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A biologic without guidelines: The YODA project and the future of bone morphogenetic protein-2 research

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... As a specialty, we should ask ourselves: at what point does financial conflict of interest become a concerning issue? Studies have shown that once physicians receive payments of $5,000, they begin to alter their behavior [23]. Although conflict of interest bias may not increase proportionately with financial incentives, it is not likely to decrease the bias either. ...
... Although conflict of interest bias may not increase proportionately with financial incentives, it is not likely to decrease the bias either. Thus, there is no true way to estimate or adjust for potential biases that stem from some of these multimillion-dollar financial relationships [23,24]. Further studies on the effects of these financial conflicts of interest on medical decision making are needed. ...
Article
Background: Financial relationships between editorial board members of peer-reviewed journals and pharmaceutical and medical device manufacturing companies can potentially lead to biases and loss of objectivity of the medical literature. The purpose of this study was to evaluate the potential financial conflicts of interest that exist among editorial board members of dermatology journals. Methods: Editorial board members for 36 dermatology journals were identified and searched using the Open Payments database on the Center for Medicare and Medicaid Services website. The total amount of general payments made to these physician editors were collected and stratified using a tier system: 1) nothing reported, 2) >$0 and <$10,000, 3) >$10,000 and <$100,000, and 4) >$100,000. Results: We identified 551 editors from 36 dermatology journals for use in our analysis. Some form of general payment was made to 87% of these physicians (480 of 551). Four journals had >25% of their editorial staff receiving >$100,000. Conclusions: Financial relationships exist between editorial board members of dermatology journals and pharmaceutical/medical device manufacturing companies, which could lead to financial conflicts of interest. Publications coming from journals with highly paid physician editors have more potential to be biased.
... However, a company took over and called it Infuse [BMP-2]. Interestingly, James Kang wrote an article [18] showing that the company had all kinds of consultants with them, but when the consultant wrote the article, usually 'no complications' was reported. We know the product works, but the big question is whether there are complications. ...
... The Orthopaedic Research Society has given a "Marshall R. Urist Award" every year since 1997. 18 John Bergfeld, M.D. is an orthopaedic surgeon and sports medicine specialist in Cleveland, OH. He is a senior surgeon in the Department of Orthopaedic Surgery at the Cleveland Clinic. ...
... The research climate is high risk, particularly for investigators involved in industry-supported research involving drugs with the potential for widespread clinical use. An example is the approval of BMP-2 for use in spine fusions 37 . During the FDA approval process, Medtronic supported seventeen clinical trials. ...
... The original publications received ongoing analysis and scrutiny in the scientific literature and in the public press. Congressional investigation ensued and the orthopaedic surgeons involved in the studies were targeted in the press, in congressional hearings, and in the scientific literature 37 . In response to these pressures, Medtronic contracted with Yale University (Yale Open Data Access project; YODA) 38,39 . ...
Article
High-quality medical care is the result of clinical decisions based upon scientific principles garnered from basic, translational, and clinical research. Information regarding the natural history of diseases and their responses to various treatments is introduced into the medical literature through the approximately one million PubMed journal articles published each year. Pharmaceutical and device companies, universities, departments, and researchers all stand to gain from research publication. Basic and translational research is highly competitive. Success in obtaining research funding and career advancement requires scientific publication in the medical literature. Clinical research findings can lead to changes in the pattern of orthopaedic practice and have implications for the utilization of pharmaceuticals and orthopaedic devices. Research findings can be biased by ownership of patents and materials, funding sources, and consulting arrangements. The current high-stakes research environment has been characterized by an increase in plagiarism, falsification or manipulation of data, selected presentation of results, research bias, and inappropriate statistical analyses. It is the responsibility of the orthopaedic community to work collaboratively with industry, universities, departments, and medical researchers and educators to ensure the integrity of the content of the orthopaedic literature and to enable the incorporation of best practices in the care of orthopaedic patients. Copyright © 2015 by The Journal of Bone and Joint Surgery, Incorporated.
... As a specialty, we should ask ourselves: at what point does financial conflict of interest become a concerning issue? Studies have shown that once physicians receive payments of $5,000, they begin to alter their behavior [23]. Although conflict of interest bias may not increase proportionately with financial incentives, it is not likely to decrease the bias either. ...
... Although conflict of interest bias may not increase proportionately with financial incentives, it is not likely to decrease the bias either. Thus, there is no true way to estimate or adjust for potential biases that stem from some of these multimillion-dollar financial relationships [23,24]. Further studies on the effects of these financial conflicts of interest on medical decision making are needed. ...
Article
BACKGROUND: Financial relationships between editorial board members of peer-reviewed journals and pharmaceutical and medical device manufacturing companies can potentially lead to biases and loss of objectivity of the medical literature. The purpose of this study was to evaluate the potential financial conflicts of interest that exist among editorial board members of dermatology journals. METHODS: Editorial board members for 36 dermatology journals were identified and searched using the Open Payments database on the Center for Medicare and Medicaid Services website. The total amount of general payments made to these physician editors were collected and stratified using a tier system: 1) nothing reported, 2) >$0 and <$10,000, 3) >$10,000 and <$100,000, and 4) >$100,000. RESULTS: We identified 551 editors from 36 dermatology journals for use in our analysis. Some form of general payment was made to 87% of these physicians (480 of 551). Four journals had >25% of their editorial staff receiving >$100,000. CONCLUSIONS: Financial relationships exist between editorial board members of dermatology journals and pharmaceutical/medical device manufacturing companies, which could lead to financial conflicts of interest. Publications coming from journals with highly paid physician editors have more potential to be biased.
... Gene therapy is arguably a safer technique compared to the application of various growth factors, as the latter could have undesirable effects on other cell types such as inducing their proliferation or tumorigenesis. For example, recent studies highlighted some adverse effects and complications related to BMP-2 administration in humans [41,42]. However, in order to develop gene therapy approaches for ACL reconstruction, a better knowledge of the mode of action of candidate growth factors on MSCs is needed. ...
Article
Full-text available
Tendon and ligament injuries are the most common problems in adult health accounting for about half of all musculoskeletal injuries. Rupture of the anterior cruciate ligament (ACL) results in the loss of whole joint stability leading to meniscal rupture, cartilage damage and early osteoarthritis. Arthroscopic reconstruction using autografts or allografts has known drawbacks such as ligament laxity, donor site morbidity and long recovery periods. In addition to the appropriate mechanical environment, several biological factors have been implicated in the ACL healing process including specialised growth factors and mesenchymal stem cells (MSCs). However, in order to produce a superior molecular and biomechanical ACL there will be always the need to provide a suitable scaffold to 'house' MSCs and to provide adequate biomechanical properties in order for the regeneration process to proceed. Understanding the mechanisms of ACL healing following cellular therapy may lead to novel, more effective and biological-based tissue engineering strategies for ACL reconstruction. The focus of this review is the current knowledge of ACL reconstruction after joint trauma when combining MSC and tissue engineering technologies.
... Lastly, the use of bone morphogenetic proteins can be a confounding factor. Concerns were addressed regarding complications associated with the use of BMP-2 in spinal indications, which include radiculitis, osteolysis, retrograde ejaculation, and ectopic bone formation [31]. For OP-1, as used in the current study, no major complications were reported associated with its use, although few case reports were published on ectopic bone formation [32,33]. ...
