Symptomatic ectopic bone formation after off-label use of recombinant human bone morphogenetic protein-2 in transforaminal lumbar interbody fusion

Chen, Nan Fu; Smith, Zachary A.; Stiner, Eric; Armin, Sean; Sheikh, Hormoz; Khoo, Larry T.

doi:10.3171/2009.4.spine0876

Cited by 128 publications

(76 citation statements)

References 30 publications

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“…36 We have previously shown that BMP genemodified MSCs secrete physiological quantities (nanograms) of BMP 28,34 over a period of few weeks compared to the mega doses used in rhBMP therapy (milligrams). Thus, the use of gene-modified MSCs might prevent recently described toxic side effects and inflammatory response induced by high doses of BMP 11,12 . In addition, gene modification could be applied to freshly isolated, noncultured MSCs 37 without the need for a cell culture phase.…”

Section: Discussionmentioning

confidence: 99%

“…6,7 Another widely used treatment includes the implantation of metal cages containing recombinant bone morphogenetic protein-2 (BMP-2). Highdose recombinant human BMP-2 (rhBMP2) has been found to cause pseudarthroses, 8,9 various infections, 10 ectopic bone formation that cause neural compression, 11 and abdominal bone growth. 12 In osteoporotic compression fractures of the spine, the use of instrumental fixation to achieve spinal fusion has a high failure rate due to low bone mass; when this procedure is combined with vertebral augmentation involving biomaterials such as poly(methyl methacrylate) (PMMA), a significant modulus mismatch with adjacent vertebrae may occur, leading to increased stress at the augmentednonaugmented junction.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Genetically Modified Mesenchymal Stem Cells Induce Mechanically Stable Posterior Spine Fusion

Sheyn

Rüthemann

Mizrahi

et al. 2010

Tissue Engineering Part A

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Most spine fusion procedures involve the use of prosthetic fixation devices combined with autologous bone grafts rather than biological treatment. We had shown that spine fusion could be achieved by injection of bone morphogenetic protein-2 (BMP-2)-expressing mesenchymal stem cells (MSCs) into the paraspinal muscle. In this study, we hypothesized that posterior spinal fusion achieved using genetically modified MSCs would be mechanically comparable to that realized using a mechanical fixation. BMP-2-expressing MSCs were injected bilaterally into paravertebral muscles of the mouse lumbar spine. In one control group BMP-2 expression was inhibited. Microcomputed tomography and histological analyses were used to evaluate bone formation. For comparison, a group of mouse spines were bilaterally fused with stainless steel pins. The harvested spines were later tested using a custom four-point bending apparatus and structural bending stiffness was estimated. To assess the degree to which MSC vertebral fusion was targeted and to quantify the effects of fusion on adjacent spinal segments, images of the loaded spine curvature were analyzed to extract rigidity of the individual spinal segments. Bone bridging of the targeted vertebrae was observed in the BMP-2-expressing MSC group, whereas no bone formation was noted in any control group. The biomechanical tests showed that MSC-mediated spinal fusion was as effective as stainless steel pin-based fusion and significantly more rigid than the control groups. Local analysis showed that the distribution of stiffness in the MSC-based fusion group was similar to that in the steel pin fusion group, with the majority of spinal stiffness contributed by the targeted fusion at L3-L5. Our findings demonstrate that MSC-induced spinal fusion can convey biomechanical rigidity to a targeted segment that is comparable to that achieved using an instrumental fixation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genetically Modified Mesenchymal Stem Cells Induce Mechanically Stable Posterior Spine Fusion

Sheyn

Rüthemann

Mizrahi

et al. 2010

Tissue Engineering Part A

View full text Add to dashboard Cite

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“…28 While BMPs have successfully induced bone formation in vivo, high dose requirements and paradoxical activities of BMPs on progenitor cells may lead to unexpected side effects such as ectopic bone formation while also rendering high treatment costs to patients. [5][6][7][8] In this study, we employed a small molecule that can effectively complement the pro-osteogenic activity of BMP-2 to maximize biological efficiency, thereby reducing the total dose requirement (cost) and minimizing potential adverse effects associated with BMP-2. Small molecular therapeutics has several advantages over protein-based therapeutics due to their lower cost and ease of manufacturing and storage compared with growth factor proteins.…”

Section: Discussionmentioning

confidence: 99%

“…Unfortunately, along with high cost, application of such high doses has revealed numerous side effects, such as vertebral osteolysis with cyst formation and life-threatening inflammatory cervical swelling, which have been well documented. [5][6][7][8] Thus, there is a need to develop alternative osteoinductive molecular strategies that can effectively complement BMP activity to maximize biological efficiency while reducing BMP dose requirement. One alternative approach is to deliver small molecule compounds targeting osteoblast differentiation that can synergistically promote bone formation with BMPs.…”

Section: Introductionmentioning

confidence: 99%

Delivery of Phenamil Enhances BMP-2-Induced Osteogenic Differentiation of Adipose-Derived Stem Cells and Bone Formation in Calvarial Defects

