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Bone morphogenetic protein and orthopaedic surgery: Can we legitimate its off-label use?

International Orthopaedics volume 38, pages 2601–2605 (2014)Cite this article

Abstract

Purpose

Bone morphogenetic proteins (BMP) are recombinant osteoinductive proteins with their primary role being to promote bone formation. The off-label use of BMP in orthopaedic surgery has dramatically increased. However, reports of complications with BMP have emerged, and the safety of these proteins in orthopaedics is questioned. The purpose of this review was to evaluate safe situations in which BMP should be used and situations in which their use should be restricted.

Method

We recorded all studies from PubMed database from 2002 (date of first authorisation for both BMPs) until January 2014 using “BMP” or “bone morphogenetic protein”. Then we screened and extracted all studies dealing with orthopaedic surgery. All situations in which BMP were used, even cases reports, were considered, and complications reported were then listed.

Results

Situations in which it seems safe and efficient to use BMP are long-bone nonunions, or arthrodesis as an alternative or combined to autograft in small-bone loss. Surgeons and patients should be aware of transient aseptic wound swelling when BMP is located superficially. The use of BMP in spine surgery for intersomatic fusion is efficient but should be restricted to approaches that respect the vertebral canal to avoid neurological complications.

Conclusion

This review is an off-label map of BMP use in orthopaedics during the past 10 years. Our results could provide a useful tool to help decisions around when to use a BMP in a specific complex, and sometimes off-label, situation.

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References

  1. Urist MR, Mikulski AJ, Nakagawa M, Yen K (1977) A bone matrix calcification-initiator noncollagenous protein. Am J Physiol 232(3):C115–C127

    CAS  PubMed  Google Scholar 

  2. Bishop GB, Einhorn TA (2007) Current and future clinical applications of bone morphogenetic proteins in orthopaedic trauma surgery. Int Orthop 31(6):721–727. doi:10.1007/s00264-007-0424-8

    Article  PubMed Central  PubMed  Google Scholar 

  3. Lissenberg-Thunnissen SN, de Gorter DJ, Sier CF, Schipper IB (2011) Use and efficacy of bone morphogenetic proteins in fracture healing. Int Orthop 35(9):1271–1280. doi:10.1007/s00264-011-1301-z

    Article  PubMed Central  PubMed  Google Scholar 

  4. Vukicevic S, Oppermann H, Verbanac D, Jankolija M, Popek I, Curak J, Brkljacic J, Pauk M, Erjavec I, Francetic I, Dumic-Cule I, Jelic M, Durdevic D, Vlahovic T, Novak R, Kufner V, Bordukalo Niksic T, Kozlovic M, Banic Tomisic Z, Bubic-Spoljar J, Bastalic I, Vikic-Topic S, Peric M, Pecina M, Grgurevic L (2014) The clinical use of bone morphogenetic proteins revisited: a novel biocompatible carrier device OSTEOGROW for bone healing. Int Orthop 38(3):635–647. doi:10.1007/s00264-013-2201-1

    Article  PubMed  Google Scholar 

  5. Fu R, Selph S, McDonagh M, Peterson K, Tiwari A, Chou R, Helfand M (2013) Effectiveness and harms of recombinant human bone morphogenetic protein-2 in spine fusion: a systematic review and meta-analysis. Ann Intern Med 158 (12):890-902. doi:10.7326/0003-4819-158-12-201306180-00006

  6. Simmonds MC, Brown JV, Heirs MK, Higgins JP, Mannion RJ, Rodgers MA, Stewart LA (2013) Safety and effectiveness of recombinant human bone morphogenetic protein-2 for spinal fusion: a meta-analysis of individual-participant data. Ann Intern Med 158 (12):877-889. doi:10.7326/0003-4819-158-12-201306180-00005

  7. Delimar D, Smoljanovic T, Bojanic I (2012) Could the use of bone morphogenetic proteins in fracture healing do more harm than good to our patients? Int Orthop 36 (3):683; author reply 685. doi:10.1007/s00264-011-1397-1

  8. Bong MR, Capla EL, Egol KA, Sorkin AT, Distefano M, Buckle R, Chandler RW, Koval KJ (2005) Osteogenic protein-1 (bone morphogenic protein-7) combined with various adjuncts in the treatment of humeral diaphyseal nonunions. Bull Hosp Jt Dis 63(1–2):20–23

    PubMed  Google Scholar 

  9. Dimitriou R, Dahabreh Z, Katsoulis E, Matthews SJ, Branfoot T, Giannoudis PV (2005) Application of recombinant BMP-7 on persistent upper and lower limb non-unions. Injury 36 Suppl 4:S51-59. doi:10.1016/j.injury.2005.10.010

