, et al. Two-year fusion rate equivalency between Grafton DBM gel and autograft in posterolateral spine fusion: a prospective controlled trial employing a side-by-side comparison in the same patient. Spine (Phila Pa 1976). 2004;29:660–666. 28. Wang JC, Alanay A, Mark D, et al. A comparison of commercially available demineralized bone matrix for spinal fusion. Eur Spine J. 2007;16:1233–1240. 29. Peterson B, Whang PG, Iglesias R, Wang JC, Lieberman JR. Osteoinductivity of commercially available demineralized bone matrix. Preparations in a spine fusion model. J Bone Joint Surg Am. 2004;86-A:2243–2250. 30. Coseo NM, Saldua N, Harrop J. Current use of biologic graft extenders for spinal fusion. J Neurosurg Sci. 2012;56:203–207. 31. Fischer CR, Cassilly R, Cantor W, Edusei E, Hammouri Q, Errico T. A systematic review of comparative studies on bone
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graft alternatives for common spine fusion procedures. Eur Spine J. 2013;22:1423–1435. Singh K, Smucker JD, Gill S, Boden SD. Use of recombinant human bone morphogenetic protein-2 as an adjunct in posterolateral lumbar spine fusion: a prospective CT-scan analysis at one and two years. J Spinal Disord Tech. 2006;19:416–423. Hamilton DK, Jones-Quaidoo SM, Sansur C, Shaffrey CI, Oskouian R, Jane JA Sr.. Outcomes of bone morphogenetic protein-2 in mature adults: posterolateral non-instrumentassisted lumbar decompression and fusion. Surg Neurol. 2008;69:457–461 [discussion 461-452]. Taghavi CE, Lee KB, Keorochana G, Tzeng ST, Yoo JH, Wang JC. Bone morphogenetic protein-2 and bone marrow aspirate with allograft as alternatives to autograft in instrumented revision posterolateral lumbar spinal fusion: a minimum two-year follow-up study. Spine (Phila Pa 1976). 2010;35:1144–1150. Delawi D, Jacobs W, van Susante JL, et al. OP-1 compared with iliac crest autograft in instrumented posterolateral fusion: a randomized, multicenter non-inferiority trial. J Bone Joint Surg Am. 2016;98:441–448. Dawson E, Bae HW, Burkus JK, Stambough JL, Glassman SD. Recombinant human bone morphogenetic protein-2 on an absorbable collagen sponge with an osteoconductive bulking agent in posterolateral arthrodesis with instrumentation. A prospective randomized trial. J Bone Joint Surg Am. 2009;91:1604–1613. Noshchenko A, Hoffecker L, Lindley EM, Burger EL, Cain CM, Patel VV. Perioperative and long-term clinical outcomes for bone morphogenetic protein versus iliac crest bone graft for lumbar fusion in degenerative disk disease: systematic review with meta-analysis. J Spinal Disord Tech. 2014;27:117–135. Carragee EJ, Hurwitz EL, Weiner BK. A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned. Spine J. 2011;11:471–491. Kaiser MG, Groff MW, Watters WC 3rd, et al. Guideline update for the performance of fusion procedures for degenerative disease of the lumbar spine. Part 16: bone graft extenders and substitutes as an adjunct for lumbar fusion. J Neurosurg Spine. 2014;21:106–132.
