S. Tim Yoon

Increased swelling complications associated with off-label usage of rhBMP-2 in the anterior cervical spine

Study Design/Setting. Independent, retrospective clinical record review with a concurrent control. Objective. To identify whether rhBMP-2 is associated with an increased incidence of clinically relevant postoperative prevertebral swelling problems in patients undergoing anterior cervical fusions. Summary of Background Data. Bone Morphogenetic Protein-2 (rhBMP-2) is FDA approved as a bone graft substitute in anterior lumbar interbody fusions. rhBMP-2 has also been used “off-label” in anterior cervical fusions. We suspected that rhBMP-2 might increase the incidence of adverse swelling events. Methods. A total of 234 consecutive patients (ages 12–82 years) undergoing anterior cervical fusion with and without rhBMP-2 over a 2-year period at one institution comprised the study population. The incidence of clinically relevant prevertebral swelling was calculated. The populations were compared and statistical significance was determined. Results. A total of 234 patients met the study criteria, 69 of whom underwent anterior cervical spine fusions using rhBMP-2; 27.5% of those patients in the rhBMP-2 group had a clinically significant swelling event versus only 3.6% of patients in the non-rhBMP-2 group. This difference was statistically significant (P < 0.0001) and remained so after controlling for other significant predictors of swelling. Conclusions. Off-label use of rhBMP-2 in the anterior cervical spine is associated with an increased rate of clinically relevant swelling events.

Adjacent segment motion after a simulated lumbar fusion in different sagittal alignments: a biomechanical analysis.

Study Design. An in vitro biomechanical study of adjacent segment motion (at L3–L4 and L5–S1) after a simulated lumbar interbody fusion of L4–L5 in different sagittal alignments was carried out. Objectives. To test the hypothesis that an L4–L5 fixation in different sagittal alignments causes increased angular motion at the adjacent levels (L3–L4 and L5–S1) in comparison with the intact spine. Summary of Background Data. Clinical experience has suggested that lumbar fusion in a nonanatomic sagittal alignment can increase degeneration of the adjacent levels. It has been hypothesized that this is the result of increased motion at these levels; however, to the authors’ knowledge no mechanical studies have demonstrated this. Methods. Eight fresh human cadaveric lumbar spines (L3–S1) were biomechanically tested. Total angular motion at L3–L4 and L5–S1 under flexion-extension load conditions (7-Nm flexion and 7-Nm extension) was measured. Each specimen was tested intact, and then again after each of three different sagittal fixation angles (at L4–L5): (1) in situ (21°lordosis), (2) hyperlordotic (31°lordosis), and (3) hypolordotic (7°lordosis). The simulated anterior/posterior fusion was performed at L4–L5 with pedicle screws posteriorly, vertebral body screws anteriorly, and an interbody dowel. Results. The averaged values for flexion-extension motion at L3–L4 were as follows: intact specimen 2.0°, in situ fixation 4.0°, hyperlordotic fixation 1.7°, hypolordotic fixation 6.5°. The averaged values for flexion-extension motions at L5–S1 were as follows: intact specimen 2.3°, in situ fixation 2.6°, hyperlordotic fixation 3.6°, hypolordotic fixation 2.9°. Conclusion. Hypolordotic alignment at L4–L5 caused the greatest amount of flexion-extension motion at L3–L4, and the differences were statistically significant in comparison with intact specimen, in situ fixation, and hyperlordotic fixation. Hyperlordotic alignment at L4–L5 caused the greatest amount of flexion-extension motion at L5–S1, and the difference was statistically significant in comparison with intact specimen but not in situ fixation or hypolordotic fixation.

