Posterolateral lumbar spine fusion with INFUSE bone graft.

BACKGROUND CONTEXT: INFUSE has been proven effective in conjunction with threaded cages and bone dowels for single-level anterior lumbar interbody fusion (ALIF). The published experience with posterolateral fusion, although encouraging, utilizes a significantly higher dose and concentration of recombinant human bone morphogenic protein-2 (rhBMP-2) and a different carrier than the commercially available INFUSE. PURPOSE: To present an assessment of fusion rate for posterolateral spine fusion with INFUSE Bone Graft. STUDY DESIGN/SETTING: Retrospective review of patients treated using INFUSE in posterolateral spine fusion in a single institution. PATIENT SAMPLE: 91 patients with minimum 2-year follow-up who underwent posterolateral spine fusion using INFUSE as an iliac crest bone graft (ICBG) substitute. OUTCOME MEASURES: Fusion rate based on fine-cut computed tomographic (CT) scans with sagittal and coronal reconstructions. METHODS: Fusion was performed using one large INFUSE kit (12 mg rhBMP-2, 1.5 mg/mL), which was prepared according to the manufacturer's instructions. The INFUSE sponge was wrapped around the local bone or graft extender and placed over the decorticated surfaces in the lateral gutters. Postoperative CT scans with reconstructions were reviewed by two independent orthopedic spine surgeons. CT scans of a comparison group of 35 patients who underwent primary single-level posterolateral fusion with ICBG were also reviewed. RESULTS: The overall group had a mean 4.38 CT fusion grade and a 6.6% nonunion rate. Primary one-level fusion cases (n=48) had a mean 4.42 fusion grade a 4.2% nonunion rate. Primary multilevel fusions (n=27) had a mean 4.65 CT grade and no nonunions detected. Assessment of the 35 primary one-level ICBG control cases demonstrated a mean CT grade of 4.35 and a nonunion rate of 11.4%. In the 16 cases of revision for prior nonunion, mean CT grade was 3.81 and 4 subjects had nonunions. Additional subgroup analysis showed that smokers (n=14) had a mean 4.32 CT grade with no nonunions. Men had a mean 4.04 CT grade and an 11.1% nonunion rate compared with a mean 4.61 CT grade and 3.6% nonunion rate in women. This difference was statistically significant (p=.036). No significant differences in fusion rate were observed based upon the specific graft extender used (p=.200). CONCLUSIONS: Posterolateral spine fusion involves a more difficult healing environment with a limited surface for healing, a gap between transverse processes and the milieu of distractive forces. Historically, only ICBG has been able to overcome these challenges and reliably generate a successful posterolateral lumbar spine fusion. In contrast to prior studies, clinically available INFUSE delivers only 12 mg rhBMP-2 at a concentration of 1.5 mg/mL. Despite the lower dose and concentration of rhBMP-2, this study suggests that fusion success with INFUSE is equivalent to ICBG for posterolateral spine fusion. As with ICBG, development of solid fusion or nonunion is a multifactorial process. The use of INFUSE is not a substitute for proper surgical technique or optimization of patient-related risk factors. Additional studies are needed to determine the incremental benefit of a greater rhBMP-2 dose or use of alternative carriers for posterolateral fusion. Finally, correlation between radiographic findings and clinical outcomes, and a cost-benefit analysis are needed. Despite these issues, this study presents compelling evidence that commercially available INFUSE is an effective ICBG substitute for one- and two-level posterolateral instrumented spine fusion.     

The perioperative cost of Infuse bone graft in posterolateral lumbar spine fusion.

BACKGROUND CONTEXT: There is mounting evidence supporting the efficacy of bone morphogenetic protein (BMP) for both anterior interbody and posterolateral lumbar fusion. However, the relative cost of BMP remains an important concern for physicians, hospitals, and payers. PURPOSE: The purpose of this study is to report on the perioperative costs for patients treated with rhBMP-2 as compared with an iliac crest bone graft (ICBG) supplemented with graft extenders. STUDY DESIGN/SETTING: A prospective randomized controlled trial of rhBMP-2/ACS (Infuse Bone Graft; Medtronic Sofamor Danek, Memphis, TN) versus ICBG+/-graft extender for lumbar spine fusion in patients over 60 years old. PATIENT SAMPLE: One hundred two patients over 60 years old who required a posterolateral lumbar spine fusion randomized between receiving rhBMP-2/ACS or ICBG. OUTCOME MEASURES: All health-care costs over the first 3 months after surgery. METHODS: As part of a prospective randomized trial of rhBMP-2/ACS versus ICBG+/-graft extender for lumbar spine fusion, all costs over the first 3 months after surgery were directly recorded by a dedicated coder funded by Norton Healthcare, Louisville, KY. A dedicated research nurse also followed all patients throughout their hospital stay and posthospitalization recovery to identify any adverse events or additional outpatient medical care. RESULTS: Fifty patients received rhBMP-2/ACS and 52 underwent ICBG harvest. The mean hospital cost for the index admission was $24,736 for the rhBMP-2/ACS group and $21,138 for the ICBG group. Mean inpatient physician costs were $5,082 in the rhBMP-2/ACS group and $5,316 in the ICBG group. Costs associated with posthospital rehabilitation averaged $4,906 in the rhBMP-2/ACS group versus $6,820 in the ICBG group. Total payer expenditure for the 3-month perioperative period averaged $33,860 in the rhBMP-2/ACS group and $37,227 in the ICBG group. CONCLUSIONS: The hospital carries the cost burden associated with the utilization of rhBMP-2/ACS. In contrast, the payer in a Diagnosis-Related Group (DRG) model achieves a net savings, based primarily on the decreased payment for inpatient rehabilitation, but also on decreased hospital reimbursement, physician costs, and other outpatient services.     

rhBMP-6 stimulated osteoprogenitor cells enhance posterolateral spinal fusion in the New Zealand white rabbit.