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Available online at www.sciencedirect.com
www.elsevier.com/locate/semss
The efficacy of autologous laminectomy bone combined with bone graft extenders in posterolateral lumbar instrumented fusion John T. Awowale, MD, and Seth K. Williams, MDn Department of Orthopedics and Rehabilitation, University of Wisconsin School of Medicine and Public Health, Madison, WI
abstra ct
Iliac crest autograft has been used successfully for many years in spinal fusion operations. The main advantages to iliac crest autograft are the easy accessibility, the robust combination of osteogenic, osteoinductive, and osteoconductive properties, and the resultant efficacy. However, autograft iliac crest bone graft has fallen out of favor in spinal fusion operations due to the morbidity associated with harvest. Various bone graft substitutes have become commercially available that provide similar fusion rates when compared to iliac crest autograft. None of the bone graft substitutes can match iliac crest bone graft in all 3 osteogenic, osteoinductive, and osteoconductive parameters, but when combined with local autologous laminectomy bone and, therefore, used as a bone graft extender, may very well come close. This article reviews the main categories of bone graft substitutes and extenders and the role of these substances when combined with local autologous laminectomy bone in posterolateral lumbar instrumented fusion operations. & 2016 Elsevier Inc. All rights reserved.
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Introduction
A spinal fusion may be defined as bony union between 2 spinal segments after surgical intervention. All spinal fusions involve surgical preparation of the bone surfaces at the fusion site and introduction of material to induce a bone healing response. For a spine fusion to occur, there must be osteogenic cells, an osteoconductive matrix to serve as a scaffold for new bone formation, and osteoinductive cell signaling to influence the formation of bone rather than nonosseous tissues. Iliac crest autograft bone has been used for many years in posterior lumbar spine fusions because of its combination of osteogenic, osteoconductive, and osteoinductive properties. The main drawback to iliac crest autograft harvest is the associated morbidity. The drive to avoid using iliac crest autograft comes from the morbidity associated with harvest, which can be substantial.
In response to the undesirable aspects of iliac crest harvest, over the past several decades, attempts have been made to develop bone graft substitutes. The best studied and most widely used bone graft substitutes are ceramic compounds, demineralized bone matrix (DBM), and bone morphogenetic proteins (BMP). Because these bone graft substitutes do not have the same osteogenic, osteoconductive, and osteoinductive properties as iliac crest autograft bone, they have come to be viewed more as bone graft extenders rather than complete substitutes. Surgeons have increasingly come to rely on these bone graft extenders in combination with local autograft bone from a laminectomy rather than bone from the iliac crest. This combination of local laminectomy autograft bone with a bone graft extender has been shown to have similar fusion rates when compared to autograft iliac crest bone graft (ICBG). Because there are a wide variety of bone graft extenders commercially available for clinical use, it is
n Correspondence to: Department of Orthopedics and Rehabilitation, UWHealth at The American Center, 4602 Eastpark Blvd, Madison, WI 53718. E-mail address: [email protected] (S.K. Williams).
http://dx.doi.org/10.1053/j.semss.2016.12.005 1040-7383/& 2016 Elsevier Inc. All rights reserved.
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important for the surgeon to understand the basic biological responses to the various bone graft substitute categories, and use this knowledge to choose specific bone graft extenders.
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conveys a very small risk of disease transmission, although the risk of disease transmission is close to zero.
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2. Basic characteristics of bone graft substitutes and extenders The basic science behind the various bone graft substitutes should be understood in order to choose the optimal substance for a particular clinical scenario. Osteoconductivity refers to a material's ability to provide a passive porous scaffold to support bone formation. Examples include ceramics and allograft bone and demineralized bone matrix (DBM). Osteoinductive substances include any material that is able to induce stem cell differentiation of autologous cells into chondroblastic or osteoblastic cell types. Substances in this category include bone morphogenic protein (BMP) and DBM. The final major category of bone graft substitutes are osteogenic substances that contain stem cells with osteogenic potential, which subsequently directly lay down new bone, the classic example being bone marrow aspirate (BMA). In the spine surgery field, the terms “bone graft substitute” and “bone graft extender” are often used when referring to these various materials and are sometimes used interchangeably. However, the difference between these terms should be recognized. A bone graft substitute is a substance or combination of substances that can be used independent of any autologous bone graft to produce a bony fusion. A bone graft extender is largely felt to be a substance that cannot reliably produce a fusion independently, but when added to autologous bone graft, will help induce a spinal fusion.
