The controversy surrounding bone morphogenetic proteins in the spine: A review of current research

Yale Journal of Biology and Medicine

Volumn 87, Issue 4, 2014, Pages 549-561

  Hustedt, Joshua W ^a   Blizzard, Daniel J ^a  

^a YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Bone morphogenetic proteins; Postoperative complications; Spinal fusion; Spine

Indexed keywords

BONE MORPHOGENETIC PROTEIN; GROWTH DIFFERENTIATION FACTOR 5; OSTEOGENIC PROTEIN 1; RECOMBINANT BONE MORPHOGENETIC PROTEIN 2;

ANTERIOR SPINE FUSION; BONE FILLER; BONE GRAFT; BONE PAIN; CERVICAL SPINE; DEVICE SAFETY; DRUG USE; HUMAN; ILIAC CREST; INTERVERTEBRAL BODY FUSION DEVICE; LUMBAR SPINE; NONHUMAN; PEDICLE SCREW; PROTEIN FUNCTION; REVIEW; SPINE SURGERY; DRUG EFFECTS; HEALTH CARE PLANNING; PATHOLOGY; SPINE; SPINE FUSION;

BONE MORPHOGENETIC PROTEINS; HEALTH PLANNING GUIDELINES; HUMANS; SPINAL FUSION; SPINE;

EID: 84930065970     PISSN: 00440086     EISSN: 15514056     Source Type: Journal    
DOI: None     Document Type: Review

References (70)