Article
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In instrumented posterolateral fusion reduction of a spondylolisthesis is appealing on theoretical grounds since this may lead to indirect decompression of the entrapped nerve roots. However, there is no consensus in the literature whether a beneficial effect of reduction on outcome can be expected. The objective of the current study was to evaluate whether a correlation between the extent of listhesis reduction and clinical improvement could be established. From two ongoing prospective studies 72 patients with a single-level instrumented posterolateral lumbar fusion for low-grade spondylolisthesis (isthmic/degenerative 51/21) were evaluated. Radiographs and clinical outcome scores were available at baseline, 6 weeks and 1 year after surgery. Changes in neuroforaminal morphology were measured on calibrated radiographs. These changes in radiographic parameters were correlated to clinical outcome (Visual Analogue Score (VAS) leg pain, Oswestry Disability Index (ODI)). Fusion status was assessed on Computed Tomography-scan at one year. A mean spondylolisthesis of 25 percent was reduced to 15 percent at 6 weeks with some loss of reduction to 17 percent at one year. The VAS and ODI significantly improved at both time intervals after surgery (p < 0.001). No significant correlations could be established between the extent of slip reduction and improvement in VAS or ODI (Pearson's correlation -0.2 and 0.07 respectively at one year); this also accounted for the other radiographic parameters. A fusion rate of 64 percent was seen on CT-scan. Clinical outcome was not related to the obtained radiographic reduction of the slipped vertebra in patients with a lumbar fusion for low grade spondylolisthesis. Loss of reduction or non-union on CT-scans had no effect on the clinical outcome. Reduction of a low-grade spondylolisthesis in spinal fusion is appealing, however, there is no evidence that it positively affects clinical outcome on the short term.Trial registration: ISRCTN43648350.
... However, concerns have been raised about the degree of control of BMP-2 release from the product and potentially serious reactions when the product is used off-label such as ectopic bone formation, nerve damage, edema and inflammation (9)(10)(11). Most recently, the possibility that BMP is cancer promoting has further clouded the view of how these products are best used (12)(13)(14). The limitations and potential complications associated with these early osteobiologic treatments has driven development of even more biologically-based approaches, which included living cells to provide more refined control over bone formation. ...
Article
This review summarizes recent efforts to create vascularized bone tissue in vitro and in vivo through the use of cell-based therapy approaches. The treatment of large and recalcitrant bone wounds is a serious clinical problem, and in the United States approximately 10% of all fractures are complicated by delayed union or non-union. Treatment approaches with the use of growth factor and gene delivery have shown some promise, but results are variable and clinical complications have arisen. Cell-based therapies offer the potential to recapitulate key components of the bone-healing cascade, which involves concomitant regeneration of vasculature and new bone tissue. For this reason, osteogenic and vasculogenic cell types have been combined in co-cultures to capitalize on the function of each cell type and to promote heterotypic interactions. Experiments in both two-dimensional and three-dimensional systems have provided insight into the mechanisms by which osteogenic and vasculogenic cells interact to form vascularized bone, and these approaches have been translated to ectopic and orthotopic models in small-animal studies. The knowledge generated by these studies will inform and facilitate the next generation of pre-clinical studies, which are needed to move cell-based orthopaedic repair strategies into the clinic. The science and application of cytotherapy for repair of large and ischemic bone defects is developing rapidly and promises to provide new treatment methods for these challenging clinical problems.
... In spinal surgery, and particular for minimally invasive techniques, alternative strategies including BMP2laden matrices [4,5], synthetic grafts [5,6] or local delivery of autologous bone marrow (BM) aspirate [5] have been employed. Recombi nant BMP2 use has recently raised safety concerns due to potential increased risks of adverse events including inflammation and possible new malignancy [7,8], while synthetic calcium phosphate grafts can only provide the osteoconductive scaffolding component. Local (BM) aspirate injections on the other hand, typically have low osteogenic cell yields and poor cellular attachment to scaf folds, which may lead to only a few osteo genic cells remaining at the intended site of repair [9]. ...
Article
Full-text available
Aim: To enumerate and characterize multipotential stromal cells (MSCs) in a cellular bone allograft and compare with fresh age-matched iliac crest bone and bone marrow (BM) aspirate. Materials & methods: MSC characterization used functional assays, confocal/scanning electron microscopy and whole-genome microarrays. Resident MSCs were enumerated by flow cytometry following enzymatic extraction. Results: Allograft material contained live osteocytes and proliferative bone-lining cells defined as MSCs by phenotypic and functional capacities. Without cultivation/expansion, the allograft displayed an 'osteoinductive' molecular signature and the presence of CD45(-)CD271(+)CD73(+)CD90(+)CD105(+) MSCs; with a purity over 100-fold that of iliac crest bone. In comparison with BM, MSC numbers enzymatically released from 1 g of cellular allograft were equivalent to approximately 45 ml of BM aspirate. Conclusion: Cellular allograft bone represents a unique nonimmune material rich in MSCs and osteocytes. This osteoinductive graft represents an attractive alternative to autograft bone or composite/synthetic grafts in orthopedics and broader regenerative medicine settings.
... This need is further emphasized by a recent YODA meta-analysis that discusses the lack of investigation Data from the National Inpatient Sample Fig. 1 Costs obtained from the National Inpatient Sample. Adjusted to 2011 dollar amounts of older and sicker patients may be a fundamental pitfall of current BMP literature [32]. Although studies have shown that this aging population may not be the majority of patients receiving BMP, the lack of data exploring the safety profile and benefits in this rapidly growing group is a cause for concern. ...
Article
Bone morphogenetic protein (BMP) utilization as an adjunct for spinal arthrodesis has gained considerable momentum among spine surgeons. Despite carrying Food and Drug Administration approval for only single level anterior lumbar interbody fusion from L4-S1, the majority of BMP administration is in "off label" settings. Over the last decade, BMP utilization has increased in all facets of spine surgery with the only exception being the anterior cervical spine, in which a downward trend resulted following the 2008 Food and Drug Administration warnings. The future application of BMP in spinal fusion, especially in anterior cervical fusions, will need to be further clarified in terms of efficacy, complications, and cost-effectiveness.
... The FDA only approves the use of BMP for anterior lumbar fusion surgery. Controversy also exists concerning BMP use in the lumbar spine with a lack of solid evidence of safety and efficacy [23]. Current clinical concern regarding the use of BMPs is due to complications of ectopic or heterotopic bone formation and radiculitis, which may cause neuropathic pain. ...
Article
Full-text available
Degenerative conditions of the lumbar spine are extremely common. Ninety percent of people over the age of 60 years have degenerative change on imaging; however, only a small minority of people will require spine surgery (Hicks et al. Spine (Phila Pa 1976) 34(12):1301-1306, 2009). This minority, however, constitutes a core element of spinal surgery practice. Whilst the patient outcomes from spinal surgeries have improved in recent years, some patients will remain with pain and disability despite technically successful surgery. Advances in regenerative medicine and stem cell therapies, particularly the use of mesenchymal stem cells and allogeneic mesenchymal precursor cells, have led to numerous clinical trials utilising these cell-based therapies to treat degenerative spinal conditions. Through cartilage formation and disc regeneration, fusion enhancement or via modification of pain pathways, stem cells are well suited to enhance spinal surgery practice. This review will focus on the outcomes of lumbar spinal procedures and the role of stem cells in the treatment of degenerative lumbar conditions to enhance clinical practice. The current status of clinical trials utilising stem cell therapies will be discussed, providing clinicians with an overview of the various cell-based treatments likely to be available to patients in the near future.
... However, these adverse events have essentially become nonexistent since improved safety and donor screening measures have been implemented. Recombinant human bone morphogenetic protein-2 (rhBMP-2) is a synthetic osteoinductive material that has known drawbacks, including high cost, no clinical guidelines, off-label usage, and a high rate of complications [6]. Osteolysis and subsidence are particularly serious adverse events associated with the use of rhBMP-2 secondary to known osteoclastogenic effects [7]. ...
Article
Full-text available
Background With the modernization of biotechnology, there has been a concerted effort to create novel biomaterials to promote arthrodesis for spine surgery. The novel use of the stem cells from bone marrow aspirate (BMA) to augment spine surgery is a burgeoning field because these cells are considered to be both osteoinductive and osteogenic. We sought to review the evidence behind the use of BMAs in spinal fusions and report the results of our own case series. Methods PubMed and EMBASE databases were searched for studies that investigated the use of stem cells for spine surgery. For our own case series, the medical records of 150 consecutive patients who underwent a lumbar spinal fusion with BMA were retrospectively reviewed for adverse events (AEs) for up to two years after surgery. Results In our case series, there were no AEs identified in 49% of our patients. Of the identified AEs, 61% were unrelated to the use of BMA (e.g., UTI and heart failure), with the remaining 39% likely unrelated to its use (e.g., back pain and anemia). There was a 92.8% arthrodesis rate with the use of BMA. Conclusions We reviewed the rationale, basic science, and clinical science for BMA usage in spine surgery and concluded that BMA is safe for use in spine surgery and is associated with a high rate of arthrodesis.