BACKGROUND CONTEXT: The nonunion rate after posterolateral spinal fusion can be as high as 35%. This has stimulated interest in the development of techniques for enhancing new bone formation, including the addition of bioactive peptides or the use of cell-based therapies, including genetically modified cells. In previous studies we have demonstrated that exposing autologous, marrow-derived osteoprogenitor cells to a recombinant human bone morphogenetic protein-6 (rhBMP-6) containing extracellular matrix induces osteoblastic differentiation, and that these cells are capable of increasing new bone formation. Growth of autologous cells on a synthetic rhBMP-6 containing matrix yields a population of stimulated osteoprogenitor cells, without the expense of adding large amounts of rhBMP-6 directly, or the risks inherent in the use of genetically altered cells. PURPOSE: This study was performed to evaluate the potential of rhBMP-6 stimulated osteoprogenitor cells (stOPC) to enhance the rate and strength of posterolateral spinal fusion. STUDY DESIGN: Prospective in vivo animal study OUTCOME MEASURES: Radiographic evidence of spinal fusion, biomechanical testing of explanted spines, histological analysis of new bone formation METHODS: Single-level posterolateral spinal arthrodeses were performed in 69 New Zealand white rabbits. Autologous marrow stem cells were concentrated and then plated on an rhBMP-6-rich extracellular matrix synthesized by genetically engineered mouse C3H10T1/2 cells. Animals in Groups I (n=18) and II (n=18) received autografts of 30M and 60M rhBMP-6 stOPCs in guanidine extracted demineralized bone matrix (gDBM), respectively, whereas those in Group III (n=13) received iliac crest bone graft (ICBG). Those in Group IV (n=10) received gDBM, and those in Group V (n=10) underwent decortication only. Assessment of fusion was made with serial radiographs, manual palpation of the explanted spines, and biomechanical testing. The fusion masses from two animals each in Groups I, II, and IV were evaluated histologically. RESULTS: Fifty-three animals were available for analysis at the conclusion of the study. In these animals, the arthrodesis rate was significantly higher after treatment with rhBMP-6 stOPCs (77% for both Groups I and II by palpation) than ICBG, gDBM, or decortication alone (Group III=55%, IV=20% and V=0%, respectively). Similarly, the peak loads to failure of the fusion masses in Groups I and II (212.5+/-37.8 N and 234.6+/-45.7 N) were significantly greater than the corresponding values in the other groups (Group III=155.9+/-36.4N, Group IV=132.7+/-59.9N, and Group V=92.8+/-18.4N), though when only the fused specimens in Groups I, II, and III were compared, only Group II was significantly different than Group III (234.6+/-45.7N and 155.9+/-36.4N, respectively). The fusion masses in the rhBMP-6 stOPC-treated animals were typified by a thin, fusiform cortical shell, newly formed trabecular bone emanating from the decorticated transverse processes, and residual unremodeled gDBM carrier particles. The fusion masses in the gDBM treated bones were morphologically similar, though they contained less newly formed bone. CONCLUSIONS: The use of rhBMP-6 stOPCs in a carrier of gDBM significantly enhanced the rate and strength of single-level posterolateral spinal arthrodeses in the New Zealand white rabbit, compared with ICBG, gDBM, and decortication alone. Our results confirm that the stimulation of marrow-derived osteoprogenitor cells by growing them on a rhBMP-6 containing extracellular matrix is feasible. Further investigation is warranted to determine the relative contribution of rhBMP-6 stimulation and the number of cells implanted, as well as strategies for optimizing the technique for clinical application.     

rhBMP-2 enhancement of posterolateral spinal fusion in a rabbit model in the presence of concurrently administered doxorubicin.

BACKGROUND CONTEXT: Spinal fusions can be necessary in patients undergoing chemotherapy with doxorubicin. In a previous study, doxorubicin was shown to decrease spinal fusion rates in a rabbit model of lumbar intertransverse process spinal fusion with autograft iliac crest bone. In the current study, we determine whether spinal fusion with recombinant human bone morphogenetic protein-2 (rhBMP-2) can overcome the inhibitory effect of doxorubicin in spinal fusion. PURPOSE: To determine if rhBMP-2 can overcome the inhibitory effects of doxorubicin (adriamycin) in an animal model of posterolateral spinal fusion. STUDY DESIGN/SETTING: Prospective, controlled, rabbit model of posterolateral lumbar fusion. OUTCOME MEASURES: Spine fusion was assessed by manual palpation (by observers blinded to the treatment group) at the level of arthrodesis. Fusion was graded according to a five-tiered classification (0-4). Posteroanterior radiographs of the excised spines were also graded in a blinded fashion using a six-point scoring system (0-5) devised to describe the amount of bone observed between the L5-L6 transverse processes. METHODS: Thirty-two New Zealand White rabbits underwent posterolateral fusion at L5-L6 with either autograft (iliac crest autograft bone) or rhBMP-2 (rhBMP-2/absorbable collagen sponge (0.86 mg/level). All animals received a dose of doxorubicin (2.5 mg/kg) known to inhibit spine fusion via the central vein of the ear immediately postoperatively. Five weeks postoperatively the rabbits were euthanized. Spine fusion was assessed by manual palpation, and graft quality was assessed with posteroanterior radiographs. RESULTS: Four of the 16 spines (25%) in the autograft group and 16 of the 16 spines (100%) in the rhBMP-2 group fused in the presence of doxorubicin administration (p<.05). There was significantly increased bone formation in the rhBMP-2 group (p<.05). One unilateral, subclinical wound infection was observed in each group at the time of euthanization (autograft [n=1, 6%] and rhBMP-2 [n=1, 6%]). CONCLUSIONS: We confirm that when autograft is used, doxorubicin decreases spinal fusion rate (25%) compared with historical controls (60-75%). More importantly, using rhBMP-2 overcomes the inhibitory effect of doxorubicin, resulting in 100% fusion in our animal model. This study suggests that rhBMP-2 has the potential to improve fusion rates in human patients undergoing chemotherapy with doxorubicin.     

