Commentary: An evolving perception of the risk of rhBMP-2 use for anterior spinal interbody fusions

Abstract

COMMENTARY ON: Carragee EJ, Mitsunaga KA, Hurwitz EL, Scuderi GJ. Retrograde ejaculation after anterior lumbar interbody fusion using rhBMP-2: a cohort controlled study. Spine J 2011;11:511–6 (in this issue). COMMENTARY ON: Carragee EJ, Mitsunaga KA, Hurwitz EL, Scuderi GJ. Retrograde ejaculation after anterior lumbar interbody fusion using rhBMP-2: a cohort controlled study. Spine J 2011;11:511–6 (in this issue). We are orthopedic surgeons who, working in Croatia, have been described as coming from different “ethnic, demographic, and training” backgrounds [[1]Smoljanovic T. Bojanic I. Pecina M. The confusion of important literature review.Spine J. 2009; 9 (author reply 428–9): 427-428Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar]. As such, perhaps we have had a unique approach to the critical analysis of reports related to the clinical use of recombinant human bone morphogenetic protein-2 (rhBMP-2; INFUSE Bone Graft; Medtronic Sofamor Danek, Memphis, TN, USA) for lumbar interbody fusion. Although there remain many unanswered questions, the issue of retrograde ejaculation (RE) has been clarified by the present study by Carragee et al. [[2]Carragee E.J. Mitsunaga K.A. Hurwitz E.L. Scuderi G.J. Retrograde ejaculation after anterior lumbar interbody fusion using rhBMP-2: a cohort controlled study.Spine J. 2011; 11: 511-516Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar]. This retrospective comparative cohort study found a higher rate of RE after open, one- or two-level, anterior lumbar interbody fusion (ALIF), including L5–S1 using rhBMP-2 (7.2%; 95% confidence interval: 2.1, 12.4) compared with a rate of 0.6% (95% confidence interval: −0.4, 1.5) in non-rhBMP-2 controls. These rates are similar to those recently reported by Burkus et al. [[3]Smoljanovic T. Siric F. Bojanic I. Six-year outcomes of anterior lumbar interbody arthrodesis with use of interbody fusion cages and recombinant human bone morphogenetic protein-2.J Bone Joint Surg Am. 2010; 92 (author reply 2615–6): 2614-2615PubMed Google Scholar] for a combined observational and randomized clinical trial of single-level ALIF, with an RE rate of 7.9% in the rhBMP-2 group compared with 1.5 in the controls. However, the history of how this serious complication apparently associated with rhBMP-2 was neglected for many years deserves a careful review. Our concerns began, in 2002, with the study by Burkus et al. [[4]Burkus J.K. Gornet M.F. Dickman C.A. Zdeblick T.A. Anterior lumbar interbody fusion using rhBMP-2 with tapered interbody cages.J Spinal Disord Tech. 2002; 15: 337-349Crossref PubMed Scopus (516) Google Scholar], a multicenter, prospective, randomized, nonblinded, US Food and Drug Administration (FDA)-approved study. In this study, 279 patients with degenerative lumbar disc disease underwent ALIF using two tapered threaded fusion cages (LT-CAGE; Medtronic Sofamor Danek). The investigational group (143 patients) received rhBMP-2 on an absorbable collagen sponge, and a control group (136 patients) received autogenous iliac crest bone graft. The results of the investigational group were reported to be better in comparison to the results of control group in some clinical and radiographic outcome measurements. The authors reported that “there were no unanticipated device-related adverse events in either treatment group.” In time, the INFUSE Bone Graft was approved by the FDA based, in part, on authors’ reported results of this study [[5]Schultz D. InFUSE™ bone graft/LT-CAGE™ lumbar tapered fusion devices—P000058. Summary of safety and effectiveness data. U.S. Food and Drug Administration, Department of Health and Human Services, Center for Devices and Radiological Health, 2002www.accessdata.fda.gov/cdrh_docs/pdf/P000058b.pdfGoogle Scholar]. However, the reporting of results in this publication was irregular. 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. 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 [[4]Burkus J.K. Gornet M.F. Dickman C.A. Zdeblick T.A. Anterior lumbar interbody fusion using rhBMP-2 with tapered interbody cages.J Spinal Disord Tech. 2002; 15: 337-349Crossref PubMed Scopus (516) Google Scholar]. Burkus et al. [[4]Burkus J.K. Gornet M.F. Dickman C.A. Zdeblick T.A. Anterior lumbar interbody fusion using rhBMP-2 with tapered interbody cages.J Spinal Disord Tech. 2002; 15: 337-349Crossref PubMed Scopus (516) Google Scholar] did not report how many patients reporting RE were in the investigational arm and how many were in the control arm. The authors instead emphasized that the complication occurred in 13.3% (4 of 30) of the men who underwent a transperitoneal approach and occurred in only 1.8% (2 of 116) of men who underwent a retroperitoneal approach. That difference was statistically significant according to Fisher exact test (p=.017). However, it was confusing to us that in a randomized controlled trial (RCT) there was no mention of how many of the patients with this serious complication were from the investigational group compared with the control group. Similar patient data were presented by Sasso et al. [[6]Sasso R.C. Burkus J.K. LeHuec J.C. Retrograde ejaculation after anterior lumbar interbody fusion: transperitoneal versus retroperitoneal exposure.Spine. 