Safety and effectiveness of recombinant human bone morphogenetic protein-2 for spinal fusion: A meta-analysis of individual-participant data

Research output: Contribution to journalArticlepeer-review


Background: Recombinant human bone morphogenetic protein-2 (rhBMP-2) is widely used to promote fusion in spinal surgery, but its safety has been questioned.

Purpose: To evaluate the effectiveness and safety of rhBMP-2.

Data Sources: Individual-participant data obtained from the sponsor or investigators and data extracted from study publications identified by systematic bibliographic searches through June 2012.

Study Selection: Randomized, controlled trials of rhBMP-2 versus iliac crest bone graft (ICBG) in spinal fusion surgery for degenerative disc disease and related conditions and observational studies in similar populations for investigation of adverse events.

Data Extraction: Individual-participant data from 11 eligible of 17 provided trials sponsored by Medtronic (Minneapolis, Minnesota) (n = 1302) and 1 of 2 other eligible trials (n = 106) were included. Additional aggregate adverse event data were extracted from 35 published observational studies.

Data Synthesis: Primary outcomes were pain (assessed with the Oswestry Disability Index [ODI] or Short Form-36), fusion, and adverse events. At 24 months, ODI scores were 3.5% lower (better) with rhBMP-2 than with ICBG (95% CI, 0.5% to 6.5%) and radiographic fusion was 12% higher (CI, 2% to 23%). At or shortly after surgery, pain was more common with rhBMP-2 (odds ratio, 1.78 [CI, 1.06 to 2.95]). Cancer was more common after rhBMP-2 (relative risk, 1.98 [CI, 0.86 to 4.54]), but the small number of events precluded definite conclusions.

Limitation: The observational studies were diverse and at risk of bias.

Conclusion: At 24 months, rhBMP-2 increases fusion rates, reduces pain by a clinically insignificant amount, and increases early postsurgical pain compared with ICBG. Evidence of increased cancer incidence is inconclusive.

Primary Funding Source: Yale University Open Data Access Project.

Recombinant human bone morphogenetic protein-2 (rhBMP-2) is widely used as an alternative to iliac crest bone graft (ICBG) to promote fusion in spinal surgery (1–2). Since the U.S. Food and Drug Administration (FDA) approved rhBMP-2 for anterior lumbar interbody fusion (ALIF) surgery (3), its use has grown rapidly, including off-label indications (2, 4). A review of publicly available data suggesting that the risk for adverse events is 10 to 50 times higher than reported in trial publications (5) raised concerns about the safety of rhBMP-2.

The Yale University Open Data Access (YODA) Project team invited Medtronic (Minneapolis, Minnesota) to provide full data from all of its trials of rhBMP-2 to allow independent reanalysis. The project team subsequently invited proposals to undertake independent evaluation and funded the Centre for Reviews and Dissemination and 1 other group to do so, thus enabling meta-analysis of individual-participant data (IPD), which is regarded as a “gold standard” approach to evidence synthesis.

We embedded our IPD meta-analysis within a systematic review and sought to examine all relevant evidence. Investigation of comparative effectiveness was restricted to randomized, controlled trials (RCTs). In addition, to investigate the safety of rhBMP-2, we sought all observational studies of its use in spinal surgery that reported adverse events. Findings of our investigation of reporting bias are presented in our full report and have been submitted for publication elsewhere.
Original languageEnglish
Pages (from-to)877-889
Number of pages13
JournalAnnals of Internal Medicine
Issue number12
Publication statusPublished - 18 Jun 2013

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