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

James, Aaron W.; LaChaud, Gregory; Shen, Jia; Asatrian, Greg; Nguyen, Vi; Zhang, Xinli; Ting, Kang; Soo, Chia

doi:10.1089/ten.teb.2015.0357

Cited by 1,131Bone Tissue Engineering MaterialsTGF-β signaling in diseasesBone Metabolism and Diseases

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

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James, Aaron W., LaChaud, Gregory, Shen, Jia, Asatrian, Greg, Nguyen, Vi, Zhang, Xinli, Ting, Kang, Soo, Chia·2016·Tissue Engineering Part B: Reviews

DOI 10.1089/ten.teb.2015.0357PMC PMC4964756

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Abstract

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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More widespread use of rhBMP-2 delivery from collagen sponges in long bone nonunions has been limited, in part due to safety concerns including edema, inflammation, ectopic bone formation, and bone cysts.
“While off-label use is permitted, more widespread use of these products in long bone nonunions has been limited, in part due to safety concerns including edema, inflammation, ectopic bone formation, and bone cysts [8].”
From Keratin Scaffold Formulation Impacts rhBMP-2 Biodistribution and Bone Regeneration in a Rat Femur Defect Model (2025) · cites this paper as [8]

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Regulation of human cranial osteoblast phenotype by FGF-2, FGFR-2 and BMP-2 signaling.
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Symptomatic ectopic bone formation after off-label use of recombinant human bone morphogenetic protein-2 in transforaminal lumbar interbody fusion
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The Efficacy of rhBMP-2 for Posterolateral Lumbar Fusion in Smokers
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The safety and efficacy of anterior cervical discectomy and fusion with polyetheretherketone spacer and recombinant human bone morphogenetic protein–2: a review of 200 patients
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Tumor Necrosis Factor α Represses Bone Morphogenetic Protein (BMP) Signaling by Interfering with the DNA Binding of Smads through the Activation of NF-κB
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A Prospective, Randomized Controlled Clinical Trial of Anterior Lumbar Interbody Fusion Using a Titanium Cylindrical Threaded Fusion Device
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Bone morphogenetic protein 2 stimulation of tumor growth involves the activation of Smad-1/5
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Evaluation of dexamethasone for reducing postoperative edema and inflammatory response after orthognathic surgery
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Expression of various growth factors for cell proliferation and cytodifferentiation during fracture repair of bone.
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Bone morphogenic protein 2 directly enhances differentiation of murine osteoclast precursors
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Bone morphogenetic protein 2 (BMP-2) induces in vitro invasion and in vivo hormone independent growth of breast carcinoma cells
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Influence of BMPs on the formation of osteoblastic lesions in metastatic prostate cancer
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Influence of rhBMP-2 on the Healing Patterns Associated With Allograft Interbody Constructs in Comparison With Autograft
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Retrograde ejaculation after anterior lumbar interbody fusion with and without bone morphogenetic protein-2 augmentation: a 10-year cohort controlled study
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Maxillary Alveolar Cleft Repair in Dogs Using Recombinant Human Bone Morphogenetic Protein-2 and a Polymer Carrier
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The Outcome of Posterolateral Fusion in Highly Selected Patients With Discogenic Low Back Pain
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Bone morphogenetic proteins: basic concepts
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Bone morphogenetic proteins in breast cancer: dual role in tumourigenesis?
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Adverse Events After Recombinant Human BMP2 in Nonspinal Orthopaedic Procedures
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Tenascin-W is found in malignant mammary tumors, promotes alpha8 integrin-dependent motility and requires p38MAPK activity for BMP-2 and TNF-alpha induced expression in vitro
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Retrograde Ejaculation After Anterior Lumbar Spine Surgery
