title: Effectiveness and harms of recombinant human bone morphogenetic protein-2 in spine fusion: a systematic review and meta-analysis.
abstract: BACKGROUND
  Recombinant human bone morphogenetic protein-2 (rhBMP-2) is used as a bone graft substitute in spinal fusion, which unites (fuses) bones in the spine. The accuracy and completeness of journal publications of industry-sponsored trials on the effectiveness and harms of rhBMP-2 has been called into question.
  
  
  OBJECTIVE
  To independently assess the effectiveness and harms of rhBMP-2 in spinal fusion and reporting bias in industry-sponsored journal publications.
  
  
  METHODS
  Individual-patient data (IPD) from 17 industry-sponsored studies; related internal documents; and searches of MEDLINE (1996 to August 2012), other databases, and reference lists.
  
  
  METHODS
  Randomized, controlled trials (RCTs) and cohort studies of rhBMP-2 versus any control and uncontrolled studies of harms.
  
  
  METHODS
  Effectiveness outcomes in IPD were recalculated using consistent definitions. Study characteristics and results were abstracted by 1 investigator and confirmed by another. Two investigators independently assessed quality using predefined criteria.
  
  
  RESULTS
  Thirteen RCTs and 31 cohort studies were included. For lumbar spine fusion, rhBMP-2 and iliac crest bone graft were similar in overall success, fusion, and other effectiveness measures and in risk for any adverse event, although rates were high across interventions (77% to 93% at 24 months from surgery). For anterior lumbar interbody fusion, rhBMP-2 was associated with nonsignificantly increased risk for retrograde ejaculation and urogenital problems. For anterior cervical spine fusion, rhBMP-2 was associated with increased risk for wound complications and dysphagia. At 24 months, the cancer risk was increased with rhBMP-2 (risk ratio, 3.45 [95% CI, 1.98 to 6.00]), but event rates were low and cancer was heterogeneous. Early journal publications misrepresented the effectiveness and harms through selective reporting, duplicate publication, and underreporting.
  
  
  CONCLUSIONS
  Outcome assessment was not blinded, and ascertainment of harms in trials was poor. No trials were truly independent of industry sponsorship.
  
  
  CONCLUSIONS
  In spinal fusion, rhBMP-2 has no proven clinical advantage over bone graft and may be associated with important harms, making it difficult to identify clear indications for rhBMP-2. Earlier disclosure of all relevant data would have better informed clinicians and the public than the initial published trial reports did.
  
  
  BACKGROUND
  Yale University and Medtronic.
authors.affiliation: Oregon Health & Science University and Portland Veterans Affairs Medical Center, Portland, OR 97239, USA.
authors.forename: Rongwei
authors.initials: R
authors.lastname: Fu
authors.forename: Shelley
authors.initials: S
authors.lastname: Selph
authors.forename: Marian
authors.initials: M
authors.lastname: McDonagh
authors.forename: Kimberly
authors.initials: K
authors.lastname: Peterson
authors.forename: Arpita
authors.initials: A
authors.lastname: Tiwari
authors.forename: Roger
authors.initials: R
authors.lastname: Chou
authors.forename: Mark
authors.initials: M
authors.lastname: Helfand
mesh_terms: D055396:Bone Morphogenetic Protein 2 / Q000009:adverse effects* / Q000627:therapeutic use*; D016265:Conflict of Interest; D004345:Drug Industry; D006801:Humans; D007085:Ilium / Q000637:transplantation; D015994:Incidence; D055959:Intervertebral Disc Degeneration / Q000601:surgery*; D009369:Neoplasms / Q000453:epidemiology; D056687:Off-Label Use; D017594:Publication Bias; D011643:Publishing / Q000592:standards; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D013123:Spinal Fusion / Q000379:methods; D016212:Transforming Growth Factor beta / Q000009:adverse effects* / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D055396:Bone Morphogenetic Protein 2; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C499469:recombinant human bone morphogenetic protein-2