James P. Lawrence

The safety and efficacy of OP-1 (rhBMP-7) as a replacement for iliac crest autograft in posterolateral lumbar arthrodesis: a long-term (>4 years) pivotal study.

Study Design. Randomized controlled trial comparing OP-1 (rhBMP-7) with iliac crest autograft in patients with symptomatic degenerative spondylolisthesis and spinal stenosis treated with decompression and uninstrumented posterolateral arthrodesis. Objective. To determine the safety and the clinical and radiographic efficacy of OP-1 (rhBMP-7) Putty as compared with an iliac crest bone autograft control in uninstrumented, single-level posterolateral spinal arthrodesis. Summary of Background Data. Preclinical and preliminary clinical data have demonstrated successful fusion and clinical outcomes with the use of OP-1 Putty in posterolateral spinal arthrodesis. No prior randomized controlled trial with adequate study power has been performed. Methods. A total of 335 patients were randomized in 2:1 fashion to receive either OP-1 Putty or autograft in the setting of an uninstrumented posterolateral arthrodesis performed for degenerative spondylolisthesis and symptomatic spinal stenosis. Patients were observed serially with radiographs, clinical examinations, and appropriate clinical indicators, including ODI, Short-Form 36, and visual analog scale scores. Serum samples were examined at regular intervals to assess the presence of antibodies to OP-1. The primary end point, Overall Success, was analyzed at 24 months. The study was extended to include additional imaging data and long-term clinical follow-up at 36+ months. At the 36+ month time point, CT scans were obtained in addition to plain radiographs to evaluate the presence and location of new bone formation. Modified Overall Success, including improvements in ODI, absence of retreatment, neurologic success, absence of device-related serious adverse events, angulation and translation success, and new bone formation by CT scan (at 36+ months), was then calculated using the 24-month primary clinical endpoints, updated retreatment data, and CT imaging and radiographic end points. Results. OP-1 Putty was demonstrated to be statistically equivalent to autograft with respect to the primary end point of modified overall success. The use of OP-1 Putty when compared to autograft was associated with statistically lower intraoperative blood loss and shorter operative times. Although patients in the OP-1 Putty group demonstrated an early propensity for formation of anti-OP-1 antibodies, this resolved completely in all patients with no clinical sequelae. Conclusion. OP-1 Putty is a safe and effective alternative to autograft in the setting of uninstrumented posterolateral spinal arthrodesis performed for degenerative spondylolisthesis and symptomatic spinal stenosis.

Back Pain in Athletes

&NA; The athlete with back pain presents a clinical challenge. Selflimited symptoms must be distinguished from persistent or recurrent symptoms associated with identifiable pathology. Athletes involved in impact sports appear to have risk factors for specific spinal pathologies that correlate with the loading and repetition demands of specific activities. For example, elite athletes who participate in longer and more intense training have higher incidence rates of degenerative disk disease and spondylolysis than athletes who do not. However, data suggest that the recreational athlete may be protected from lumbar injury with physical conditioning. Treatment of athletes with acute or chronic back pain usually is nonsurgical, and symptoms generally are selflimited. However, a systematic approach to the athlete with back pain, involving a thorough history and physical examination, pertinent imaging, and treatment algorithms designed for specific diagnoses, can facilitate symptomatic improvement and return to play. There are no reliable studies examining the long‐term consequences of athletic activity on the lumbar spine.

The management of spinal injuries in patients with ankylosing spondylitis or diffuse idiopathic skeletal hyperostosis: a comparison of treatment methods and clinical outcomes.

Study Design A retrospective review of 12 patients with ankylosing spondylitis (AS) and 18 patients with diffuse idiopathic skeletal hyperostosis (DISH) treated at a single institution for spinal injuries between the years 2000 and 2006. Objective To independently evaluate patients with these diagnoses who sustained spinal injuries and directly compare their treatment methods and clinical outcomes. Summary of Background Data AS and DISH are disorders characterized by abnormal ossification of the spinal column, which predisposes these patients to spinal injuries with potentially devastating consequences. Methods Patient and surgical data were obtained from medical records and appropriate imaging studies. Neurologic status was recorded using the American Spinal Injury Association (ASIA) impairment scale for spinal cord injuries, and clinical outcomes were assessed using Odom criteria. Results Most of these injuries involved the subaxial cervical spine between C5 and C7. In all, 41.2% of AS patients were considered to be ASIA A, whereas 44.4% of DISH patients were classified as ASIA E. Surgery was performed in 83.3% of AS patients and 66.7% of DISH patients, and the overall complication rates were 41.7% and 33.3%, respectively. There were no statistically significant differences between the survivorship and outcomes of the AS and DISH groups and 81.3% of all respondents were classified as having excellent or good outcomes. There were 4 deaths, all of which were considered to be related to the use of halo-vest immobilization. Conclusions Although the rate of neurologic injury was high for both groups, AS patients were more likely to exhibit neurologic deficits and undergo operative management. Although the majority of these spinal injuries were treated surgically, stable fractures without any associated neurologic deficits were often successfully managed with immobilization. Complications were observed with both operative and nonoperative treatments, although all of the deaths occurred in conjunction with the use of the halo-vest orthosis.