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Allograft bone and demineralized bone matrix
The most common human tissue-based graft materials are processed formulations of allograft bone. Allograft bone chips or croutons have been widely used. This substance is largely osteoconductive in nature. Its major disadvantages are a small risk of disease transmission, immunogenic potential, and the relative lack of osteoinductive properties. Demineralized bone matrix (DBM) is a type of processed allograft created by acid treatment of allograft bone. The acid extraction process decalcifies the allograft's mineralized component while retaining the collagenous and noncollagenous components including a small amount of growth factors, including bone morphogenetic proteins (BMPs).1 Commercially available DBM products on the market include InterGros, Optecures, DBXs, and Graftons. These products come in various forms including paste, gel, putty, powder, or moldable strips. Because of this acid processing, DBM has greater osteoinductive properties than allograft bone and is therefore the allograft preparation of choice in spine surgery. However, DBM is primarily osteoconductive and conveys a relatively weak osteoinductive effect when compared to synthetic BMP or autograft bone, which will be discussed later. Advantages with DBM include a combination of osteoconductive and osteoinductive effects. The main disadvantage is its human tissue origin, which limits the supply and
Growth factors/bone morphogenetic proteins
There are several growth factors that guide differentiation of osteoblasts. The most clinically relevant are in the transforming growth factor beta family. Within this family are multiple BMPs. Of the various identified BMPs, the only ones found to positively effect osteogenesis are BMP 2, 4, 6, 7, and 9. Furthermore, the only BMPs currently on the market are recombinant BMP-2 (Infuses) and recombinant BMP-7 (OP1s). BMPs are small proteins that serve as signaling agents for cells, thus making them osteoinductive in nature, but they have also been described as providing an indirect osteogenic effect as they stimulate migration of surrounding native stem cells. Commercially available BMPs are deployed in combination with an osteoconductive scaffold such as DBM, ceramics, or autograft bone. Studies of BMP in combination with autologous bone have shown significantly higher fusion rates as well as biomechanically stronger fusions when compared to fusions with autograft bone alone.2 There are also many studies that show a decreased operative time and decreased blood loss with BMP use versus iliac crest bone graft.3 Disadvantages of BMP include its significantly higher price compared to that of other bone graft substitutes with studies showing posterolateral lumbar fusions incurring a total cost increase on average of $4815 with BMP versus conventional iliac crest bone graft use.4
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Bone marrow aspirate
Bone marrow aspirate contains native mesenchymal stem cells that can differentiate and proliferate into osteoprogenitor cells.5 However, aspirated bone marrow injected without a stable scaffold shows considerable fluid runoff without a maintained local concentration of mesenchymal cells. To combat the effects of runoff with BMA it is combined with a scaffold typically consisting of collagen, DBM, ceramics, bioactive glass, or different combinations of the 4. The combination of one of these scaffolds with BMA may theoretically be used as a bone graft substitute, providing osteoinductive and osteogenic properties. Advantages include the autologous source and the potential to be true bone graft substitutes. Disadvantages include the small quantity of mesenchymal cells in bone marrow aspirate, which are thought to be 0.001–0.01% of the total nucleated cells in marrow. Enrichment techniques such as centrifugation of the BMA have shown promising spinal fusion results at 3 years.6,7
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Ceramics
Ceramics are synthetic substances that are purely osteoconductive. This is a category that includes a variety of compounds including different formulations of calcium phosphates and calcium sulfates. The most common chemical formulations of calcium phosphate are β-tricalcium phosphate (β-TCP) and hydroxyapatite. Commercially available preparations include Conduits and MasterGrafts, which
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are composed primarily of β-TCP, as well as ProOsteons and Healoss, which are composed primarily of hydroxyapatite. Commercially available calcium sulfates include Osteosets, BonePlasts, and Calceons. These substances are commercially sold either as an isolated ceramic or as a combination of different ceramics at various ratios. These ceramics and ceramic combinations have various binding, biodegradability, and mechanical properties. The optimal theoretical ceramic characteristic is a stable scaffold for bone formation that resorbs at a rate consistent with fusion development, allowing bone to take its place. Calcium sulfate has the fastest resorption rate and has been shown to fully or almost fully resorb by 6 weeks.8 Hydroxyapatite is a highly stable calcium phosphate that normally occurs in human bone. When used as a bone graft extender it is resorbed over several years, which can make it difficult to identify the fusion mass radiographically as it develops. β-TCP is resorbed over several months, a time frame that is thought to be ideal for bone formation.9 Current products on the market for lumbar spinal fusion are mostly combinations of β-TCP or hydroxyapatite with collagen in different ratios, examples including Vitosss and Healoss. The main advantage of ceramics over allograft bone stems from the lack of dependence on a human source, which simplifies the production process and eliminates the risk of disease transmission and immunogenicity. The primary disadvantage is the absence of any inherent osteoinductive properties.
