Aggressive end plate decortication as a cause of osteolysis after rhBMP-2 use in cervical spine interbody fusion

Smoljanović, Tomislav; Čimić, Mislav; Bojanić, Ivan

doi:10.1016/j.spinee.2009.10.001

Cited by 11 publications

(6 citation statements)

References 12 publications

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“…Once BMP-2 was declared to be FDA approved for one particular surgical procedure coupled with reporting ''near perfect'' safety, 143 this caused an extensive escalation of use in a wide range of orthopaedic procedures. Larger clinical trials were able to unearth more clinically relevant adverse events previously unknown.…”

Section: Discussionmentioning

confidence: 99%

A Review of the Clinical Side Effects of Bone Morphogenetic Protein-2

James

LaChaud

Shen

et al. 2016

Tissue Engineering Part B: Reviews

851

769

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Bone morphogenetic protein-2 (BMP-2) is currently the only Food and Drug Administration (FDA)-approved osteoinductive growth factor used as a bone graft substitute. However, with increasing clinical use of BMP-2, a growing and well-documented side effect profile has emerged. This includes postoperative inflammation and associated adverse effects, ectopic bone formation, osteoclast-mediated bone resorption, and inappropriate adipogenesis. Several large-scale studies have confirmed the relative frequency of adverse events associated with the clinical use of BMP-2, including life-threatening cervical spine swelling. In fact, the FDA has issued a warning of the potential life-threatening complications of BMP-2. This review summarizes the known adverse effects of BMP-2, including controversial areas such as tumorigenesis. Next, select animal models that replicate BMP-2's adverse clinical effects are discussed. Finally, potential molecules to mitigate the adverse effects of BMP-2 are reviewed. In summary, BMP-2 is a potent osteoinductive cytokine that has indeed revolutionized the bone graft substitute market; however, it simultaneously has accrued a worrisome side effect profile. Better understanding of these adverse effects among both translational scientists and clinicians will help determine the most appropriate and safe use of BMP-2 in the clinical setting.

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Section: Discussionmentioning

confidence: 99%

A Review of the Clinical Side Effects of Bone Morphogenetic Protein-2

James

LaChaud

Shen

et al. 2016

Tissue Engineering Part B: Reviews

851

769

View full text Add to dashboard Cite

show abstract

“…Exogenous BMP2 has been demonstrated to induce bone formation, but adverse effects including ectopic bone formation, osteolysis, and seroma formation have been reported [11,12]. Soft tissue inflammation was seen as early as 3 hours after subcutaneous BMP2 implantation in a rat model, an effect dependent on BMP2 dose [39,40].…”

Section: Discussionmentioning

confidence: 99%

“…Although it has been demonstrated to increase osteogenesis in lumbar spine fusions [7,8], inflammatory complications including seroma and osteolysis have been reported [9–12]. Titanium (Ti) dental implants that were dip-coated with BMP2 at concentrations typically used spine fusions also caused bone resorption in the mandible [10].…”

Section: Introductionmentioning

confidence: 99%

Coordinated regulation of mesenchymal stem cell differentiation on microstructured titanium surfaces by endogenous bone morphogenetic proteins