... Safety is always a major concern regarding the clinical use of biologics and this has become particularly true for rhBMP-2/ACS. Adverse effects related to on-and off-label rhBMP-2/ACS use for spine surgery have gained considerable attention and publication of independent reviews of earlier publications and data disclosure under the Yale Open Data Access (YODA) project (Carragee et al. 2012;Laine et al. 2013;Resnick and Bozic 2013). Safety data for application of rhBMP-2/ACS in craniofacial settings are mostly limited to that reported in industrysponsored studies. ...
Chapter
Surgical placement of dental implants is governed by the prosthetic design and the morphology and quality of the alveolar bone. Often, implant placement may be difficult, if at all possible, due to alveolar ridge aberrations. In consequence, prosthetically dictated implant positioning commonly entails bone augmentation procedures. We herein discuss the unique biologic potential, the clinical relevance, and perspectives of bone morphogenetic protein (BMP) technologies (focus on rhBMP-2) for alveolar bone augmentation. We also address merits and short-comings of current treatment protocol including bone biomaterials and guided bone regeneration (GBR). In perspective, our studies suggest that BMPs have an unparalleled, dose-dependent potential to augment alveolar bone and in turn support dental implant fixation and functional loading. Inclusion of BMPs for alveolar augmentation to facilitate dental implant fixation may thus not only enhance predictability of existing clinical protocol but radically change current treatment paradigms making conventional “grafting” and GBR procedures altogether obsolete.
... In spinal surgery, and particular for minimally invasive techniques, alternative strategies including BMP2laden matrices [4,5], synthetic grafts [5,6] or local delivery of autologous bone marrow (BM) aspirate [5] have been employed. Recombi nant BMP2 use has recently raised safety concerns due to potential increased risks of adverse events including inflammation and possible new malignancy [7,8], while synthetic calcium phosphate grafts can only provide the osteoconductive scaffolding component. Local (BM) aspirate injections on the other hand, typically have low osteogenic cell yields and poor cellular attachment to scaf folds, which may lead to only a few osteo genic cells remaining at the intended site of repair [9]. ...
Conference Paper
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Background: Spinal arthrodeses rely on the use of autograft bone or bone graft substitutes to bridge vertebrae. The aim of this study was to investigate the presence of pre-osteoblast, multipotential stromal cells (MSCs) in a clinically-used bone allograft material (Osteocel Plus) and to compare their abundance with freshly collected, bone marrow aspirates (BMA) and autograft bone. Methods: Scanning electron microscopy was used to visualise cells in situ. A novel flow cytometric technique was developed to enumerate MSCs and hematopoietic-lineage cells (HLCs) following their enzymatic removal from bone. Whole genome microarrays were utilized to characterize the allograft-resident cells in comparison with osteoblasts and fibroblasts. Results: The surface of the allograft contained viable stromal cells capable of growing on-bone and migrating out to form plastic-adherent cultures. Compared to BMA or autograft bone, in which CD271bright MSC frequency was only 0.023% and 0.25% of total live cells, respectively, the cellular component of the allograft was highly enriched for MSCs (average CD271bright MSC frequency 37%). Cell lysates freshly-extracted from the allograft had a molecular signature consistent with MSCs and osteoblasts including the expression of osteogenic transcription factors, bone matrix proteins and bone morphogenetic proteins. The MSC identity of cellular allograft-resident stromal cells was confirmed following standard culture-expansion and differentiation. Conclusions: The presence of highly-pure, bone-anchored and living MSCs represents a unique feature of the Osteocel Plus allograft material. Viable cellular allografts may be suitable for broad use in spinal surgery and bone defect reconstruction instead of autograft bone. Clinical relevance: This study provides the first direct evaluation of MSCs in viable cellular bone allograft and comparative analysis with BM aspirates and autograft bone. This has implications for understanding MSC biology in the pre-clinical and clinical setting and for developing novel bone repair strategies using MSCs.
... The influence of exogenous substances, such as non-steroidal anti-inflammatory drugs and nicotine, on the rate of bone growth has been well characterized, 3,4 and according recommendations for care have been made standard. Recombinant human bone morphogenic proteins have been developed to accelerate bone apposition and, despite controversies surrounding complications and appropriate indications, [5][6][7] have demonstrated success in patients with comorbidities known to inhibit proper bone healing. 8 Beyond mechanical joint stability and an optimal biochemical environment, it is well known that the state of mechanical stress is influential in bone metabolism. ...
Article
Full-text available
Lumbar interbody fusion is a common treatment for a variety of spinal pathologies. It has been hypothesized that insufficient mechanical loading of the interbody graft can prevent proper fusion of the joint. The purpose of this study was to evaluate the mechanical stability and anterior column loading sharing characteristics of a posterior dynamic system compared to titanium rods in an anterior lumbar interbody fusion (ALIF) model. Range of motion, interpedicular kinematics and interbody graft loading were measured in human cadaveric lumbar segments tested under a pure moment flexibility testing protocol. Both systems provided significant fixation compared to the intact condition and to an interbody spacer alone in flexion extension and lateral bending. No significant differences in fixation were detected between the devices. A significant decrease in graft loading was detected in flexion for the titanium rod treatment compared to spacer alone. No significant differences in graft loading were detected between the spacer alone and posterior dynamic system or between the posterior dynamic system and the titanium rod. The results of this study indicate that the posterior dynamic system provides similar fixation compared to that of a titanium rod, however, studies designed to evaluate the efficacy of fixation in a cadaver model may not be sufficiently powered to establish differences in load sharing using the techniques described here.
... The passage of time, analysis of benefits and a proper understanding of the risks led to a marked decline in the use of steroids and now recommendations are that these should not be used in spinal cord injury [10]. More recently, there has been significant controversy regarding the use of recombinant human bone morphogenetic protein-2 (rhBMP-2) augmenting spinal fusion, leading to hostile interchanges between protagonists and antagonists both in the scientific literature11121314 and in the lay media. A recent Yale University open data access project led to the publication of two systematic reviews on patient level data from all clinical trials conducted by Medtronic [15, 16] . ...
Article
Full-text available
The recent publication in this journal of papers by Albert and colleagues [1, 2] from Denmark suggesting that low grade anaerobic bacterial infection may be the underlying cause of significant persistent chronic back pain in a well-defined group of patients has precipitated an unprecedented response in the medical and lay media. In the midst of claim and counterclaim, these studies represent a significant and substantial change in our understanding of the pathophysiology of back pain in some patient groups, and the importance of this should not be lost amidst the negative, unstructured and unscientific response to this study.
... This lack of success has led investigators to suggest that bone grafting procedures 13,65 reviewed in 66 , coupled with biochemical agents, may be the best strategy for treating pre-collapse osteonecrosis 9 . Compared with existing orthopedic biomaterials including recombinant Bone Morphogenetic Protein 2 (BMP2), whose use has been linked to life-threatening adverse events including cancers 67,68 and allogeneic cell products that have no clear mechanism of action 69,70 , a WNT protein therapeutic represents a potentially safer, more efficacious means to accelerate bone healing. Our approach avoids potential issues with acquired resistance because L-WNT3A treatment of a patient's autograft results in enhanced Wnt signaling only in the autograft and not in surrounding tissues. ...