1. Resnick DK. Evidence-based spine surgery. Spine (Phila Pa 1976). 2007;32(11):S15-9.
2. Hsu WK, Wang JC. The use of bone mor-phogenetic protein in spine fusion. Spine J. 2008;8(3):419-25.
3. Burkus JK, Gornet MF, Dickman CA, Zde-blick TA. Anterior lumbar interbody fusion using rhBMP-2 with tapered interbody cages. J Spinal Disord Tech. 2002;15(5):337-49.
4. Carragee EJ, Hurwitz EL, Weiner BK. A critical review of recombinant human bone mor-phogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned. Spine J. 2011;11(6):471-91.
5. Haid RW Jr, Branch CL Jr, Alexander JT, Burkus JK. Posterior lumbar interbody fusion using recombinant human bone morphogenetic protein type 2 with cylindrical interbody cages. Spine J. 2004;4(5):527-38; discussion 38-9.
6. Mroz TE, Wang JC, Hashimoto R, Norvell DC. Complications Related to Osteobiolog-ics Use in Spine Surgery A Systematic Review. Spine. 2010;35(9):S86-104.
7. Smoljanovic T, Bojanic I, Pecina M. The Use of Bone Morphogenetic Protein in Lumbar Spine Surgery. J Bone Joint Surg Am. 2009;91A(8):2045-6.
8. Agarwal R, Williams K, Umscheid CA, Welch WC. Osteoinductive bone graft substitutes for lumbar fusion: a systematic review Clinical article. J Neurosurg Spine. 2009;11(6):729-40.
9. Resnick DK, Choudhri TF, Dailey AT, Groff MW, Khoo L, Matz PG, et al. Guidelines for the performance of fusion procedures for degenerative disease of the lumbar spine. Part 16: bone graft extenders and substitutes. J Neurosurg Spine. 2005;2(6):733-6.
10. Kraiwattanapong C, Boden SD, Louis-Ugbo J, Attallah E, Barnes B, Hutton WC. Comparison of Healos/bone marrow to IN-FUSE(rhBMP-2/ACS) with a collagen-ceramic sponge bulking agent as graft substitutes for lumbar spine fusion. Spine. 2005;30(9):1001-7.
11. Zlotolow DA, Vaccaro AR, Salamon ML, Albert TJ. The role of human bone morpho-genetic proteins in spinal fusion. J Am Acad Orthop Surg. 2000;8(1):3-9.
12. Carlisle E, Fischgrund JS. Bone morpho-genetic proteins for spinal fusion. Spine J. 2005;5(6 Suppl):240S-9S.
13. Axelrad TW, Einhorn TA. Bone morphogenetic proteins in orthopaedic surgery. Cytokine Growth Factor Rev. 2009;20(5-6):481-8.
14. Cahill KS, Chi JH, Day A, Claus EB. Prevalence, Complications, and Hospital Charges Associated With Use of Bone-Morphogenetic Proteins in Spinal Fusion Procedures. JAMA. 2009;302(1):58-66.
15. Fu R, Selph S, McDonagh M, Peterson K, Ti-wari A, Chou R, et al. Effectiveness and harms of recombinant human bone morpho-genetic protein-2 in spine fusion: a systematic review and meta-analysis. Ann Intern Med. 2013;158(12):890-902.
16. Simmonds MC, Brown JV, Heirs MK, Hig-gins JP, Mannion RJ, Rodgers MA, et al. Safety and effectiveness of recombinant human bone morphogenetic protein-2 for spinal fusion: a meta-analysis of individual-participant data. Ann Intern Med. 2013;158(12):877-89.
17. Life-threatening complications associated with recombinant human bone morpho-genetic protein in cervical spine fusion. US Food and Drug Administration [Internet]. 2008. [cited 25 Jul 2013]. Available from: http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/PublicHealthNotifica-tions/ucm062000.htm.
18. Carrey-Rou J, McGinty T. Medtronic Surgeons Held Back, Study Says. Wall Street Journal. June 29, 2011.
19. Carter JD, Swearingen AB, Chaput CD, Rahm MD. Clinical and radiographic assessment of transforaminal lumbar interbody fusion using HEALOS collagen-hydroxyapatite sponge with autologous bone marrow aspirate. Spine J. 2009;9(6):434-8.
20. Armstrong D. Medtronic paid the surgeon accused of falsifying study nearly $800,000. Wall Street Journal. June 18, 2009.
21. Boden SD, Zdeblick TA, Sandhu HS, Heim SE. The use of rhBMP-2 in interbody fusion cages - Definitive evidence of osteoinduction in humans: A preliminary report. Spine. 2000;25(3):376-81.
22. Glassman SD, Dimar JR, Burkus K, Hardacker JW, Pryor PW, Boden SD, et al. The efficacy of rhBMP-2 for posterolateral lumbar fusion in smokers. Spine. 2007;32(15):1693-8.
23. Burkus JK, Heim TE, Gornet MF, Zdeblick TA. Is INFUSE bone graft superior to auto-graft bone? An integrated analysis of clinical trials using the LT-CAGE lumbar tapered fusion device. J Spinal Disord Tech. 2003;16(2):113-22.
24. Burkus JK, Gornet MF, Shuler TC, Kleeman TJ, Zdeblick TA. Six-Year Outcomes of Anterior Lumbar Interbody Arthrodesis with Use of Interbody Fusion Cages and Recom-binant Human Bone Morphogenetic Protein-2. J Bone Joint Surg Am. 2009;91(5):1181-9.
25. Burkus JK, Sandhu HS, Gornet MF, Longley MC. Use of rhBMP-2 in combination with structural cortical allografts: Clinical and ra-diographic outcomes in anterior lumbar spinal surgery. J Bone Joint Surg Am. 2005;87(6):1205-12.
