Chapter 16 Biology of Spine Fusion
In 2001, more than 185,000 spinal arthrodeses were performed in the United States, the majority of which were posterolateral lumbar intertransverse process fusions. From 1997 to 2003, spine fusions climbed from the 41st most common inpatient procedure to the 19th, with resultant increases in spending on lumbar fusion procedures (from 75 to 482 million dollars).1,2 The number of fusion procedures continues to increase, as does the complexity of devices available for treatment of various spine disorders. Nonunion rates, however, for single-level fusions have been reported to be as great as 35% and even higher in multilevel procedures.3 Pseudarthroses often result in outcomes that are less than optimal, and often necessitate further surgery.
Local Factors
To achieve a successful fusion, multiple factors must work in concert. These include the local environment of the fusion and systemic factors, with or without the use of fusion enhancers (Box 16-1). Mechanical and biologic factors are closely linked, and any cogent discussion of the biology of spine fusion must be limited to a particular mechanical situation (e.g., compressive forces–anterior column, tensile forces–intertransverse process). This chapter focuses primarily on the biology involved with fusion in the submuscular lumbar intertransverse process environment. To cover the differences and details of all potential fusion environments in the spine is beyond the scope of this chapter. Moreover, one must be cautious in extrapolating results of healing and fusion properties for bone graft substitutes in one region of the spine for another.4 Nevertheless, some of the principles are applicable and important for anyone who has dedicated a career to the advancement of spine surgery.
Graft Properties: Osteoinduction, Osteogenicity, Osteoconduction, and Connectivity
The choice of graft material has profound implications for the success or failure of arthrodesis. The ideal graft is osteogenic, osteoinductive, and osteoconductive. A balance of these entities, with or without instrumentation, ensures a favorable environment for fusion. Osteoinduction is the stimulation of multipotential stem cells to differentiate into functioning osteogenic cells. This is mediated by growth factors in the bone matrix itself (i.e., BMPs). Urist et al. introduced this concept in their studies of the osteoinductive properties of demineralized bone matrix (DBM).5,6
Graft Material
Autograft
Autogenous iliac crest bone in the past has been considered the “gold standard” of graft material. Historically, it has been the most successful graft source in spine fusion. Cancellous autograft has the requisite matrix proteins, mineral, and collagen for the ideals of osteoinductivity, osteogenicity, and osteoconductivity. Its large trabecular surface makes it highly connective as well. Donor site complication rates as high as 25% to 30% have been reported, although a rate of 8% seems more realistic and is more commonly cited.7,8 Morbidity may be associated with an increased incidence of blood loss, chronic donor site pain, increased operative time, infection, and nerve injury. Furthermore, the quantity of bone available is limited, and may be insufficient for long-segment fusions, or in patients who have had previous graft harvests.
Demineralized Bone Matrix
Demineralized bone matrix (DBM) is present in a variety of forms, each of which has a variable degree of osteoinductivity.4 Current data support its use as a bone graft extender but not as a pure substitute or enhancer.9 Autogenous and allograft DBMs are osteoinductive due to the presence of low doses of BMPs (~0.1% by weight).10 Collagenous and noncollagenous proteins serve as osteoconductive material that is left after the demineralization process. Preliminary animal studies have shown efficacy of DBM as a carrier molecule for recombinant human bone morphogenetic protein (rhBMP-2) in ectopic bone formation or as a graft alternative in experimental posterolateral arthrodesis.11,12 A study by Louis-Ugbo et al. used a non-human primate posterolateral fusion model to test a specific formulation of DBM, which was more porous than its predecessor. With this new formulation they found robust fusions and suggested that it exhibited properties of both a graft enhancer and extender.13 A recent prospective randomized study by Cammisa et al. looked at 2-year fusion rates in the posterolateral environment in 120 human patients. They concluded that DBM could function as an adequate graft extender and promote adequate fusions when mixed with a small amount of autogenous bone graft.14
Allograft
The desire to avoid donor site morbidity led to increased use of allograft bone in spine surgery. This was made practical by advances in procurement, sterilization, preparation, and storage.15 Although allograft bone is widely used in spine surgery, concerns regarding fusion rates and disease transmission remain. Allograft is not osteogenic, because there are no surviving cells in the graft. Because of the processing and storage requirements of allograft, some of the osteoinductive potential is lost. It also carries a small but real risk of disease transmission and may elicit an immune response from the recipient.16–21
Immunogenicity and maintenance of osteoinductive and osteoconductive properties are affected by these processing and preservation techniques. Bone usually is frozen or freeze-dried as soon as possible after harvest. Both methods decrease immunogenicity and allow for extended storage. Freezing does not diminish the mechanical properties of the bone, and it may be stored at −70°C for 5 years. Freeze-drying further reduces immunogenicity and inactivates viral agents, but it reduces the mechanical strength of the graft.22–24 Freeze-dried bone may be stored under vacuum, at room temperature, for an indefinite period.
The most common sterilization methods are high-dose gamma irradiation and ethylene oxide gas sterilization.18 Both alter the structure of matrix proteins, decreasing the osteoinductive capacity and mechanical strength of the bone.23 Other sterilization methods such as autoclaving are even more destructive, and generally are not used.