Article
Full-text available
The Wnt pathway is a new target in bone therapeutic space. WNT proteins are potent stem cell activators and pro-osteogenic agents. Here, we gained insights into the molecular and cellular mechanisms responsible for liposome-reconstituted recombinant human WNT3A protein (L-WNT3A) efficacy to treat osteonecrotic defects. Skeletal injuries were coupled with cryoablation to create non-healing osteonecrotic defects in the diaphysis of the murine long bones. To replicate clinical therapy, osteonecrotic defects were treated with autologous bone graft, which were simulated by using bone graft material from syngeneic ACTB-eGFP-expressing mice. Control osteonecrotic defects received autografts alone; test sites received autografts treated ex vivo with L-WNT3A. In vivo µCT monitored healing over time and immunohistochemistry were used to track the fate of donor cells and assess their capacity to repair osteonecrotic defects according to age and WNT activation status. Collectively, analyses demonstrated that cells from the autograft directly contributed to repair of an osteonecrotic lesion, but this contribution diminished as the age of the donor increased. Pre-treating autografts from aged animals with L-WNT3A restored osteogenic capacity to autografts back to levels observed in autografts from young animals. A WNT therapeutic approach may therefore have utility in the treatment of osteonecrosis, especially in aged patients.
... Original pre-clinical research using recombinant human BMP-2 (RhBMP-2) and RhBMP-7 showed promising results in terms of augmenting spinal fusions [50,100]. Although the rise in the use of RhBMP-2 in particular has sparked controversy regarding high rates of complications and off-label uses, there is evidence supporting its use in appropriate clinical situations [16,82]. ...
Article
Spinal fusion surgery is performed all over the world to help patients with cervical and thoracolumbar pathology. As outcomes continue to improve in patients with spine-related pathology, it is important to understand how we got to modern day spinal fusion surgery. Scientific innovations have ranged from the first spinal fusions performed with basic instrumentation in the late nineteenth century to contemporary tools such as pedicle screws, bone grafts, and interbody devices. This article tracks this technological growth so that surgeons may better serve their patients in treating spine-related pain and disability.
... Swelling/inflammation in the neck, painful seroma, ectopic bone formation, retrograde ejaculation [61][62][63][64][65][66][67][68][69][70][71][72] BMP-7 Bone resorption [73,74] future science group Bone tissue in the clinic Review others), angiogenic (PDGF, VEGF, among others), inflammation-control (TNFα, interleukins, interferon-γ, among others) and systemic factors (Vitamin D, growth hormone, calcitonin, parathyroid hormone, among others) [44][45][46][47]. These cell signaling molecules have been studied extensively in the laboratory but few have been used in therapies that have gone through clinical trials. ...
... rhBMP-2 has experienced increased use in clinical practice, and has been discussed extensively in recent literature. [37][38][39][40][41][42][43][44][45][46][47][48][49] ...
Article
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Background: Insufficient data exist on bone graft substitute materials efficacy; two thirds lack any clinical data.1,2 This prospective animal study identified efficacy differences among commercially available materials of several classes. Methods: Historically validated muscle pouch osteoinduction study (OIS) and posterolateral fusion (PLF) were performed in an athymic rat model. Grafting material products implanted were demineralized bone matrix (DBM)-based allografts (Accell EVO3, DBX Mix, DBX Strip, Grafton Crunch, Grafton Flex, Grafton Matrix, Grafton Putty, Magnifuse, and Progenix Plus), allografts (OsteoSponge, MinerOss), cellular allograft (Osteocel Plus), ceramics (Mozaik Strip), or activated ceramics (Actifuse ABX Putty, Vitoss BA). After 4 weeks, OIS specimens were evaluated ex vivo by histologic osteoinductivity. After 8 weeks, PLF ex vivo specimens were evaluated for fusion by manual palpation (FMP), radiography (FXR), and histology (FHISTO). Results: OIS: No materials exhibited a rejection reaction on histology. All DBM-based materials exhibited osteoinductive potential as new bone formation at > 88% of implanted sites. One plain allograft (OsteoSponge) formed bone at 25% of sites. No bone formed for one ceramic (Mozaik Strip), three activated ceramics (Actifuse ABX Putty), or one cellular allograft, regardless of human bone marrow aspirate (hBMA) when added. PLF: Among the 10 DBMs, 6 had FMP of 100% (Accell EVO3, DBX Mix, DBX Strip, Grafton Flex, Grafton Putty, Magnifuse), 2 had FMP of 94% (Grafton Crunch, Grafton Matrix), and 2 conditions had FMP of 0% (Progenix Plus, Progenix Plus + athymic rat iliac crest bone graft [arICBG]). Ceramics (Mozaik Strip), activated ceramics (Actifuse ABX Putty, Vitoss BA), plain allograft (OsteoSponge, MinerOss (PLF study), and cellular allograft (Osteocel Plus) demonstrated 0% FMP. ArICBG demonstrated 13% FMP. Conclusions: Eight DBM-based materials (Accell EVO3, DBX Mix, DBX Strip, Grafton Crunch, Grafton Flex, Grafton Matrix, Grafton Putty, Magnifuse) demonstrated excellent (> 90% FMP) efficacy in promoting fusion via bone healing. Two DBM conditions (Progenix Plus, Progenix Plus + arICBG) showed no manual palpation fusion (FMP). Systematically, over the 2 studies (OIS and PLF), cellular (Osteocel Plus), plain allografts (OsteoSponge, MinerOss; PLF study), ceramic (Mozaik Strip), and activated ceramics (Actifuse ABX Putty, Vitoss BA) demonstrated poor FMP efficacy (< 10%). Clinical relevance: When selecting DBMs, clinicians must be cognizant of variability in DBM efficacy by product and lot. While theoretically osteoinductive, cellular allograft and activated ceramics yielded poor in vivo efficacy. Whole allograft and ceramics may provide osteoconductive scaffolding for mixed-material grafting; however, surgeons should be cautious in using them alone. Direct clinical data are needed to establish efficacy for any bone graft substitute.
... Similarly, it is hypothesised that BMP antagonists, such as NOG and DAN family, are responsible for the reported spinal nonunion, although recombinant human BMP2 (rhBMP2) and rhBMP7 are administered in the orthopaedics in very high doses (Govender et al., 2002;Friedlaender et al., 2001;Haid et al., 2004) probably to compensate for the inhibitory activity of the BMP antagonists. In a clinical setting, inactivating these antagonists may represent a better therapeutic option to enhance bone regeneration, rather than the administration of excessive and non-physiological concentrations of BMPs that also raises safety issues (Carragee et al., 2012). The synthesis of an engineered BMP2 variant called L51P with a substitution of leucine to proline at codon position 51 was previously reported (Keller et al., 2004). ...
Article
Full-text available
Spinal fusion is hampered by the presence of remaining intervertebral disc (IVD) tissue and leads to spinal non-union. While the exact mechanism remains unknown, we hypothesise that factors preventing disc ossification, such as antagonists of the bone morphogenetic proteins (BMP), could be responsible for this process. The objective of this study was to investigate spinal non-union using an in vitro human model with a focus on the BMP signalling components and to identify factors contributing to the incomplete and delayed ossification. Human bone marrow-derived mesenchymal stromal cells (MSC) were cocultured with IVD cells in the presence of L51P, a BMP2 variant with osteoinductive potential. The ossification of MSC was evaluated by quantitative reverse transcription polymerase chain reaction (qPCR), alkaline phosphatase (ALP) activity and alizarin red staining. Endogenous expression of major BMP antagonists, namely Gremlin (GREM1), Noggin (NOG) and Chordin (CHRD) was detected in IVD-derived cells, with abundance in nucleus pulposus cells. Osteogenesis of MSC was hindered by IVD cells as shown by reduced alizarin red staining, ALP activity and qPCR. L51P, added to the cocultures, restored mineralisation, blocking the activity of the BMP antagonists secreted by IVD cells. It is possible that the BMP antagonists secreted by IVD cells are responsible for spinal non-unions. The inhibition of BMP antagonists with L51P may result in an efficient and more physiological osteoinduction rather than delivery of exogenous osteogenic factors. Therefore, L51P might represent an attractive therapeutic candidate for bone healing.
... Both teams of investigators reached to the same conclusion: Despite the higher rate of cancer appearance, the overall absolute risk of carcinogenesis due to the use of rhBMP2 for spinal fusion is generally low [40] . However, Carragee et al [41] supported that despite access to Medtronic trial data, the YODA project will not be able to resolve many, if not most, fundamental safety and efficacy issues on various current uses because there are inadequate trials available. ...
