Spine Surgeons React to BMP-2 Cancer Data

By John Fauber, Reporter, Milwaukee Journal Sentinel/MedPage Today

CHICAGO -- Spine surgery patients who got a bone growth stimulating agent as part of a clinical trial were three to five times more likely to develop cancer two to three years after being implanted with the product, according to a new analysis reported here.

The report is the latest cautionary note involving Medtronic's bone morphogenetic protein-2, or BMP-2, a popular genetically engineered product used in spinal fusion surgery as an alternative to using a small amount of a patient's own bone.

The analysis led by Eugene Carragee, MD, a Stanford University orthopedic surgeon, who presented the findings at the North American Spine Society's annual meeting, echoes findings in a Journal Sentinel/MedPage Today investigative report earlier this month. That story showed an elevated cancer risk in the clinical trial of an investigative Medtronic product containing BMP-2.

If approved it would be marketed under the brand name Amplify. Medtronic currently manufactures another BMP-2 product under the brand name InFuse. That product is FDA approved.

"This is a provocative study that should make surgeons most concerned," said Dan Spengler, MD, a professor of orthopedic surgery at Vanderbilt University Medical School. "I can't see a justification for its use except in extreme cases."

Carragee's analysis drilled down into data from a pivotal trial in which 239 patients were treated with the Amplify product and 224 controls, who had spinal fusion using autologous hip bone grafts.

Among those who underwent follow-up about three years after the surgery, 5% of those who got Amplify, or 12 patients, were diagnosed with a new cancer, compared with 1.3%, or three patients, who got a graft of their own hip bone. The difference was statistically significant P=0.02.

After two to three years of follow up, Amplify patients were four to five times more likely to develop at least one new malignancy, the analysis found. Viewed another way, one extra patient would be expected to develop cancer out of every 20 to 25 treated with Amplify.

Cancer cases that were diagnosed after spinanl fusion surgery among 239 patients who were implanted with BMP-2 as part of the Amplify clinical trial.


The cancer findings were not discussed when the findings were initially published.

"Who do we believe?" asked John Jacquemin, MD, an orthopedic surgeon from Cincinnati in response to Carragee's presentation. "When the literature comes out, what's real and what is not?"

Jacquemin said he was especially troubled by allegations of bias in papers written by doctors with financial conflicts.

"That scares me and troubles me," he said.

Jerry Knirk, MD, an orthopedic surgeon from New Hampshire, said he was concerned that most funding for medical devices comes from corporations.

"Money corrupts," he said.

The authors of the 2009 paper mentioned the cancer link only in a table accompanying the paper. The text itself never addressed the concern of whether BMP-2 might fuel cancer.

It was written by six physician authors. The first three authors of the paper - or entities they are associated with - received about $10 million from Medtronic, mostly in royalties, in 2010 alone. The royalties were for other products, not for BMP-2.

While the authors failed to warn of the cancer concern, the Journal Sentinel/MedPage Today found a full airing of the cancer question in more than 1,000 pages of U.S. Food and Drug Administration records. That information included FDA reports and information filed with the agency by Medtronic as part of its application to win approval for Amplify.

At a 2010 Amplify hearing, for example, an FDA staffer said "the primary statistical concern is an apparent association with malignancy."

Since coming on the market in 2002, BMP-2 has become popular in spinal surgery. By stimulating bone growth, it can eliminate the need to harvest a small amount of a patient's own bone for use in a spinal fusion surgery.

The product was approved for a narrow use after an earlier clinical trial showed it worked about as well as a standard hip bone graft in a specific kind of spinal fusion surgery. But doctors quickly began using BMP-2 in other, unapproved ways, known as "off-label" use. That helped fuel annual sales of $700 million.

Carragee said only a small portion of BMP-2 use follows the protocols of how the product originally was approved by the FDA. Most of its use is in so-called off-label applications.

He noted the doses of BMP-2 as well as the carrier used in the Amplify clinical trial are commercially available and as such are used off-label by surgeons.

Carragee said he thinks BMP-2 may fuel existing cancers.

He said in theory as people get older they have more cancer cells in their body, which the immune system tries to keep in check.

The addition of BMP-2, especially in higher doses, may disturb that balance and allow a cancer to grow, he said.

"At higher doses in people who are older and who have less resiliency to cancer, it's more worrisome," he said. "I would say, why risk it?"