Although allograft usually has performed well in both cervical and lumbar interbody fusions, in which the graft is subject to compression, the results in the posterolateral lumbar environment, in which primary tensile forces exist, have not been as favorable.25–33 This result has led many surgeons to use allograft as an autograft expander rather than a pure substitute for posterolateral arthrodeses.
Xenograft
The use of bone graft taken from other species has been reported in the orthopaedic literature, but these alternatives to autograft never were incorporated into widespread use. Despite processing, xenografts remain immunogenic and provoke a host response. The graft may become encapsulated from the host’s response, with resultant blockade to revascularization. Ivory and cow horn resist incorporation into host bone and are no longer used. Bovine bone, both freeze-dried and deproteinized, remains weakly antigenic. Both of these types of xenografts have been used in spine surgery with limited success, and therefore they are not recommended as a graft material.34–37
Ceramics
Calcium phosphate (CaPO4) ceramics, including hydroxyapatite (HA) and tricalcium phosphate (TCP), have been widely used in orthopaedic and spine surgery.38 These osteoconductive, biodegradable materials are compatible with the remodeling of bone necessary to achieve optimal strength of a construct. Other, nonresorbable materials remain in the fusion mass, leaving permanent stress risers and prolonging strength deficiencies.
To be useful as a graft material, synthetic materials must have several properties. They must be compatible with local tissues, remain chemically stable in body fluids, and be able to withstand sterilization. Furthermore, they must be available in useful shapes and sizes, be cost-effective, and have reliable quality control. CaPO4 ceramics qualify, and have been widely used in dentistry and maxillofacial surgery, as well as in animal models for experimental spinal research.21,39–47 A wide body of literature exists discussing the use of these materials in human spine surgery.38,46,48–51
Both HA and TCP ceramics are inherently brittle. They may be prepared as either a compact or a porous material. The greater crystallinity and density of the compact form results in greater strength and resistance to dissolution in vivo, whereas porous versions more closely approximate cancellous bone and enhance bony ingrowth (at the expense of more rapid degradation). Under physiologic conditions, HA is resorbed very slowly, whereas TCP generally is resorbed within 6 weeks of implantation.25
Natural coral has been used to augment or even replace autograft, with some success.52–55 The calcium carbonate (CaCO3) in coral is hydrothermally converted to CaPO4. The structural geometry of coral is similar to that of cancellous bone, making it highly osteoconductive and connective.
Animal Studies
The use of CaPO4 ceramic as a spine fusion bone graft substitute has been studied extensively in animal models. Flatley et al. used porous blocks of a 1:1 ratio of calcium HA and TCP ceramic in a rabbit posterolateral fusion model.21 At 12 weeks, histologic sections demonstrated bone ingrowth reaching the central portion of the block with no fibrous barrier between the new bone and the ceramic. Holmes et al. used coralline HA in a canine posterior facet model.46 Although the distribution of bone ingrowth was similar to that seen in autograft controls, they reported no solid fusions, even at 6 months. Using coral porites (calcium carbonate) and a 65:35 HA:TCP biphasic ceramic, Guigui et al. found a 100% rate of fusion in a sheep model, comparable to the fusion rate of autograft in another study by this same group.56,57
The use of composites of ceramic and an osteoinductive agent such as DBM, autograft, or recombinant BMP also has been investigated (see Growth Factors, later in this chapter).58–60 Ragni and Lindholm, in a rabbit interbody fusion model, found that the addition of DBM enhanced the incorporation of an HA block. Animals treated with an HA/DBM composite showed significantly earlier fusion consolidation than those treated with autograft or either HA or DBM alone. By 6 months, however, results of the autograft were comparable to those with the composite.61 Zerwekh et al. compared a collagen/HA-TCP ceramic/autograft composite with autograft alone in a canine posterior fusion model.62 Histologic comparisons of bone ingrowth were similar in both groups at 12 months, as were the results of biomechanical testing. Working in a canine segmental posterior spine fusion model, Muschler et al. compared fusions with autograft, collagen/HA-TCP ceramic composite, collagen/HA-TCP ceramic/autograft composite, and collagen/HA-TCP ceramic/bone matrix protein composite, and with no graft.63 Autograft had a significantly superior union score. Ceramic composite alone performed no better than the no-graft control. The addition of bone matrix protein, however, improved the union score, making it comparable with the composite/autograft treatment.
Human Studies
The clinical efficacy of ceramics, either alone or as part of a composite, has yet to be fully elucidated. Studies suggest that these entities do have beneficial effects. Passuti et al., in a study of 12 severely scoliotic patients, used internal fixation and blocks of 3:2 HA-TCP ceramic alone or mixed with autogenous cancellous bone.49 After 15 months average follow-up, radiographs demonstrated fusion in all patients. Histologic examination of biopsy material from two of the subjects revealed new bone formed directly on the ceramic surface and ingrowth into the macropores. Similarly, Pouliquen et al. successfully used natural coral as a graft substitute in 49 patients with idiopathic scoliosis.54 Although the results were favorable, their small patient populations, single diagnosis, and average patient age of 14 years limited these studies. Acharya et al. designed a prospective matched case study examining the effect of a hydroxyapatite–bioactive glass ceramic composite as a stand-alone graft versus autogenous bone in posterolateral spine fusion.64 The study was halted early, because at 1 year fusion was found to be inferior with the bone substitute as a stand-alone graft compared with autograft.