Article
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Bone morphogenetic proteins are osteoinductive factors which have gained popularity in orthopaedic surgery and especially in spine surgery. The use of recombinant human bone morphogenetic protein-2 has been officially approved by the United States Food and Drug Administration only for single level anterior lumbar interbody fusion, nevertheless it is widely used by many surgeons with off-label indications. Despite advantages in bone formation, its use still remains a controversial issue and several complications have been described by authors who oppose their wide use.
Article
A retrospective database review was carried out to evaluate the trends and demographics of rhBMP utilization in single-level posterior lumbar fusion (PLF) in the United States. Patients who underwent single-level PLF from 2005 to 2011 were identified by searching ICD-9 diagnosis and procedure codes in the PearlDiver Patient Records Database (PearlDiver Technologies, Fort Wayne, IN, USA), a national database of orthopaedic insurance records. The year of procedure, age, gender, and region of the United States were recorded for each patient. Results were reported for each variable as the incidence of procedures identified per 100,000 patients searched in the database. Totally 5158 patients had single-level PLF in this study. The average rate of single-level PLF with rhBMP utilization maintained at a relatively stable level (19.1-23.5 %) from 2005 to 2009, but sharply decreased to 6.8 % in 2010 and 6.9 % in 2011. The overall incidence of single-level PLF without rhBMP (1.37 cases per 100,000 patients) was more than five times of the incidence of single-level PLF with rhBMP (0.27 cases per 100,000 patients) (P < 0.01). The average rate of single-level PLF with rhBMP utilization is highest in Midwest (18.7 %), followed by West (18.4 %), South (16.4 %) and Northeast (11.5 %). The highest incidence of single-level PLF with rhBMP was observed in the group aged 70-74 years with an incidence of 0.33 per 100,000 patients. The incidence of rhBMP utilization in single-level PLF increased from 2006 to 2009, but dropped to a low level in 2010 and 2011. The Northeast region had the lowest incidence of rhBMP utilization. The group aged 70-74 years trended to have the higher incidence of single-level PLF with rhBMP utilization.
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Remodeling of the human bony skeleton is constantly occurring with up to 10% annual bone volume turnover from osteoclastic and osteoblastic activity. A shift toward resorption can result in osteoporosis and pathologic fractures, while a shift toward deposition is required after traumatic, or surgical injury. Spinal fusion represents one such state, requiring a substantial regenerative response to immobilize adjacent vertebrae through bony union. Autologous bone grafts were used extensively prior to the advent of advanced therapeutics incorporating exogenous growth factors and biomaterials. Besides cost constraints, these applications have demonstrated patient safety concerns. This study evaluated the regenerative ability of a nanostructured, magnesium-doped, hydroxyapatite/type I collagen scaffold (MHA/Coll) augmented by autologous platelet-rich plasma (PRP) in an orthotopic model of posterolateral lumbar spinal fusion. After bilateral decortication, rabbits received either the scaffold alone (Group 1) or scaffold with PRP (Group 2) to the anatomic right side. Bone regeneration and fusion success compared to internal control were assessed by DynaCT with 3-D reconstruction at 2, 4, and 6 weeks postoperatively followed by comparative osteogenic gene expression and representative histopathology. Both groups formed significantly more new bone volume than control, and Group 2 subjects produced significantly more trabecular and cortical bone than Group 1 subjects. Successful fusion was seen in one Group 1 animal (12.5%) and 6/8 Group 2 animals (75%). This enhanced effect by autologous PRP treatment appears to occur via astounding upregulation of key osteogenic genes. Both groups demonstrated significant gene upregulation compared to vertebral bone controls for all genes. Group 1 averaged 2.21-fold upregulation of RUNX2 gene, 3.20-fold upregulation of SPARC gene, and 3.67-fold upregulation of SPP1 gene. Depending on anatomical subgroup (cranial, mid, caudal scaffold portions), Group 2 had significantly higher average expression of all genes than both control and Group 1–RUNX2 (8.23–19.74 fold), SPARC (18.67–55.44 fold), and SPP1 (46.09–90.65 fold). Our data collectively demonstrate the osteoinductive nature of a nanostructured MHA/Coll scaffold, a beneficial effect of augmentation with autologous PRP, and an ability to achieve clinical fusion when applied together in an orthotopic model. This has implications both for future study and biomedical innovation of bone-forming therapeutics.
Article
Background content The risks and benefits of recombinant human bone morphogenetic protein-2 (BMP) in posterior lumbar interbody fusion (PLIF) and transforaminal lumbar interbody fusion (TLIF) have been widely reported. However, the BMP dose associated with such reports varied widely. Additionally, data on the location of BMP placement on complications and fusion is lacking. Purpose To determine the minimally effective dose (MED) of BMP which results in optimal fusion rates while minimizing complications; to determine the effects of the location of BMP placement has on fusion rates and complications. Study Design Systematic review and meta-analysis. Study Sample Adult patients undergoing PLIF/TLIF for degenerative indications. Outcome Measures Rates of radiculitis, fusion, osteolysis, heterotopic bone formation and new cancer diagnosis. Methods PubMed, Embase, and Cochrane Database were used to identify studies published between 1/1/2011-8/1/2019 reporting BMP usage in adult patients who underwent PLIF/TLIF degenerative indications. A qualitative and quantitative synthesis was performed to evaluate the MED of BMP and the effect of location of BMP placement on fusion and complications. Complications were defined as osteolysis, heterotopic bone growth, radiculitis, and rate of new cancer diagnosis. Complications and fusion outcomes were each pooled according to commercially available BMP doses. Additionally, complications and fusion outcomes were pooled according to four location groups (interbody cage only, interbody cage + posterolateral gutter [PLG], cage + interspace, and interspace + PLG). Heterogeneity was assessed with Q and I² statistics. Results Twenty-two articles, totaling 2,729 patients were included. Sixteen studies reported fusion and 15 reported complications. Among fusion studies, the mean BMP/level ranged from 1.28-12 mg/level. Among complication studies, the mean BMP/level ranged from 6.7-23.6 mg/level. The pooled overall fusion rate was 94.0% (91.4-95.8 CI). There was no significant difference in fusion and complication rates between different BMP doses. Thirteen studies included data on the location of BMP placement with 1,823 patients. At each BMP location, the fusion rate was not significantly different across the dose ranges (1.28-12 mg/level). We found the fusion rate to be marginally higher in the interspace + PLG group compared to the other groups. When BMP was placed in the interbody cage there was a mild increase in the rate of osteolysis compared to other placement locations. Conclusion Fusion and complication rates did not differ significantly between different doses of BMP with the lowest MED for fusion as low as 1.28 mg/level. The location of BMP placement does not significantly affect fusion or complication rates.
Article
The aim of this systematic review was to evaluate clinical and safety data for recombinant human bone morphogenetic protein-2 (rhBMP-2) in an absorbable collagen sponge (ACS) carrier when used for alveolar ridge/maxillary sinus augmentation in humans. Clinical studies/case series published 1980 through June 2012 using rhBMP-2/ACS were searched. Studies meeting the following criteria were considered eligible for inclusion: >10 subjects at baseline and maxillary sinus or alveolar ridge augmentation not concomitant with implant placement. Seven of 69 publications were eligible for review. rhBMP-2/ACS yielded clinically meaningful bone formation for maxillary sinus augmentation that would allow placement of regular dental implants without consistent differences between rhBMP-2 concentrations. Nevertheless, the statistical analysis showed that sinus augmentation following autogenous bone graft was significantly greater (mean bone height: 1.6 mm, 95% CI: 0.5-2.7 mm) than for rhBMP-2/ACS (rhBMP-2 at 1.5 mg/mL). In extraction sockets, rhBMP-2/ACS maintained alveolar ridge height while enhancing alveolar ridge width. Safety reports did not represent concerns for the proposed indications. rhBMP-2/ACS appears a promising alternative to autogenous bone grafts for alveolar ridge/maxillary sinus augmentation; dose and carrier optimization may expand its efficacy, use, and clinical application.
