In November 1965, a landmark article in Science1 demonstrated that the demineralized extracellular matrix of bone possesses a property that allows it to induce the formation of new bone when implanted into a nonskeletal site, an effect that initially was known as “bone autoinduction.” Certain members of a family of proteins, later known as bone morphogenetic proteins (BMPs), were shown to be responsible for this effect. Twenty-three years later, scientists cloned recombinant human BMP-2 (rhBMP-2) and touted its potential ability to change skeletal surgery. Clinicians and scientists waited with bated breath for the U.S. Food and Drug Administration (FDA) to grant regulatory approval to this protein.
In this issue of JBJS Reviews, Hsu reviews the role of rhBMP-2 in spine surgery. The article provides the historical perspective on the development of this recombinant protein and the results of different preclinical and clinical studies that led to its approval and widespread use. However, despite the many clinical success stories that have accompanied the use of rhBMP-2 in the spine, adverse events have been noteworthy. In particular, anterior lumbar interbody fusion with use of rhBMP-2 has been associated with osteolysis and retrograde ejaculation. Off-label use, as in the cervical spine, has been associated with inflammatory responses that have led to near fatal outcomes. Perhaps the greatest concern is that the use of rhBMP-2 is potentially associated with the formation of new cancers. Carragee et al. reviewed the data on the use of rhBMP-2 from industry-sponsored publications and FDA summaries and concluded that there was indeed a significantly higher risk of new cancers among patients who had been exposed to this factor2. Indeed, inappropriate use of the protein in relation to its regulatory approval status has been common, and concerns have been raised that much of the key information in the literature was provided by investigators who received substantial compensation from Medtronic, the company that markets rhBMP-2.
To address these concerns, and in an admirably bold move, Medtronic commissioned an independent review of the available data in the industry-sponsored clinical trials involving rhBMP-2 through the Yale Open Data Access (YODA) Project. Two studies that had been performed by research groups at different institutions (University of York and Oregon Health & Science University) provided an unbiased, comprehensive review of individual patient data, patient data from clinical trials sponsored by Medtronic, and selected case series and case reports from the peer-reviewed literature3,4. Both groups had access to the same data, and each group was allowed to determine its own inclusion and exclusion criteria, statistical methods, and conclusions. The results showed substantial agreement among both sets of investigators. Both sets of investigators concluded that while rhBMP-2 does lead to high fusion rates in the lumbar spine, there were no significant differences in outcomes when compared with those for patients who were managed with iliac crest bone graft. Both studies demonstrated a significantly higher incidence of leg and/or back pain in the immediate postoperative period (up to six weeks) among the patients who received rhBMP-2; however, no other differences were noted between the groups. There was agreement that the use of rhBMP-2 in the anterior aspect of the cervical spine posed a clear safety risk and, although the York study demonstrated a nonsignificantly higher incidence of cancer in the rhBMP-2 group, the group from Oregon Health & Science University demonstrated a significantly higher incidence of cancer at twenty-four months.
On the basis of these findings, we need to reassess the role of rhBMP-2 in the spine, draw the appropriate conclusions, and articulate the appropriate precautions. There is no question that rhBMP-2 is an active molecule that enhances lumbar spinal fusion. However, it does not lead to improved clinical outcomes in comparison with those for patients who undergo the same operation with iliac crest bone graft. Second, physicians and patients need to understand the risks associated with the use of rhBMP-2 in the spine, particularly the higher incidence of leg and/or back pain, retrograde ejaculation, and, potentially, cancer. Finally, the off-label use of rhBMP-2 can lead to devastating complications and should be strongly discouraged.
The bottom line is that orthopaedic surgery has benefitted from years of basic-science and preclinical studies that have led to the development of a powerful and effective protein that enhances skeletal healing and fusion. However, rhBMP-2 is associated with a number of risks, and guidelines should be established for its use. Physicians must have realistic expectations regarding clinical outcomes as the use of iliac crest bone ultimately leads to equivalent results. Most importantly, physicians must counsel their patients about the use of this material in relation to anticipated outcomes and potential risks and complications.
So, has the promise been kept? I think it has. However, it has come with a set of findings that may temper our enthusiasm for the use of rhBMP-2 in certain settings and with a dose of baggage that only now has begun to be clarified.
- Copyright © 2014 by The Journal of Bone and Joint Surgery, Incorporated