Mechanical Stability
Fusion rate is affected by the mechanical stability of the involved segments.65–70 As a result, internal segmental instrumented fixation has commonly been used to achieve higher rates of fusion, an approach that is supported by various studies in the literature.65–67,70–72 Even in the presence of a rigid construct, nonunion still occurs in up to 10% to 15% of patients, especially when hardware loosening or failure occurs.71–75 Fusion level, number of segments involved, patient weight and activity level, and postoperative bracing all influence the rate of fusion.76
Animal Studies: Spinal Instrumentation
The effects of spinal instrumentation and stability have been investigated in various animal models.77–81 Although this approach can tell us much about short-term effects of instrumentation failure, caution must be exercised in extrapolating this information to the long-term effects in the human body at the bone/instrumentation interface. McAfee et al. created a canine instability model to study both the effect of spinal instrumentation on fusion success and the radiographic incidence of fusion with respect to spinal stability.66–68 At 6 months, radiographs revealed a greater probability of fusion in the instrumented animals than in the noninstrumented animals. The instrumented fusions also were more rigid. Likewise, Zdeblick et al. demonstrated both an increased rate of fusion and a more rigid fusion when anterior instrumentation was used in a canine model of an unstable burst fracture at L5.70 These results also were replicated by Shirado.82 Kotani et al. showed that after solid posterolateral arthrodesis was achieved in a sheep model, transpedicular fixation continued to provide mechanical support.83
The biologic activity of the graft material may partly determine the need for internal fixation. Fuller et al. showed that rigid fixation improved bone ingrowth into a calcium carbonate block in a canine anterior thoracic interbody fusion model.84,85 Because ceramics are not osteoinductive, a mechanically stable environment is crucial for ingrowth. Osteoinductive graft substitutes, on the other hand, may not be as reliant on construct rigidity.
Nagel et al. developed a sheep model of delayed union and nonunion.69 Posterior lumbar laminar and facet fusions with iliac crest graft were performed on seven sheep. Six of the seven sheep developed nonunions at the L6-S1 interspace; all cephalad interspaces fused (21 of 21). Eight normal sheep underwent in vivo flexion-extension radiographs. Five normal sheep spines were studied ex vivo, using displacement transducers to test stiffness, displacement, and strain in flexion-extension. The lumbosacral level demonstrated significantly more motion than the other levels, suggesting that motion was a major factor in determining the success of fusion in this sheep model. Similar observations have been made in dogs.86 The increased stability and decreased motion that instrumentation provides would seem valuable in such instances.
Human Studies: Spinal Instrumentation
Contradictory human studies of the effects of spinal instrumentation have been widely reported. Zdeblick discussed 124 patients undergoing fusion for different conditions.72 Patients were randomized into three groups, all having dorsolateral autograft fusions. Patients in group 1 were not instrumented, those in group 2 were instrumented with a semirigid pedicle screw system, and individuals in group 3 had rigid pedicle screw instrumentation implanted. The rigid group had a significantly higher fusion rate (95%) than the noninstrumented group (65%). The instrumented groups together had 95% excellent or good results, whereas the noninstrumented patients had only 71% good or excellent outcomes (a statistically significant result).
Bridwell et al. described 44 patients with degenerative spondylolisthesis.71 Patients were individualized into three groups: no fusion; noninstrumented posterolateral fusion; and pedicle screw instrumented posterolateral fusion. Patients with more than 10 degrees or 3 mm of motion were automatically assigned to the instrumentation group. There was an 87% fusion rate in the instrumented group versus a 30% rate in noninstrumented patients, yet there was no significant clinical difference in successful outcomes between the noninstrumented and unfused groups (30% vs. 33%). Successful outcomes in the instrumented group (83%) were significantly greater than in the nonfusion group. Fischgrund et al. also demonstrated a markedly increased rate of fusion in their patients with instrumentation (83% vs. 45%), yet found no difference in clinical outcome.
In their meta-analysis, Mardjetko et al. reviewed 25 papers describing 889 patients with degenerative spondylolisthesis.87 Five of the included studies described patients undergoing decompression and posterolateral arthrodesis with pedicle screw instrumentation. Although there was a trend toward an increased rate of fusion in the instrumented versus noninstrumented patients (93% vs. 86%), it did not reach significance (P = .08). The clinical outcome was better in the uninstrumented group: 90% versus 86%. However, the authors acknowledged several limitations of their review: data from different treatments over 20 years; variable study designs and quality; and possible dilution of data from the stronger, better-designed studies that suggested an advantage to instrumentation.
