Bradley K. Weiner

A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned

BACKGROUND CONTEXT Increasingly, reports of frequent and occasionally catastrophic complications associated with use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in spinal fusion surgeries are being published. In the original peer review, industry-sponsored publications describing the use of rhBMP-2 in spinal fusion, adverse events of these types and frequency were either not reported at all or not reported to be associated with rhBMP-2 use. Some authors and investigators have suggested that these discrepancies were related to inadequate peer review and editorial oversight. PURPOSE To compare the conclusions regarding the safety and related efficacy published in the original rhBMP-2 industry-sponsored trials with subsequently available Food and Drug Administration (FDA) data summaries, follow-up publications, and administrative and organizational databases. STUDY DESIGN Systematic review. METHODS Results and conclusions from original industry-sponsored rhBMP-2 publications regarding safety and related efficacy were compared with available FDA data summaries, follow-up publications, and administrative and organizational database analyses. RESULTS There were 13 original industry-sponsored rhBMP-2 publications regarding safety and efficacy, including reports and analyses of 780 patients receiving rhBMP-2 within prospective controlled study protocols. No rhBMP-2-associated adverse events (0%) were reported in any of these studies (99% confidence interval of adverse event rate <0.5%). The study designs of the industry-sponsored rhBMP-2 trials for use in posterolateral fusions and posterior lateral interbody fusion were found to have potential methodological bias against the control group. The reported morbidity of iliac crest donor site pain was also found to have serious potential design bias. Comparative review of FDA documents and subsequent publications revealed originally unpublished adverse events and internal inconsistencies. From this review, we suggest an estimate of adverse events associated with rhBMP-2 use in spine fusion ranging from 10% to 50% depending on approach. Anterior cervical fusion with rhBMP-2 has an estimated 40% greater risk of adverse events with rhBMP-2 in the early postoperative period, including life-threatening events. After anterior interbody lumbar fusion rates of implant displacement, subsidence, infection, urogenital events, and retrograde ejaculation were higher after using rhBMP-2 than controls. Posterior lumbar interbody fusion use was associated with radiculitis, ectopic bone formation, osteolysis, and poorer global outcomes. In posterolateral fusions, the risk of adverse effects associated with rhBMP-2 use was equivalent to or greater than that of iliac crest bone graft harvesting, and 15% to 20% of subjects reported early back pain and leg pain adverse events; higher doses of rhBMP-2 were also associated with a greater apparent risk of new malignancy. CONCLUSIONS Level I and Level II evidence from original FDA summaries, original published data, and subsequent studies suggest possible study design bias in the original trials, as well as a clear increased risk of complications and adverse events to patients receiving rhBMP-2 in spinal fusion. This risk of adverse events associated with rhBMP-2 is 10 to 50 times the original estimates reported in the industry-sponsored peer-reviewed publications.

Microdecompression for Lumbar Spinal Canal Stenosis

STUDY DESIGN A description of the technique for lumbar microdecompression and a prospective study of the outcomes. OBJECTIVE To describe and analyze a technique that affords an excellent decompression while minimizing damage to surrounding tissues. SUMMARY OF BACKGROUND DATA Commonly used techniques of lumbar decompression that include bilateral takedown of paraspinal musculature and aggressive bony resection can result in significant iatrogenic sequelae. A less destructive alternative is needed. METHODS Unilateral limited takedown of multifidus was undertaken, and ipsilateral decompression performed. The contralateral side then was addressed under the midline structures with microscopic visualization--thereby preserving the supra-/interspinous ligament complex and the contralateral musculature. Thirty consecutive patients undergoing the procedure were analyzed prospectively and after a follow-up period by independent observers using a modified validated functional outcome score and patient satisfaction measures. RESULTS The technique affords an excellent decompression while minimizing destruction to tissues not directly involved in the pathologic process. Functional outcome scores doubled, and 87% of patients reported high satisfaction rates. CONCLUSIONS Lumbar microdecompression is a minimally invasive technique that appears to provide excellent functional outcomes.