Posterolateral lumbar intertransverse process spine arthrodesis with recombinant human bone morphogenetic protein 2/hydroxyapatite-tricalcium phosphate after laminectomy in the nonhuman primate.

STUDY DESIGN: A nonhuman primate lumbar intertransverse process arthrodesis model was used to evaluate recombinant human bone morphogenetic protein 2 (rhBMP-2) in a hydroxyapatite-tricalcium phosphate (HA-TCP) carrier as a complete bone graft substitute. OBJECTIVES: To assess the ability of a ceramic material to serve as a carrier for various doses of rhBMP-2 as a bone graft substitute in a primate model of posterolateral intertransverse process spinal fusion after laminectomy. SUMMARY OF BACKGROUND DATA: The reported non-union rates for posterolateral lumbar spine fusion with autogenous iliac crest bone range from 5-35%. Recombinant human bone morphogenetic protein 2 has shown potential to serve as a bone graft substitute for posterolateral intertransverse process spine fusion. Although a resorbable collagen sponge was a suitable carrier in rabbits and dogs, it was too compressible for the paraspinal muscles in rhesus monkeys. This failure of the collagen carrier has prompted evaluation of the feasibility of an alternative carrier material and the required dose of rhBMP-2. METHODS: Twenty-one adult rhesus monkeys underwent a laminectomy at L4-L5 followed by bilateral intertransverse process arthrodesis via the same midline incision (n = 16) or a minimally invasive video-assisted posterolateral approach (n = 5). Bone graft implants on each side consisted of either 5 cm3 of autogenous iliac crest bone or 60:40 HA-TCP blocks (1.2 x 0.5 x 3.7 cm) loaded with a solution containing 0, 6, 9, or 12 mg of rhBMP-2 per side. The monkeys were killed 24 weeks after surgery. Inspection, manual palpation, radiography, and histology were used to assess fusion and to detect any bony growth into the laminectomy defect. RESULTS: Fusion was not achieved in any of the monkeys treated with autogenous iliac crest bone graft. Both of the monkeys treated with the HA-TCP blocks with 0 mg rhBMP-2 achieved fusion. All 15 monkeys treated with the HA-TCP blocks and either of the three doses of rhBMP-2 achieved solid fusion. Two animals had extension of the fusion on one side because of malpositioned ceramic block. The results in animals fused via the minimally invasive video-assisted technique were the same as inthose fused with the open technique. Histologic analysis showed some ingrowth of bone into the ends but not-through the ceramic block in the absence of rhBMP-2. When the ceramic blocks were loaded with rhBMP-2 there was a dose-dependent increase in the amount and quality of bone throughout the ceramic carrier based on qualitative assessment. No significant bone encroachment on the exposed thecal sac through the laminectomy defect was observed in any of the monkeys. CONCLUSION: Hydroxyapatite-tricalcium phosphate proved to be a suitable carrier for rhBMP-2 in the posterolateral spine fusion model in rhesus monkeys. Even in the presence of a laminectomy defect, there was no evidence of bone induction outside the confines of the ceramic carrier.     

Bone union rate with recombinant human bone morphogenic protein-2 versus autologous iliac bone in PEEK cages for anterior lumbar interbody fusion

Purpose

Autologous iliac crest bone graft (ICBG) is the gold standard material for spinal fusion. Bone graft substitutes, such as recombinant human bone morphogenic protein 2 (rhBMP-2) have been developed to promote spinal fusion and address morbidity issues related to ICBG harvesting. The objective of this study was to compare bone fusion rates after anterior lumbar interbody fusion (ALIF) between ICBG and rhBMP-2 by examining thin-cut computed tomography (CT) images at the one year follow-up.

Methods

Fifty one patients (62 levels) who underwent single- or two-level ALIF via the video-assisted minimally invasive anterior approach in our institution were assessed. Radiolucent cages were inserted in all cases. Each cage has a middle beam delimiting two chambers. Grafting was performed as follows: one chamber was filled with autologous ICBG, and the other chamber was filled with 6 mg of rhBMP-2. Thin-cut CT-scan multiplanar reconstruction analyses were performed to assess the rate and quality of bone fusion at one year of follow-up.

Results

Fusion was observed in 55 levels (88.7 %), with significant differences in fusion rates with rhBMP-2 and ICBG (71 % vs. 88.7 %) (P=0.001). Osteogenesis in the rhBMP-2 chamber had a centripetal pattern in all cases, leaving a central void in 97.7 % of cases representing 38.3 % of the surface of its chamber (range 0–80.3 %). In ICBG chambers, graft resorption was present in 44.4 %, representing 9.8 % of the chamber surface (range 0–52.2 %).