Fusion success is also affected by the physical stresses placed on the graft.88 In human beings, 80% of the load at a motion segment is transmitted through the intervertebral disc. Graft placed ventrally, in the interbody region, is thus primarily subjected to compression. This compressive force promotes fusion, presumably by stimulating vascular ingrowth and the proliferation of mesenchymal cells. Dorsally placed graft experiences tensile forces, as does graft placed in the intertransverse process region. Under these less favorable mechanical conditions, fusion is more dependent on biologic factors.
Facet preparation for fusion has been shown to increase motion of the involved segment. Although many surgeons routinely include facet fusion in posterolateral intertransverse process arthrodeses, biomechanical studies have demonstrated a resultant decrease in stability.89,90 The developing fusion preparation decreases the surface area incorporated into the fusion mass, and may result in a less rigid fusion. Rigid instrumentation allows the facets to be prepared and incorporated without sacrificing stability. However, in the osteoporotic patient, the screw-bone interface often is weak. Even with instrumentation, facet preparation may not be appropriate in these individuals.
Overall, it is generally agreed that spinal instrumentation decreases the rate of pseudarthrosis. However, in some situations, especially with single-level fusions, no significant clinical benefit may be obtained. Additionally, although a positive relation exists between radiographic fusion and clinical outcome, no absolute convincing correlation has been demonstrated.91 Currently, prospective randomized blinded clinical trials examining the effects of instrumentation have not yet been completed.
Graft Site Preparation
Preparation of the bony anatomy into which the graft is placed is of paramount importance in achieving a successful fusion. The exposed area of viable, vascular bone should be maximized. This is done by decortication, which may be accomplished with curettes, rongeurs, osteotomes, or a power bur precision drill. Use of a high-speed bur may result in thermal necrosis, which may be minimized with continuous irrigation, use of a drill with deep flutes, and minimizing contact time between bur and bone. As the surface area of decorticated bone increases, so does the connectivity and the availability of osteogenic cells and exposed matrix proteins. Furthermore, a large surface is helpful in forming a bony bridge strong enough to carry the mechanical load.
Soft Tissue Bed
Hurley et al. evaluated the role of these factors in a canine dorsal spine fusion model.86 Thirty-seven animals underwent a modified Hibbs fusion (control), a Hibbs fusion with a fluid-permeable/cell-impermeable membrane interposed between fusion site and muscle mass, or with a membrane impermeable to both cells and fluids. Fusion was achieved in all 12 animals with the semipermeable membrane, whereas no animals with the impermeable membrane had a successful fusion.
Radiation has a detrimental effect on a healing spine fusion that is especially pronounced in the first few postoperative weeks. This effect may be caused by cytotoxicity, but is probably a product of the resultant vasculitis and inhibition of angiogenesis that follows radiation treatment. In the long term, radiation also can induce osteonecrosis and dense hypovascular scars, creating a poor fusion environment. Studies suggest that a 3- to 6-week delay in radiation would be beneficial to the fusion process.92,93 Use of vascularized grafts anastomosed to nonirradiated vessels also may increase the chance of successful fusion.
Systemic Factors
Nicotine
Smokers have a higher rate of pseudarthrosis than do nonsmokers.27,28,73,94,95 Cigarette smoke retards osteogenesis and inhibits graft revascularization. Tobacco smoke extracts calcitonin resistance, increases fracture end resorption, and interferes with osteoblastic function.8,96,97
A direct relation between systemic nicotine and spinal pseudarthrosis has been demonstrated in a rabbit model. Silcox et al. performed L5-6 posterolateral intertransverse process arthrodeses with autologous iliac crest graft in 28 rabbits.98 The animals were implanted with osmotic mini-pumps, delivering either saline (control) or nicotine equivalent to a human who smokes 1 to 1.5 packs per day. At 5 weeks, 56% of control animals had a solid fusion by manual palpation; no solid fusions were seen in the nicotine-exposed animals (P = .02).
Drugs
Drugs taken during the perioperative period can have a detrimental effect on the process of fusion. Chemotherapeutic agents administered in the early postoperative period inhibit bone formation and arthrodesis.99–101 Nonsteroidal anti-inflammatory drugs (NSAIDs) suppress the inflammatory response, and may inhibit spine fusion.102
Dimar et al. performed three-level dorsal fusions in 39 rats. Half the animals received indomethacin, 3 mg/kg/day, on 6 of 7 days, and the other animals received saline.103 Treatment was started 1 week preoperatively, and continued for 12 weeks after surgery. In the control rats, 27 of 60 levels achieved solid or moderate fusions, whereas only 4 of 42 levels were similarly fused in the indomethacin group (P < .001). Weaknesses of this study included the following: the experimental model used had not been well characterized, fusion assessment was not rigidly defined, and the indomethacin dose was significantly greater on a milligram-per-kilogram basis than that used in human beings.
