The Infuse Retrograde Ejaculation Controversy

Tomislav Smoljanović, M.D., Ph.D., thought he spotted an inconsistency in the 2002 multicenter, prospective, randomized, non-blinded FDA-approved study of Infuse for spine fusion surgery. In the study, 279 patients with degenerative lumbar disc disease were treated with an anterior lumbar interbody fusion (ALIF) approach and two tapered threaded cages (Medtronic’s LT-Cage) were implanted in each patient.

One hundred forty-three of the patients received Infuse (rhBMP-2) and the remaining patients (n=136) received autogenous iliac crest bone grafts.

Smoljanović’s Challenge

But Dr. Smolijanpvić, a young 30-something physician just two years out of residency, thought that the study’s results were “irregular.” Said Dr. Smoljanović: “Although results were generally compared item for item between the rhBMP-2 groups and controls, there were two outcome measurements that were not: adverse events related to harvesting of the iliac crest graft and RE (retrograde ejaculation). Although the first one is logical as no bone graft was harvested from the rhBMP-2 patients, the lack of documented comparison of RE between the control and rhBMP-2 others drew our attention. Apparently, six male patients (4.1% of 146 male subjects) complained of RE after surgery.”

So Dr. Smoljanović asked the study’s authors for clarification.

Dr. Smoljanović is Croatian and practices at the University Hospital Center in Zagreb, Croatia. In 2000, Dr. Smoljanović represented Croatia in the Olympic games as a rower. He asked some of his rowing friends in the U.S. to help him translate his letters to the study authors.

At first Dr. Smoljanović’s letters to the study’s authors (all of them) were ignored. Said Dr. Smoljanović in explaining the causes for his letter to go unanswered: “We are orthopedic surgeons who, working in Croatia, have been described as coming from different ‘ethnic, demographic or training’ backgrounds. As such, perhaps we have had a unique approach to the critical analysis of reports related to the clinical use of recombinant human bone morphogenic protein-2.”

Eventually, Dr. Smoljanović did manage to get a letter published in the Journal of Bone and Joint Surgery.

In his letter, Dr. Smoljanović questioned the conclusions from a study conducted by Burkus JK, Gornet MF, Dickman CA and Zdeblick TA and published in the Journal of Spinal Disorders Tech in 2002.

“During the ALIF procedure described in the study by Burkus et al., there was no barrier used to protect superior hypograstric plexus from rhBMP-2 exposure. This sympathetic plexus crosses the lumbosacral junction in retroperitoneal space immeddiately ventral to the interbody cages containing rhBMP-2. Damage or inflammation of the plexus at the point may result in RE.”

Burkus et al., responded to Dr. Smoljanović’s letter and told the young surgeon that in their study 6.4% of the rhBMP-2 exposed male patients in the study developed retrograde ejaculation. The control group of non-rhBMP-2 treated male patients reported just a 1.5% rate of  retrograde ejaculation problems.

Model of Bone morphogenetic protein 2 created using Cn3D

Still, said Smoljanivić, “Despite reporting the higher rate of RE in the rhBMP-2 group, the authors nonetheless categorically denied any relationship between the rhBMP-2 use and the onset of RE. In our opinion, this categorical denial was not credible.”

Carragee Joins Fray

Apparently Dr. Smoljanivić wasn’t alone. The higher rate of RE caught the attention of Stanford Univeristy’s Eugene J. Carragee, M.D., Professor at Stanford’s School of Medicine and Division Chief of Spinal Surgery. “While we have always known there is a risk of male infertility with some spine surgeries, the risk when performing a spinal fusion with a particular biologic bone growth factor appears to be greater than originally reported in industry sponsored publications [emphasis added], ” said Carregee.

Industry sponsered publications? (the Burkus et al. study was published in the Journal of Spinal Disorders & Techniques, editer-in-chief Thomas Zdeblick M.D. and published by Wolters Kluwer). The Journal of Spinal Disorders website (http://journals.lww.com/jspinaldisorders/pages/default.aspx ) doesn’t indicate any industry sponsorship but it does list a large group of editors and reviewers from major institutions in the U.S. and abroad. Perhaps Carragee was thinking of another publication—maybe Orthopedics This Week?

Anyway, Dr. Carragee embarked on a review of past studies of the use of rhBMP-2 in spinal fusion surgery and reported that he and his fellow investigators (Kyle A. Mitsunaga, M.D. with the Stanford University School of Medicine, Eric L. Hurwitz, D.C., Ph.D. with the University of Hawaii’s John Burns School of Medicine and Gaetano J. Scuderi M.D. with Stanford University’s School of Medicine) had found that indeed there is a higher incidence of RE in male patients undergoing one or two level ALIF spinal fusion surgeries with rhBMP-2 (7.2%) when compared with those without rhBMP-2 (0.6%). In the single-level ALIF surgeries the restrospective study conducted by Carragee et al., found the rate of RE was 6.7% of all male patients treated with rhBMP-2 versus 0% in the untreated group.