Comparison of allograft to autograft in multilevelanterior cervical discectomy and fusion with rigid plate fixation

BACKGROUND CONTEXT A relatively high pseudarthrosis rate is associated with multilevel anterior cervical discectomy and fusion (ACDF). Anterior plate fixation increases fusion rate in multilevel ACDF. A debate still exists between the effectiveness of allograft versus autograft in plated multilevel ACDF. PURPOSE To determine the efficacy of allograft versus autograft in fusion rate and clinical outcome in patients undergoing two- and three-level ACDFs with rigid anterior plate fixation. STUDY DESIGN A retrospective radiographic and clinical review to assess fusion, risk factors and clinical outcome of 80 consecutive patients who underwent ACDF with rigid anterior plate fixation involving two and three levels with either allograft or autograft. PATIENT SAMPLE There were 45 patients (56%) who had autogenous iliac crest tricortical grafts and 35 patients (44%) who received tricortical allograft with an average age of 49 years who were treated by multilevel ACDF with rigid anterior plate fixation at a single institution. Thirty-three Peak polyaxial (Depuy-Acromed, Rayham, MA), 26 Orion (Sofamor-Danek, Memphis, TN), 16 Atlantis (Sofamor-Danek, Memphis, TN) and 5 Synthes (Paoli, PA) anterior cervical plating systems were used. All patients underwent ACDF (61 two-level, 19 three-level) by a Smith Robinson technique. All patients had burring of the end plates, 2-mm distraction of the motion segment and graft countersunk 2 mm from the anterior vertebral border. Anterior cervical plate with unicortical screw purchase was used in all cases. Segmental screw fixation was performed in 46 patients. Soft collars were worn postoperatively for 3 to 4 weeks. OUTCOME MEASURES Follow-up lateral neutral, flexion and extension radiographs were used to assess fusion. The radiographs were reviewed by an independent blinded observer in assessing fusion grades between autograft versus allograft. Clinical outcomes were rated excellent, good, fair and poor based on Odoms criteria. METHODS Fusion rate and postoperative clinical outcome were assessed in 80 patients who underwent two- or three-level ACDF with rigid anterior plate fixation. Additional risk factors were also analyzed. RESULTS Radiographic fusion was assessed in all patients (mean, 16 months). Seventy-eight patients (97.5%) achieved solid arthrodesis. Pseudarthrosis occurred in two patients who had allograft for two-level and three-level fusions. Nonsegmental screws were used in the two-level nonunion case. Postoperative dysphagia developed in one two-level nonunion patient, and revision surgery was performed in the other nonunion three-level patient. Twenty-three patients were smokers, and 26 patients had work-related injuries. Clinical outcome (mean, 20 months) was excellent in 23, good in 48 and fair in 9 patients. No statistical significance was noted between demographics, history of tobacco use, graft-type, end plate preparation technique, intermediate segmental screws, plate-type, clinical outcome of fused and nonfused patients and presence of work-related injuries (p>.05). CONCLUSIONS A high fusion rate of 97.5% was obtained for multilevel ACDF with rigid plating with either autograft or allograft. In this study, nonunion occurred in patients with allograft but this difference was not statistically significant. Fusion was obtained in 97.8% of patients with segmental screw fixation and 97.1% with nonsegmental screw fixation. Nonsegmental screw fixation may contribute to less than adequate stability and contribute to a higher rate of nonunion, but such effects could not be discerned from this study. Excellent and good clinical outcome was noted in 88.8% of the patients. Proper patient selection and meticulous operative technique is essential to obtain high fusion rates and optimal clinical outcome, which is more important than graft type.

Perioperative and delayed complications associated with the surgical treatment of cervical spondylotic myelopathy based on 302 patients from the AOSpine North America Cervical Spondylotic Myelopathy Study

