The Controversy Surrounding Bone Morphogenetic Proteins in the Spine: A Review of Current Research

Bone morphogenetic proteins have been in use in spinal surgery since 2002. These proteins are members of the TGF-beta superfamily and guide mesenchymal stem cells to differentiate into osteoblasts to form bone in targeted tissues. Since the first commercial BMP became available in 2002, a host of research has supported BMPs and they have been rapidly incorporated in spinal surgeries in the United States. However, recent controversy has arisen surrounding the ethical conduct of the research supporting the use of BMPs. Yale University Open Data Access (YODA) recently teamed up with Medtronic to offer a meta-analysis of the effectiveness of BMPs in spinal surgery. This review focuses on the history of BMPs and examines the YODA research to guide spine surgeons in their use of BMP in spinal surgery.

[1]  M. Salamon,et al.  The Role of Human Bone Morphogenetic Proteins in Spinal Fusion , 2000, The Journal of the American Academy of Orthopaedic Surgeons.

[2]  S. Boden,et al.  The Use of rhBMP-2 in Interbody Fusion Cages: Definitive Evidence of Osteoinduction in Humans: A Preliminary Report , 2000, Spine.

[3]  Manohar M. Panjabi,et al.  Evaluation of OP-1 as a Graft Substitute for Intertransverse Process Lumbar Fusion , 2001, Spine.

[4]  C. Dickman,et al.  Anterior Lumbar Interbody Fusion Using rhBMP-2 With Tapered Interbody Cages , 2002, Journal of spinal disorders & techniques.

[5]  B. Cunningham,et al.  Osseointegration of autograft versus osteogenic protein-1 in posterolateral spinal arthrodesis: emphasis on the comparative mechanisms of bone induction. , 2002, The spine journal : official journal of the North American Spine Society.

[6]  S. Boden,et al.  Use of Recombinant Human Bone Morphogenetic Protein-2 to Achieve Posterolateral Lumbar Spine Fusion in Humans: A Prospective, Randomized Clinical Pilot Trial 2002 Volvo Award in Clinical Studies , 2002, Spine.

[7]  T. Zdeblick,et al.  Is INFUSE Bone Graft Superior to Autograft Bone? An Integrated Analysis of Clinical Trials Using the LT-CAGE Lumbar Tapered Fusion Device , 2003, Journal of spinal disorders & techniques.

[8]  David S Baskin,et al.  A Prospective, Randomized, Controlled Cervical Fusion Study Using Recombinant Human Bone Morphogenetic Protein-2 With the CORNERSTONE-SR™ Allograft Ring and the ATLANTIS™ Anterior Cervical Plate , 2003, Spine.

[9]  T. Albert,et al.  A pilot safety and efficacy study of OP-1 putty (rhBMP-7) as an adjunct to iliac crest autograft in posterolateral lumbar fusions , 2003, European Spine Journal.

[10]  Daniel H. Kim,et al.  Evaluation of HealosMP52 Osteoinductive Bone Graft for Instrumented Lumbar Intertransverse Process Fusion in Sheep , 2004, Spine.

[11]  E. Dawson,et al.  A Prospective, Randomized Controlled Clinical Trial of Anterior Lumbar Interbody Fusion Using a Titanium Cylindrical Threaded Fusion Device , 2004, Spine.

[12]  T. Albert,et al.  A Pilot Study Evaluating the Safety and Efficacy of OP-1 Putty (rhBMP-7) as a Replacement for Iliac Crest Autograft in Posterolateral Lumbar Arthrodesis for Degenerative Spondylolisthesis , 2004, Spine.

[13]  C. Branch,et al.  Posterior lumbar interbody fusion using recombinant human bone morphogenetic protein type 2 with cylindrical interbody cages. , 2004, The spine journal : official journal of the North American Spine Society.

[14]  Thomas M. Reilly,et al.  Analysis of Operative Complications in a Series of 471 Anterior Lumbar Interbody Fusion Procedures , 2005, Spine.

[15]  B. Walters,et al.  Guidelines for the performance of fusion procedures for degenerative disease of the lumbar spine. Part 16: bone graft extenders and substitutes. , 2005, Journal of neurosurgery. Spine.

[16]  J. Burkus,et al.  Use of rhBMP-2 in combination with structural cortical allografts: clinical and radiographic outcomes in anterior lumbar spinal surgery. , 2005, The Journal of bone and joint surgery. American volume.

[17]  J. Fischgrund,et al.  Bone morphogenetic proteins for spinal fusion. , 2005, The spine journal : official journal of the North American Spine Society.

[18]  T. Albert,et al.  Comparison of OP-1 Putty (rhBMP-7) to Iliac Crest Autograft for Posterolateral Lumbar Arthrodesis: A Minimum 2-Year Follow-up Pilot Study , 2005, Spine.

[19]  K. Bulsara,et al.  Safety of transforaminal lumbar interbody fusion and intervertebral recombinant human bone morphogenetic protein-2. , 2005, Journal of neurosurgery. Spine.