26. Pradhan BB, Bae HW, Dawson EG, Patel VV, Delamarter RB. 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. Spine. 2006;31(10):E277-84.
27. Slosar PJ, Josey R, Reynolds J. Accelerating lumbar fusions by combining rhBMP-2 with allograft bone: a prospective analysis of in-terbody fusion rates and clinical outcomes. Spine J. 2007;7(3):301-7.
28. Hansen SM, Sasso RC. Resorptive response of rhBMP2 simulating infection in an anterior lumbar interbody fusion with a femoral ring. J Spinal Disord Tech. 2006;19(2):130-4.
29. Vaidya R, Sethi A, Bartol S, Jacobson M, Coe C, Craig JG. Complications in the Use of rhBMP-2 in PEEK Cages for Interbody Spinal Fusions. J Spinal Disord Tech. 2008;21(8):557-62.
30. Vaidya R, Weir R, Sethi A, Meisterling S, Hakeos W, Wybo CD. Interbody fusion with allograft and rhBMP-2 leads to consistent fusion but early subsidence. J Bone Joint Surg Br. 2007;89(3):342-5.
31. Kang B-U, Choi W-C, Lee S-H, Jeon SH, Park JD, Maeng DH, et al. An analysis of general surgery-related complications in a series of 412 minilaparotomic anterior lum-bosacral procedure. J Neurosurg Spine. 2009;10(1):60-5.
32. Sasso RC, Best NM, Mummaneni PV, Reilly TM, Hussain SM. Analysis of operative complications in a series of 471 anterior lumbar interbody fusion procedures. Spine. 2005;30(6):670-4.
33. Sasso RC, Kitchel SH, Dawson EG. A prospective, randomized controlled clinical trial of anterior lumbar interbody fusion using a titanium cylindrical threaded fusion device. Spine. 2004;29(2):113-21.
34. Carragee EJ, Mitsunaga KA, Hurwitz EL, Scuderi GJ. Retrograde ejaculation after anterior lumbar interbody fusion using rhBMP-2: a cohort controlled study. Spine J. 2011;11(6):511-6.
35. Jarrett CD, Heller JG, Tsai L. Anterior Exposure of the Lumbar Spine With and Without an “Access Surgeon” Morbidity Analysis of 265 Consecutive Cases. J Spinal Disord Tech. 2009;22(8):559-64.
36. Boden SD, Kang J, Sandhu H, Heller JG. 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. Spine. 2002;27(23):2662-73.
37. Carreon LY, Glassman SD, Djurasovic M, Campbell MJ, Puno RM, Johnson JR, et al. RhBMP-2 Versus Iliac Crest Bone Graft for Lumbar Spine Fusion in Patients Over 60 Years of Age A Cost-Utility Study. Spine. 2009;34(3):238-43.
38. Dawson E, Bae HW, Burkus JK, Stambough JL, Glassman SD. Recombinant Human Bone Morphogenetic Protein-2 on an Ab-sorbable Collagen Sponge with an Osteocon-ductive Bulking Agent in Posterolateral Arthrodesis with Instrumentation A Prospective Randomized Trial. J Bone Joint Surg Am. 2009;91(7):1604-13.
39. Glassman SD, Carreon LY, Djurasovic M, Campbell MJ, Puno RM, Johnson JR, et al. RhBMP-2 Versus Iliac Crest Bone Graft for Lumbar Spine Fusion. Spine. 2008;33(26):2843-9.
40. Hamilton DK, Smith JS, Reames DL, Williams BJ, Shaffrey CI. Use of recombi-nant human bone morphogenetic protein-2 as an adjunct for instrumented posterior arthrodesis in the occipital cervical region: An analysis of safety, efficacy, and dosing. J Craniovertebr Junction Spine. 2010;1(2):107-12.
41. Lee KB, Taghavi CE, Hsu MS, Song KJ, Yoo JH, Keorochana G, et al. The efficacy of rhBMP-2 versus autograft for posterolateral lumbar spine fusion in elderly patients. Eur Spine J. 2010;19(6):924-30.
42. Brower RS, Vickroy NM. A case of psoas ossification from the use of BMP-2 for pos-terolateral fusion at L4-L5. Spine. 2008;33(18):E653-5.
43. Garrett MP, Kakarla UK, Porter RW, Sonntag VKH. Formation of Painful Seroma and Edema After the Use of Recombinant Human Bone Morphogenetic Protein-2 in Posterolat-eral Lumbar Spine Fusions. Neurosurgery. 2010;66(6):1044-9.
44. Joseph V, Rampersaud YR. Heterotopic bone formation with the use of rhBMP2 in posterior minimal access interbody fusion - A CT analysis. Spine. 2007;32(25):2885-90.
45. Meisel HJ, Schnoring M, Hohaus C, Minkus Y, Beier A, Ganey T, et al. Posterior lumbar interbody fusion using rhBMP-2. Eur Spine J. 2008;17(12):1735-44.
46. Wong DA, Kumar A, Jatana S, Ghiselli G, Wong K. Neurologic impairment from ec-topic bone in the lumbar canal: a potential complication of off-label PLIF/TLIF use of bone morphogenetic protein-2 (BMP-2). Spine J. 2008;8(6):1011-8.
47. Geibel PT, Boyd DL, Slabisak V. The Use of Recombinant Human Bone Morphogenic Protein in Posterior Interbody Fusions of the Lumbar Spine A Clinical Series. J Spinal Dis-ord Tech. 2009;22(5):315-20.
48. Villavicencio AT, Burneikiene S, Nelson EL, Bulsara KR, Favors M, Thramann J. Safety of transforaminal lumbar interbody fusion and intervertebral recombinant human bone morphogenetic protein-2. J Neurosurg Spine. 2005;3(6):436-43.
49. Rihn JA, Makda J, Hong J, Patel R, Hilibrand AS, Anderson DG, et al. The use of RhBMP-2 in single-level transforaminal lumbar inter-body fusion: a clinical and radiographic analysis. Eur Spine J. 2009;18(11):1629-36.