Glassman et al. performed a retrospective review of 288 patients who had undergone L4-S1 instrumented, autologous iliac crest graft spine fusions.104 Ketorolac had been administered to 167 of them; the remaining 121 did not receive NSAIDs. Using surgical exploration, hardware failure, and tomograms to determine fusion, they found 4% pseudarthroses in the control group, versus 17% in the ketorolac group (P < .001). The odds ratio indicated that nonunion was approximately five times more likely in those individuals who received ketorolac. There are several problems with this retrospective study: the number of surgeons involved in the cases varied, and the patients received varying numbers of ketorolac doses, beginning at different postoperative times. Their results, however, are supported in a more controlled animal study by Martin et al., who, working in a rabbit model, compared fusion in animals receiving ketorolac or saline.105 They found 35% fusions in the ketorolac-treated animals versus 75% in the controls (P = .037).
Cyclo-oxygenase 2 (COX-2) inhibitors are specific for the isoform of the enzyme targeted by NSAIDs. Long et al. investigated the effect of orally administered celecoxib on spine fusion in the rabbit model.106 They compared rabbits receiving celecoxib, 10 mg/kg daily, with groups receiving either indomethacin, 10 mg/kg, or saline. They found a significant difference between the rate of fusion in controls versus that of the indomethacin group, while animals that received celecoxib fused at an intermediate rate. The study was limited by its small size and the use of a relatively high dose of indomethacin compared with that used in humans.
Osteoporosis
The most common metabolic bone disease in the United States, osteoporosis commonly is assumed to be a negative factor in bone healing. The decreased bone density that is the hallmark of osteoporosis makes stabilization with instrumentation difficult in this population. Additionally, there may be changes in marrow quality and bone turnover rate. Older animals have a decreased capacity for osteoinduction.107 In terms of fusion potential, a decrease in the number of osteogenic stem cells in elderly patients may be more important than absolute bone mass.
Hormones
Hormones affect bone formation both directly and indirectly and probably influence spine fusion as well. These chemical messengers have complex interactions, both positive and negative, with bone-forming and bone-absorbing cells.
Growth hormone, via somatomedins, exerts a stimulatory effect on cartilage and bone formation.108,109 In vivo experimental research has revealed that growth hormone stimulates bone healing by increasing gastrointestinal absorption of calcium, as well as by increasing bone formation and mineralization.110,111 Thyroid hormone, which acts synergistically with growth hormone, is required for somatomedin synthesis by the liver. Furthermore, thyroid hormone has a direct stimulatory effect on cartilage growth and maturation, thereby positively influencing bone healing.
Corticosteroids have been shown both experimentally and clinically to be detrimental to bone healing, increasing bone resorption and decreasing bone formation. They inhibit and promote osteoblastic differentiation and also decrease the synthesis of viable bone matrix.112–114
Estrogens and androgens play important roles in skeletal maturation, as well as in the prevention of age-associated bone loss. Their effects on bone healing, however, remain controversial. Some studies indicate they may stimulate bone formation, whereas others do not support this positive effect.115–117 Neither affects bone collagen synthesis, but estrogens may increase bone mineralization by increasing serum levels of parathyroid hormone and vitamin D3.118
Fusion Enhancers
Electrical Stimulation
Since 1974, when Dwyer et al. first demonstrated improved spine fusion rates,119 electrical stimulation has been increasingly accepted as an aid to spine fusion. Electrical stimulation theoretically alters the naturally occurring strain-generated charges present in healing bone toward those that are ideal for bone fusion.120 Since that time, various devices have gained approval from the U.S. Food and Drug Administration (FDA) for use as adjuncts to fusion: (1) direct current electrical stimulation (DCES), (2) inductive coupling devices such as pulsed electromagnetic fields (PEMFs) and combined magnetic fields (CMFs), and (3) capacitive coupling devices. These devices have been shown to have varying effectiveness.119
Electrical Devices
DCES uses an implanted generator that delivers a constant 20- to 40-microampere (μA) current to the fusion bed, for 6 to 9 months. The effective stimulation area is 5 to 8 mm from the cathode. Although the exact mechanism of action is not fully understood, several physiologic effects have been demonstrated. The current attracts charged proteins by electrophoresis, bone, cartilage, and endothelial cells by galvanotaxis, and depolarizes cell membranes. Faradaic reactions at the bone-electrode interface reduce oxygen tension and increase pH, similar to what is seen at the growth plate in healing fractures. Increased pH has been shown to increase osteoblastic bone formation and to inhibit resorption by osteoclasts.121,122
PEMFs utilize inductive coupling to generate an electromagnetic field across the fusion area via external coils that are worn from 3 to 8 hours per day for 3 to 6 months. A varying magnetic field induces an electric current, which is hypothesized to stimulate bone healing, possibly by depolarizing cell membranes and increasing calcium influx into bone cells.123–125 Regardless of the exact mechanism, PEMFs have been shown to increase the levels of BMP-2 and BMP-4 in rat calvarial cells.126,127
A less commonly usedtilized inductive coupling device is the CMF. Like the PEMF, it also is worn externally, usually for 30 minutes per day, and combines a static magnetic field with a time-variable field. Although animal data showed increased bone stiffness at the 30-minute dose, the effect was far greater with treatment given 24 hours per day.128
Capacitive coupling devices also are noninvasive and employ alternating currents, conductive gels, and electrodes. Fredricks et al.129 in a rat fusion model (previously described by Boden et al.130) showed up-regulation of various factors required for bone fusion with the use of this form of electrical stimulation.