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Posterior lumbar interbody fusion using rhBMP-2
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Does Bone Morphogenetic Protein Increasethe Incidence of Perioperative Complicationsin Spinal Fusion?
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BMP induced inflammation: A comparison of rhBMP‐7 and rhBMP‐2
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Formation of Painful Seroma and Edema After the Use of Recombinant Human Bone Morphogenetic Protein-2 in Posterolateral Lumbar Spine Fusions
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Recombinant Human Bone Morphogenetic Protein-2-Induced Radiculitis in Elective Minimally Invasive Transforaminal Lumbar Interbody Fusions
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Anterior Exposure of the Lumbar Spine With and Without an “Access Surgeon”
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Increase in VEGF secretion from human fibroblast cells by bioactive glass S53P4 to stimulate angiogenesis in bone
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Recombinant Human Bone Morphogenetic Protein‐2 Potentiates the In Vivo Osteogenic Ability of Marrow/Hydroxyapatite Composites
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Bone morphogenetic proteins and their receptor signaling in prostate cancer.
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A Study of the Role of Nell-1 Gene Modified Goat Bone Marrow Stromal Cells in Promoting New Bone Formation
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BMP2 promotes migration and invasion of breast cancer cells via cytoskeletal reorganization and adhesion decrease: an AFM investigation
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Use of Bone Morphogenetic Protein-2 for Adult Spinal Deformity
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Adjacent vertebral body osteolysis with bone morphogenetic protein use in transforaminal lumbar interbody fusion
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The Roles of Bone Morphogenetic Proteins and Their Signaling in the Osteogenesis of Adipose-Derived Stem Cells
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The use of RhBMP-2 in single-level transforaminal lumbar interbody fusion: a clinical and radiographic analysis
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Cancer Risk from Bone Morphogenetic Protein Exposure in Spinal Arthrodesis
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BMP2-Induced Inflammation Can Be Suppressed by the Osteoinductive Growth Factor NELL-1
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Risk of Cancer After Lumbar Fusion Surgery With Recombinant Human Bone Morphogenic Protein-2 (rh-BMP-2)
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Cancer After Spinal Fusion
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Inflammatory Characteristics of rhBMP-2 In Vitro and in an In Vivo Rodent Model
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Cytokine-Mediated Inflammatory Reaction Following Posterior Cervical Decompression and Fusion Associated With Recombinant Human Bone Morphogenetic Protein-2
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Histopathologic inflammatory response induced by recombinant bone morphogenetic protein-2 causing radiculopathy after transforaminal lumbar interbody fusion
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High-dose bone morphogenetic protein–induced ectopic abdomen bone growth
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Bone Regeneration in the Rat Mandible with Bone Morphogenetic Protein‐2: A Comparison of Two Carriers
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An analysis of general surgery–related complications in a series of 412 minilaparotomic anterior lumbosacral procedures
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Bone morphogenetic proteins in bone tumors
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Orthotopic bone formation by implantation of apatite‐coated poly(lactide‐co‐glycolide)/hydroxyapatite composite particulates and bone morphogenetic protein‐2
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Effectiveness of Diphosphonates in Preventing ???Osteoporosis??? of Disuse in the Rat
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Repair of Ulnar Segmental Defect by Recombinant Human Bone Morphogenetic Protein-2 in Dogs.
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Overexpression of BMP-2/4, -5 and BMPR-IA associated with malignancy of oral epithelium
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Occipitocervical Fusion Using Recombinant Human Bone Morphogenetic Protein-2
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Clinical sequelae after rhBMP-2 use in a minimally invasive transforaminal lumbar interbody fusion