50. Rihn JA, Patel R, Makda J, Hong J, Anderson DG, Vaccaro AR, et al. Complications associated with single-level transforaminal lumbar interbody fusion. Spine J. 2009;9(8):623-9.
51. Chen NF, Smith ZA, Stiner E, Armin S, Sheikh H, Khoo LT. Symptomatic ectopic bone formation after off-label use of recom-binant human bone morphogenetic protein-2 in transforaminal lumbar interbody fusion Report of 4 cases. J Neurosurg Spine. 2010;12(1):40-6.
52. Balseiro S, Nottmeier EW. Vertebral osteoly-sis originating from subchondral cyst end plate defects in transforaminal lumbar inter-body fusion using rhBMP-2. Report of two cases. Spine J. 2010;10(7):e6-e10.
53. Baskin DS, Ryan P, Sonntag V, Westmark R, Widmayer MA. A prospective, randomized, controlled cervical fusion study using re-combinant human bone morphogenetic pro-tein-2 with the CORNERSTONE-SR (TM) allograft ring and the ATLANTIS (TM) anterior cervical plate. Spine. 2003;28(12):1219-24.
54. Shields LBE, Raque GH, Glassman SD, Campbell M, Vitaz T, Harpring J, et al. Adverse effects associated with high-dose re-combinant human bone morphogenetic protein-2 use in anterior cervical spine fusion. Spine. 2006;31(5):542-7.
55. Tumialan LM, Pan J, Rodts GE, Mummaneni P V. The safety and efficacy of anterior cervical discectomy and fusion with poly-etheretherketone spacer and recombinant human bone morphogenetic protein-2: a review of 200 patients. J Neurosurg Spine. 2008;8(6):529-35.
56. Grauer J, Patel T, Erulkar J, Troiano N, Pan-jabi M, Friedlaender G. 2000 Young Investigator Research Award winner. Evaluation of OP-1 as a graft substitute for intertransverse process lumbar fusion. Spine (Phila Pa.). 2001;26(2):127-33.
57. Cunningham BW, Shimamoto N, Sefter JC, Dmitriev AE, Orbegoso CM, McCarthy EF, et al. Osseointegration of autograft versus os-teogenic protein-1 in posterolateral spinal arthrodesis: emphasis on the comparative mechanisms of bone induction. Spine J. 2002;2(1):11-24.
58. Vaccaro AR, Patel T, Fischgrund J, Anderson DG, Truumees E, Herkowitz H, et al. A pilot safety and efficacy study of OP-1 putty (rhBMP-7) as an adjunct to iliac crest auto-graft in posterolateral lumbar fusions. Eur Spine J. 2003;12(5):495-500.
59. Vaccaro AR, Anderson DG, Patel T, Fis-chgrund J, Truumees E, Herkowitz HN, 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. Spine. 2005;30(24):2709-16.
60. Vaccaro AR, Patel T, Fischgrund J, Anderson DG, Truumees E, Herkowitz HN, 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 spondylolis-thesis. Spine. 2004;29(17):1885-92.
61. Vaccaro AR, Whang PG, Patel T, Phillips FM, Anderson DG, Albert TJ, et al. The safety and efficacy of OP-1 (rhBMP-7) as a replacement for iliac crest autograft for pos-terolateral lumbar arthrodesis: minimum 4-year follow-up of a pilot study. Spine J. 2008;8(3):457-65.
62. Munns J, Park D, Singh K. Role of os-teogenic protein-1/bone morphogenetic pro-tein-7 in spinal fusion. Orthopedic Research and Reviews. 2009;1:11-21.
63. Magit DP, Maak T, Trioano N, Raphael B, Hamouria Q, Polzhofer G, et al. Healos/re-combinant human growth and differentiation factor-5 induces posterolateral lumbar fusion in a New Zealand white rabbit model. Spine. 2006;31(19):2180-8.
64. Kim DH, Jahng TA, Fu TS, Zhang HY, Novak SA. Evaluation of HealosMP52 os-teoinductive bone graft for instrumented lumbar intertransverse process fusion in sheep. Spine. 2004;29(24):2800-8.
65. Neen D, Noyes D, Shaw M, Gwilym S, Fair-lie N, Birch N. Healos and bone marrow aspirate used for lumbar spine fusion - A case controlled study comparing healos with au-tograft. Spine. 2006;31(18):E636-40.
66. Khoueir P, Oh BC, DiRisio DJ, Wang MY. Multilevel anterior cervical fusion using a collagen-hydroxyapatite matrix with iliac crest bone marrow aspirate: An 18-month follow-up study. Neurosurgery. 2007;61(5):963-70.
67. Ploumis A, Albert TJ, Brown Z, Mehbod AA, Transfeldt EE. 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. J Neuro-surg Spine. 2010;13(2):211-5.
68. Badrinath R, Bohl DD, Hustedt JW, Webb ML, Grauer JN. Only prolonged time from abstraction found to affect viable nucleated cell concentrations in vertebral body bone marrow aspirate. Spine J. 2014;14(6):990-5.
69. Hustedt JW, Jegede KA, Badrinath R, Bohl DD, Blizzard DJ, Grauer JN. Optimal aspiration volume of vertebral bone marrow for use in spinal fusion. Spine J. 2013;13(10):1217-22.
70. Risbud MV, Shapiro IM, Guttapalli A, Di Martino A, Danielson KG, Beiner JM, et al. Osteogenic potential of adult human stem cells of the lumbar vertebral body and the iliac crest. Spine (Phila Pa 1976). 2006;31(1):83-9.