Fan

Cui

et al. 2015

Tissue Engineering Part A

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Bone morphogenetic proteins (BMPs) have been widely used for bone repair in the craniofacial region. However, its high dose requirement in clinical applications revealed adverse effects and inefficient bone formation, along with high cost. Here, we report a novel osteoinductive strategy to effectively complement the osteogenic activity of BMP-2 using phenamil, a small molecule that can induce osteogenic differentiation via stimulation of BMP signaling. Treatment of adipose-derived stem cells (ASCs) with BMP-2 in combination with phenamil significantly promoted the in vitro osteogenic differentiation of ASCs. The efficacy of the combination strategy of phenamil + BMP-2 was further confirmed in a mouse calvarial defect model using scaffolds consisting of poly(lactic-co-glycolic acid) and apatite layer on their surfaces designed to slowly release phenamil and BMP-2. Six weeks after implantation, the scaffolds treated with phenamil + BMP-2 significantly promoted mouse calvarial regeneration as demonstrated by micro-computerized tomography and histology, compared with the groups treated with phenamil or BMP-2 alone. Moreover, the combination treatment reduced the BMP-2 dose without compromising calvarial healing efficacy. These results suggest promising complementary therapeutic strategies for bone repair in more efficient and cost-effective manners.

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“…Joseph et al reported a 20.8 % rate of heterotopic bone formation with rhBMP-2 compared with 8.3 % in the controls following an MIS-TLIF [37]. Similarly, Chen et al reviewed 147 patients who underwent an MIS-TLIF and reported that 10.8 % (4 out of 37 patients) of patients who received rhBMP-2 developed ectopic bone formation in the spinal canal and neuroforamen that resulted in delayed neural complaints after the initial resolution of clinical symptoms [38].…”

Section: Neuroforaminal Bone Formationmentioning

confidence: 99%

Point-counter-point debate: the association between recombinant human bone morphogenetic protein utilization and complications in spine surgery

Siemionow

Sundberg

Tyrakowski³

et al. 2014

Curr Rev Musculoskelet Med

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Bone morphogenetic proteins (BMPs) have been utilized in spine surgery for over 10 years as a bone graft substitute. Potential BMP-related adverse effects including retrograde ejaculation and heterotopic neuroforaminal bone formation have been described. Additionally, some studies have suggested an association between BMP and cancer. Inconsistencies exist in the published spine literature with regards to the incidence and association of complications with BMP utilization. In a point-counterpoint format, this article discusses the current evidence concerning the relationship between the utilization of BMP in spinal fusion and the risk of cancer, retrograde ejaculation (RE), neuroforaminal bone formation, and its role in anterior cervical spine surgery and adolescents.Keywords Bone morphogenetic protein . Retrograde ejaculation . Anterior cervical fusion . Neuroforaminal bone growth . Cancer Point-counterpointRetrograde Ejaculation (RE) RE occurs secondary to impaired function of the internal vesicle sphincter muscle. Anterior lumbar approaches, particularly at the L5-S1 level, carry a greater potential for damage to the superior hypogastric sympathetic plexus, which innervates the internal vesicle sphincter muscle. Other etiologies of RE including diabetes, benign prostate hypertrophy and its treatment, multiple sclerosis, pelvic trauma, and pelvic or rectal surgery [1][2][3][4][5][6]. RE following anterior lumbar spine surgery is also purported to be related to the surgical approach [7][8][9].Burkus et al first published a prospective, randomized, nonblinded FDA-approved study concerning the use of rhBMP-2 in ALIF [8]. Six males (4.1 %; 6/146) reported RE following surgery, of which 4 underwent a transperitoneal approach (TPA) (13.3 %; 4 of all 30 males that underwent TPA) and 2 underwent a retroperitoneal approach (RPA) (1.8 %; 2 of 116 males that underwent RPA). Since the difference in RE between the TPA and RPA groups was statistically significant the authors concluded that a TPA was associated with a higher risk of RE. No comparison in RE between the investigational and control group was performed. The reported differences between the 2 approaches persisted at the 2-year follow-up period [10]. However, in 2010 Smoljanovic et al reviewed the data by Burkus et al [11] and reported that all 6 patients with RE had received rhBMP-2. Thus, the prevalence of RE in the investigational group (rhBMP-2) would have been 7.7 % (6/78 males), which was significantly greater than the control group (ICBG). The reason for ignoring the relationship between RE and rhBMP-2 was questioned, which sparked an intense debate over the potential association between the utilization of rhBMP-2 and RE.Correlation between rhBMP-2 utilization and RE Curr Rev Musculoskelet Med (2014) 7:200-207 DOI 10.1007/s12178-014-9219-x patients (7.2 %) in the rhBMP-2 group developed RE while only 1 of 174 patients (0.6 %; 1/69) reported RE in the control group. Significant differences in RE were also evident among patients that underwent a singl...

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Symptomatic ectopic bone formation after off-label use of recombinant human bone morphogenetic protein-2 in transforaminal lumbar interbody fusion

Cited by 128 publications

References 30 publications

Genetically Modified Mesenchymal Stem Cells Induce Mechanically Stable Posterior Spine Fusion

Genetically Modified Mesenchymal Stem Cells Induce Mechanically Stable Posterior Spine Fusion

Delivery of Phenamil Enhances BMP-2-Induced Osteogenic Differentiation of Adipose-Derived Stem Cells and Bone Formation in Calvarial Defects

Point-counter-point debate: the association between recombinant human bone morphogenetic protein utilization and complications in spine surgery

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