Article
Nationwide estimates examining Bone Morphogenetic Protein (BMP) use with cervical spine fusions have been limited to perioperative outcomes. Determined the one-year risk of complications, cervical revision fusions, hospital re-admissions and healthcare services utilization. A retrospective cohort study from 2002 to 2009 utilizing a nationwide claims database. There were 61,937 primary cervical spine fusions of which 1,677 received BMP. Complications, revision fusions, 30-day hospital readmission and healthcare utilization. Data for these analyses come from the Thompson Reuters MarketScan® Commercial Claims and Encounters Database © 2010. Patients were aged 18 to 64 receiving and not receiving BMP with a primary (C2-C7) cervical spine fusion. All outcomes were defined by ICD-9 and CPT codes. Complications were analyzed as any complication and stratified by nervous system, wound, and dysphagia or hoarseness. Cervical revision fusions were determined in the one-year follow-up. Hospital re-admission discharge records defined thirty-day hospital re-admission and reason for re-admission. The utilization of at least one healthcare service of cervical spine imaging, epidural usage or rehabilitation service was examined. Poisson regression models were used to estimate the relative risk (RR) and 95% confidence intervals (CI). Linear regression was used to determine time to hospital re-admission. Results were stratified by anterior or posterior and circumferential approach. Patients receiving BMP were 29% more likely to have a complication (adjusted relative risk [aRR]=1.29 ((95% CI 1.14 to 1.46)) and nervous system complication (aRR=1.42 ((95% CI 1.10 to 1.83)). Cervical revision fusions were more likely among patients receiving BMP (aRR=1.69 ((95% CI 1.35 to 2.13)). The risk of 30-day re-admission was greater with BMP use (aRR=1.37 ((95% CI 1.07 to 1.73)), and re-admission occurred on average 27.4% sooner. Patients receiving BMP were more likely to receive computed tomography scans (aRR=1.34 ((95% CI 1.06 to 1.70)) and epidurals with anterior surgical approaches (aRR=1.29 ((95% CI 1.00 to 1.65)). These findings question both the safety and effectiveness of off-label BMP use in primary cervical spine fusions.
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Bone is a vital tissue of the body and a key component of the musculoskeletal system, which routinely overcomes insult and degeneration through its highly regenerative capabilities. However, in certain circumstances bone fails to properly heal and treatment is required. The current standard of care therapies have significant shortcomings. Advances in bioprinting and tissue engineering hold much promise for improving both the quality and efficiency of bone reconstructive therapies. Bioprinting, technically, does not yet occur because custom resorbable scaffolds are not currently constructed with growth factors or autologous cells; however, recent research has been rapidly expanding the 3D printing techniques as well as 3D printable materials with properties finely tuned to reconstruct patient-specific defects. This research seems to be leading toward a future of resorbable scaffolds that incorporate appropriate growth factors and osteoprogenitor cells. Time will reveal whether these therapies will become widely available and standard-of-care.
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Study design: Retrospective database analysis. Objective: A nationwide population-based database was analyzed to assess the utilization trends of bone morphogenetic protein (BMP) in spine fusion surgery from 2002-2011. Summary of background data: The utilization of off-label BMP in spine procedures is not well characterized. The purpose of this study was to analyze a population-based database to characterize the national trends of BMP utilization in terms of incidence, demographics, costs, and mortality. Methods: Data from the Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project was queried for each year from 2002-2011. Patients undergoing an anterior cervical fusion or posterior cervical fusion, anterior lumbar fusion or posterior lumbar fusion, or a posterior thoracic fusion were identified and separated into cohorts. The frequency of BMP utilization was assessed in each surgical cohort by year. Patient demographics, hospital parameters, costs, and mortality rates were assessed. Results: The adjusted annual number of procedures with BMP increased from 1116 in 2002 to 79,294 in 2011 (P < 0.001), representing 26.9% of all spinal fusion procedures. The rate of BMP utilization within each surgical cohort also significantly increased during the 10-year period (P < 0.001). The posterior lumbar fusion cohort accounted for the majority of spinal fusions that used BMP, representing 76.8% of all spinal fusions between 2002 and 2011. The anterior lumbar fusion cohort was associated with the highest proportion of BMP utilization, peaking at 56.9% of all anterior lumbar interbody fusions in 2006. The trend of BMP utilization in the anterior cervical fusion cohort peaked in 2007 with 10.6% of cases and then declined to 6.4% in 2011. There was a statistically significant trend of older patients with increasing comorbidities receiving BMP during this period. Hospital costs (adjusted for inflation) significantly increased an average of $9560 from 2002-2010. There were no significant trends with regard to the length of hospitalization stay and mortality rates during this period. Conclusion: This nonconflicted study demonstrates that the utilization of BMP has dramatically increased from 2002-2011. Interestingly, off-label application of BMP accounts for the vast majority of BMP utilization. The increase in the total hospital costs is likely multifactorial; older patients with more comorbidities undergoing surgery as well as the increasing utilization of BMP are all likely contributory factors. The length of hospitalization stay and mortality rates did not increase during the 10-year period.
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Background context: The use of recombinant human bone morphogenetic protein (BMP) in the thoracolumbar spine remains controversial, with many questioning the risks and benefits of this new biologic. Purpose: To describe national trends, incidence of complications, and revision rates associated with BMP use in thoracolumbar spine procedures. Study design/setting: Administrative database study. Patient sample: A matched cohort of 52,259 patients undergoing thoracolumbar fusion surgery from 2006 to 2010 were identified in the MarketScan database. Patients without BMP treatment were matched 2:1 to patients receiving intraoperative BMP. Outcome measures: Revision rates and postoperative complications. Methods: The MarketScan database was used to select patients undergoing thoracolumbar fusion procedures, with and without intraoperative BMP. We ascertained outcome measures using either International Classification of Disease, ninth revision, or Current Procedural Terminology coding, and matched groups were evaluated using a bivariate and multivariate analyses. Kaplan-Meier estimates of fusions failure rates were also calculated. Results: Patients receiving intraoperative BMP underwent fewer refusions, decompressions, posterior and anterior revisions, or any revision procedure (single level 4.53% vs. 5.85%, p<.0001; multilevel 5.02% vs. 6.83%, p<.0001; overall cohort 4.73% vs. 6.09%, p<.0001). After adjusting for comorbidities, demographics, and levels of procedure, BMP was not associated with the postoperative development of cancer (odds ratio 0.92). Bone morphogenetic protein use was associated with an increase in any complication at 30 days (15.8% vs. 14.9%, p=.0065), which is only statistically significant among multilevel procedures (19.74% vs. 18.02%, p=.0013). Thirty-day complications in multilevel procedures associated with BMP use included new dysrhythmia (4.68% vs. 4.01%, p=.0161) and delirium (1.08% vs. 0.69%, p=.0024). A new diagnosis of chronic pain was associated with BMP use in both single-level (2.74% vs. 2.15%, p=.0019) and multilevel (3.7% vs. 2.52%, p<.0001) procedures. Bone morphogenetic protein was negatively associated with infection in single-level procedures (2.12% vs. 2.64%, p=.0067) and wound dehiscence in multilevel procedures (0.84% vs. 1.18%, p=.0167). Conclusions: In national data analysis of thoracolumbar procedures, we found that BMP was associated with decreased incidence of revision spinal surgery and with a slight increased risk of overall complications at 30 days. Although no BMP-associated increased risk of malignancy was found, lack of long-term follow-up precludes detection of between-group differences in malignancies and other rare events that may not appear until later.
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The original 13 Food and Drug Administration industry-sponsored recombinant human bone morphogenetic protein-2 (rhBMP-2) trials investigating its use in spinal fusion all reported no associated adverse events. However, subsequent series of studies began reporting complication rates that were much higher than those that were initially published. Critical analysis of the original rhBMP-2 industry-associated data found systematic alignment favoring positive outcomes with no proven clinical advantage over bone graft. The sources of potential bias leading to inaccurate reporting of original rhBMP-2 efficacy and safety profile include flawed study design, methodological technique, data reporting and analysis, and significant financial conflict of interest. As such, to ensure the integrity of the scientific literature, further measures should be taken by researchers, surgeons, authors, journal editors and reviewers to assess for potential sources of bias.