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Local Administration of Bone Morphogenetic Protein-2 and Bisphosphonate During Non-Weight-Bearing Treatment of Ischemic Osteonecrosis of the Femoral Head
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Osteolysis in Transforaminal Lumbar Interbody Fusion with Bone Morphogenetic Protein-2
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INTERBODY FUSION WITH ALLOGRAFT AND RHBMP-2 LEADS TO CONSISTENT FUSION BUT EARLY SUBSIDENCE
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Bone morphogenetic proteins in development and progression of breast cancer and therapeutic potential (Review)
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Bone Morphogenetic Protein‐2 and Vascular Endothelial Growth Factor in Bone Tissue Regeneration: New Insight and Perspectives
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Acute airway obstruction in cervical spinal procedures with bone morphogenetic proteins
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Recombinant Human BMP-2 for the Treatment of Open Tibial Fractures
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Bone regeneration using a naturally grown HA/TCP carrier loaded with rh BMP‐2 is independent of barrier‐membrane effects
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Outcomes for Single-Level Lumbar Fusion
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Retrograde ejaculation following single-level anterior lumbar surgery with or without recombinant human bone morphogenetic protein–2 in 5 randomized controlled trials
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NELL‐1 binds to APR3 affecting human osteoblast proliferation and differentiation
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Recombinant human bone morphogenetic protein‐2 and pancreatic cancer: a retrospective cohort study
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Resorptive Response of rhBMP2 Simulating Infection in an Anterior Lumbar Interbody Fusion With a Femoral Ring
Hansen, S. M., & Sasso, R. C. (2006) · Journal of Spinal Disorders & Techniques · doi:10.1097/01.bsd.0000168512.61351.3a · Cited by 40 · see citing works
Bone morphogenetic protein–binding peptide reduces the inflammatory response to recombinant human bone morphogenetic protein-2 and recombinant human bone morphogenetic protein-7 in a rodent model of soft-tissue inflammation
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Bone repair in rat mandible by rhBMP-2 associated with two carriers
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Wound Complications Associated With Bone Morphogenetic Protein-2 in Orthopaedic Trauma Surgery
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Basic science and spine literature document bone morphogenetic protein increases cancer risk
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Bone morphogenetic protein 2 enhances mouse osteoclast differentiation via increased levels of receptor activator of NF-κB ligand expression in osteoblasts
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Case Report: An Autopsy Case of Malignant Mesothelioma with Osseous and Cartilaginous Differentiation (Bone Morphogenetic Protein-2 in Mesothelial Cells and Its Tumor)
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Vertebral osteolysis originating from subchondral cyst end plate defects in transforaminal lumbar interbody fusion using rhBMP-2. Report of two cases
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Vascular endothelial growth factor-A signaling in bone marrow-derived endothelial progenitor cells exposed to hypoxic stress
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Positive Selection for Bone Morphogenetic Protein Receptor Type-IB Promotes Differentiation and Specification of Human Adipose-Derived Stromal Cells Toward an Osteogenic Lineage
McArdle, A., Chung, M. T., Paik, K. J., Duldulao, C., Chan, C. K. F., Rennert, R. C., Walmsley, G. G., Senarath-Yapa, K., Hu, M. S.-M., Seo, E., et al. (2014) · Tissue Engineering Part A · doi:10.1089/ten.tea.2014.0101 · Cited by 32 · see citing works
Complications of rhBMP-2 utilization for posterolateral lumbar fusions requiring reoperation: a single practice, retrospective case series report
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Bone morphogenetic protein–induced inflammatory cyst formation after lumbar fusion causing nerve root compression
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Insulin-Like Growth Factor-1 and Bone Morphogenetic Protein-2 Jointly Mediate Prostaglandin E2-Induced Adipogenic Differentiation of Rat Tendon Stem Cells
Liu, J., Chen, L., Zhou, Y. L., Liu, X., & Tang, K. (2014) · PLoS ONE · doi:10.1371/journal.pone.0085469 · Cited by 30 · see citing works
