Complications of Recombinant Human BMP-2 for Treating Complex Tibial Plateau Fractures: A Preliminary Report

Boraiah, Sreevathsa; Paul, Omesh; Hawkes, David; Wickham, Matthew; Lorich, Dean G.

doi:10.1007/s11999-009-1039-8

Cited by 137 publications

(94 citation statements)

References 49 publications

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“…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. 25 Thus, improving the safety and efficacy of BMP2-based skeletal repair is crucial.…”

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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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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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“…[11][12][13] However, the introduction of growth factors to a system for use in the craniofacial region carries risks of tissue overgrowth, nerve impingement, and additional regulatory challenges. 14 To that effect, strategies utilizing in vivo bioreactors without exogenous growth factors are being explored. Specifically, poly(methyl methacrylate) (PMMA)-based chambers have been filled with different scaffold materials and implanted against the periosteum of sheep rib for tissue generation.…”

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confidence: 99%

Autologously Generated Tissue-Engineered Bone Flaps for Reconstruction of Large Mandibular Defects in an Ovine Model

Tatara

Kretlow

Spicer

et al. 2015

Tissue Engineering Part A

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“…Moreover, they showed to be a valid approach in combination with allografts, as an alternative to ABG, leading to the same beneficial effects but avoiding the drawbacks related to invasive autologous bone harvesting procedures [23]. The negative results reported were related to the higher rate of complications in the rhBMPs group, i.e., heterotopic ossification or calcification [25,30], local oedema, or calcinosis [30].…”

Section: Discussionmentioning

confidence: 99%

“…Considering the potential adverse events of BMPs, this systematic review on the treatment of bone fractures, non union, and osteonecrosis, also focused on the literature evidence of complications related to these orthopaedic conditions. The analysis of the comparative studies underlining a higher percentage of complications, showed that the majority of complications after BMPs treatment were related to heterotopic ossification, which were reported in 3 papers on fracture repair [25,29,34], in 2 papers on non union treatment [40,44], and in 1 paper on osteonecrosis [59] involving both rhBMP-2 and 7. Moreover, other described complications were infections [26,55], peripheral oedema, heterotopic ossification/soft-tissues calcification, new or increased pain [26], and the development of distal tibiofibular synostosis (1/52) described with rhBMP-7 for non-union treatment [52].…”

Section: Complicationsmentioning

confidence: 99%

Clinical application of bone morphogenetic proteins for bone healing: a systematic review

Krishnakumar

Roffi

Reale

et al. 2017

International Orthopaedics (SICOT)

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Purpose This paper documents the existing evidence on bone morphogenetic proteins (BMPs) use for the treatment of bone fractures, non-union, and osteonecrosis, through a review of the clinical literature, underlying potential and limitations in terms of cost effectiveness and risk of complications. Methods A systematic review was performed on the PubMed database using the following string: (bone morphogenetic proteins OR BMPs) and (bone repair OR bone regeneration) including papers from 2000 to 2016. The search focused on clinical trials dealing with BMPs application to favor bone regeneration in bone fractures, non-union, and osteonecrosis, in English language, with level of evidence I, II, III, and IV. Relevant data (type of study, number of patients, BMPs delivery material, dose, site, follow-up, outcome, and adverse events) were extracted and analyzed. Results Forty-four articles met the inclusion criteria: 10 randomized controlled trials (RCTs), 7 comparative studies, 18 case series, and 9 case reports. rhBMP-2 was documented mainly for the treatment of fractures, and rhBMP-7 mainly for non-unions and osteonecrosis. Mixed results were found among RCTs and comparative papers: 11 reported positive results for BMPs augmentation, 3 obtained no significant effects, and 2 showed negative results. The only study comparing the two BMPs showed a better outcome with rhBMP-2 for non-union treatment. Conclusion Clinical evidence on BMPs use for the treatment of fractures, non-union, and osteonecrosis is still controversial, with the few available reports being mainly of low quality. While positive findings have been described in many studies, mixed results are still present in the literature in terms of efficacy and adverse events. The difficulties in drawing clear conclusions are also due to the studies heterogeneity, mainly in terms of different BMPs applied, with different concomitant treatments for each bone pathology. Therefore, further research with well-designed studies is needed in order to understand the real potential of this biological approach to favour bone healing.

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Complications of Recombinant Human BMP-2 for Treating Complex Tibial Plateau Fractures: A Preliminary Report

Abstract: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Cited by 137 publications

References 49 publications

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

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

Autologously Generated Tissue-Engineered Bone Flaps for Reconstruction of Large Mandibular Defects in an Ovine Model

Clinical application of bone morphogenetic proteins for bone healing: a systematic review

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