  10. Moghaddam A, Elleser C, Biglari B, Wentzensen A, Zimmermann G (2010) Clinical application of BMP 7 in long bone non-unions. Arch Orthop Trauma Surg 130(1):71–76. doi:10.1007/s00402-009-0982-x

    Article  PubMed  Google Scholar 

  11. Ronga M, Baldo F, Zappala G, Cherubino P (2006) Recombinant human bone morphogenetic protein-7 for treatment of long bone non-union: an observational, retrospective, non-randomized study of 105 patients. Injury 37 Suppl 3:S51-56. doi:10.1016/j.injury.2006.08.024

  12. Evans RO, Goldberg JA, Bruce WJ, Walsh W (2004) Reoperated clavicular nonunion treated with osteogenic protein 1 and electrical stimulation. J Shoulder Elbow Surg 13 (5):573-575. doi:10.1016/S105827460400076X

  13. Clark RR, McKinley TO (2010) Bilateral olecranon epiphyseal fracture non-union in a competitive athlete. Iowa Orthop J 30:179–181

    PubMed Central  PubMed  Google Scholar 

  14. Friedlaender GE, Perry CR, Cole JD, Cook SD, Cierny G, Muschler GF, Zych GA, Calhoun JH, LaForte AJ, Yin S (2001) Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. J Bone Joint Surg Am 83-A Suppl 1(Pt 2):S151–S158

    Google Scholar 

  15. Zimmermann G, Wagner C, Schmeckenbecher K, Wentzensen A, Moghaddam A (2009) Treatment of tibial shaft non-unions: bone morphogenetic proteins versus autologous bone graft. Injury 40 Suppl 3:S50-53. doi:10.1016/S0020-1383(09)70012-9

  16. Kanakaris NK, Calori GM, Verdonk R, Burssens P, De Biase P, Capanna R, Vangosa LB, Cherubino P, Baldo F, Ristiniemi J, Kontakis G, Giannoudis PV (2008) Application of BMP-7 to tibial non-unions: a 3-year multicenter experience. Injury 39 Suppl 2:S83-90. doi:10.1016/S0020-1383(08)70019-6

  17. Obert L, Deschaseaux F, Garbuio P (2005) Critical analysis and efficacy of BMPs in long bones non-union. Injury 36 Suppl 3:S38-42. doi:10.1016/j.injury.2005.07.033

  18. Wysocki RW, Cohen MS (2007) Ectopic ossification of the triceps muscle after application of bone morphogenetic protein-7 to the distal humerus for recalcitrant nonunion: a case report. J Hand Surg Am 32 (5):647-650. doi:10.1016/j.jhsa.2007.03.001

  19. Boraiah S, Paul O, Hawkes D, Wickham M, Lorich DG (2009) Complications of recombinant human BMP-2 for treating complex tibial plateau fractures: a preliminary report. Clin Orthop Relat Res 467(12):3257–3262. doi:10.1007/s11999-009-1039-8

    Article  PubMed Central  PubMed  Google Scholar 

  20. Bilic R, Simic P, Jelic M, Stern-Padovan R, Dodig D, van Meerdervoort HP, Martinovic S, Ivankovic D, Pecina M, Vukicevic S (2006) Osteogenic protein-1 (BMP-7) accelerates healing of scaphoid non-union with proximal pole sclerosis. Int Orthop 30(2):128–134. doi:10.1007/s00264-005-0045-z

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Bibbo C, Patel DV, Haskell MD (2009) Recombinant bone morphogenetic protein-2 (rhBMP-2) in high-risk ankle and hindfoot fusions. Foot Ankle Int 30 (7):597-603. doi:10.3113/FAI.2009.0597

  22. Schuberth JM, DiDomenico LA, Mendicino RW (2009) The utility and effectiveness of bone morphogenetic protein in foot and ankle surgery. J Foot Ankle Surg 48 (3):309-314. doi:10.1053/j.jfas.2009.01.011

  23. El-Amin SF, Hogan MV, Allen AA, Hinds J, Laurencin CT (2010) The indications and use of bone morphogenetic proteins in foot, ankle, and tibia surgery. Foot Ankle Clin 15 (4):543-551. doi:10.1016/j.fcl.2010.08.001

  24. Fourman MS, Borst EW, Bogner E, Rozbruch SR, Fragomen AT (2014) Recombinant Human BMP-2 Increases the Incidence and Rate of Healing in Complex Ankle Arthrodesis. Clin Orthop Relat Res 472(2):732–739. doi:10.1007/s11999-013-3261-7