Conclusion

RhBMP-2 was inferior to ICBG in terms of rate and quality of bone fusion in one- or two-level ALIF.     

Single-level instrumented posterolateral fusion of the lumbar spine with a local bone graft versus an iliac crest bone graft: a prospective, randomized study with a 2-year follow-up

The iliac crest bone grafting (ICBG) technique for lumbar posterolateral fusion surgery is widely used; however, donor site problems such as pain and sensory disturbance have been reported. Local bone is available for fusion surgery, but its reliability as a graft has not been fully reported. In the current study, we examined single-level instrumented posterolateral fusion with a local bone graft versus an ICBG in a prospective randomized study. Eighty-two patients diagnosed with L4 degenerated spondylolisthesis were divided into two groups at random. Forty-two patients underwent instrumented posterolateral fusion with a local bone graft (L4–L5 level), and 40 patients underwent instrumented posterolateral fusion with an ICBG (L4–L5 level). Rate and duration of bone union, visual analog scale (VAS) score, Japanese orthopedic association score (JOAS), Oswestry Disability Index (ODI), and complications were evaluated before and 2 years after therapy. VAS score, JOAS, and ODI were not significantly different between the two groups before and after surgery (P > 0.05). Rate and average duration of bone union were 90% and 8.5 months in the local bone graft group, and 85% and 7.7 months in the ICBG group, but without significant difference (P > 0.05). Prolonged surgical time and complications such as donor site pain (8 patients) and sensory disturbance (6 patients) were observed in the ICBG group. If single-level posterolateral fusion was performed, local bone graft technique has the same bone union rate compared with ICBG, requires less surgical time, and has fewer complications.     

The use of rhBMP-2 in interbody fusion cages. Definitive evidence of osteoinduction in humans: a preliminary report

STUDY DESIGN: A prospective randomized controlled human clinical pilot trial. OBJECTIVES: To determine the feasibility of using rhBMP-2/collagen as a substitute for autogenous bone graft inside interbody fusion cages to achieve arthrodesis in humans. SUMMARY OF BACKGROUND DATA: Preclinical studies have shown rhBMP-2 to be an effective substitute for autogenous bone graft, but there are no studies to date documenting such efficacy for human spine fusion. METHODS: Fourteen patients with single-level lumbar degenerative disc disease refractory to nonoperative management were randomized to receive lumbar interbody arthrodesis with a tapered cylindrical threaded fusion cage filled with rhBMP-2/collagen sponge or autogenous iliac crest bone. Patients were evaluated with radiographs, sagittally reformatted computed tomography scans, and Short Form-36 and Oswestry outcome questionnaires. RESULTS: All 11 patients who received rhBMP-2 were judged by three independent radiologists to have solid fusions (at 6, 12, and 24 months postimplantation), whereas only 2 of the 3 control patients, who received the standard treatment of autogenous iliac crest bone, were deemed to be fused. The Oswestry Disability Questionnaire scores of the rhBMP-2 group improved sooner (after 3 months) than those of the autograft group, with both groups demonstrating similar improvement at 6 months. Short Form 36 scores continued to improve up to 24 months. CONCLUSION: The arthrodesis was found to occur more reliably in patients treated with rhBMP-2-filled fusion cages than in controls treated with autogenous bone graft, although the sample size was limited. There were no adverse events related to the rhBMP-2 treatment. This study is one of the first to show consistent and unequivocal osteoinduction by a recombinant growth factor in-humans.     

重组人骨形态发生蛋白-2/异体骨复合骨用于兔腰椎融合的显微CT研究

目的 观察重组人骨形态发生蛋白-2/异体骨复合骨、自体骨与异体骨分别用于兔腰椎融合后,不同时间点融合骨组织微结构的变化.方法 成年雄性新西兰大白兔45只,随机分为3组,每组15只.在每只兔的L5、L6横突间行腰椎后路植骨融合术,各组分别植入复合骨条,自体髂骨条以及单纯异体髂骨条,每组于术后第3、4、5周各处死5只大白兔,分离保存融合节段标本.用显微cT扫描后行骨组织定量分析.结果 术后3个时间点中,复合骨组和自体骨组新生骨小梁的强度和形态均要优于异体骨组且差异有统计学意义(P＜0.05).第3周,复合骨组的组织骨密度(TMD)为(433.98±2.64)mg/cm3,高于自体骨组(424.81±4.69)mg/cm3(P＜0.05);第4周,复合骨组的骨小梁厚度(Tb.Th)为(0.097±0.004)mm,高于自体骨组(0.082±0.003)mm(P＜0.01);第5周,复合组的组织矿含量(TMC)为(7.70±0.30)mg,高于自体骨组(7.00±0.24)mg(P＜0.01).结论 在兔腰椎后路横突间植骨融合中,重组人骨形态发生蛋-2/异体骨复合骨的成骨效应不低于自体骨,优于异体骨.     

Posterolateral intertransverse process spinal arthrodesis with rhBMP-2 in a nonhuman primate: important lessons learned regarding dose, carrier, and safety.

