Adverse Effects Associated With High-Dose Recombinant Human Bone Morphogenetic Protein-2 Use in Anterior Cervical Spine Fusion

Shields, Lisa B. E.; Raque, George H.; Glassman, Steven D.; Campbell, Mitchell; Vitaz, Todd W.; Harpring, John; Shields, Christopher B.

doi:10.1097/01.brs.0000201424.27509.72

Cited by 630 publications

(467 citation statements)

References 28 publications

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“…Scaffold-based BMP delivery, especially on an absorbable collagen sponge (eg, ACS-rhBMP-2), has become popular as a clinical therapeutic alternative, at least in the United States, on the basis of promising animal and clinical results [20,24,35,37,38,46]. However, evidence of large doses of rhBMP-2 leading to instances of heterotopic ossification, excessive inflammation, or poor bone structure has led to concerns regarding its clinical use, where an exact dose-response relationship has not been determined [6,37,38,47]. It is thought that research that demonstrates efficacy with use of lower doses and/or a more sustained delivery of rhBMP-2 could thus lead to increased use of rhBMP-2 in place of autografts.…”

Section: Discussionmentioning

confidence: 99%

Hydrogel-based Delivery of rhBMP-2 Improves Healing of Large Bone Defects Compared With Autograft

Krishnan

Priddy

Esancy

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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Background Autologous bone grafting remains the gold standard in the treatment of large bone defects but is limited by tissue availability and donor site morbidity. Recombinant human bone morphogenetic protein-2 (rhBMP-2), delivered with a collagen sponge, is clinically used to treat large bone defects and complications such as delayed healing or nonunion. For the same dose of rhBMP-2, we have shown that a hybrid nanofiber mesh-alginate (NMA-rhBMP-2) delivery system provides longer-term release and increases functional bone regeneration in critically sized rat femoral bone defects compared with a collagen sponge. However, no comparisons of healing efficiencies have been made thus far between this hybrid delivery system and the gold standard of using autograft. Questions/purposes We compared the efficacy of the NMA-rhBMP-2 hybrid delivery system to morselized autograft and hypothesized that the functional regeneration of large bone defects observed with sustained BMP delivery would be at least comparable to autograft treatment as measured by total bone volume and ex vivo mechanical properties. Methods Bilateral critically sized femoral bone defects in rats were treated with either live autograft or with the NMA-rhBMP-2 hybrid delivery system such that each animal received one treatment per leg. Healing was monitored by radiography and histology at 2, 4, 8, and 12 weeks. Defects were evaluated for bone formation by longitudinal micro-CT scans over 12 weeks (n = 14 per group). The bone volume, bone density, and the total new bone formed beyond 2 weeks within the defect were calculated from micro-CT reconstructions and values compared for the 2-, 4-, 8-, and 12-week scans within and across the two treatment groups. Two animals were used for bone labeling with subcutaneously injected dyes at 4, 8, and 12 weeks followed by histology at 12 weeks to

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Section: Discussionmentioning

confidence: 99%

Hydrogel-based Delivery of rhBMP-2 Improves Healing of Large Bone Defects Compared With Autograft

Krishnan

Priddy

Esancy

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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“…Its practical application is limited by the significant cost of application, which can be up to U$7000 per fusion level 45,46 . despite the early enthusiasm researchers expressed for using rhBMP-2 to enhance spinal fusion, there are significant risks associated with using BMP' s supraphysiological doses including inflammatory reaction, effusion, seroma, ectopic bone formation and other untoward side effects not appreciated earlier in their use 47 . BMP-2 has been approved by the FdA for its use in conjunction with threaded cages and bone dowels for singlelevel ALIFs, and has been successfully used in postero-lateral fusion associated with local bone or bone expander 48 .…”

Section: Bone Grafts and Adjuncts To Fusionsmentioning

confidence: 99%

Degenerative lumbar stenosis: update

Joaquim

Sansur

Hamilton

et al. 2009

Arq. Neuro-Psiquiatr.