[20]  W. Hutton,et al.  Comparison of Healos/Bone Marrow to INFUSE(rhBMP-2/ACS) With a Collagen-Ceramic Sponge Bulking Agent as Graft Substitutes for Lumbar Spine Fusion , 2005, Spine.

[21]  T. Albert,et al.  Osteogenic Potential of Adult Human Stem Cells of the Lumbar Vertebral Body and the Iliac Crest , 2006, Spine.

[22]  J. Grauer,et al.  Healos/Recombinant Human Growth and Differentiation Factor-5 Induces Posterolateral Lumbar Fusion in a New Zealand White Rabbit Model , 2006, Spine.

[23]  R. Delamarter,et al.  Graft Resorption With the Use of Bone Morphogenetic Protein: Lessons From Anterior Lumbar Interbody Fusion Using Femoral Ring Allografts and Recombinant Human Bone Morphogenetic Protein-2 , 2006, Spine.

[24]  Matthew Shaw,et al.  Healos and Bone Marrow Aspirate Used for Lumbar Spine Fusion: A Case Controlled Study Comparing Healos With Autograft , 2006, Spine.

[25]  R. Sasso,et al.  Resorptive Response of rhBMP2 Simulating Infection in an Anterior Lumbar Interbody Fusion With a Femoral Ring , 2006, Journal of spinal disorders & techniques.

[26]  S. Glassman,et al.  Adverse Effects Associated With High-Dose Recombinant Human Bone Morphogenetic Protein-2 Use in Anterior Cervical Spine Fusion , 2006, Spine.

[27]  R. Vaidya,et al.  Interbody fusion with allograft and rhBMP-2 leads to consistent fusion but early subsidence. , 2007, The Journal of bone and joint surgery. British volume.

[28]  J. Reynolds,et al.  Accelerating lumbar fusions by combining rhBMP-2 with allograft bone: a prospective analysis of interbody fusion rates and clinical outcomes. , 2007, The spine journal : official journal of the North American Spine Society.

[29]  Y. R. Rampersaud,et al.  Heterotopic Bone Formation With the Use of rhBMP2 in Posterior Minimal Access Interbody Fusion: A CT Analysis , 2007, Spine.

[30]  Michael Y. Wang,et al.  MULTILEVEL ANTERIOR CERVICAL FUSION USING A COLLAGEN‐HYDROXYAPATITE MATRIX WITH ILIAC CREST BONE MARROW ASPIRATE: AN 18‐MONTH FOLLOW‐UP STUDY , 2007, Neurosurgery.

[31]  S. Boden,et al.  The Efficacy of rhBMP-2 for Posterolateral Lumbar Fusion in Smokers , 2007, Spine.

[32]  D. Resnick.  Evidence-Based Spine Surgery , 2007, Spine.

[33]  43. Anterior Exposure of the Lumbar Spine With and Without an “Access Surgeon”: Morbidity Analysis of 265 Consecutive Cases , 2007 .

[34]  S. Jatana,et al.  Neurologic impairment from ectopic bone in the lumbar canal: a potential complication of off-label PLIF/TLIF use of bone morphogenetic protein-2 (BMP-2). , 2008, The spine journal : official journal of the North American Spine Society.

[35]  R. Brower,et al.  A case of psoas ossification from the use of BMP-2 for posterolateral fusion at L 4 – L 5 , 2009 .

[36]  T. Albert,et al.  The use of bone morphogenetic protein in lumbar spine surgery. , 2009, The Journal of bone and joint surgery. American volume.

[37]  R. Vaidya,et al.  Complications in the Use of rhBMP-2 in PEEK Cages for Interbody Spinal Fusions , 2008, Journal of spinal disorders & techniques.

[38]  U. Mansmann,et al.  Posterior lumbar interbody fusion using rhBMP-2 , 2008, European Spine Journal.

[39]  John R. Johnson,et al.  RhBMP-2 Versus Iliac Crest Bone Graft for Lumbar Spine Fusion: A Randomized, Controlled Trial in Patients Over Sixty Years of Age , 2008, Spine.

[40]  Jeffrey C. Wang,et al.  The use of bone morphogenetic protein in spine fusion. , 2008, The spine journal : official journal of the North American Spine Society.

[41]  P. Mummaneni,et al.  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. , 2008, Journal of neurosurgery. Spine.

[42]  T. Albert,et al.  The safety and efficacy of OP-1 (rhBMP-7) as a replacement for iliac crest autograft for posterolateral lumbar arthrodesis: minimum 4-year follow-up of a pilot study. , 2008, The spine journal : official journal of the North American Spine Society.

[43]  Kern Singh,et al.  Role of osteogenic protein-1/bone morphogenetic protein-7 in spinal fusion , 2009 .

[44]  T. Schuler,et al.  Six-year outcomes of anterior lumbar interbody arthrodesis with use of interbody fusion cages and recombinant human bone morphogenetic protein-2. , 2009, The Journal of bone and joint surgery. American volume.