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.

Efficacy of Autologous Growth Factors in Lumbar Intertransverse Fusions

Study Design and Objectives. A retrospective, consecutive series with “blinded” radiographic review was performed to evaluate two groups undergoing lumbar fusion: one with and one without autologous growth factors (AGF). Summary of Background Data. AGF has been shown to promote bone formation in vitro and in vivo in animal studies. Accordingly, it has been promoted to augment lumbar intertransverse fusions. To date, however, no controlled studies have been performed to assess its ability to do so in humans. This article presents the first such study. Materials and Methods. Two groups were studied. The control group consisted of 27 consecutive patients who underwent a single-level intertransverse lumbar fusion using iliac crest bone graft for either degenerative disk disease (DDD) or degenerative spondylolisthesis from January 1999 to November 1999. The AGF group consisted of 32 consecutive patients undergoing an identical procedure for the same indications with iliac crest bone graft augmented with AGF from January 2000 to November 2000. Fusions were assessed radiographically at 1 and 2 years by two independent spine surgeons on AP and lateral flexion/extension radiographs. Results. The fusion rate for the control group was 24 of 27, or 91%. The fusion rate for the AGF group was 18 of 32 or 62%. Conclusions. In this study, the use of AGF resulted in inferior rates of arthrodesis compared with autogenous bone graft alone. Although it is important to note there are several techniques available to produce AGF and that the concentration of AGF may differ between individuals, based on the authors’ findings, they cannot recommend the use of AGF for this indication until further clinical studies, perhaps altering these variables, prove otherwise.

A challenge to integrity in spine publications: years of living dangerously with the promotion of bone growth factors

A challenge to integrity in spine publications: years of living dangerously with the promotion of bone growth factors Eugene J. Carragee, MD*, Alexander J. Ghanayem, MD, Bradley K. Weiner, MD, David J. Rothman, PhD, Christopher M. Bono, MD Department of Orthopedic Surgery, Stanford University School of Medicine, 450 Broadway, Mail Code 6342, Redwood, CA 94063, USA Department of Orthopedic Surgery, Loyola University Medical Center, Maywood, IL, USA Department of Orthopedic Surgery, The Methodist Hospital, Houston, TX, USA Department of Social Medicine and Department of History, Columbia University College of Physicians and Surgeons, New York, NY, USA Department of Orthopedic Surgery, The Spine Journal, Brigham & Women’s Hospital, Boston, MA, USA Received 1 June 2011; accepted 1 June 2011

Spine update: The biopsychosocial model and spine care

Study Design. Spine Update on the biopsychosocial model. Objective. To review and discuss the strengths and weaknesses of the application of the model to spine care. Summary of Background Data. The biopsychosocial model of illness has had (and will continue to have) a significant impact on spine care. It has changed—in a positive way—the ways in which view spinal disease, treat patients, and assess outcomes. To date, however, little discussion has taken place regarding concerns over its implementation. Methods. Using texts covering the general theory of the biopsychosocial model and the literature as the model is applied to spine care, a review was undertaken, evaluating the strengths and weaknesses of the theory’s application to our field. Results. Just as the biomedical model allowed, and continues to allow, significant medical advances via the objective study of pathoanatomic disease; the biopsychosocial model has afforded similar advances by placing the disease back into the patient and emphasizing illness experienced within the patient’s unique biologic, psychological, social, and economic milieu. Thus, the strength of the model is its service as a clear reminder that clinical decisions about how to manage a patient with persistent low back pain living in difficult social conditions are more complex than those for patients who are not. Concerns regarding the model, however, are real and include its application as the primary mode to assess outcomes with a blind eye toward other potential factors; the medical/historical tendency to overweigh psychosocial factors when underlying pathology is not clearly defined; whether or not the theory underlying the model is falsifiable/scientific; whether it affords explanatory or predictive power; whether its implementation improves outcomes; and whether it contributes to the “medicalization” of patients with back pain. Conclusion. The biopsychosocial model has been readily adapted to all aspects of spine care with many positive implications. There are, however, some concerns and negative implications and awareness of these should afford a better appreciation of when and where the model can be most usefully applied.