OBJECT Rates of complications associated with the surgical treatment of cervical spondylotic myelopathy (CSM) are not clear. Appreciating these risks is important for patient counseling and quality improvement. The authors sought to assess the rates of and risk factors associated with perioperative and delayed complications associated with the surgical treatment of CSM. METHODS Data from the AOSpine North America Cervical Spondylotic Myelopathy Study, a prospective, multicenter study, were analyzed. Outcomes data, including adverse events, were collected in a standardized manner and externally monitored. Rates of perioperative complications (within 30 days of surgery) and delayed complications (31 days to 2 years following surgery) were tabulated and stratified based on clinical factors. RESULTS The study enrolled 302 patients (mean age 57 years, range 29-86) years. Of 332 reported adverse events, 73 were classified as perioperative complications (25 major and 48 minor) in 47 patients (overall perioperative complication rate of 15.6%). The most common perioperative complications included minor cardiopulmonary events (3.0%), dysphagia (3.0%), and superficial wound infection (2.3%). Perioperative worsening of myelopathy was reported in 4 patients (1.3%). Based on 275 patients who completed 2 years of follow-up, there were 14 delayed complications (8 minor, 6 major) in 12 patients, for an overall delayed complication rate of 4.4%. Of patients treated with anterior-only (n = 176), posterior-only (n = 107), and combined anterior-posterior (n = 19) procedures, 11%, 19%, and 37%, respectively, had 1 or more perioperative complications. Compared with anterior-only approaches, posterior-only approaches had a higher rate of wound infection (0.6% vs 4.7%, p = 0.030). Dysphagia was more common with combined anterior-posterior procedures (21.1%) compared with anterior-only procedures (2.3%) or posterior-only procedures (0.9%) (p < 0.001). The incidence of C-5 radiculopathy was not associated with the surgical approach (p = 0.8). The occurrence of perioperative complications was associated with increased age (p = 0.006), combined anterior-posterior procedures (p = 0.016), increased operative time (p = 0.009), and increased operative blood loss (p = 0.005), but it was not associated with comorbidity score, body mass index, modified Japanese Orthopaedic Association score, smoking status, anterior-only versus posterior-only approach, or specific procedures. Multivariate analysis of factors associated with minor or major complications identified age (OR 1.029, 95% CI 1.002-1.057, p = 0.035) and operative time (OR 1.005, 95% CI 1.002-1.008, p = 0.001). Multivariate analysis of factors associated with major complications identified age (OR 1.054, 95% CI 1.015-1.094, p = 0.006) and combined anterior-posterior procedures (OR 5.297, 95% CI 1.626-17.256, p = 0.006). CONCLUSIONS For the surgical treatment of CSM, the vast majority of complications were treatable and without long-term impact. Multivariate factors associated with an increased risk of complications include greater age, increased operative time, and use of combined anterior-posterior procedures.

The Effect of Bone Morphogenetic Protein-2 on Rat Intervertebral Disc Cells in Vitro

Study Design. An in vitro experiment to determine the molecular and cellular effect of recombinant human bone morphogenetic protein-2 on cultured rat intervertebral disc cells was performed. Objectives. To determine the effect of recombinant human bone morphogenetic protein-2 on cell proliferation, production of sulfated-glycosaminoglycan, and the expression of genes specific for chondrocytes (Type II collagen, aggrecan, and Sox9) in cultured rat intervertebral disc cells. Summary of Background Data. Intervertebral disc degeneration is associated with cellular and biochemical changes, which include decreased synthesis of cartilage specific gene products such as Type II collagen and aggrecan. Although bone morphogenetic protein-2 is known to induce chondrogenesis during new bone formation, the effects on intervertebral disc cells have not been characterized. Method. Cells were isolated from the anulus fibrosus and transition zones of lumbar discs from Sprague-Dawley rats. The cells were grown in monolayer and treated with recombinant human bone morphogenetic protein-2 (0, 10, 100, 1000 ng/mL) in Dulbecco’s Modified Eagle Medium/F-12 with 1% fetal bovine serum (day 0). On days 2, 4, and 7 after recombinant human bone morphogenetic protein-2 treatment, sulfated-glycosaminoglycan content in the media was quantified using 1,9-dimethylmethylene blue staining. The results were normalized according to culture duration and cell number. On day 7, mRNA was extracted for reverse transcriptase-polymerase chain reaction and real-time polymerase chain reaction to quantitate mRNAs of Type I collagen, Type II collagen, aggrecan, Sox9, osteocalcin, and glyceraldehyde phosphate dehydrogenase. Cell number was determined with a hemocytometer. Results. Recombinant human bone morphogenetic protein-2 at 100 and 1000 ng/mL yielded a 17% and 42% increase in cell number on day 4, and a 59% and 79% on day 7, respectively. Recombinant human bone morphogenetic protein-2 at 10 ng/mL had no effect on cell number. Sulfated-glycosaminoglycan increase was greatest at day 7, increasing by 1.3-, 2.1-, and 3.6-fold with recombinant human bone morphogenetic protein-2 treatments of 10, 100, and 1000 ng/mL, respectively. Increases in mRNA levels of Type II collagen, aggrecan, Sox9, and osteocalcin were observed with recombinant human bone morphogenetic protein-2 concentrations of 100 and 1000 ng/mL on day 7 as determined by reverse transcriptase-polymerase chain reaction. No detectable increase in mRNA level of Type I collagen was observed with any levels of recombinant human bone morphogenetic protein-2. Real-time polymerase chain reaction showed the greatest effect at 1000 ng/mL recombinant human bone morphogenetic protein-2, leading to an 11.5-fold increase in aggrecan, a 4.6-fold increase in Type II collagen, a 5.3-fold increase in Sox9, and a 1.9-fold increase in osteocalcin mRNA above untreated controls at day 7. Conclusion. The results of this study show that recombinant human bone morphogenetic protein-2 enhances disc matrix production and chondrocytic phenotype of intervertebral disc cells. Recombinant human bone morphogenetic protein-2 increases cell proliferation and sulfated-glycosaminoglycan (proteoglycan) synthesis. It increases mRNA of Type II collagen, aggrecan, and Sox9 genes (chondrocyte specific genes), and osteocalcin, but not Type I collagen or glyceraldehyde phosphate dehydrogenase.