Olivares-Navarrete¹,

Hyzy²,

Haithcock³

et al. 2015

Bone

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Human mesenchymal stem cells (MSCs) differentiate into osteoblasts on microstructured titanium (Ti) surfaces without addition of medium supplements, suggesting that surface-dependent endogenous mechanisms are involved. They produce bone morphogenetic proteins (BMPs), which regulate MSC differentiation and bone formation via autocrine/paracrine mechanisms that are modulated by changes in BMP mRNA and protein, receptors, and inhibitors (Noggin, Cerberus, Gremlin 1, and Chordin). We examined expression of BMPs, their receptors and their inhibitors over time and used BMP2-silenced cells to determine how modulating endogenous BMP signaling can affect the process. MSCs were cultured on tissue culture polystyrene or Ti [PT (Ra<0.4μm); sandblasted/acid-etched Ti (SLA, Ra=3.2μm); or hydrophilic-SLA (modSLA)]. BMP mRNAs and proteins increased by day 4 of culture. Exogenous BMP2 increased differentiation whereas differentiation was decreased in BMP2-silenced cells. Noggin was regulated by day 2 whereas Gremlin 1 and Cerberus were regulated after 6 days. Osteoblastic differentiation increased in cells cultured with blocking antibodies against Noggin, Gremlin 1, and Cerberus. Endogenous BMPs enhance an osteogenic microenvironment whereas exogenous BMPs are inhibitory. Antibody blocking of the BMP2 inhibitor Cerberus resulted in IL-6 and IL-8 levels that were similar to those observed when treating cells with exogenous BMP2, while antibodies targeting the inhibitors Gremlin or Noggin did not. These results suggest that microstructured titanium implants supporting therapeutic stem cells may be treated with appropriately selected agents antagonistic to extracellular BMP inhibitors in order to enhance BMP2 mediated bone repair while avoiding undesirable inflammatory side effects observed with exogenous BMP2 treatment.

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“…14 Thus, it is important to appropriately control signaling by BMPs as they can also stimulate heterotopic bone formation or inflammation. [14][15][16][17][18] This study is based on the hypothesis that implant surface properties could be used to augment bone formation peri-implant without confounding factors associated with exogenous osteoanabolic agents. As a first step, we took advantage of an in vitro model in which human MSCs are cultured on titanium-aluminum-vanadium (Ti6Al4V) substrates with macro/micro/nanostructured surfaces that mimic the physical properties of an osteoclast resorption pit.…”

Section: Introductionmentioning

confidence: 99%

Growth factors produced by bone marrow stromal cells on nanoroughened titanium–aluminum–vanadium surfaces program distal MSCs into osteoblasts via BMP2 signaling

Berger

Bosh

Jacobs

et al. 2020

Journal Orthopaedic Research

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Statement of Clinical Significance: There remains the need to develop materials and surfaces that can increase the rate of implant osseointegration. Though osteoanabolic agents, like bone morphogenetic protein (BMP), can provide signaling for osteogenesis, the appropriate design of implants can also produce an innate cellular response that may reduce or eliminate the need to use additional agents to stimulate bone formation. Studies show that titanium implant surfaces that mimic the physical properties of osteoclast resorption pits regulate cellular responses of bone marrow stromal cells (MSCs) by altering cell morphology, transcriptomes, and local factor production to increase their differentiation into osteoblasts without osteogenic media supplements required for differentiation of MSCs on tissue culture polystyrene (TCPS). The goal of this study was to determine how cells in contact with biomimetic implant surfaces regulate the microenvironment around these surfaces in vitro. Two different approaches were used. First, unidirectional signaling was assessed by treating human MSCs grown on TCPS with conditioned media from MSC cultures grown on Ti6Al4V biomimetic surfaces. In the second set of studies, bidirectional signaling was assessed by coculturing MSCs grown on mesh inserts that were placed into culture wells in which MSCs were grown on the biomimetic Ti6Al4V substrates. The results show that biomimetic Ti6Al4V surface properties induce MSCs to produce factors within 7 days of culture that stimulate MSCs not in contact with the surface to exhibit an osteoblast phenotype via endogenous BMP2 acting in a paracrine signaling manner.

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Aggressive end plate decortication as a cause of osteolysis after rhBMP-2 use in cervical spine interbody fusion

Cited by 11 publications

References 12 publications

A Review of the Clinical Side Effects of Bone Morphogenetic Protein-2

A Review of the Clinical Side Effects of Bone Morphogenetic Protein-2

Coordinated regulation of mesenchymal stem cell differentiation on microstructured titanium surfaces by endogenous bone morphogenetic proteins

Growth factors produced by bone marrow stromal cells on nanoroughened titanium–aluminum–vanadium surfaces program distal MSCs into osteoblasts via BMP2 signaling

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