[45]  Jeffrey C. Wang,et al.  The efficacy of rhBMP-2 versus autograft for posterolateral lumbar spine fusion in elderly patients , 2010, European Spine Journal.

[46]  H. Bae,et al.  Recombinant human bone morphogenetic protein-2 on an absorbable collagen sponge with an osteoconductive bulking agent in posterolateral arthrodesis with instrumentation. A prospective randomized trial. , 2009, The Journal of bone and joint surgery. American volume.

[47]  A. Day,et al.  Prevalence, complications, and hospital charges associated with use of bone-morphogenetic proteins in spinal fusion procedures. , 2009, JAMA.

[48]  Sang-Ho Lee,et al.  An analysis of general surgery-related complications in a series of 412 minilaparotomic anterior lumbosacral procedures. , 2009, Journal of neurosurgery. Spine.

[49]  John R. Johnson,et al.  RhBMP-2 Versus Iliac Crest Bone Graft for Lumbar Spine Fusion in Patients Over 60 Years of Age: A Cost-Utility Study , 2009, Spine.

[50]  T. Albert,et al.  The use of RhBMP-2 in single-level transforaminal lumbar interbody fusion: a clinical and radiographic analysis , 2009, European Spine Journal.

[51]  T. Einhorn,et al.  Bone morphogenetic proteins in orthopaedic surgery. , 2009, Cytokine & growth factor reviews.

[52]  William C Welch,et al.  Osteoinductive bone graft substitutes for lumbar fusion: a systematic review. , 2009, Journal of neurosurgery. Spine.

[53]  D. Boyd,et al.  The Use of Recombinant Human Bone Morphogenic Protein in Posterior Interbody Fusions of the Lumbar Spine: A Clinical Series , 2009, Journal of spinal disorders & techniques.

[54]  J. Heller,et al.  Anterior Exposure of the Lumbar Spine With and Without an “Access Surgeon”: Morbidity Analysis of 265 Consecutive Cases , 2009, Journal of spinal disorders & techniques.

[55]  M. Rahm,et al.  Clinical and radiographic assessment of transforaminal lumbar interbody fusion using HEALOS collagen-hydroxyapatite sponge with autologous bone marrow aspirate. , 2009, The spine journal : official journal of the North American Spine Society.

[56]  T. Albert,et al.  Complications associated with single-level transforaminal lumbar interbody fusion. , 2009, The spine journal : official journal of the North American Spine Society.

[57]  T. Albert,et al.  Healos graft carrier with bone marrow aspirate instead of allograft as adjunct to local autograft for posterolateral fusion in degenerative lumbar scoliosis: a minimum 2-year follow-up study. , 2010, Journal of neurosurgery. Spine.

[58]  D. Norvell,et al.  Complications Related to Osteobiologics Use in Spine Surgery: A Systematic Review , 2010, Spine.

[59]  V. Sonntag,et al.  Formation of Painful Seroma and Edema After the Use of Recombinant Human Bone Morphogenetic Protein‐2 in Posterolateral Lumbar Spine Fusions , 2010, Neurosurgery.

[60]  C. Shaffrey,et al.  Use of recombinant human bone morphogenetic protein-2 as an adjunct for instrumented posterior arthrodesis in the occipital cervical region: An analysis of safety, efficacy, and dosing , 2010, Journal of craniovertebral junction & spine.

[61]  E. Nottmeier,et al.  Vertebral osteolysis originating from subchondral cyst end plate defects in transforaminal lumbar interbody fusion using rhBMP-2. Report of two cases. , 2010, The spine journal : official journal of the North American Spine Society.

[62]  N. Chen,et al.  Symptomatic ectopic bone formation after off-label use of recombinant human bone morphogenetic protein-2 in transforaminal lumbar interbody fusion. , 2010, Journal of neurosurgery. Spine.

[63]  Bradley K Weiner,et al.  A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned. , 2011, The spine journal : official journal of the North American Spine Society.

[64]  E. Hurwitz,et al.  Retrograde ejaculation after anterior lumbar interbody fusion using rhBMP-2: a cohort controlled study. , 2011, The spine journal : official journal of the North American Spine Society.

[65]  Mark C Simmonds,et al.  Safety and Effectiveness of Recombinant Human Bone Morphogenetic Protein-2 for Spinal Fusion , 2013, Annals of Internal Medicine.

[66]  Arpita Tiwari,et al.  Effectiveness and Harms of Recombinant Human Bone Morphogenetic Protein-2 in Spine Fusion , 2013, Annals of Internal Medicine.

[67]  J. Grauer,et al.  Optimal aspiration volume of vertebral bone marrow for use in spinal fusion. , 2013, The spine journal : official journal of the North American Spine Society.

[68]  J. Grauer,et al.  Only prolonged time from abstraction found to affect viable nucleated cell concentrations in vertebral body bone marrow aspirate. , 2014, The spine journal : official journal of the North American Spine Society.