Cancer risk after use of recombinant bone morphogenetic protein-2 for spinal arthrodesis.

BACKGROUND Recombinant human bone morphogenetic protein-2 (rhBMP-2) is a growth factor known to have in vitro effects on the growth and invasiveness of cancer. It has been approved by the U.S. Food and Drug Administration in limited doses for single-level anterior spinal arthrodesis, but it is commonly used off-label and at high doses. The effect of rhBMP-2 on the risk of cancer has been a concern. We sought to evaluate the risk of new cancers in patients receiving high-dose rhBMP-2. METHODS We used publicly available data from a pivotal, multicenter, randomized controlled trial of patients with degenerative lumbar spine conditions who underwent a single-level instrumented posterolateral arthrodesis with either high-dose rhBMP-2 in a compression-resistant matrix (CRM) (rhBMP-2/CRM; n = 239) or autogenous bone graft (control group; n = 224). We compared the risks of new cancers in the rhBMP-2/CRM and control groups at two and five years after surgery. RESULTS At two years, with 86% follow-up, there were fifteen new cancer events in eleven patients in the rhBMP-2/CRM group compared with two new cancer events in two patients in the control group treated with autogenous bone graft. The incidence rate of new cancer events per 100 person-years was 3.37 (95% confidence interval [CI], 1.89 to 5.56) in the rhBMP-2/CRM group at two years compared with 0.50 (95% CI, 0.06 to 1.80) in the control group. The incidence rate ratio was 6.75 (95% CI, 1.57 to 60.83; p = 0.0026) at two years. Calculated in terms of the number of patients with one or more cancer events two years after the surgery, the incidence rate per 100 person-years was 2.54 (95% CI, 1.27 to 4.54) in the rhBMP-2/CRM group compared with 0.50 (95% CI, 0.06 to 1.82) in the control group at two years; the incidence rate ratio was 5.04 (95% CI, 1.10 to 46.82; p = 0.0194). At five years, there was a 37% loss of follow-up, but a significantly greater incidence of cancer events was still observed in the rhBMP-2/CRM group. CONCLUSIONS A high dose of 40 mg of rhBMP-2/CRM in lumbar spinal arthrodesis was associated with an increased risk of new cancer.

Osteoinductive molecules in orthopaedics: basic science and preclinical studies.