Human Studies
Kane published the first large multicenter study of the use of DCES in dorsolateral spine fusion.131 Eighty-two patients treated with DCES were compared to a historical control population of 150 patients fused without electrical stimulation. The DCES group had a 91% fusion rate, significantly higher than the 81% in the control subjects. Of note, the DCES group had a significantly higher rate of revision surgery for pseudarthroses. The report also described a prospective, randomized control study in a “difficult to fuse” population of patients who had failed one or more previous attempts at fusion, were undergoing multilevel arthrodeses, had grade II spondylolisthesis, or had other risk factors. The 31 patients in the stimulation group had a significantly higher fusion rate of 81%, compared with 54% of the 28 patients in the control population.
Recent work has lent further support to the use of DCES in dorsolateral spine fusion. Reports indicate that DCES increases the percentage rate of fusion in dorsolateral pedicle screw–instrumented fusions.132,133 Furthermore, DCES has been shown to increase the fusion rate in smokers from 66% to 83%.133
Simmons was the first to report on the use of PEMF in spine fusion. He described treatment of pseudarthroses after posterior lumbar interbody fusion in 13 patients, 77% of whom progressed to fusion without further surgery.134 In the more demanding environment of posterior pseudarthroses, Lee reported a 67% success rate with PEMF.135 Bose followed 48 patients who received posterolateral fusion in addition to instrumentation.136 He reported fusion success of 98%; however, there was no control population in this study. Marks demonstrated twice the percentage of successful lumbar fusions in females when compared with control populations without the device.137
Linovitz et al. reported on a double-blind, randomized, placebo-controlled population of patients on the use of CMF in noninstrumented fusions.138 The study found that 64% of patients with active devices had fused by 9 months, compared with 43% of patients with placebo devices. Stratification by gender showed that the difference was significant only for the female patients in the study. The reasons for this remain unclear.
Although there seems to be support for the use of electrical stimulation in spine fusion, not all modalities are equally effective. Currently, DCES appears to have the greatest effect. Furthermore, all of these devices are expensive. Guidelines for determining which patients would best be served by their use has yet to be fully elucidated.
Growth Factors
BMPs are a group of proteins belonging to the transforming growth factor (TGF)-β family. During the more than 35 years since they were first described by Urist,5 they have been found to play important roles in both endochondral and intramembranous bone formation, as well as in fracture healing. Recently, a great deal of attention has been paid to a possible role for these proteins in spine fusion, and also to concerns over adverse events and increased costs associated with these molecules.
Animal Studies
Preclinical work on the use of BMP in posterolateral spine fusions has been reported by many researchers.139–145 Many of these early experimental studies demonstrated faster fusion rates when compared to controls. Cook et al., using osteogenic protein 1 (OP-1) in a canine facet and interlaminar fusion model, obtained solid fusions in 12 weeks, as compared with 26 weeks for autogenous graft.146 In a similar model, Muschler et al. found no difference between autograft and rhBMP-2 at 3 months, though the model was criticized for its intrinsically high fusion rate of the control arm.147
A canine intertransverse-process fusion model demonstrated solid fusion with rhBMP-2 within 3 months, whereas autologous iliac crest graft animals had not fused at that point.143 This same model was used to demonstrate that rhBMP-2 could produce solid fusions without decoration.144 Using a rabbit intertransverse process fusion model they developed, Schimandle et al. achieved 100% fusion with rhBMP-2, compared with 42% fusion in the autograft group.148 Martin et al. demonstrated that rhBMP-2 was further able to overcome the inhibitory effect of ketorolac in the model used by Schimandle and Boden.105 Grauer et al. and Patel et al. then established that OP-1 had the same effects in reference to fusion, but required higher dosages of the BMP compound.149,150
Sandhu et al. and Fishgrund et al. reported improved fusion rates with an rhBMP-2 soaked collagen sponge in a canine model for spine fusion compared to controls.140,142 Martin et al., on the other hand, failed to show improvement in posterolateral fusions in nonhuman primates when using the same concentration of rhBMP-2 as in the canine studies. They listed one potential cause of this discrepancy originating from compression of the BMP out of the sponge by the surrounding tissues. A protective shield was then placed over the absorbable collagen sponge (ACS), and they were then able to achieve successful fusions at lower concentrations.151
Several other studies also have examined the effectiveness of these agents in nonhuman primates. Boden et al. tested bBMPx in the lumbar spine of adult rhesus monkeys.152 Four of the four animals implanted with 3 mg or more of the bovine protein achieved a posterolateral intertransverse process fusion, whereas none of the six animals implanted with a lower dose fused. However, a second study demonstrated only 40% fusion with this same dose, and 54% with a 5-mg dose, although the autograft animals showed only 21% fusion.153
A more robust carrier than the collagen sponge alone may be needed to promote fusion in the posterolateral environment. Boden et al. developed a more rigid porous biphasic calcium phosphate (BCP) ceramic carrier that provided a scaffold for new bone and then resorbed over time. They were able to achieve fusion at three different concentrations of rhBMP-2/ACS.139 Additional carriers have been developed that are based on the original BCP ceramic concept with the same excellent results in the rabbit and primate models.154,155
Akamura et al. and Barnes et al. used compression resistant matrix (CRM) carriers (15% hydroxyapatite, 85% β-tricalcium phosphate ceramic collagen matrix) and noted that the carrier, collagen sponge, and concentration of rhBMP-2 are all important in promoting a solid fusion in nonhuman primates.156,157 Barnes et al. failed to achieve a solid posterolateral arthrodesis when the CRM was not used with rhBMP-2 and the collagen sponge. Like the BCP ceramic carrier in the study by Boden discussed earlier, one explanation for this observation by Barnes et al. could be that the CRM provides a better scaffold for bone growth than the ACS alone.