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-We present a literature review of the diagnosis and treatment of acquired lumbar spinal stenosis (LS), with a brief description of new surgical techniques. LS is the most common cause of spinal surgery in individuals older than 65 years of age. Neurogenic claudication and radiculopathy result from compression of the cauda equina and lumbosacral nerve roots by degenerated spinal elements. Surgical decompression is a well established treatment for patients with refractory, or moderate to severe clinical symptoms. However, the variety of surgical options is vast. New techniques have been developed with the goal of increasing long term functional outcomes. In this article we review lumbar decompression and fusion as treatment options for LS but also present other recent developments. Prospective long term studies are necessary to know which procedures would result in optimal patient outcome.Key WordS: acquired lumbar stenosis, surgical treatment, new techniques, fusion. estenose lombar degenerativa: atualização resumo -Apresentamos uma revisão de literatura do diagnóstico e tratamento da estenose lombar (eL) adquirida, enfatizando as novas técnicas de manejo cirúrgico. A eL é a causa mais comum de cirurgia na coluna de pacientes com mais de 65 anos de idade. Claudicação neurogênica e radiculopatias são sintomas resultantes da compressão das raízes lombossacrais pelos elementos degenerados. A descompressão cirúrgica é um procedimento bem estabelecido para pacientes com sintomas severos ou refratários ao tratamento clínico. Contudo, as opções cirúrgicas são amplas. Novas técnicas de fusão e artrodese são úteis para melhorar os resultados funcionais. Neste artigo, varias alternativas cirúrgicas são apresentadas, incluindo as novas tecnologias na área. evidências científicas mais contundentes com seguimento longo são necessárias para a incorporação destas práticas na atividade médica de rotina.PALAvrAS-CHAve: estenose lombar adquirida, tratamento cirúrgico, novas técnicas, fusão.

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“…19 Based on data from nonhuman primates, the minimum effective human BMP2 concentration was initially set at 1.5 mg/mL (total dose, 4.2 to 12 mg) in pilot and pivotal trials in humans and is currently the approved concentration for clinical use. 19e21 Unfortunately, the high BMP2 concentrations required for osteogenesis in humans are associated with significant adverse effects, including an FDA warning of life-threatening cervical swelling, 22 ectopic bone formation (U.S. Food and Drug Administration, http://www.fda. gov/MedicalDevices/Safety/AlertsandNotices/PublicHealth Notifications/ucm062000.htm, last accessed September 28, 2011), 23 osteoclastogenesis, 24 and inconsistent bone formation.…”

mentioning

confidence: 99%

Novel Wnt Regulator NEL-Like Molecule-1 Antagonizes Adipogenesis and Augments Osteogenesis Induced by Bone Morphogenetic Protein 2

Shen

James

Zhang

et al. 2016

The American Journal of Pathology

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The differentiation factor NEL-like molecule-1 (NELL-1) has been reported as osteoinductive in multiple in vivo preclinical models. Bone morphogenetic protein (BMP)-2 is used clinically for skeletal repair, but in vivo administration can induce abnormal, adipose-filled, poorquality bone. We demonstrate that NELL-1 combined with BMP2 significantly optimizes osteogenesis in a rodent femoral segmental defect model by minimizing the formation of BMP2-induced adipose-filled cystlike bone. In vitro studies using the mouse bone marrow stromal cell line M2-10B4 and human primary bone marrow stromal cells have confirmed that NELL-1 enhances BMP2-induced osteogenesis and inhibits BMP2-induced adipogenesis. Importantly, the ability of NELL-1 to direct BMP2-treated cells toward osteogenesis and away from adipogenesis requires intact canonical Wnt signaling. Overall, these studies establish the feasibility of combining NELL-1 with BMP2 to improve clinical bone regeneration and provide mechanistic insight into canonical Wnt pathway activity during NELL-1 and BMP2 osteogenesis. The novel abilities of NELL-1 to stimulate Wnt signaling and to repress adipogenesis may highlight new treatment approaches for bone loss in osteoporosis. NEL-like molecule-1 (NELL-1) is an osteoinductive growth factor first identified through its overexpression in pathologically fusing suture specimens from patients with craniosynostosis. 1,2 Transgenic Nell1-overexpressing mice recapitulate craniosynostosis-like phenotypes, exhibiting gross calvarial bone overgrowth and increased osteoblast differentiation. 3 Conversely, Nell1 deficiency severely disrupts bone growth, as mice with nonsense mutations in Nell1 die perinatally with major skeletal anomalies in the craniofacial complex, spine, and long bones. 4e6 Highlighting the central role of NELL-1 in skeletal development, NELL-1 mediates key downstream effects of the master osteogenic regulator runt-related transcription factor 2 (RUNX2) 7 and can partially rescue RUNX2 loss of function. 8 NELL-1 can also transiently activate mitogen-activated protein kinase signaling to induce RUNX2 phosphorylation and osteogenic differentiation. 9 Recently, we

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Adverse Effects Associated With High-Dose Recombinant Human Bone Morphogenetic Protein-2 Use in Anterior Cervical Spine Fusion

Cited by 630 publications

References 28 publications

Hydrogel-based Delivery of rhBMP-2 Improves Healing of Large Bone Defects Compared With Autograft

Hydrogel-based Delivery of rhBMP-2 Improves Healing of Large Bone Defects Compared With Autograft

Degenerative lumbar stenosis: update

Novel Wnt Regulator NEL-Like Molecule-1 Antagonizes Adipogenesis and Augments Osteogenesis Induced by Bone Morphogenetic Protein 2

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