Furthermore, Carragee et al., stated that the data in their retrospective review closely matched the data regarding RE found in the FDA-approved trial of rhBMP-2.

Conflict of Issue Subtext

The prevailing subtext of Carragee’s study is that the risk of RE associated with using rhBMP-2 was minimized if not altogether ignored by the clinical investigators who’d conducted the original rhBMP-2 studies. And that it was a young surgeon in Croatia who noticed the inconsistencies in prvevious studies and when he brought his concerns to the attention of the orginal study’s authors—was rebuffed.

The issue is conflict of interest. Did the fact that these original studies that were sponsored by Medtronic play a role in keeping information about rhBMP-2’s RE risk from physicians and therefore patients?

James Kang, M.D. a member of the University of Pittsburgh’s Department of Orthopaedic Surgery, provided the best answer, we think, to that question in a commentary he wrote for The Spine Journal:

“In this era of public scrutiny over surgeon’s conflicts of interest, it would seem prudent to carefully assess studies that may strongly influence how surgeons practice their art. Although corporate-sponsered research is absolutely needed to help advance innovation and patient care, we must come to the hard realization that the data analysis and interpretation in such studies can be biased in favor of the funding sources. After all, it is against our nature to publish a negative result or an adverse event that condemns a product that is being studied if we are being funded by the sponsors of the product. [emphasis added] Therefore, it is of critical importance that independent studies (such as by Carrage et al.) be published so that the practicing surgeon gets a balanced view of the ‘truth’.”

Public Media

The public media has not been so kind. The Madison, Wisconsin newspaper (where Thomas Zdeblick M.D.—the editor-in-chief of the Journal of Spinal Disorders—practices) jumped on this story and listed all of the consulting revenues that Zdeblick received from Medtronic (none of which, by the way, were for rhBMP-2) and made him the villian of this story—in his own home town. It was rough. In cases like this, there is no balance for the surgeon. Zdeblick has been at the forefront of clinical research and making spine surgery safer and more consistenty successful for decades. Thousands of patients have their lives back because of Dr. Zdeblick.

The Study Itself

Carragee, in choosing to study rhBMP-2, selected one of the most popular and successful biologic products ever introduced for clinical use. Since its FDA approval and with broad adoption, a number of adverse reactions, including inflammatory reactions in soft tissue, heterotopic bone formation, radiculitis, osteolysis, and cage or graft subsidence have been reported in the literature.

In terms of one potential adverse event, RE, the original FDA study of rhBMP-2 in anterior lumbar interbody fusion (ALIF) reported 12 retrograde ejaculation (RE) events (8%) in the rhBMP-2 groups compared with (1.4%) in the control group. But the study didn’t establish whether these RE events were due to rhBMP-2 or something else.

So Carragee et al., decided to conduct a retrospective analysis of prospectively gathered outcomes data on consecutive subjects having an ALIF spine surgery procedure with and without rhBMP-2 use. The purpose of the study was to compare the incidence of RE after ALIF in patients with and without rhBMP-2 use.

Carragee et al., chose male patients with the diagnosis of lumbar spondylosis or spondylolisthesis and for whom the treatment of choice was to receive an ALIF spine surgery of the lowest one or two lumbar levels with and without rhBMP-2.

Carragee and his colleagues then dove into Stanford’s high-volume spine surgery practice and selected data for male subjects having ALIF for one- (L5/S1) or two-level (L4/L5, L5/S1) lumbar fusion. In particular, they looked for any record of a retrograde ejaculation diagnosis.

Carragee et al., also tried to match the two groups of male subjects in terms of age and additional procedures performed. When they had finished compiling the data, the investigators found that they had data on 69 male patients who’d received an L5/S1ALIF with rhBMP-2 and 174 male patients who’d received ALIFs performed without rhBMP-2.

Of those male patients uncovered in their data search, 24 and 64 were two-level ALIFs performed with and without rhBMP-2, respectively.

In the data, Carragee et al., found five RE events (7.2%) reported in the rhBMP-2 group and 1 (0.6%) in the control group. Looking at single-level L5/S1ALIF procedures, the investigators found that there was a 6.7%and 0% rate of RE in the rhBMP-2 versus control groups, respectively.

At one year after surgery, three of six affected subjects reported resolution of the RE.

Carragee’s conclusion was that the previous reports of higher rates of RE in patients receiving rhBMP-2 as part of an ALIF spine surgery were consistent with the clinical data assembled at Stanford.

For Dr. Smoljanović, no one is ignoring him now. Based on his ability to critically read these studies, he’s probably an ideal candidate for editorship of one of the peer review journals. Just a thought.