Recombinant osteoinductive proteins have been used successfully in canine and rabbit models of posterolateral intertransverse process arthrodesis, but little is known about the ability of these compounds to achieve fusion in nonhuman primates. The goals of this investigation were to compare different combinations of recombinant human bone morphogenetic protein-2 (rhBMP-2) dosages and carriers in a nonhuman primate model of posterolateral intertransverse process spinal fusion and to determine the feasibility of using rhBMP-2 in the presence of exposed dura in a laminectomy model. Posterolateral intertransverse process arthrodeses were performed at L4-5 in 29 rhesus monkeys. The most striking findings were as follows: rhBMP-2 could induce bone in a nonhuman primate spine; the presence of a laminectomy defect with exposed dura did not preclude the safe use of rhBMP-2 for posterolateral fusion; soft tissue compression of the collagen sponge carrier prevented bone induction at standard BMP doses, presumably due to squeezing of the protein out of the sponge; and longer rhBMP-2 loading time into the collagen carrier and mechanical protection from the soft tissue compression both allowed more bone induction at a lower dose of rhBMP-2.     

Posterolateral lumbar fusion using Escherichia coli–derived rhBMP-2/hydroxyapatite in the mini pig

Background contextHydroxyapatite (HA) is used as a bone graft extender for posterolateral spinal fusion in human. It is also useful as a recombinant human bone morphogenetic protein (rhBMP)-2 carrier because of its high affinity for rhBMP-2.PurposeTo assess the osteoinductivity of Escherichia coli–derived rhBMP-2 (E-BMP-2) using HA granules as a carrier and to evaluate the bone-forming ability depending on the different dosages of E-BMP-2.Study designA mini-pig lumbar posterolateral fusion model using microcomputed tomography (μCT) scanning.Patient sampleThirty-one adult male mini pigs were randomized into a single control group (n=8) without E-BMP-2 and two experimental groups with two different doses of E-BMP-2 (1 mg per side, n=8 and 3 mg per side, n=15).Outcome measuresOutcome was measured by plain radiography, manual palpation, CT, three-dimensional μCT, and histologic examinations.MethodsBilateral intertransverse process arthrodesis was performed, and E-BMP-2 (0, 1.0, 3.0 mg per side) was implanted into the intertransverse space using HA granules as a carrier.ResultsThree mini pigs were removed because of death. Among 28 experimental subjects, 19 animals achieved solid bony union. The fusion rates were 37.5% for control group, 71.4% for 1 mg group, and 84.6% for 3 mg group. Fusion rates were significantly different among groups (p=.031). However, there was no statistically significant difference in fusion rates between 1 and 3 mg groups (p=.587). Thirty-eight intertransverse fusion masses of 19 subjects underwent μCT scanning. The bone volumes determined by μCT were 12,603±3,240 mm³ for control group, 18,718±3,000 mm³ for 1 mg group, and 26,768±7,256 mm³ for 3 mg group, and the difference between groups was statistically significant (p<.001).ConclusionsThis study shows that E-BMP-2 has osteoinductive activity in dose-dependent fashion, and porous HA granule is suitable for E-BMP-2 carrier in a porcine posterolateral fusion model. These preliminary findings suggest that E-BMP-2–adsorbed porous HA granules could be a novel effective bone graft substitute.     

Osseointegration of autograft versus osteogenic protein-1 in posterolateral spinal arthrodesis: emphasis on the comparative mechanisms of bone induction.

BACKGROUND CONTEXT: Recent studies have documented increased fusion success afforded by bone morphogenetic proteins versus autogenous graft for posterolateral spinal arthrodesis. PURPOSE: The current study was designed to investigate the time-course maturation processes of lumbar posterolateral arthrodeses performed with Osteogenic Protein-1 (Stryker Biotech, Inc., Hopkinton, MA, USA) (rhOP-1) versus "gold standard" autograft. STUDY DESIGN: The primary focus of this study was to compare the histologic mechanisms of posterolateral osseointegration produced by "hot topic" growth factors. METHODS: A total of 36 coonhounds were equally divided into one of four postoperative time periods of 4, 8, 12 and 24 weeks (nine animals per period). Posterolateral arthrodesis treatments included 1) autograft alone, 2) autograft plus rhOP-1, or 3) rhOP-1 alone. The treatments and animals were divided such that a value of n=6 was obtained for each treatment group per time period and no one animal received the same treatment at both operative sites. Functional spinal unit (FSU) fusion status was assessed using radiographic analysis, biomechanical testing and undecalcified histopathologic and histomorphometric analyses. RESULTS: Radiographic differences in fusion maturation between the treatment groups were evident as early as the 4-week time interval and continued through the 24-week time period. The Osteogenic Protein-1 treatments demonstrated an accelerated rate of radiographic fusion by 4 weeks, which plateaued after the 8-week time period (22% autograft, 88% autograft/rhOP-1 and 66% rhOP-1). In contradistinction, the so-called "gold standard" autograft alone treatments reached a maximum of 50% fusion by the 6-month interval. Biomechanical testing of the FSUs indicated lower flexion-extension and axial rotation range of motion levels for both rhOP-1 treatments versus autograft alone at the 8- and 12-week time periods, respectively (p<.05). Histomorphometric analysis yielded no difference in the posterolateral trabecular bone area (mm(2)) between the three treatments (p>.05), and histopathology indicated no significant histopathologic changes. The most distinctive finding in this study deals with the mechanisms of posterolateral ossification. Based on plain and polarized light microscopy, bone induction and development for the rhOP-1 treatments, with and without autograft, was the result of intramembranous ossification, whereas the process of osseointegration for autograft alone was endochondral bone formation. By the 24-week interval, no discernable differences in trabecular histomorphology were evident based on the different mechanisms of ossification. CONCLUSIONS: This serves as the first study to document the mechanisms of bone induction and fusion maturation between posterolateral arthrodeses treated with autograft versus rhOP-1. The histological data served to corroborate the radiographic and biomechanical findings, because the rhOP-1 treatments consistently demonstrated increased fusion rates and lower range of motion levels compared with the autograft group, particularly at the 8-week postoperative time period. The improvements in these fusion criteria for Osteogenic Protein-1 versus autograft were considered secondary to the differing mechanisms of bone induction. When implanted for posterolateral arthrodesis, rhOP-1 induces an intramembranous healing response, obviating the need for the cartilage intermediate phases found in endochondral bone development. The mechanism of increased speed and incidence of fusion using growth factors (rhOP-1) is delineated by this comprehensive study of preferential intramembranous ossification.     