Immunogenicity of bone morphogenetic proteins

OBJECT The object of this paper is to review the immunogenicity of bone morphogenetic proteins (BMPs) and to compare the results of the immunogenicity characterization and clinical consequences between recombinant human (rh)BMP-2 and recombinant human osteogenic protein-1 (rhOP-1/BMP-7). METHODS The immunogenicity of therapeutic proteins and its clinical effects were reviewed. The characteristics of BMPs were also described in terms of immunogenicity. The methods and results of antibody detection in various clinical trials of rhBMP-2 and rhOP-1 were compared, including the most recent studies using a systematic characterization strategy with both a binding assay and bioassay. RESULTS Similar to all recombinant human proteins, rhBMPs induce immune responses in a select subgroup of patients. Adverse effects from this response in these patients, however, have not been reported with antibody formation to either rhBMP-2 or rhOP-1. Overall, the incidence of antibody formation was slightly higher in rhOP-1 trials than in rhBMP-2 trials. CONCLUSIONS Although they occur in a subgroup of patients, the immune responses against rhBMPs have no correlation with any clinical outcome or safety parameter. Clinicians, however, must be aware of the potential complications caused by the immunogenicity of BMPs until more studies clearly elucidate their safety.

Percutaneous techniques for minimally invasive posterior lumbar fusion

Percutaneous pedicle screw fixation for lumbar posterolateral instrumented fusion is an attractive alternative to standard open techniques. The technical aspects of this procedure can be challenging and even frustrating when first learning the technique. However, once these techniques have been mastered, they offer a safe, less invasive, less traumatic, more aesthetic method for performing fusion. The authors have outlined a step-by-step method for performing this surgery, and include a case series that demonstrates excellent results in patients treated with this procedure.

ISSLS Prize Winner: Dynamic Loading-Induced Convective Transport Enhances Intervertebral Disc Nutrition

Study Design. Experimental animal study of convective transport in the intervertebral disc. Objective. To quantify the effects of mechanical loading rate on net transport into the healthy and degenerative intervertebral disc in vivo. Summary of Background Data. Intervertebral disc degeneration is linked with a reduction in transport to the avascular disc. Enhancing disc nutrition is, therefore, a potential strategy to slow or reverse the degenerative cascade. Convection induced by mechanical loading is a potential mechanism to augment diffusion of small molecules into the disc. Methods. Skeletally mature New Zealand white rabbits with healthy discs and discs degenerated via needle puncture were subjected to low rate axial compression and distraction loading for 2.5, 5, 10, 15, or 20 minutes after a bolus administration of gadodiamide. Additional animals with healthy discs were subjected to high-rate loading for 10 minutes or no loading for 10 minutes. Transport into the disc for each loading regimen was quantified using post–contrast-enhanced magnetic resonance imaging. Results. Low-rate loading resulted in the rapid uptake and clearance of gadodiamide in the disc. Low-rate loading increased net transport into the nucleus by a mean 16.8% and 12.6% in healthy and degenerative discs, respectively. The kinetics of small molecule uptake and clearance were accelerated in both healthy and degenerative discs with low-rate loading. In contrast, high-rate loading reduced transport into nucleus by a mean 16.8%. Conclusion. These results illustrate that trans-endplate diffusion can be enhanced by forced convection in both healthy and degenerative discs in vivo. Mechanical loading–induced convection could offer therapeutic benefit for degenerated discs by enhancing uptake of nutrients and clearance of by-products. Level of Evidence: 4

rhBMP-2 (ACS and CRM formulations) overcomes pseudarthrosis in a New Zealand white rabbit posterolateral fusion model.

Study Design. The study design consisted of a New Zealand white rabbit model of pseudarthrosis repair. Study groups consisting of no graft, autograft, or recombinant human bone morphogenetic protein-2 (rhBMP-2) with absorbable collagen sponge (ACS) or compression resistant matrix (CRM) were evaluated. Objective. To evaluate the relative efficacy of bone graft materials (autograft, ACS, and CRM). Summary of Background Data. rhBMP-2 has been shown to have a 100% fusion rate in a primary rabbit fusion model, even in the presence of nicotine, which is known to inhibit fusion. Methods. Seventy-two New Zealand white rabbits underwent posterolateral lumbar fusion with iliac crest autograft. To establish pseudarthroses, nicotine was administered to all animals. At 5 weeks, the spines were explored and all pseudarthroses were redecorticated and implanted with no graft, autograft, rhBMP-2/ACS, or rhBMP-2/CRM. At 10 weeks, fusions were assessed by manual palpation and histology. Results. Eight rabbits (11%) were lost to complications. At 5 weeks, 66 (97%) had pseudarthroses. At 10 weeks, attempted pseudarthrosis repairs were fused in 1 of 16 of no graft rabbits (6%), 5 of 17 autograft rabbits (29%), and 31 of 31 rhBMP-2 rabbits (with ACS or CRM) (100%). Histologic analysis demonstrated more mature bone formation in the rhBMP-2 groups. Conclusions. The 2 rhBMP-2 formulations led to significantly higher fusion rates and histologic bone formation than no graft and autograft controls in this pseudarthrosis repair model.

