When The Spine Journal published “Retrograde ejaculation after anterior lumbar interbody fusion using rhBMP-2: A cohort controlled study” last summer, it created an uproar that reached far beyond the boundaries of the orthopaedic community. The paper’s conclusion—that male patients undergoing spinal fusion using recombinant human bone morphogenetic protein-2 (rhBMP-2) should be counseled about an increased risk of sterility—raised concerns that the initial studies on the use of rhBMP-2 were flawed and their results were misrepresented, due in part to the fact that the studies were funded by industry and that participating surgeons had relationships with industry.
In fact, noted Alexander J. Ghanayem, MD, professor of orthopaedic surgery and rehabilitation and division director of spine surgery at Loyola University Medical Center in Maywood, Ill., the problem wasn’t sterility, but retrograde ejaculation (RE)—an entirely different issue.
Speaking at the 2012 annual meeting of the Association of Bone and Joint Surgeons, Dr. Ghanayem began by defining terms.
“Sterility,” he said, “is the inability to produce sperm. Impotence is the inability to maintain an erection. Retrograde ejaculation is simply a delivery problem. Men who have this problem [retrograde ejaculation] are not sterile; they just can’t deliver the sperm the way it naturally occurs.”
According to Dr. Ghanayem, studies have shown considerable variability in the incidence of RE among men who undergo spinal fusion—regardless of the use of rhBMP-2. “Based on my review of the literature, when BMP is not used, the rate of retrograde ejaculation after surgery ranges from 0 percent to 12.5 percent. When BMP is used, the range goes from 0 percent to 10 percent,” he noted.
A single team’s results
Dr. Ghanayem reported on his experience in performing anterior lumbar interbody fusion (ALIF) using rhBMP-2 during the period from May 2004 to June 2011. He noted that he was using the product “off-label”; although the U.S. Food and Drug Administration (FDA) has approved the use of rhBMP-2 for ALIF, that approval is limited to a particular device, and he was using a different device. Supplemental allograft cancellous bone was used to fill large voids.
Prior to 2009, he noted, the smallest kit available held 4.2 mg of rhBMP-2. A frugal man, he would use the entire kit for a one-level surgery, but split it if he were performing a two-level surgery. “In 2009, a 2.1 mg kit was introduced, and we used that for each level,” he said.
In every case, preoperative ejaculation function was determined and the risk of RE was discussed. Patients also reported on ejaculation function after surgery. Of the 152 surgeries, the following 11 patients were excluded from the analysis:
- Four patients had erectile dysfunction preoperatively, which did not change after the surgery.
- Two patients (both older than age 65) did not want to discuss RE.
- Three patients had isolated L3-4 fusions.
- One patient had a revision transperitoneal approach.
- One patient did not receive rhBMP-2.
Of the remaining 141 patients, only two experienced RE after surgery.
Of the two patients, one experienced transient RE and the other had persistent RE at 2 years follow-up. Dr. Ghanayem found no statistical difference related to the rhBMP-2 dose. The overall permanent rate of RE was 0.7 percent.
“It seemed that the only risk factor in our group was being 44 years of age; both patients who experienced RE after surgery were that age,” he said.
What made the difference?
“The FDA Investigational Device Exemption (IDE) study only documented episodic rates of RE, whereas the study published in The Spine Journal looked at both episodic and permanent rates. The authors of the IDE study did not believe that the rhBMP-2 resulted in an increased risk of RE, whereas the authors of The Spine Journal study did believe that there was a relationship,” said Dr. Ghanayem.
Although both studies had rates of RE that ranged from 4.3 percent to 7.3 percent, Dr. Ghanayem noted that his outcomes were closer to those of the control groups (less than 1.5 percent) and addressed several possible reasons.
“We were a single surgical team, well-controlled in what we were doing. We began performing fusions at a slow rate and had the opportunity to learn from others. We had a chance to look at the technical issues and the complications reported in other studies. We did not perforate the end plates, because you do not want to expose the end plates or cancellous bone to rhBMP-2,” reported Dr. Ghanayem, who also noted that other primary causes of RE were not explored in any of the studies.
“In conclusion,” he said, “we believed that rhBMP-2 is safe to use with the anterior lumbar spine, particularly with respect to the risk of RE for patients undergoing ALIF.”
During the subsequent question-and-answer period, audience members raised several concerns, including the issue of dose. Because the natural dose of rhBMP-2 can be measured in nanograms, using a lower dose may deliver the same healing effect without aggravated side effects.
With regard to questions of conflicts of interest, Dr. Ghanayem supported full disclosure. “Let the learner decide what’s relevant,” he said. “If one author has a relationship with a company that makes a competing product, or another author has a longstanding relationship with a government agency, well, that may or may not be relevant. But they are relationships that may represent a source of bias in interpreting data.”
Dr. Ghanayem reports the following disclosures: resident research support through the Department of Veteran Affairs Chicago Association for Research & Education in Science (CARES) program, which is supported by Synthes; DePuy, a Johnson & Johnson Company; and Medtronic; Journal of Spinal Disorders and Techniques; OMeGA Medical Grants Association, Lumbar Spine Research Society, North American Spine Society, Cervical Spine Research Society, American Orthopaedic Association, International Society for Study of the Lumbar Spine. His co-author is John Santaniello, MD, associate professor of surgery, Loyola University Medical Center, who has no conflicts.
Mary Ann Porucznik is managing editor of AAOS Now. She can be reached at email@example.com
- Men who undergo spinal fusion may experience retrograde ejaculation after surgery regardless of whether rhBMP-2 is used.
- In this cohort-controlled study, by a single surgical team that used rhBMP-2 during spinal fusion, outcomes with regard to retrograde ejaculation were similar to those from control groups in previous FDA IDE studies.
- Based on their results, the authors conclude that rhBMP-2 is safe to use, particularly with respect to the risk of RE for patients undergoing ALIF.