    Article  PubMed  Google Scholar 

  25. Hawkins BJ (2010) Biologics in foot and ankle surgery. Foot Ankle Clin 15 (4):577-596. doi:10.1016/j.fcl.2010.07.003

  26. DeVries JG, Nguyen M, Berlet GC, Hyer CF (2012) The effect of recombinant bone morphogenetic protein-2 in revision tibiotalocalcaneal arthrodesis: utilization of the Retrograde Arthrodesis Intramedullary Nail database. J Foot Ankle Surg 51 (4):426-432. doi:10.1053/j.jfas.2012.03.007

  27. Kanakaris NK, Mallina R, Calori GM, Kontakis G, Giannoudis PV (2009) Use of bone morphogenetic proteins in arthrodesis: clinical results. Injury 40 Suppl 3:S62-66. doi:10.1016/S0020-1383(09)70014-2S0020-1383(09)70014-2

  28. Pecina M, Jelic M, Martinovic S, Haspl M, Vukicevic S (2002) Articular cartilage repair: the role of bone morphogenetic proteins. Int Orthop 26(3):131–136. doi:10.1007/s00264-002-0338-4

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Tannoury C, An HS (2014) Complications with Use of Bone Morphogenetic Protein-2 (BMP-2) in Spine Surgery. Spine J. doi:10.1016/j.spinee.2013.08.060

  30. Singh K, Ahmadinia K, Park DK, Nandyala SV, Marquez-Lara A, Patel AA, Fineberg SJ (2014) Complications of spinal fusion with utilization of bone morphogenetic protein: a systematic review of the literature. Spine (Phila Pa 1976) 39(1):91–101. doi:10.1097/BRS.0000000000000004

    Article  Google Scholar 

  31. Vaidya R, Sethi A, Bartol S, Jacobson M, Coe C, Craig JG (2008) Complications in the use of rhBMP-2 in PEEK cages for interbody spinal fusions. J Spinal Disord Tech 21 (8):557-562. doi:10.1097/BSD.0b013e31815ea897

  32. Balseiro S, Nottmeier EW (2010) Vertebral osteolysis originating from subchondral cyst end plate defects in transforaminal lumbar interbody fusion using rhBMP-2. Report of two cases. Spine J 10 (7):e6-e10. doi:10.1016/j.spinee.2010.04.013

  33. Helgeson MD, Lehman RA, Jr., Patzkowski JC, Dmitriev AE, Rosner MK, Mack AW (2011) Adjacent vertebral body osteolysis with bone morphogenetic protein use in transforaminal lumbar interbody fusion. Spine J 11 (6):507-510. doi:10.1016/j.spinee.2011.01.017

  34. Saigal G, Quencer R, Guest JD, Cristescu MM, Lebwohl N (2012) Vertebral body osteolysis following the use of bone morphogenetic protein in spinal surgery: a mimicker of infection. J Neuroradiol 39 (5):354-359. doi:10.1016/j.neurad.2012.03.005

  35. Smoljanovic T, Bojanic I, Cimic M (2009) Bone morphogenetic protein. J Neurosurg Spine 11 (1):92-93; author reply 93-94. doi:10.3171/2009.2.SPINE08953L

  36. Deutsch H (2010) High-dose bone morphogenetic protein-induced ectopic abdomen bone growth. Spine J 10 (2):e1-4. doi:10.1016/j.spinee.2009.10.016

  37. Anderson CL, Whitaker MC (2012) Heterotopic ossification associated with recombinant human bone morphogenetic protein-2 (infuse) in posterolateral lumbar spine fusion: a case report. Spine (Phila Pa 1976) 37(8):E502–E506. doi:10.1097/BRS.0b013e318238870b

    Article  Google Scholar 

  38. Joseph V, Rampersaud YR (2007) Heterotopic bone formation with the use of rhBMP2 in posterior minimal access interbody fusion: a CT analysis. Spine (Phila Pa 1976) 32 (25):2885-2890. doi:10.1097/BRS.0b013e31815b7596

  39. Chen NF, Smith ZA, Stiner E, Armin S, Sheikh H, Khoo LT (2010) Symptomatic ectopic bone formation after off-label use of recombinant human bone morphogenetic protein-2 in transforaminal lumbar interbody fusion. J Neurosurg Spine 12(1):40–46. doi:10.3171/2009.4.SPINE0876

    Article  PubMed  Google Scholar 

  40. Glassman SD, Gum JL, Crawford CH, 3rd, Shields CB, Carreon LY (2011) Complications with recombinant human bone morphogenetic protein-2 in posterolateral spine fusion associated with a dural tear. Spine J 11 (6):522-526. doi:10.1016/j.spinee.2010.05.016