Human Studies
Human trials using rhBMP-7 and rhBMP-2 in posterolateral fusion have been reported, both with and without instrumentation.158–165 A safety and efficacy study of OP-1 for posterolateral spinal arthrodesis had been completed by 2001.166 Sixteen patients with degenerative spondylolisthesis, undergoing noninstrumented posterolateral fusion, were randomized to receive either autograft and OP-1 or autograft alone. At 6 months, 9 of the 12 autograft/OP-1 patients had fused, versus only 2 of 4 autograft-alone patients, although the difference was not statistically significant. Clinically, 83% of the OP-1 patients had 20% or better improvement in their Oswestry score, whereas only 50% of the autograft-alone patients had this level of success. Again, the difference was not statistically significant. Of note, OP-1 had no adverse effects.
This initial pilot study has since turned into a larger prospective series with long-term follow-up. The rhOP-1 (rhBMP-7) data for posterolateral spine fusion support increased rates of fusion in the rhBMP-7 group versus control (55% vs. 40%).162 At 4 years of follow-up, Vaccaro et al. have achieved similar fusion results with rhOP-1 when compared with iliac crest autograft in posterolateral fusions.167
Luque168 and Boden et al.159 pioneered early clinical studies of rhBMP-2 in the posterolateral fusion environment. Luque examined two patient cohorts in a prospective, randomized, open-label trial of rhBMP-2, with a biphasic calcium phosphate (BCP) carrier in patients undergoing single-level lumbar fusions for degenerative instability. The first group (seven patients) received rhBMP-2/BCP unilaterally, with autograft on the contralateral side. Eighty-six percent of the rhBMP-2 sides fused by 12 months, whereas only 57% of the autograft-treated sides fused. The second group received a higher rhBMP-2/BCP dose bilaterally, without autograft; at 12 months, 100% had fused. Oswestry scores improved by 15 or more points in 85.7% of cohort 1 patients and in 100% of cohort 2 individuals. Boden et al. performed a prospective randomized clinical pilot trial of rhBMP-2 with BCP carrier versus autograft. All 20 patients with BMP-2 and the BCP carrier had solid fusions judged by CT scans, as evaluated independently. Nine of these patients had no internal fixation. The BMP-2 patients did better than autograft patients at an average of 17 months of follow-up in terms of fusion success and clinical outcome.
Dimar et al. also demonstrated that the rhBMP-2 group had better fusion rates compared with iliac crest bone graft (83% vs. 73%, respectively) for patients receiving posterolateral instrumented fusions in a large prospective randomized study comparing rhBMP-2 with iliac crest (98 patients). Outcome measures such as the Oswestry Low Back Pain Disability Index, and leg and back pain scores, however, were similar over time.160 These trends toward improved posterolateral fusion rates and outcome scores also were reported by Dawson et al. using rhBMP-2, ACS, and a ceramic bulking agent in a multicenter prospective randomized pilot study without instrumentation.158
Bone Morphogenetic Proteins: Adverse Events
Benglis et al. have listed a number of adverse events linked to the use of BMPs, including ectopic bone formation, swelling/hematoma/dsyphagia with anterior cervical discectomy and fusion (ACDF), bony resorption/graft subsidence with lumbar interbody fusions, and painful seroma/mass effect in minimally invasive lumbar surgery.169
Ectopic Bone Formation: Animal Studies
Ectopic bone formation and its association with the use of BMP has been documented in both animal and clinical studies. The proposed mechanism is leakage of the molecule into unwanted sites from the carrier causing new both growth over the canal, inside the foramen, or the fusion of unwanted levels. This theory, however, is controversial, and many authors have failed to show any ectopic bone formation in both experimental and human studies, even in the presence of a laminectomy defect.142,151,170–172 Two studies in lower mammals (rabbits173 and mice174) examined the effects of high doses of BMPs on the exposed thecal sac. In both models, analysis revealed new bone growth and some compression on the neural elements; however, both studies failed to demonstrate any changes in behavior (e.g., motor) in the experimental animals versus the controls. Hsu et al. failed to induce ectopic bone formation in rodents when rhBMP-2 was used in high concentrations without an ACS. They raise the question of the significance of BMP elution without association of a carrier.175
Ectopic Bone Formation: Human Studies
Posterior and Transforaminal Lumbar Interbody Fusions
In the FDA-approved investigational device exemption (IDE) study examining rhBMP-2/ACS in posterior lumbar interbody fusions (PLIF), the study was stopped due to evidence on postoperative CT scans of bone encroachment into the spinal canal when compared with the control patients with autograft.176 There were, however, no clinical symptoms due to this nerve root compression. A later publication by Villavicencio et al. describes the use of rhBMP-2/ACS in transforaminal lumbar interbody fusion (TLIF) without bone encroachment into the vertebral canal.177 These authors recommend that the sponge be placed ventrally in front of the graft and away from the thecal sac to potentially avoid this complication.