Evaluation of the osteoinductive potential of a bio-inspired scaffold mimicking the osteogenic niche for bone augmentation.

Augmentation of regenerative osteogenesis represents a premier clinical need, as hundreds of thousands of patients are left with insufficient healing of bony defects related to a host of insults ranging from congenital abnormalities to traumatic injury to surgically-induced deficits. A synthetic material that closely mimics the composition and structure of the human osteogenic niche represents great potential to successfully address this high demand. In this study, a magnesium-doped hydroxyapatite/type I collagen scaffold was fabricated through a biologically-inspired mineralization process and designed to mimic human trabecular bone. The composition of the scaffold was fully characterized by XRD, FTIR, ICP and TGA, and compared to human bone. Also, the scaffold microstructure was evaluated by SEM, while its nano-structure and nano-mechanical properties were evaluated by AFM. Human bone marrow-derived mesenchymal stem cells were used to test the in vitro capability of the scaffold to promote osteogenic differentiation. The cell/scaffold constructs were cultured up to 7 days and the adhesion, organization and proliferation of the cells were evaluated. The ability of the scaffold to induce osteogenic differentiation of the cells was assessed over 3 weeks and the correlate gene expression for classic genes of osteogenesis was assessed. Finally, when tested in an ectopic model in rabbit, the scaffold produced a large volume of trabecular bone in only two weeks, that subsequently underwent maturation over time as expected, with increased mature cortical bone formation, supporting its ability to promote bone regeneration in clinically-relevant scenarios. Altogether, these results confirm a high level of structural mimicry by the scaffold to the composition and structure of human osteogenic niche that translated to faster and more efficient osteoinduction in vivo--features that suggest such a biomaterial may have great utility in future clinical applications where bone regeneration is required.

Treatment of lumbar disc herniation: Evidence-based practice.

Clinical question: What is the best treatment for lumbar disc herniations? Results: For patients failing six weeks of conservative care, the current literature supports surgical intervention or prolonged conservative management as appropriate treatment options for lumbar radiculopathy in the setting of disc herniation. Surgical intervention may result in more rapid relief of symptoms and restoration of function. Implementation: While surgery appears to provide more rapid relief, many patients will gradually get better with continued nonoperative management; thus, patient education and active participation in decision-making is vital.

The mechanical effects of suture anchor insertion angle for rotator cuff repair.

Twelve matched pairs of humerii were instrumented with suture anchor at 90 degrees, 75 degrees, 45 degrees, and 30 degrees relative to the cortical border at the junction of the greater tuberosity and articular surface. Two fixtures were inserted into each specimen at different angles and loaded to failure. Suture anchors failed at an average of 171, 219, 169, and 192 N with 90 degrees, 75 degrees, 45 degrees, and 30 degrees insertion angles, respectively. No statistical difference was detected between groups (P=.08). Although previous authors have prescribed angles < or =45 degrees to improve pull-out strength, the current in vitro data does not support these recommendations.

Multiscale Patterning of a Biomimetic Scaffold Integrated with Composite Microspheres

The ideal scaffold for regenerative medicine should concurrently mimic the structure of the original tissue from the nano- up to the macroscale and recapitulate the biochemical composition of the extracellular matrix (ECM) in space and time. In this study, a multiscale approach is followed to selectively integrate different types of nanostructured composite microspheres loaded with reporter proteins, in a multi-compartment collagen scaffold. Through the preservation of the structural cues of the functionalized collagen scaffold at the nano- and microscale, its macroscopic features (pore size, porosity, and swelling) are not altered. Additionally, the spatial confinement of the microspheres allows the release of the reporter proteins in each of the layers of the scaffold. Finally, the staged and zero-order release kinetics enables the temporal biochemical patterning of the scaffold. The versatile manufacturing of each component of the scaffold results in the ability to customize it to better mimic the architecture and composition of the tissues and biological systems.