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Bioactive glass
Bioactive glass is a group of synthetic silica-based bioactive materials that are osteoconductive in nature and act similarly to ceramics but show various rates of bioactivity and resorption rates based on their chemical composition, specifically the amount of silicone dioxide they contain. One of the commercially available Vitosss formulations is a combination of bioactive glass, collagen, and β-TCP. Compared to ceramics, bioactive glass theoretically promotes local bone turnover by its rate of chemical dissolution, ideally being replaced with native bone. Advantages of bioactive glass are a rapid interaction with surrounding soft tissues, forming a biologically active hydroxyapatite layer at its surface allowing it to rapidly incorporate with bone.10 A disadvantage of degradable bioactive glass is that some studies show they may resorb too quickly to allow for bony fusion.11
3. Autologous bone graft overview: Cortical versus cancellous The primary sources of autograft bone for spinal fusions are the iliac crest and local bone from the laminectomy that is commonly performed along with the fusion. The iliac crest is comprised mainly of cancellous bone, which is an abundant source of osteoblastic stem cells and bone progenitor cells. Due to its osteogenic, osteoconductive, and osteoinductive properties, it has been used with a reasonably high degree of success for many years in spinal fusions and as a consequence is the standard to which other bone graft materials and substitutes are compared. The main disadvantage to iliac
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crest harvest is the increased operative time and the associated morbidity, including pain, blood loss, cutaneous nerve injury, and infection, and there is a limit to the amount of bone that can be harvested.12,13 Cortical bone has fewer osteoblastic stem cells and is less biologically active than cancellous bone for several reasons. Cortical bone is much denser and has less surface area than cancellous bone, which decreases the osteoconductive potential and reduces the accessibility of osteoinductive factors because they are located deep within the osteons. Vascular ingrowth is less robust through the dense cortical bone, and remodeling takes longer compared to cancellous bone. One advantage of cortical bone over cancellous bone is the superior mechanical strength, although this is only applicable when harvested as a structural graft such as with a tricortical iliac crest autograft, and this is generally not applicable to posterolateral lumbar fusions.
4.