Osteoinductive molecules are characterized by their ability to promote the formation of bone. Most osteoinductive molecules are cytokines, which are extracellular proteins or peptides that mediate cell to cell signaling. Examples of osteoinductive cytokines are certain bone morphogenetic proteins and some growth and differentiation factors. Some osteoinductive molecules are not secreted molecules. LIM mineralization protein-1 is an example of an intracellular osteoinductive molecule. Significant advances have been made in characterizing the molecular composition and mechanism of action of these osteoinductive molecules. Preclinical studies with these molecules have provided better understanding of the doses, formulation, and delivery mechanism necessary for effective bone formation in model systems of spinal fusion and other orthopaedic problems. The current authors will review the most important basic science and preclinical studies involving these osteoinductive molecules.

Disc degeneration in the rabbit: a biochemical and radiological comparison between four disc injury models.

Study Design. A biochemical and radiologic comparison of 4 disc injury models to produce disc degeneration in the rabbit was carried out in 2 experiments. Objectives. To develop a reliable animal model of intervertebral disc degeneration. Summary of Background Data. In order to study various interventions for retarding or preventing disc degeneration, a reliable animal model of disc degeneration is needed. Methods. First experiment: 7 New Zealand white rabbits (1 year old, 3.5–4.5 kg body weight) were used to test 4 different disc injury models; intradiscal injection of Camptothecin (an apoptotic agent) using a 23-gauge needle at L2–L3, nucleus aspiration using a 21-gauge needle at L3–L4, 3 anulus punctures using a 21-gauge needle at L4–L5, and 1 anulus puncture using a 18-gauge needle at L5–L6. The L1–L2 level was used as a control. Rabbits were killed 12 weeks later. Lumbar spinal magnetic resonance images were assessed using 4 grades of disc degeneration. The water content of the nucleus was measured. Dimethylmethylene blue (DMMB) assay was used to measure the sulfated-glycosaminoglycan content. Second experiment: the 21-gauge 3-puncture and the 18-gauge 1-puncture models, thought most effective in producing disc degeneration in the first experiment, were again used in a second study. Six rabbits were killed 8 weeks later, the water and sulfated-glycosaminoglycan contents being measured as in the first experiment. Results. In the first experiment, the water content in the aspiration and puncture models was significantly decreased. Only the sulfated-glycosaminoglycan content in the aspiration model showed a significant decrease as compared to the control. Disc heights and magnetic resonance grades documented significant degeneration occurring in the aspiration and puncture models. In the second experiment, the water content showed a significant decrease in the 21-gauge 3-puncture model, whereas neither of the results for the sulfated-glycosaminoglycancontent showed a significant difference as compared to the control data. Conclusion. In the first experiment, the 21-gauge 3-puncture and the 18-gauge 1-puncture models produced the most consistent disc degeneration in the rabbit lumbar spine. When these 2 models were again studied in the second experiment, the 21-gauge 3-puncture technique was superior in producing disc degeneration over a shorter period of time.

Effect of bone morphogenetic protein-2 (BMP-2) on matrix production, other BMPs, and BMP receptors in rat intervertebral disc cells.

Objective An in vitro experiment study using rat disc cells was carried out to determine the effect of bone morphogenetic protein-2 (BMP-2) on extracellular matrix production, other BMPs, and BMP receptors (BMPRs). Methods Cells from the anulus fibrosus and transition zone were harvested and cultured. When the cells reached 80% confluence, BMP-2 was added to reach a final concentration of 200 ng/mL. Three days later, the culture media were collected for the assay of sulfated glycosaminoglycans (sGAG) and collagen types I and II. The cells were harvested for RNA extraction to determine the genes expressed. All experiments were performed at least three times to ensure repeatability. Results BMP-2 significantly increased aggrecan and collagen type II mRNA expression 8.30 and 4.61 times, respectively, and decreased versican mRNA expression 0.54 times as compared with control. Collagen type I production and mRNA level were not changed. BMP-2 significantly increased transforming growth factor-β1 (TGFβ1) and BMP-7 mRNA expression 2.32 and 2.45 times, respectively, compared with control. There was no significant change in BMP-6 mRNA expression. BMPR type IB and II mRNA expressions were increased and BMPR type 1A mRNA expression was decreased, but none of these differences was significant. Conclusions The results of this study show that in rat intervertebral disc cells, BMP-2 increases aggrecan and collagen type II mRNA expression and decreases versican gene expression. BMP-2 also up-regulates mRNA expression for BMP-7 and TGFβ but has no significant effect on the BMPRs.

