BMP s: The future of nonunion treatment or do we have a problem?

Transcription

1 BMP s: The future of nonunion treatment or do we have a problem? Michael D. McKee, MD, FRCS(C) Professor, Division of Orthopaedics, St. Michael s Hospital, University of Toronto, Toronto, Canada Disclosure Studies supported by: - OTA, COA, ASES, AO, PSI - Zimmer Inc. - Stryker, Olympus Biotech I am a consultant for Acumed, Stryker, Zimmer, Olympus Biotech (OP-1) Receive royalties from Stryker, Lippincott 1

2 BMP studiesrandomized, prospective Animal defect models Human defect models Human nonunion trials Spinal fusion trials Human fracture trials rhbmp-7 Use in Tibial Nonunions Objective Establish safety and efficacy of BMP-7 in a challenging tibial nonunion model Methods 122 patients with 124 recalcitrant nonunions were enrolled between 1992 and 1996 Each patient was treated with an intramedullary rod and BMP-7 Implant or fresh bone autograft Friedlaender GE, et al. J Bone Joint Surg Am. 2001;83-A(suppl 1): Clinical Analysis % Success MO 9 MO 12 MO 24 MO Followup Visit (months) 70 OP-1 Autograft 2

3 Ronga M et. al. rhbmp-7 for treatment of long bone nonunion: An observational, retrospective, non-randomized study of 105 patients Injury, 2006, 37S, S51-S patients, 46 tibiae - 89% success rate with rhbmp-7, mean time to union 8 months Giannoudis PV et. al. Clinical applications of BMP-7; The UK perspective Injury, 2005, 36S, S47-S50 - multi-center, retrospective, 653 cases, (tibial nonunions most common use) - 82% union rate, but most has additional autograft Jones AL et. al. rhbmp-2 and allograft compared with autogenous bone graft for reconstruction of diaphyseal tibial fractures with cortical defects: A randomized clinical trial. JBJS(A) 2006(&): Tibial fractures with residual defect randomized to rhbmp-2 and allograft or autograft 15 patients in each group, mean defect 4 cm (1-7cm) 10 / 15 autograft versus 13 / 15 rhbmp-2 healed without further intervention Prospective Nonunion Study 61 patients Age: 47 years (range: 28 to 79 years) All atrophic, aseptic nonunion Mean: 2.1 prior operative interventions (range: 0 to 7) 28 patients had failed autogenous iliac crest bone grafting No autograft or other bone substitute used 3

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5 Results All patients followed to definitive outcome Mean follow-up was 26 months (range: 10 to 62 months) 54/61 (88%) patients healed their nonunion at a mean of 5.5 months (range: 2 to 12 months) Adverse events after rhbmp-2 in nonspinal orthopaedic surgery Woo EJ, CORR, reported cases Half required another OR 80% of cases involved unapproved uses Important safety concerns 5

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7 Blinders Shoulder pain after antegrade humeral nailing Habernak H, Orthner E A locking nail for fractures of the humerus JBJS(B) 1991 all cases regained full shoulder movement with no functional impairment by an average of six weeks. Habernak H Letter to the editor JBJS(B) 1998 This inevitably leads to damage of the cuff When we reviewed the 19 active patients in 1991 we did not assess their shoulders and this should have been addressed YODA Yale University Open Access (YODA) Project Independently reviewed original data from 13 RCT s and 31 cohort studies of BMP-2 (spinal fusions) Early journal publications misrepresented the effectiveness and harms through selective reporting, duplicate publication, and underreporting. 7

8 Bone morphogenetic protein (BMP) for fracture healing in adults Garrison KR et al. Cochrane Database Syst Rev 2010 Eleven RCt s ( all high risk for bias ) Time to healing comparable to controls in 10 / 11 studies Pooled RR for achieving union was 1.02 (0.90 to 1.15) this means there was no difference Withdrawl of a paper Kukla T et al. Recombinant human morphogenetic protein -2 for type III open segmental tibial fractures from combat injuries in Iraq JBJS(B) 2005 Reported BMP-2 (92% success) better than ICBG (76% success) at WRAMC US Army investigation: A number of serious questions were raised regarding the validity of the information and the conclusions made in the article Paper formally withdrawn and author banned rhbmp-7 (OP-1) In May 2014 Olympus Biotech announced it was stopping production of OP-1 8

9 Where does that leave us? When to use a BMP in 2014 Failed prior autograft Autograft not available - quantity of autograft an issue - intrinsically poor bone quality - morbid obesity Minimize hospital stay / complications Patient preference 9

10 Nonunion and BMP s in 2014 Nonunion is a difficult clinical problem Standard treatment is mechanical stabilization and biological stimulation Gold standard: Addition of autogenous bone graft Morbidity of iliac crest bone grafting is significant, with a major complication rate ranging up to 10% BMP-2 is a reasonable alternative in selected cases 10