Experimental spinal fusion with use of recombinant human bone morphogenetic protein 2.

STUDY DESIGN: Posterolateral lumbar spinal fusion with use of recombinant human bone morphogenetic protein 2 (rhBMP-2) was tested in rabbits by implanting composites of rhBMP-2 and collagen carrier. OBJECTIVES: To examine the bone-formation-inducing activity of rhBMP-2 and find the optimal amount of rhBMP to add to a collagen carrier to constitute bone-formation-inducing implants to be substituted for bone graft in posterolateral spinal fusion in rabbits. SUMMARY OF BACKGROUND DATA: In animal models, rhBMP-2--impregnated collagen has been successfully used for posterolateral spinal fusion, indicating that it is a potential substitute for the autogenous corticocancellous bone graft currently used most routinely in posterolateral lumbar spinal fusion. METHODS: Nine rabbits were divided into three equal groups. The bilateral L4-L5 transverse processes were exposed, and collagen strips impregnated with rhBMP-2 (10, 50, or 200 micrograms) were placed on the left transverse processes, and collagen strips alone were inserted on the right. All rabbits were killed 24 weeks after surgery. The implanted sites were assessed for new bone formation and bony fusion by radiography and histologic examination. RESULTS: New bone formation was noted in intertransverse spaces on the left side of all rabbits except one (10 micrograms rhBMP-2). Twelve weeks after implantation, no new bone formation was seen on the right side of all animals. The newly formed bone masses were significantly larger in the 50-microgram and 200-microgram rhBMP-2 groups than in the 10-microgram rhBMP-2 group (P < 0.01), but there was no significant difference between bone formation in the 50-microgram and 200-microgram groups (P = 0.647). CONCLUSIONS: The rhBMP-2/collagen composite implant was an effective bone graft substitute for achieving posterolateral spinal fusion. When combined with a collagen carrier, the optimal rhBMP-2 dose for achieving posterolateral spinal fusion seemed to be approximately 50 micrograms per segment in rabbits.     

Evaluation of a new formulation of demineralized bone matrix putty in a rabbit posterolateral spinal fusion model

Background contextAlternatives to autologous bone graft (ABG) with osteoconductive, osteoinductive, and osteogenic potential continue to prove elusive. Demineralized bone matrix (DBM) however, with its osteoconductive and osteoinductive potential remains a viable option to ABG in posterolateral spine fusion.PurposeTo compare the efficacy of a new formulation of DBM putty with that of ABG in a rabbit posterolateral spinal fusion model.Study designEfficacy of a new formulation of DBM was studied in an experimental animal posterolateral spinal fusion model.MethodsTwenty-four male New Zealand White rabbits underwent bilateral posterolateral spine arthrodesis of the L5–L6 intertransverse processes, using either ABG (control group, n=12) or DBM (DBM made from rabbit bone) putty (test group, n=12). The animals were killed 12 weeks after surgery and the lumbar spines were excised. Fusion success was evaluated by manual palpation, high resolution X-rays, microcomputed tomography imaging, biomechanical four-point bending tests, and histology.ResultsTwo animals were lost because of anesthetic related issues. Manual palpation to assess fusion success in the explanted lumbar spines showed no statistical significant difference in successful fusion in 81.8% (9/11) of DBM group and 72.7% (8/11) of ABG group (p=.99). Reliability of these assessments was measured between three independent observers and found near perfect agreement (intraclass correlation cofficient: 0.92 and 0.94, respectively). Fusion using high resolution X-rays was solid in 10 of the DBM group and 9 of the ABG group (p=.59). Biomechanical testing showed no significant difference in stiffness between the control and test groups on flexion, extension, and left lateral and right lateral bends, with p values accounting for .79, .42, .75, and .52, respectively. The bone volume/total volume was greater than 85% in the DBM treated fusion masses. Histologic evaluation revealed endochondral ossification in both groups, but the fusion masses were more mature in the DBM group.ConclusionsThe DBM putty achieved comparable fusion rates to ABG in the rabbit posterolateral spinal fusion model.     

Recombinant human bone morphogenetic protein-2 versus autogenous iliac crest bone graft for lumbar fusion: a meta-analysis of ten randomized controlled trials

Background

Recombinant human bone morphogenetic protein-2 (rhBMP-2) as a substitute for iliac crest bone graft (ICBG) has been increasingly widely used in lumbar fusion. It has been proven non-inferior in fusion success and clinical outcomes when compared with ICBG. However, increasingly, some potentially uncommon and serious complications associated with the use of rhBMP-2 have been of great concern to surgeons. The purpose of this study was to determine whether rhBMP-2 could be considered an effective and, more importantly, a relatively safe substitute for ICBG in lumbar fusion.