Autologous laminectomy bone graft
Bone collected during a laminectomy is predominantly cortical in nature. It is an obvious source of bone graft material, and rather than be discarded, is commonly used as part of a lumbar spine fusion. The main drawback other than the cortical nature of the bone is the limited quantity, which is thought to be approximately 15 cc per level to reliably lead to fusion.14 Laminectomy bone is collected during the decompression by manually collecting the bone fragments as they are removed with a rongeur or a Kerrison punch rongeur in the form of bone chips, or by collecting the shavings that result during the use of a high-speed burr. Microscopic examination of burr shavings showed no evidence of cellular damage, thus implying maintained cellular viability and osteogenic potential.15 Eder et al.16 used tissue culture methods to examine the osteogenic potential of burr shavings and laminectomy bone chips. There was no difference in cellular viability in the 2 groups, but the laminectomy bone chip group had higher osteoblast migration rates and more rapid population doubling times. Defino et al.17 determined that cell proliferation and osteoblastic phenotype development was actually greater in vertebral lamina bone than iliac crest bone. There are several clinical studies evaluating the fusion rate with the use of local autologous laminectomy bone alone. Ohtori et al. randomized patients undergoing a single-level posterior lumbar decompression and fusion to receive local bone graft alone or iliac crest autograft and compared fusion rates. There was no statistical difference, with radiographic fusion rates of 90%.18 Lee et al.19 presented a case series of 182 patients who underwent a single-level posterior lumbar fusion with local laminectomy bone alone, with a 93% fusion rate. A 98% fusion rate was reported in a case series of 92 patients undergoing posterior lumbar 1- to 4-level fusion with local autograft bone alone.20 Herkowitz presented a series of 112 consecutive cases and found higher fusion rates (75%) in patients undergoing 1- to 4-level fusions with iliac crest compared to patients undergoing fusion with local laminectomy bone alone (65%).21 In analyzing the subgroups, there was no difference in fusion rates in patients undergoing
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single-level fusions, and the authors felt this was related to the bone graft volume because many of these patients underwent multi-level laminectomies with just single-level fusions, which therefore provided more local bone graft than is possible with a single-level laminectomy.21 This basic science and clinical evidence supports the principle of using laminectomy bone as part of a posterolateral lumbar spinal fusion, and even used alone in some circumstances such as when performing a multi-level laminectomy and single-level fusion. The data are limited, however, and in practice, this reflects the more common scenario of attempting to extend the osteogenic potential of local autologous laminectomy bone by including a bone graft substitute.
5. Autologous laminectomy bone graft plus bone graft extenders Ceramic bone graft extenders with local laminectomy bone are reasonably well studied in patients undergoing posterolateral lumbar fusions. Chen et al.22 reported a 91% fusion rate with local laminectomy autograft bone combined with calcium sulfate, though there was no control group. In another study, fusion rates were statistically equal at approximately 85% when calcium sulfate beads with local autograft laminectomy bone were placed on one side of a posterolateral lumbar instrumented fusion and compared to iliac crest autograft bone placed on the contralateral side. One drawback to this study was the placement of all of the laminectomy bone on one side of the spine, which does not typically occur in practice and may have helped the fusion by increasing the amount of autologous bone present.23 Nickoli and Hsu performed a systematic review of ceramic-based bone graft extenders in lumbar spine fusions. Local autologous bone graft used in exclusive combination with ceramic extenders resulted in a fusion rate of 89.8% in 10 studies with 453 total patients. The type of ceramic product used did not appear to affect the fusion rate. Ceramics used in combination with local autograft bone demonstrated the highest fusion rates, and ceramics used with bone marrow aspirate or platelet concentrations had the lowest fusion rates.24 Alsaleh et al. performed a systematic review of osteoconductive bone graft extenders with either bone marrow aspirate or local autograft bone in posterolateral thoracolumbar spine fusions, identifying 13 studies with 768 patients that met inclusion criteria. The