Immunogenicity of osteogenic protein 1: results from a prospective, randomized, controlled, multicenter pivotal study of uninstrumented lumbar posterolateral fusion

OBJECT The aim in this study was to detect and quantify antibody responses against recombinant human osteogenic protein 1 (OP-1) and to compare these responses to patient clinical outcomes and safety information. METHODS A controlled, open-label, randomized, prospective, multicenter pivotal study was performed in which patients with single-level Grade I or II degenerative lumbar spondylolisthesis (Meyerding classification) and spinal stenosis underwent decompression and uninstrumented posterolateral spinal arthrodesis. Three hundred thirty-six patients were randomized in a 2:1 fashion to receive either OP-1 Putty or autogenous iliac crest bone graft. Patients were evaluated at regular postoperative intervals for radiographic results, clinical outcomes, and safety parameters for more than 36 months. Serum samples were collected over this period and evaluated for the presence of anti–OP-1 antibodies and neutralizing activity by using a battery of in vitro binding assays (including enzyme-linked immunosorbent assay [ELISA]) and cell-based bioassays, respectively. RESULTS Antibodies were predominantly seen in the OP-1–treated patients, although some responses were recorded preoperatively and in patients receiving autograft alone. Antibody production peaked in the 6-week to 3-month postoperative time frame and diminished thereafter. Neutralizing antibodies (Nabs) were detected at 1 time point at least in 25.6% of the patients treated with OP-1 Putty, but were not found in any patient following the 24-month postoperative time period. A single autograft patient (1.2%) also presented with OP-1 Nabs. An anti–OP-1 antibody status did not correlate with any measure of patient outcomes or adverse events. CONCLUSIONS Recombinant human OP-1 (bone morphogenetic protein 7), like many recombinant human proteins, induces an immune response following its use as a bone graft alternative. This response was transient and diminished over time, and there was no statistical evidence to suggest an association between Nab status and any of the efficacy or safety criteria that were examined.

Patient perception of outcomes following failed spinal instrumentation with polyetheretherketone rods and titanium rods.

Study Design. A structured questionnaire. Objective. The purpose of this study was to determine whether material rod composition and its imaging characteristics can determine patient perceptions of pain, outcome, and need for revision surgery in the context of the failure of spinal instrumentation following lumbar arthrodesis. Summary of Background Data. Patient perceptions of radiographic images in the context of failed spinal instrumentation may influence clinical outcomes and patient satisfaction. Due to radiolucency, failed polyetheretherketone (PEEK) rods may be perceived differently by patients than more traditional materials. Methods. Patients presenting primarily with chief complaints of back pain completed a 2-page, 22-question questionnaire containing 3 alternative radiographic images of failed rod instrumentation following posterolateral lumbar arthrodesis. The images represented failed rods composed of either PEEK, PEEK with a longitudinal radio-opaque marker, or traditional titanium. Statistical analysis with the Cochran Q test was performed to determine whether there were statistical differences in the responses. Results. The responses suggested a preference for the images representing PEEK instrumentation as being associated with superior clinical outcomes, the least pain, the most comfort, and the least likelihood of required revision surgery. Conclusion. PEEK rods possess radiolucent properties that can alter patient perceptions of clinical outcomes when compared with images of other equally unfavorable scenarios. The significance of these patient perceptions must still be demonstrated. However, they may play an important role in clinical outcomes and patient satisfaction.

Complications in spinal deformity surgery: issues unrelated directly to intraoperative technical skills.

Study Design. Literature review of complications unrelated directly to surgical skills involved in spinal deformity surgery. Objective. Highlight complications associated with perioperative issues. Summary of Background Data. Complications can arise from mundane events that arise during the operative experience, but are not directly related to surgical skills. Methods. Literature reviews that touches on the more common potential complication events that do not involve direct surgical expertise. Results. The topics of positioning, nutrition, blood loss, comorbidities, OR time, and pulmonary and GI concerns are discussed as basics that could derail a surgical outcome even with an otherwise uneventful surgical technique. The need for vigilance is stressed and the nuances of understanding these are discussed. Conclusion. Mundane events can derail a perfectly executed surgical undertaking. Attention to detail, team work, close monitoring, and checklist type focus will help to improve, focus, and avoid these preventable complications that have nothing to do with direct surgical skills.