Methods

Randomized controlled trials that compared rhBMP-2 with ICBG for lumbar fusion were identified by computer and manual searching. The risk of bias and clinical relevance of the included studies were assessed. Publication bias was explored using funnel plot and statistical tests (Egger??s test and Begg??s test). Meta-analyses were performed using the Cochrane systematic review methods.

Results

Ten randomized controlled trials (1,342 patients) met the inclusion criteria. Compared with ICBG, the use of rhBMP-2 significantly decreased the risk of fusion failure at all time intervals (6?months: p?<?0.0001, RR?=?0.55, 95?% CI?=?0.42?C0.72; 12?months: p?=?0.0003, RR?=?0.53, 95?% CI?=?0.37?C0.75; 24?months: p?<?0.00001, RR?=?0.31, 95?% CI?=?0.21?C0.46) and the rate of reoperation (p?=?0.0001, RR?=?0.52, 95?% CI?=?0.37?C0.72). There was no statistical difference in clinical improvement on the Oswestry Disability Index, although a favorable trend in the rhBMP-2 group was found (p?=?0.12, RR?=?0.73, 95?% CI?=?0.49?C1.08). Subgroup analyses stratified by the type of surgical procedure yielded similar results. Owing to the different data formats, meta-analysis on adverse events was not performed.

Conclusion

RhBMP-2 was superior to the ICBG for achieving fusion success and avoiding reoperation. However, evidence from the Food and Drug Administration document and subsequent independent studies has demonstrated that original, industry-sponsored trials underestimated rhBMP-2-related adverse events. There are still security risks in the use of rhBMP-2.     

Adjuncts in posterior lumbar spine fusion: comparison of complications and efficacy

Purpose

The purpose of this study was to define the efficacy of recombinant human Bone Morphogenetic Protein-2 (rhBMP-2) and Demineralized Bone Matrix (DBM) compared to autograft in posterior lumbar spine fusion by comparing complication rates.

Methods

During a 7-year period (2003–2009), all patients undergoing posterior lumbar fusion were retrospectively evaluated within a large orthopedic surgery private practice. Patient demographics, comorbidities, number of levels, type of surgery, and types of bone void filler and osteobiologics were analyzed. Complications were defined as reoperation secondary to failed symptomatic fusion, hyper-reaction with fluid collections, bone overgrowth, and infections.

Results

1,398 patients were evaluated with 41.1?% males and 58.9?% females. Mean age was 60?years and BMI 30.6?kg/m2. Patients were subdivided in treatment groups: rhBMP-2, 947 (67.7?%), DBM 306 (21.9?%), and autograft 145 (10.4?%). The overall infection rate was 2.1?%. No significant differences were found between the three groups. The incidence of seroma formation was higher in the BMP group (3.2?%) than in the DBM or autograft group (2.0 and 1.4?%, respectively) but this was not significant (p?=?0.286 and p?=?0.245, respectively). 103 patients (7.4?%) underwent redo surgery for clinically significant nonunion. We found significantly fewer nonunions (4.3?%) in the rhBMP-2 group (p?Conclusion ICBG is the gold standard. DBM leads to comparable fusion rates and does not increase infection or seroma formation. rhBMP-2 supplementation instead of ICBG or bone marrow aspirate results in higher fusion rates compared to autograft alone or autograft plus DBM.     

The time-dependent effect of ibandronate on bone graft remodeling in an ovariectomized rat spinal arthrodesis model

Background contextIn osteoporotic patients undergoing spinal arthrodesis, the use of bisphosphonates (BPs) remains controversial with regard to bone fusion. There is no consensus about the appropriate time to give BPs to patients with osteoporosis undergoing spinal arthrodesis.PurposeWe aimed to study the effect of BPs, given at different times, on the bone response to osteoporotic spinal arthrodesis.Study design/settingRadiological, histologic, and molecular assessments of bone formation after the different administration time of ibandronate in an ovariectomized (OVX) rat spinal fusion model.MethodsFemale Sprague-Dawley rats (n=100) were OVX (n=80) or non-OVX operated (n=20) and randomized into five groups: non-OVX, osteoporosis, and osteoporosis with early, simultaneous, and late BP groups. Eight weeks after ovariectomy, lumbar spinal arthrodesis was performed using autologous tailbones. Animals were killed 4 and 8 weeks after arthrodesis, and bone formation was assessed by measuring bone mineral density (BMD), messenger RNA expression, manual palpation, radiological evaluation, and histomorphometry.ResultsCompared with late administration, early administration of ibandronate increased femur BMD in OVX rats and did not hinder bone fusion. Radiological analysis showed that groups given early ibandronate had increased bone volume in the grafted site 8 weeks after surgery. Histomorphometric analysis showed that ibandronate positively affected endochondral and intramembranous ossification. In the OVX groups, ibandronate increased bone turnover to a level similar to that in the non-OVX group. These findings suggested that early administration of ibandronate did not inhibit osteogenesis, including endochondral and intramembranous ossification and fusion rate.ConclusionsOur results suggest that the early administration of BPs may not hinder the bone fusion of osteoporotic patients undergoing spinal arthrodesis.     