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The choice among the many options of approach and adjunct techniques in planning a posterior lumbar fusion can be problematic. Debates remain as to whether solid fusion has an advantage over pseudarthrosis regarding long-term symptom deterioration and whether an instrumented or a noninstrumented approach will best serve clinically and/or cost effectively, particularly in elderly patients. Increased motion resulting in higher rates of nonunion and the use of nonsteroidal anti-inflammatory drugs have been studied in animal models and are presumed risk factors, despite the lack of clinical investigation. Smoking is a proven risk factor for pseudarthrosis in both animal models and level III clinical studies. Recent long-term studies and image/clinical assessment of lumbar fusions and pseudarthrosis show that, although imaging remains a key area of difficulty in assessment, including an instrumented approach and a well-selected biologic adjunct, as well as achieving a solid fusion, all carry important long-term clinical advantages in avoiding revision surgery for nonunion.
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Background: Usage of recombinant human bone morphogenetic protein (rhBMP) in anterior cervical discectomy and fusion (ACDF) procedures is controversial. Studies suggest increased rates of dysphagia, hematoma or seroma, and severe airway compromise in anterior cervical spine procedures using rhBMP. The purpose of the present study was to determine and describe national utilization trends and complication rates associated with rhBMP usage in anterior cervical spine procedures. Methods: The MarketScan database from 2006 to 2010 was retrospectively queried to identify 91,543 patients who underwent ACDF with or without cervical corpectomy. Patient selection and outcomes were ascertained with use of ICD-9-CM (International Classification of Diseases, Ninth Revision, Clinical Modification) and CPT (Current Procedural Terminology) coding. A total of 3197 patients were treated with rhBMP intraoperatively. Mean follow-up was 588 days (interquartile range [IQR], 205 to 886 days) in the non-treated cohort and 591 days (IQR, 203 to 925 days) in the rhBMP-treated cohort. Multivariate logistic regression as well as propensity score analysis were used to evaluate the association of rhBMP usage with postoperative complications. Results: In propensity score-adjusted models, rhBMP usage was associated with an increased risk of any complication (odds ratio [OR] = 1.34, 95% confidence interval [CI] = 1.2 to 1.5) and specific complications such as hematoma or seroma (OR = 1.8, 95% CI = 1.4 to 2.3), dysphagia (OR = 1.3, 95% CI = 1.1 to 1.5), and any pulmonary complication (OR = 1.5, 95% CI = 1.2 to 1.8) within thirty days postoperatively. There were no significant differences in the rates of readmission, in-hospital mortality, referral to pain management, new malignancy, or reoperation between the two cohorts. Usage of rhBMP was associated with a mean increase of $5545 (19%) in total payments to the hospital and primary physician (p < 0.001). Conclusions: We found an increased overall rate of postoperative complications in patients receiving rhBMP for cervical spinal fusion procedures compared with patients not receiving rhBMP. Hematoma or seroma, pulmonary complications, and dysphagia were also more common in the rhBMP cohort. Usage of rhBMP in a case was associated with $311 greater payments to the surgeon and $4213 greater payments to the hospital. Level of evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
Article
Study design: Retrospective longitudinal cohort. Objective: We sought to demonstrate the minimally effective bone morphogenetic protein (BMP) dose to achieve fusion in minimally invasive transforaminal lumbar interbody fusions. Summary of background data: Multiple studies have been conducted, which used a wide range of BMP doses for lumbar fusions highlighting associated risks and benefits. There is, however, a paucity in the literature in determining the minimally effective dose. Methods: Consecutive patients who underwent transforaminal lumbar interbody fusion from 2009 to 2014 were reviewed. Fusion was determined by a combination of computed tomography and dynamic x-ray by independent radiologists. We used backward stepwise multiple logistic regression with fusion as the dependent variable to determine whether BMP dose/level was a significant predictor for fusion. To determine the minimally effective dose of BMP/level, separate logistic regressions for different BMP dose ranges and sensitivity analyses were used. A P value ≤0.025 was considered significant. Results: There were 1102 interspaces among 690 patients. Average BMP dose was 1.28 mg/level. Overall fusion was 95.2% with a mean follow-up of 19 months. BMP dose/level was a significant predictor for fusion. Odds of fusion increased by 2.02 when BMP dose range was increased from (0.16-1 mg/level) to (1.0-2 mg/level), but fusion odds did not increase when BMP dose increased to more than 2 mg/level. Conclusion: BMP dose/level was a significant predictor for fusion. There was a significant increase in odds of fusion when BMP dose increased from 0.16 to 1 mg/level to 1.0 to 2 mg/level. No benefit from increasing the dose more than 2 mg/level was found, suggesting 1.0 mg/level to be the minimally effective BMP dose. Level of evidence: 3.
Article
In the past few years, stem cells have become the focus of research by regenerative medicine professionals and tissue engineers. Embryonic stem cells, although capable of differentiating into cell lineages of all three germ layers, are limited in their utilization due to ethical issues. In contrast, the autologous harvest and subsequent transplantation of adult stem cells from bone marrow, adipose tissue or blood have been experimentally utilized in the treatment of a wide variety of diseases ranging from myocardial infarction to Alzheimer's disease. The physiologic consequences of stem cell transplantation and its impact on functional recovery have been studied in countless animal models and select clinical trials. Unfortunately, the bench to bedside translation of this research has been slow. Nonetheless, stem cell therapy has received the attention of spinal surgeons due to its potential benefits in the treatment of neural damage, muscle trauma, disk degeneration and its potential contribution to bone fusion.
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Over the last few decades, arthroscopy has become the gold standard for the surgical management of most joint diseases, with innumerable investigations performed around the world in order to improve this technology. In the same period, advances in imaging and noninvasive modalities have improved the ability to diagnose and treat sports injuries. Likewise, enhanced understanding of the structure and function of musculoskeletal tissues has increasingly allowed surgeons to individualize the treatment for a patient. Additional advances in technology offer the possibility of quantifying what were previously subjective clinical exam findings, while the identification of disease biomarkers will enable earlier recognition and treatment of damaged tissue. In the event that injury does occur, the application of biologics in the context of arthroscopic surgery may improve healing and facilitate recovery. Despite the promising future of arthroscopy and technology in sports medicine, rigorous research is required before implementing any novel approach in order to protect the patient and maximize outcomes.
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COMMENTARY ON: Woo EJ. Recombinant human bone morphogenetic protein-2: adverse events reported to the Manufacturer and User Facility Device Experience database. Spine J 2012;12:894-9 (in this issue).
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The clinical use of bone morphogenetic protein (BMP) in spinal fusion surgery has recently become controversial. After its approval by the US FDA in July 2002, BMP was adopted by many spine surgeons as a replacement for the more traditional iliac crest bone graft to avoid the complications associated with bone graft harvest. However, as broad clinical use escalated, reports increased of potentially serious complications associated with BMP. Controversy continues, particularly regarding the safety of BMP and whether it should routinely replace iliac crest bone graft for spinal fusion surgery.
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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.
Article
Systematic review. The objectives of this systematic review were to identify the character and rates of complications in patients after the use of BMP in spine fusion surgery and to determine whether there is a dose-response relationship of BMP with complications. BMP is used on-label for ALIF with LT-CAGE and off-label for various spine fusion applications in the cervical, thoracic, and lumbar spines because of its effectiveness in promoting arthrodesis. Multiple studies published over the past several years have highlighted complications associated with BMP in a variety of clinical fusion scenarios. There are no systematic reviews on this topic, and thus, the complication profile of off-label use or physician directed use of BMP in spinal fusion surgery is not well characterized. Some of the reported complications are unique to BMP, which underscores the need for this thorough literature review. A systematic review of the English language literature was performed for articles published between 1990 and June 2009. Electronic databases and reference lists of key articles were searched to identify articles examining the use of BMP in spine surgery. Two independent reviewers assessed the level of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria and disagreements were resolved by consensus. Two hundred forty-' articles that assessed outcomes after BMP use in spinal surgery were identified from the literature; of these, 31 articles were selected for inclusion. We determined that multiple complications are associated after the use of rhBMP-2 in both cervical and lumbar spine fusion surgery. There is a mean incidence of 44%, 25%, and 27% of resorption, subsidence, and interbody cage migration reported for lumbar spine interbody fusion surgery although reoperation or long-term detrimental effect was rare. Cervical studies report a mean 5.8% of postoperative soft tissue problems, including dysphagia, when rhBMP-2 is used for ventral cervical fusion. It was determined that the strength of evidence of the peer-reviewed literature that report on types of complications is high for the lumbar and low for the cervical spine, respectively, and that the current strength of evidence on rates of complications with BMP is moderate and low, respectively. The complication profile of BMP-2 for ALIF with LT-CAGE is well characterized. Because of the lack of substantive data, the same is not true for other types of lumbar fusions, or for cervical or thoracic fusion applications. BMP has been associated with a variety of unique complications in the ventral cervical and lumbar spines. The published data on BMP fail to precisely profile this product's use in fusion surgery; hence, it should be used only after a careful consideration of the relevant data. Well-designed and executed studies are necessary to completely define the incidence of various complications relative to type of BMP, type and region of fusion, surgical technique, dose, and carrier, and importantly, to define the natural history and management of associated complications.