  41. Choudhry OJ, Christiano LD, Singh R, Golden BM, Liu JK (2012) Bone morphogenetic protein-induced inflammatory cyst formation after lumbar fusion causing nerve root compression. J Neurosurg Spine 16(3):296–301. doi:10.3171/2011.11.SPINE11629

    Article  PubMed  Google Scholar 

  42. Smucker JD, Rhee JM, Singh K, Yoon ST, Heller JG (2006) Increased swelling complications associated with off-label usage of rhBMP-2 in the anterior cervical spine. Spine (Phila Pa 1976) 31 (24):2813-2819. doi:10.1097/01.brs.0000245863.52371.c2

  43. Perri B, Cooper M, Lauryssen C, Anand N (2007) Adverse swelling associated with use of rh-BMP-2 in anterior cervical discectomy and fusion: a case study. Spine J 7 (2):235-239. doi:10.1016/j.spinee.2006.04.010

  44. Shahlaie K, Kim KD (2008) Occipitocervical fusion using recombinant human bone morphogenetic protein-2: adverse effects due to tissue swelling and seroma. Spine (Phila Pa 1976) 33 (21):2361-2366. doi:10.1097/BRS.0b013e318183971d

  45. Anticevic D, Jelic M, Vukicevic S (2006) Treatment of a congenital pseudarthrosis of the tibia by osteogenic protein-1 (bone morphogenetic protein-7): a case report. J Pediatr Orthop B 15 (3):220-221. doi:10.1097/01.bpb.0000194439.75378.ac

  46. Spiro AS, Babin K, Lipovac S, Stenger P, Mladenov K, Rupprecht M, Rueger JM, Stuecker R (2011) Combined treatment of congenital pseudarthrosis of the tibia, including recombinant human bone morphogenetic protein-2: a case series. J Bone Joint Surg Br 93 (5):695-699. doi:10.1302/0301-620X.93B5.25938

  47. Pannier S (2011) Congenital pseudarthrosis of the tibia. Orthop Traumatol Surg Res 97 (7):750-761. doi:10.1016/j.otsr.2011.09.001

  48. Richards BS, Oetgen ME, Johnston CE (2010) The use of rhBMP-2 for the treatment of congenital pseudarthrosis of the tibia: a case series. J Bone Joint Surg Am 92 (1):177-185. doi:10.2106/JBJS.H.01667

  49. Cheng TL, Murphy CM, Cantrill LC, Mikulec K, Carpenter C, Schindeler A, Little DG (2014) Local delivery of recombinant human bone morphogenetic proteins and bisphosphonate via sucrose acetate isobutyrate can prevent femoral head collapse in Legg-Calve-Perthes disease: a pilot study in pigs. Int Orthop 38(7):1527–1533. doi:10.1007/s00264-013-2255-0

    Article  PubMed  Google Scholar 

  50. Steib JP, Bouchaib J, Walter A, Schuller S, Charles YP (2010) Could an osteoinductor result in degeneration of a neurofibroma in NF1? Eur Spine J 19(Suppl 2):S220–S225. doi:10.1007/s00586-010-1416-8

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Pediatric Orthopedic Department. Grenoble University Hospital, Grenoble Alpes University, BP 217, 38043, Grenoble Cedex 09, France

    Aurélien Courvoisier

  2. Department of Orthopedics and Traumatology – Cochin Hospital, Paris. Paris 5 University, 27 Rue du Faubourg Saint-Jacques, Paris, 75014, France

    Frederic Sailhan

  3. Department of Orthopedics and Traumatology – Pellegrin Hospital. Bordeaux University Hospital, Bordeaux Segalen University, 146 Rue Léo Saignat, 33076, Bordeaux, France

    Olivier Laffenêtre

  4. Department of Orthopedics and Traumatology – Jean Minjoz Hospital, Besançon University Hospital, 3 Boulevard Alexandre Fleming, 25030, Besançon, France

    Laurent Obert

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  1. Aurélien Courvoisier
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  2. Frederic Sailhan
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  3. Olivier Laffenêtre
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  4. Laurent Obert
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From the French Study Group of BMP in Orthopedic Surgery

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Correspondence to Aurélien Courvoisier.

Additional information

The French Study Group of BMP in Orthopedic Surgery can also be reached at www.GTEBO.eu.

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Courvoisier, A., Sailhan, F., Laffenêtre, O. et al. Bone morphogenetic protein and orthopaedic surgery: Can we legitimate its off-label use?. International Orthopaedics (SICOT) 38, 2601–2605 (2014). https://doi.org/10.1007/s00264-014-2534-4

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