The use of bone morphogenetic protein in thoracolumbar spine procedures: analysis of the MarketScan longitudinal database
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RhBMP-2 use in lumbar fusion surgery is associated with transient immediate post-operative leg pain
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BMP-2 Promotes Oral Squamous Carcinoma Cell Invasion by Inducing CCL5 Release
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An osteogenesis-related transcription factor, core-binding factor A1, is constitutively expressed in the chondrocytic cell line TC6, and its expression is upregulated by bone morphogenetic protein-2
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Postoperative Cervical Myelopathy and Cord Compression Associated with the Use of Recombinant Bone Morphogenetic Protein-2 in Posterior Cervical Decompression, Instrumentation, and Arthrodesis
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Signaling Crosstalk between PPARγand BMP2 in Mesenchymal Stem Cells
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The use of recombinant human BMP-2 as a salvage procedure in the pediatric spine: a report on 3 cases
Mladenov, K. V., Kunkel, P., & Stuecker, R. D. (2009) · European Spine Journal · doi:10.1007/s00586-009-1179-2 · Cited by 25 · see citing works
Smad1/5 and Smad4 Expression Are Important for Osteoclast Differentiation
Tasca, A. W., Stemig, M., Broege, A., Huang, B., Davydova, J., Zwijsen, A., Umans, L., Jensen, E. D., Gopalakrishnan, R., & Mansky, K. C. (2015) · Journal of Cellular Biochemistry · doi:10.1002/jcb.25092 · Cited by 24 · see citing works
BMP-2 Adverse Reactions Treated With Human Dose Equivalent Dexamethasone in a Rodent Model of Soft-Tissue Inflammation
Xiong, C., Daubs, M. D., Montgomery, S. R., et al. (2013) · Spine · doi:10.1097/brs.0b013e31829cf348 · Cited by 21 · see citing works
Six-year outcomes of anterior lumbar interbody arthrodesis with use of interbody fusion cages and recombinant human bone morphogenetic protein-2.
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Use of Autogenous Bone Graft Compared With RhBMP in High-risk Patients
Lee, K., Johnson, J. S., Song, K., et al. (2012) · Journal of Spinal Disorders & Techniques · doi:10.1097/bsd.0b013e3182440162 · Cited by 20 · see citing works
Letters
Smoljanović, T., & Pecina, M. M. (2008) · Spine · doi:10.1097/brs.0b013e3181606894 · Cited by 19 · see citing works
Contralateral psoas seroma after transpsoas lumbar interbody fusion with bone morphogenetic protein-2 implantation
Taher, F., Lebl, D. R., Hughes, A. P., et al. (2013) · The Spine Journal · doi:10.1016/j.spinee.2012.11.052 · Cited by 17 · see citing works
Aggressive end plate decortication as a cause of osteolysis after rhBMP-2 use in cervical spine interbody fusion
Smoljanović, T., Čimić, M., & Bojanić, I. (2010) · The Spine Journal · doi:10.1016/j.spinee.2009.10.001 · Cited by 15 · see citing works
Bone morphogenetic protein 2 enhances PGE2-stimulated osteoclast formation in murine bone marrow cultures
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Authors: James, A. W., LaChaud, G., Shen, J., Asatrian, G., Nguyen, V., Zhang, X., Ting, K., & Soo, C.
Affiliations: University of California, Los Angeles (US)
Corresponding author: Ting, Kang
Soo, Chia
ORCID: James, Aaron W.
LaChaud, Gregory
Shen, Jia
Nguyen, Vi
Zhang, Xinli
Ting, Kang
Soo, Chia
Venue: Tissue Engineering Part B: Reviews
Publisher: SAGE Publications
Published: 2016-08
Volume: 22
Issue: 4
Pages: 284-297
ISSN: 1937-3368 (ISSN-L)
1937-3376
DOI: 10.1089/ten.teb.2015.0357
PMC: PMC4964756
OpenAlex: W2261324366
Cited by: 1,131
References: 183
Citations by year: 2026: 127 · 2025: 124 · 2024: 130 · 2023: 161 · 2022: 124 · 2021: 143 · 2020: 119 · 2019: 82 · 2018: 72 · 2017: 37 · 2016: 10 · 2013: 1
FWCI: 4.79
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.liebertpub.com/nv/resources-tools/text-and-data-mining-policy/121/ (tdm)
Locations: Tissue Engineering Part B Reviews (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Musculoskeletal Transplant Foundation (K08 AR068316)
National Institutes of Health
National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR061399, K08AR068316, R01AR066782)
Topics: Physical Sciences › Engineering › Biomedical Engineering › Bone Tissue Engineering Materials
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
Keywords: BMP-2, bone graft substitutes, ectopic bone formation, osteoclast resorption, adipogenesis, postoperative inflammation, carcinogenesis, osteoinduction
MeSH terms: Animals, Bone Resorption, Humans, Spinal Fusion, Transforming Growth Factor beta, Bone Morphogenetic Protein 2

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

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