Article
INFUSE (recombinant human bone morphogenetic protein-2 [rh-BMP-2]; Medtronic, Memphis, TN, USA) is approved by the Federal Drug Administration (FDA) only for use with the lumbar tapered fusion device (LT Cage; Medtronic) to perform single-level anterior lumbar interbody fusions (ALIF: L2-S1 levels). INFUSE, however, is widely utilized in an "off-label" capacity for anterior and/or posterior cervical, thoracic, and lumbar surgery. Nevertheless, Medicare and other insurance companies, are now increasingly denying reimbursement (average cost of a "large" INFUSE to the hospital without overhead $5000-6000) to hospitals for INFUSE when utilized "off-label". This commentary looks at several representative studies citing the cons associated with utilizing INFUSE in spinal surgery, contraindications, complications, and cost factors. There are multiple cons of utilizing INFUSE in an "off-label" capacity for spinal surgery. Direct contraindications include pregnancy, allergy to titanium, allergy to bovine type I collagen or rhBMP-2, infection, tumor, liver or kidney disease, immunosuppression (e.g., lupus, HIV/AIDS); contraindications are also seen in those receiving radiation, chemotherapy, or steroids. Reported complications include exuberant/ectopic bone formation, paralysis (cord, nerve damage), dural tears, bowel-bladder and sexual dysfunction, respiratory failure, inflammation of adjacent tissues, fetal developmental complications, scar, excessive bleeding, and even death. Complications are so prevalent in the anterior cervical spine, that many surgeons no longer use it in this region. Similarly, INFUSE complications and indications for posterior lumbar interbody fusions (PLIFs) and transforaminal interbody lumbar fusions (TLIFs) should also be reexamined. More surgeons need to question the safety, efficacy, and appropriate "off-label" use of INFUSE in all spine surgeries.
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The purpose of this article is to relate recent actions by the United States Department of Justice, the Institute of Medicine, the Association of American Medical Colleges (AAMC), and others to the specific challenges confronting the specialty of orthopaedic surgery. Further, it strives to reconcile the duty and value propositions associated with the orthopaedic surgeon-medical device company relationship, with the persistent risks that are attendant to that relationship, and to develop a new path—one that strives to restore the integrity of scientific investigation and day-to-day clinical decision making, while providing justification for future physician-industry interaction. To consider the topic in perspective, it is interesting to assess the origins of the current model of physician-industry interaction as they relate specifically to the issues currently confronting the specialty of orthopaedic surgery. In 1980, novel legislation in the field of intellectual property, the Bayh-Dole Act, for the first time allowed universities and nonprofit organizations to replace the government as the principal beneficiaries of commercial development resulting from basic-science and clinical research. In essence, the act transferred the ownership of discoveries made with the help of federal research grants to the universities and small businesses where those discoveries were made. On the face of it, the Bayh-Dole Act made sense. Convinced that government ownership had deterred the development of incentives necessary to promote innovation and had severely inhibited productivity, supporters saw the act as a remedy for the depressed American economy in the 1970s. The goal of the act was specific—to address the concern that American firms were not using academic research efficiently for commercialization—and it intended to remedy that shortcoming by facilitating patenting and licensing by U.S. universities of inventions from federally funded research. If successful, it could help to usher in a new era of innovation in America. It was an interesting …
Article
Previous studies have demonstrated the ability of recombinant human bone morphogenetic protein to achieve a solid fusion in anterior lumbar interbody arthrodesis. The purpose of this study was to compare iliac crest bone graft and recombinant human bone morphogenetic protein-2, combined with a carrier consisting of bovine collagen and beta-tricalcium phosphate-hydroxyapatite to create a compression-resistant matrix, for instrumented single-level posterolateral arthrodesis. Four hundred and sixty-three patients with symptomatic single-level lumbosacral degenerative disease with no greater than grade-1 spondylolisthesis were treated with single-level instrumented posterolateral arthrodesis through an open midline approach. Patients were randomly assigned to either the recombinant human bone morphogenetic protein-2 matrix group (239 patients) or the autogenous iliac crest bone-graft group (224 patients). The Oswestry Disability Index, Short Form-36, and back and leg pain scores were determined preoperatively and at 1.5, three, six, twelve, and twenty-four months postoperatively. Radiographs and computed tomography scans were made at six, twelve, and twenty-four months postoperatively to evaluate for fusion. The mean operative time and mean blood loss in the recombinant human bone morphogenetic protein-2 matrix group (2.5 hours and 343.1 mL, respectively) were significantly less than those in the iliac crest bone-graft group (2.9 hours and 448.6 mL). Both groups showed similar improvements in clinical outcomes and reduced pain. At twenty-four months, 60% of the iliac crest bone-graft group reported donor-site pain. At twenty-four months, fusion was evident in 96% of the patients in the recombinant human bone morphogenetic protein-2 matrix group compared with 89% in the iliac crest bone-graft group (p = 0.014). There was a significant difference (p = 0.011) in the rate of failures because of nonunion (eighteen patients with an iliac crest bone graft compared with six patients with the recombinant human bone morphogenetic protein-2 matrix). Also, the number of patients requiring second surgeries was significantly higher in the iliac crest bone-graft group (thirty-six patients) compared with the recombinant human bone morphogenetic protein-2 matrix group (twenty patients) (p = 0.015). The use of recombinant human bone morphogenetic protein-2 in instrumented posterolateral lumbar arthrodesis decreases operative time and blood loss and produces earlier and higher fusion rates than does iliac crest bone graft. Clinical outcomes are similar to those with iliac crest bone graft. Thus, the need for harvesting iliac crest bone is eliminated along with the morbidities associated with the harvest procedure.
Article
Bone morphogenetic proteins (BMP) are being increasingly used in orthopaedic surgery. These small molecules are capable of inducing bone formation when delivered in the appropriate concentration and on the appropriate scaffold. Not all BMPs are equally effective, and there are currently only two Food and Drug Administration (FDA)-approved "on-label" applications. There are potential complications related to off-label use of BMPs that need to be understood. When used properly, these molecules have the potential to eliminate the need for iliac crest bone graft harvest and improve the speed and success of bone healing.
Teaching Arrangements: Mayo Clinic (B) IC: Royalties: Nu-vasive (C)
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Speaking/Teaching Arrangements: Mayo Clinic (B). IC: Royalties: Nu-vasive (C);
Zimmer Spine (A) RAD: Con-sulting: UpToDate (A, paid directly to institution); Board of Directors: Foundation for Informed Medical Decision-Making (B)
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Research Support (Investigator Salary): Zimmer Spine (A). RAD: Con-sulting: UpToDate (A, paid directly to institution); Board of Directors: Foundation for Informed Medical Decision-Making (B);
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Trips/Travel: World Spine Care (B), The Spine Journal (A);
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Investigator Salary): NIH (C, Paid directly to institution)
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E.J. Carragee et al. / The Spine Journal 12 (2012) 877–880 (Investigator Salary): NIH (C, Paid directly to institution);