Swelling, Hematoma, and Dysphagia in Anterior Cervical Discectomy and Fusion
Neck swelling, hematoma, dysphagia, and respiratory failure have been reported with the use of rhBMP-2/ACS in ACDF surgery. Five clinical reports totaling 264 patients were analyzed by Benglis et al. in their review on adverse events of BMPs.169 The studies were by no means standardized, varying in the concentrations of rhBMP-2/ACS used, types of interbody, location of the rhBMP-2, levels fused, and type of anterior construct (discectomy vs. corpectomy).178–182 The reported complication rates associated with these studies ranged from 5% to 27%, which were higher than historical controls examining complications following ACDF without the use of BMPs. These adverse events, in general, appear to be related to the use of increased dosages and the potential initiation of inflammatory cascades in the soft tissues of anterior cervical procedures. As noted in a study by Baskin et al., only very small doses of rhBMP-2 are needed per level to induce postoperative fusion (one-seventh of a small Infuse kit, Medtronic Sofamor Danek, Memphis, TN).183A large, prospective IDE study currently is underway to investigate the clinical outcomes, fusion rates, and adverse events for single-level ACDFs with rhBMP-2.
Bony Resorption and Graft Subsidence
Some in vitro studies have shown that BMPs also may exhibit some osteoclastic activity.184 This phenomenon could be a function of its interaction with certain interleukins.185 Various groups are beginning to note robust bone loss during the resorption phase of bone growth associated with the use of BMPs in interbody fusions of the lumbar spine, ranging from resultant instrumentation failure, graft loosening, and subsidence, to migration.186–190
Bone Morphogenetic Proteins and the Rising Costs of Health Care
With the rising cost of health care and current legislation targeted at reducing these costs, the pressures on surgeons to perform more “economical” surgery becomes increasingly relevant.169 Hospitals traditionally receive a particular payment for a procedure referred to as a diagnosis related group or DRG. They often do not receive additional funding to cover the cost of devices used in the spinal procedure (e.g., interbody fusion cages, BMP). Despite these upfront increases in initial costs, some groups have published literature supporting a long-term reduction in expenses when using rhBMP-2 versus iliac crest autograft in spine fusions.191–194 Nevertheless, rhBMP-2 is an expensive molecule, averaging $3600 to $5200 in 2010 for a small and large kit, respectively (personal correspondence with Medtronic/Sofamor Danek), with the hospital carrying most of the cost burden.192
A recent article published by Cahill et al. examined the increasing trends in the usage of BMPs in spine fusion surgery. They reviewed a retrospective cohort of 328,468 patients undergoing spine fusion procedures from 2002 to 2006, focusing on certain aspects such as complications, length of stay, and hospital charges. Usage within the United States has increased from 0.69% of all fusions in 2002 to 24.6% of all fusions in 2006. The main point of the article was that increases in hospital charges were noted to be between 11% and 41% (greatest increase seen for anterior cervical fusion).195
Future Directions and Emerging Technologies
Mesenchymal stem cells (MSCs) are the precursor cells to the bone-producing osteoblast. The osteoblast cell produces an extracellular matrix that ultimately becomes calcified. Research in bone marrow aspirate (BMA) fusion models has not shown clear evidence supporting its use as a stand-alone bone substitute, but it is potentially effective as a graft extender.196 Decortication is one traditional means of “recruiting” these osteoprogenitor cells to the site of a fusion. Work is ongoing in the development of techniques to increase the concentration of MSCs by either cellular retention (e.g., membranes that facilitate attachment of MSCs) or cellular expansion (e.g., in vitro culture of an aspirate) methods.197 The next step in the evolution of therapies to promote bone fusion may lie in the field of tissue engineering, where genes inserted into in vitro cultures of MSCs could be placed into a site of fusion and provide a continuous extracellular supply of proteins such as BMPs.196, 198, 199 Current work in gene therapy modulation exists only in preclinical animal experiments and has not yet been extended to human clinical studies.200
Benglis D., Wang M.Y., Levi A.D. A comprehensive review of the safety profile of bone morphogenetic protein in spine surgery. Neurosurgery. May 2008;62(5 Suppl. 2):ONS423-ONS431. discussion ONS431
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Resnick D.K., Choudhri T.F., Dailey A.T., et al. Guidelines for the performance of fusion procedures for degenerative disease of the lumbar spine. Part 12: pedicle screw fixation as an adjunct to posterolateral fusion for low-back pain. J Neurosurg Spine. 2005;2(6):700-706.
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