risk for bias was determined to be relatively high and there was generally a low methodological quality across all studies. Local autologous bone with a bone graft extender demonstrated similar fusion rates to autograft iliac crest bone graft, and performed better than bone marrow aspirate combined with a bone graft extender. In subgroup analyses the bone graft extender tricalcium phosphate, and a combination of tricalcium phosphate and hyaluronic acid, appeared to perform better than calcium phosphate. There was only one study each with bioactive glass and mineralized collagen.25 Demineralized bone matrix is not extensively studied as a bone graft extender in posterolateral lumbar spine fusions. Kang et al. performed a prospective randomized trial
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comparing DBM with local laminectomy bone to autograft ICBG in single-level lumbar instrumented fusions. Forty-one patients completed follow up, with a fusion rate of 86% in the DBM group and 92% in the ICBG group, which was not a statistically significant difference.26 Cammisa et al. performed posterolateral lumbar instrumented fusions on 120 patients, placing DBM with local autograft bone on one side of the spine and autograft ICBG on the contralateral side. Fusion occurred on the DBM side in 52% of patients and the ICBG side 54% of the time. Though this fusion rate is not particularly impressive, the DBM performed as well as the ICBG.27 Animal studies not only demonstrate robust fusion rates with DBM in most cases but also highlight the sometimesdramatic variability from one commercially available preparation to the next.28,29 Review articles identified just several other lower quality human studies that supported the use of DBM as a bone graft extender when used along with local autologous laminectomy bone.30,31 Bone morphogenetic proteins have been studied on a limited basis with local laminectomy bone in posterolateral lumbar fusions. Singh et al. performed CT scans on 50 patients who underwent a posterolateral lumbar instrumented fusion with either ICBG alone or ICBG with BMP-2 and local autologous laminectomy bone. The BMP with local autograft group had a 97% fusion rate, whereas the ICBG group without BMP had a 77% fusion rate.32 Hamilton et al.33 published a retrospective case series with an 80% fusion rate in patients undergoing noninstrumented posterolateral lumbar fusions using BMP-2 and local autograft bone. Taghavi et al.34 reported a 100% fusion rate in patients undergoing a posterolateral lumbar instrumented fusion with BMP-2 and local autograft bone, compared to a 78% fusion rate with bone marrow aspirate combined with allograft bone. Iliac crest autograft bone with local laminectomy bone was found to have superior CT-confirmed fusion rates compared to BMP-7 with local laminectomy bone in a randomized controlled trial.35 Bone morphogenetic proteins have been more extensively studied in combination with ceramics, the combination being considered a bone graft substitute. Dawson et al. performed a randomized controlled trial comparing BMP-2 combined with a tricalcium phosphate and hydroxyapatite bulking agent to autogenous iliac crest bone graft in posterolateral instrumented fusions. The fusion rate was 95% in the BMP group and 70% in the ICBG group, and the overall success rate was superior (81%) in the BMP group compared to the ICBG group (55%).36 BMP-2 with a ceramic extender demonstrated a superior fusion rate (88%) when compared to iliac crest bone graft (73%) in posterolateral lumbar instrumented fusions in a randomized controlled trial.3 Noshchenko et al. performed a systematic review and meta-analysis of perioperative and long-term clinical outcomes for BMP versus iliac crest autograft and found that BMP-2 appeared to have a lower nonunion rate compared to ICBG. Adverse perioperative events were similar between groups. In total, 50% of patients in the ICBG group were still experiencing graft site harvest pain 2 years after surgery.37 Carragee et al. performed a critical review of BMP-2 trials in spinal surgery and estimated that the incidence of adverse events was 10–50-fold underreported. In posterolateral fusions specifically, the incidence
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of adverse effects associated with BMP-2 use were equivalent to or greater than the use of iliac crest autograft, with 15–20% of patients experiencing early back and leg pain.38 The American Association of Neurological Surgeons and the Congress of Neurological Surgeons Joint Guidelines Committee evaluated bone graft extenders and substitutes in lumbar fusions, and published updated guidelines in 2014. Both DBM and calcium phosphates were independently found to be efficacious as bone graft extenders when combined with local laminectomy bone. BMP-2 was efficacious as a bone graft substitute when combined with calcium phosphates and as a bone graft extender when combined with local laminectomy bone.39
