Advisory on rhBMP-2 in "The Spine Journal" Had a Greater Effect on Practice Than FDA Warning

Samuel K. Cho, MD, and Jeffrey C. Wang, MD, comment on the findings, and how peer-reviewed journals influence practice.

Use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in spine surgery remains a controversial topic. In 2008, the FDA released an advisory on potentially devastating complications of rhBMP-2 when used in anterior cervical spine fusion.1 In 2011, an independent review of available data on rhBMP-2 published in The Spine Journal revealed emerging safety concerns with rhBMP-2.2

New findings published in the September issue of The Spine Journal suggest that the 2011 warnings in The Spine Journal had a more profound impact on practice patterns in terms of decreasing rhBMP-2 use than the 2008 FDA warning.

“The findings suggest that practicing spine surgeons are sensitive and responsive to what is published in scientific journals,” said coauthor Samuel K. Cho, MD.
Bone morphogenetic protein 2 (BMP-2) protein. Wireframe representation combined with semi-transparent molecular surface.“I am happy that these findings validate that information in a highly-respected peer-reviewed journal has been shown to have an impact [on practice],” commented SpineUniverse editorial board member Jeffrey C. Wang, MD. “In this day and age, with ‘fake news’ as well as so many different publications and newsletters, it is nice to see validation that a scientific journal has an impact on behavior.”

Findings Based on Nationwide Database
Dr. Cho and colleagues conducted a retrospective cross-sectional study to examine the use of rhBMP-2 in all patients (n=4,167,079) who underwent spinal fusion surgery at institutions participating in the Nationwide Inpatient Sample from 2002 to 2013.

The prevalence of rhBMP-2 for all fusions reached a high of 30.27 in 2010 and decreased steadily thereafter to a low of 14.36 in 2013.

Analysis showed a greater decrease in rhBMP-2 use after The Spine Journal warning was published compared with after the FDA advisory was issued for all fusion procedures (P=0.006), primary fusions (P=0.006), and revision fusions (P=0.004). This same pattern was observed for lumbosacral procedures (P=0.0008) as well as anterior and posterior lumbosacral fusions (P≤.0001 for both).

In contrast, anterior cervical fusion was the only procedure for which a greater decline in rhBMP-2 use was found after issuance of the FDA advisory versus after publication of The Spine Journal article (P=0.02).

Accessibility May Have Played a Role in the Findings
The greater impact of The Spine Journal paper may be related to greater availability of the information, Dr. Cho said.

“Most surgeons read scientific journals within their specialty and have easy access to them,” Dr. Cho told SpineUniverse. In contrast, the FDA warning might not have been accessed by spine surgeons as readily, and described the risk only in anterior cervical spine fusions, rather than all fusions as in The Spine Journal paper, he said.

Validation That Findings in Peer-Reviewed Journals Influence Practice
“The key message is that information that is more widely disseminated, probably has a greater impact,” commented Dr. Wang, who is Chief of Orthopaedic Spine Service and Co-Director and Professor of Orthopaedic Surgery and Neurosurgery at the USC Spine Center at Keck Medical Center of USC in Los Angeles. “Certainly, warnings from companies, manufacturers, and regulatory agencies do make an impact. However, when put into a highly regarded scientific journal that is credible, peer-reviewed, and has great science, it probably has more of an impact.”

“It is important for surgeons to have a justification for everything they do,” Dr. Wang continued. “Guidelines can be misinterpreted, and then used by some parties to dictate behavior. In the end, the physician must put patient safety at the top of the list. Everything else is secondary. For those who do not know the evidence and the literature, perhaps guidelines put forth based on evidence may help with making decisions.”

“I see other countries starting to use rhBMP-2 as well as international usage of different formulations of rhBMP-2, and I think [that all surgeons] should learn from the published literature on how to best make decisions on their usage. Guidelines in these situations, could be beneficial.”

Potential Risks Associated With BMP-2
The 2011 review in The Spine Journal found that rhBMP-2 was associated with risk of osteolysis, subsidence, increased reoperation rate, retrograde ejaculation, urinary retention, increased delayed infections, bone overgrowth, and radiculitis. In addition, potentially increased incidence of malignancy and adverse effects on the central nervous system (eg, early back and leg morbidity) were found with use of rhBMP-2 in the spine, Dr. Cho and colleagues explained in their paper.

Is BMP Linked to Cancer?
In 2015, Dr. Cho and colleagues published a literature review that demonstrated no effect of rhBMP-2 on the development of de novo cancer.3 However, because the agent is a growth factor, 43% of studies suggested that BMP-2 may enhance tumor function in select cancer types.

“Based our review, rhBMP-2 is not a carcinogen, but rather is a growth factor,” Dr. Cho said, adding that other researchers have published findings. “If a patient has an undiagnosed malignant tumor and receives BMP near the area of those cancerous cells, then BMP can potentially expedite the course of that tumor.”

“The review also indicated that rhBMP-2 has diverse roles at the basic science level,” Dr. Cho explained. “It can actually promote the growth of certain cancer types, such as lung cancer, but may suppress the growth of other cancer cell types.”

Several other clinical studies also suggest that rhBMP-2 does not increase the incidence of new cancer diagnosis even when high doses were utilized, Dr. Cho said.4,5

“At the end of the day, rhBMP-2 is like any new technology. Appropriate, judicious use of the product is needed,” Dr. Cho said. Ongoing dialogue and research on appropriate use of rhBMP-2 will help promote patient safety and improve the practice of spine surgery, he added.

Disclosures
Dr. Cho disclosed no relevant financial relationships.
Dr. Wang disclosed no relevant financial relationships.

Updated on: 10/03/17
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