退行性腰椎滑脱后路手术临床分析

目的 探讨退行性腰椎滑脱的后路手术治疗,比较后路腰椎管减压内固定并后外侧植骨及椎体间联合后外侧植骨术的临床疗效.方法 37例退行性腰椎滑脱患者采用后路减压、后外侧植骨内固定(A组21例)和椎体间联合后外侧植骨内固定(B组16例)手术,对两组术后植骨融合率及临床症状改善情况进行分析比较.根据术前、术后X线片和JOA评分评价植骨融合率及临床症状改善程度.结果 平均随访42个月.A组骨融合率为86%,B组为94%,两组无显著性差异.A组JOA评分优良率为90%,B组为94%,两组无显著性差异.结论 后路后外侧植骨内固定和椎间联合后外侧植骨内固定术均是有效的手术方法,但椎间联合后外侧植骨融合术的骨融合率较高.     

The effect of anti-resorptive therapies on bone graft healing in an ovariectomized rat spinal arthrodesis model

Bone grafting is commonly used to treat skeletal disorders associated with a large bone defect or unstable joint. Spinal arthrodesis surgery, which is the most common application of bone graft, is performed in the elderly and anti-resorptive therapy is sometimes started postoperatively in patients with bone fragility due to osteoporosis, despite insufficient knowledge about the effects of these drugs on bone graft healing. Therefore, we studied the effect of bisphosphonates (BP) and selective estrogen receptor modulators (SERM) on bone graft healing in an ovariectomized rat spinal arthrodesis model. Female Sprague-Dawley rats (n=100) were ovariectomized or sham-operated, and randomized into four groups: Sham (sham-operated+vehicle), Ovx (ovariectomy+vehicle), Ovx-Rlx (ovariectomy+raloxifene, 1 mg/kg/day), and Ovx-Aln (ovariectomy+alendronate, 0.01 mg/kg/day). Four weeks after ovariectomy, lumbar spinal arthrodesis surgery was performed using an autologous bone graft. Animals were killed 2, 4, and 8 weeks after surgery, and fusion assessment, three-dimensional micro-computed tomography, histomorphometry, mRNA expression analysis, and serum bone metabolic marker analysis were performed. The results indicated that neither BP nor SERM significantly altered the fusion rate, but the bone graft healing process was differentially affected. BP inhibited endochondral ossification and graft bone resorption, but induced the growth of a larger, denser fusion mass compared to Ovx by strongly suppressing osteoclastic activity. SERM mildly suppressed bone remodeling, but did not significantly inhibit the ossification process, leading to a fusion mass comparable with that of Sham animals. These findings suggested that spinal fusion surgery outcome is not likely to be altered by BP or SERM treatment started immediately after spinal arthrodesis surgery; however, to avoid adverse effects of BP on bone graft healing, BP treatment should be delayed during the immediate postoperative period.     

Complications of rhBMP-2 utilization for posterolateral lumbar fusions requiring reoperation: a single practice,retrospective case series report

Background context

Recombinant human bone morphogenetic protein-2 (rhBMP-2) (INFUSE, Medtronic, Memphis, TN, USA) has been used off-label for posterolateral lumbar fusions for many years.

Purpose

The goal of this study was to evaluate the complications requiring reoperation associated with rhBMP-2 application for posterolateral lumbar fusions.

Study design/setting

During a 7-year period of time (2002–2009), all patients undergoing lumbar posterolateral fusion using rhBMP-2 (INFUSE) were retrospectively evaluated within a large orthopedic surgery private practice.

Patient sample

A total of 1,158 consecutive patients were evaluated with 468 (40.4%) males and 690 (59.6%) females.

Outcome measures

Complications related to rhBMP were defined as reoperation secondary to symptomatic failed fusion (nonunion), symptomatic seroma formation, symptomatic reformation of foraminal bone, and infection.

Methods

Inclusion criteria were posterolateral fusion with rhBMP-2 implant and age equal to or older than 18 years. Surgical indications and treatment were performed in accordance with the surgeon's best knowledge, discretion, and experience. Patients consented to lumbar decompression and arthrodesis using rhBMP-2. All patients were educated and informed of the off-label utilization of rhBMP-2. Patient follow-up was performed at regular intervals of 2 weeks, 6 weeks, 12 weeks, 6 months, 1 year, and later if required or indicated.

Results

Average age was 59.2 years, and body mass index was 30.7 kg/m². Numbers of levels fused were 1 (414, 35.8%), 2 (469, 40.5%), 3 (162, 14.0%), 4 (70, 6.0%), 5 (19, 1.6%), 6 (11, 0.9%), 7 (7, 0.6%), 8 (4, 0.3%), and 9 (2, 0.2%). Patients having complications requiring reoperation were 117 of 1,158 (10.1%): symptomatic nonunion requiring redo fusion and instrumentation 41 (3.5%), seroma with acute neural compression 32 (2.8%), excess bone formation with delayed neural compression 4 (0.3%), and infection requiring debridement 26 (2.2%). Nonunion was related to male sex and previous BMP exposure. Seroma formation was significantly higher in patients with higher doses of rhBMP-2 (p=.050) and with more than 12 mg of rhBMP-2 (χ²=0.025). Bone reformation and neural compression at the laminectomy and foraminotomy sites occurred in a delayed fashion. Infection was associated with obesity and respiratory disease. Infections were noted with a greater BMP dose (p<.001), more than 12 mg (χ²<0.001), fusion more than three levels (χ²<0.001), and reexposed to BMP (χ²=0.023).

Conclusions

rhBMP-2 utilization for posterolateral lumbar fusions has a low symptomatic nonunion rate. Prior rhBMP-2 exposure and male sex were related to symptomatic nonunion formation. rhBMP-2–associated neural compression acutely with seroma formation and delayed with foraminal bone formation is concerning and associated with higher rhBMP-2 concentrations.