Nonoperative management of cervical myelopathy: a systematic review

Study Design. Systematic review. Objective. To conduct a systematic review investigating the evidence of (1) efficacy, effectiveness, and safety of nonoperative treatment of patients with cervical myelopathy; (2) whether the severity of myelopathy affects outcomes of nonoperative treatment; and (3) whether specific activities or minor injuries are associated with neurological deterioration in patients with myelopathy or asymptomatic stenosis being treated nonoperatively. Summary of Background Data. Little is known about the appropriate role of nonoperative treatment in the management of cervical myelopathy, which is typically considered a surgical disorder. Methods. A systematic search was conducted in PubMed and the Cochrane Collaboration Library for articles published between January 1, 1956, and November 20, 2012. We included all articles that compared nonoperative treatments or observation with surgery for patients with cervical myelopathy or asymptomatic cervical cord compression to determine their effects on clinical outcomes, including myelopathy scales (Japanese Orthopaedic Association, Nurick), general health scores (36-Item Short Form Health Survey), and pain (neck and arm). Nonoperative treatments included physical therapy, medications, injections, orthoses, and traction. We also searched for articles evaluating the effect of specific activities or minor trauma in neurological outcomes. Case reports and studies with less than 10 patients in the exposure group were excluded. Results. Of 54 citations identified from our search, 5 studies reported in 6 articles met inclusion criteria. In 1 randomized controlled study, there was low evidence that nonoperative treatment may yield equivalent or better outcomes than surgery in those with mild myelopathy. For moderate to severe myelopathy, nonoperative treatment had inferior outcomes versus surgery in 2 cohort studies, despite the fact that surgically treated patients were worse at baseline. There was insufficient evidence to determine whether specific activities or minor trauma is a risk factor for neurological deterioration in those with myelopathy or asymptomatic cord compression. Conclusion. There is a paucity of evidence for nonoperative treatment of cervical myelopathy, and further studies are needed to determine its role more definitively. In particular, for the patient with milder degrees of myelopathy, randomized studies comparing nonoperative with surgical treatment would be particularly helpful, as would trials comparing specific types of nonoperative treatments with the natural history of myelopathy. Evidence-Based Clinical Recommendations. Recommendation 1. Because myelopathy is known to be a typically progressive disorder and there is little evidence that nonoperative treatment halts or reverses its progression, we recommend not routinely prescribing nonoperative treatment as the primary modality in patients with moderate to severe myelopathy. Overall Strength of Evidence. Low Strength of Recommendation. Strong Recommendation 2. If there is a role for nonoperative treatment as a primary treatment modality, it may be in the patient with mild myelopathy. However, it is not clear which specific forms of nonoperative treatment provide any benefit compared with the natural history. If nonoperative treatment is selected, we suggest care be taken to observe for neurological deterioration. Overall Strength of Evidence. Low Strength of Recommendation. Weak Recommendation 3. In those with asymptomatic spondylotic cord compression but no clinical myelopathy, the available literature neither supports nor refutes the notion that minor trauma is a risk factor for neurological deterioration. We suggest that patients should be counseled about this uncertainty. Overall Strength of Evidence. Low Strength of Recommendation. Weak Recommendation 4. In those with a clinical diagnosis of cervical spondylotic myelopathy but no ossification of the posterior longitudinal ligament, the available studies did not specifically address the issue of neurological deterioration secondary to minor trauma. However, in those with underlying ossification of the posterior longitudinal ligament, trauma may be more likely to cause worsening of existing myelopathy or even initiate symptoms in those who were previously asymptomatic. We suggest that patients should be counseled about these possibilities. Overall Strength of Evidence. Low Strength of Recommendation. Weak