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Conclusion
Autograft iliac crest bone graft has been used successfully for many years in posterolateral lumbar instrumented fusion surgery. Over the past decade, there has been a trend toward using local laminectomy bone along with a bone graft extender rather than ICBG. This is mainly to minimize the morbidity associated with ICBG harvest rather than an attempt to improve the fusion rate. Local autologous laminectomy bone has been shown to have osteogenic potential and is an effective adjunct in inducing spinal fusion, but in most cases it is not available in sufficient quantity to be used alone. Three main classes of bone graft extenders have been shown to be effective when used along with local autologous laminectomy bone, which are DBM, ceramics, and BMP. However, there are limitations to the conclusions that can be drawn from the available studies, especially with demineralized bone matrix products. The studies have not been able to establish a particular ceramic or DBM product that is superior to the others, nor have they established particular circumstances when one should be used instead of the other. BMP-2 is an effective bone graft extender and appears to be superior to BMP-7, but there has been recent focus on the adverse effects of BMP, which were likely underreported in the most commonly cited studies. Other classes of bone graft extenders such as bioactive glass and bone marrow aspirate, are not well enough studied to draw conclusions about their efficacy. BMP with ceramics, and bone marrow aspirate with ceramics, show the greatest potential as a true bone graft substitute, though there are not enough data to justify their routine use for posterolateral lumbar fusions. Local laminectomy bone is usually available during posterolateral lumbar fusion surgeries, thus producing a need for a bone graft extender rather than a bone graft substitute, and BMP, DBM, and ceramics are all reasonable considerations under these circumstances. It is up to the surgeon to choose an osteoinductive, osteoconductive, or combination bone graft extender for each individual patient depending on the clinical circumstances.
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20. Hirunyachote P, Adulkasem W. Posterolateral fusion with autogenous laminospinous process bone graft. J Med Assoc Thai. 2002;85:1105–1112. 21. Sengupta DK, Truumees E, Patel CK, et al. Outcome of local bone versus autogenous iliac crest bone graft in the instrumented posterolateral fusion of the lumbar spine. Spine (Phila Pa 1976). 2006;31:985–991. 22. Chen CL, Liu CL, Sun SS, Han PY, Lee CS, Lo WH. Posterolateral lumbar spinal fusion with autogenous bone chips from laminectomy extended with OsteoSet. J Chin Med Assoc. 2006;69:581–584. 23. Chen WJ, Tsai TT, Chen LH, et al. The fusion rate of calcium sulfate with local autograft bone compared with autologous iliac bone graft for instrumented short-segment spinal fusion. Spine (Phila Pa 1976). 2005;30:2293–2297. 24. Nickoli MS, Hsu WK. Ceramic-based bone grafts as a bone grafts extender for lumbar spine arthrodesis: a systematic review. Global Spine J. 2014;4:211–216. 25. Alsaleh KA, Tougas CA, Roffey DM, Wai EK. Osteoconductive bone graft extenders in posterolateral thoracolumbar spinal fusion: a systematic review. Spine (Phila Pa 1976). 2012;37: E993–E1000. 26. Kang J, An H, Hilibrand A, Yoon ST, Kavanagh E, Boden S. Grafton and local bone have comparable outcomes to iliac crest bone in instrumented single-level lumbar fusions. Spine (Phila Pa 1976). 2012;37:1083–1091. 27. Cammisa FP Jr., Lowery G, Garfin SR, et al. Two-year fusion rate equivalency between Grafton DBM gel and autograft in posterolateral spine fusion: a prospective controlled trial employing a side-by-side comparison in the same patient. Spine (Phila Pa 1976). 2004;29:660–666. 28. Wang JC, Alanay A, Mark D, et al. A comparison of commercially available demineralized bone matrix for spinal fusion. Eur Spine J. 2007;16:1233–1240. 29. Peterson B, Whang PG, Iglesias R, Wang JC, Lieberman JR. Osteoinductivity of commercially available demineralized bone matrix. Preparations in a spine fusion model. J Bone Joint Surg Am. 2004;86-A:2243–2250. 30. Coseo NM, Saldua N, Harrop J. Current use of biologic graft extenders for spinal fusion. J Neurosurg Sci. 2012;56:203–207. 31. Fischer CR, Cassilly R, Cantor W, Edusei E, Hammouri Q, Errico T. A systematic review of comparative studies on bone
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