2003; 28: 1023-1026PubMed Google Scholar] 1 year later, in 2003. However, again there was no breakdown of the rates of RE in rhBMP-2 patients and those without. It was instead concluded by the authors that the transperitoneal approach to the lumbar spine at L4–L5 and L5–S1 has a 10 times greater chance of causing RE in men than a retroperitoneal approach. That conclusion was challenged by Birch and Shaw [[7]Birch N. Shaw M. Retrograde ejaculation after anterior lumbar interbody fusion.Spine. 2004; 29: 106-107Crossref PubMed Scopus (17) Google Scholar], who found it to be at odds with their clinical experience. Birch and Shaw stated that either their patients have been extraordinarily lucky over the time or that there were confounding factors in the Sasso et al. study that might have contributed to the high rate of RE. Birch and Shaw did not discuss the confounding factor of rhBMP-2 (as the information was not provided by Burkus et al. [[4]Burkus J.K. Gornet M.F. Dickman C.A. Zdeblick T.A. Anterior lumbar interbody fusion using rhBMP-2 with tapered interbody cages.J Spinal Disord Tech. 2002; 15: 337-349Crossref PubMed Scopus (516) Google Scholar] or Sasso et al. [[6]Sasso R.C. Burkus J.K. LeHuec J.C. Retrograde ejaculation after anterior lumbar interbody fusion: transperitoneal versus retroperitoneal exposure.Spine. 2003; 28: 1023-1026PubMed Google Scholar]), but such a comment by highly experienced spinal surgeons was an indication that further clarification of the issue was required. Sasso et al. did not respond to Birch and Shaw’s letter [[7]Birch N. Shaw M. Retrograde ejaculation after anterior lumbar interbody fusion.Spine. 2004; 29: 106-107Crossref PubMed Scopus (17) Google Scholar]. One may ask how rhBMP-2 can be associated with RE, an uncommon complication resulting from an inability of the internal vesical sphincter, a muscle at the base of the bladder, to contract during ejaculation. It has been suggested by in vitro studies that rhBMP-2 exposure involves a notable host inflammatory response preceding the bone induction cascade [8Marusic A. Grcevic D. Katavic V. et al.Role of B lymphocytes in new bone formation.Lab Invest. 2000; 80: 1761-1774Crossref PubMed Scopus (34) Google Scholar, 9Marusic A. Katavic V. Grcevic D. Lukic I.K. Genetic variability of new bone induction in mice.Bone. 1999; 25: 25-32Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar]. This effect has been associated with the release of cytokines causing a local inflammatory response. Muchow et al. [[10]Muchow R.D. Hsu W.K. Anderson P.A. Histopathologic inflammatory response induced by recombinant bone morphogenetic protein-2 causing radiculopathy after transforaminal lumbar interbody fusion.Spine J. 2010; 10: e1-e6Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar] histopathologically demonstrated this inflammatory process associated with rhBMP-2 use in spinal fusion. An increased incidence of postoperative radiculitis has been reported with the off-label use of rhBMP-2 during transforaminal interbody fusion [11Mindea S.A. Shih P. Song J.K. Recombinant human bone morphogenetic protein-2-induced radiculitis in elective minimally invasive transforaminal lumbar interbody fusions: a series review.Spine. 2009; 34 (discussion 1485): 1480-1484Crossref PubMed Scopus (79) Google Scholar, 12Rihn J.A. Patel R. Makda J. et al.Complications associated with single-level transforaminal lumbar interbody fusion.Spine J. 2009; 9: 623-629Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar]. Most of these patients had no identifiable structural cause of postoperative radiculitis. Furthermore, the rate of postoperative radiculitis appeared to be significantly reduced (from 20.4% to 5.4%) when the annulotomy site was sealed to protect the exposed nerve root and dura from the rhBMP-2 placed within the intervertebral space [[12]Rihn J.A. Patel R. Makda J. et al.Complications associated with single-level transforaminal lumbar interbody fusion.Spine J. 2009; 9: 623-629Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar]. During the ALIF procedure described in the study by Burkus et al. [[4]Burkus J.K. Gornet M.F. Dickman C.A. Zdeblick T.A. Anterior lumbar interbody fusion using rhBMP-2 with tapered interbody cages.J Spinal Disord Tech. 2002; 15: 337-349Crossref PubMed Scopus (516) Google Scholar], there was no barrier used to protect superior hypogastric plexus from rhBMP-2 exposure. This sympathetic plexus crosses the lumbosacral junction in retroperitoneal space immediately ventral to the interbody cages containing rhBMP-2. Damage or inflammation of the plexus at this point may result in RE. In 2010, Burkus et al. responded to a letter from us in the Journal of Bone and Joint Surgery regarding RE rates [3Smoljanovic T. Siric F. Bojanic I. Six-year outcomes of anterior lumbar interbody arthrodesis with use of interbody fusion cages and recombinant human bone morphogenetic protein-2.J Bone Joint Surg Am. 2010; 92 (author reply 2615–6): 2614-2615PubMed Google Scholar, 13Smoljanovic T. Bojanic I. Cimic M. Re: Boden SD, Zdeblick TA, Sandhu HS, et al. The use of rhBMP-2 in interbody fusion cages. Definitive evidence of osteoinduction in humans: a preliminary report. Spine 2000; 25:376–81.Spine. 2010; 35 (author reply E1011): E1010-E1011Crossref Scopus (3) Google Scholar, 14Smoljanovic T. Bojanic I. Rakovac M. Re: Sasso RC, Burkus JK, LeHuec JC. Retrograde ejaculation after anterior lumbar interbody fusion: transperitoneal versus retroperitoneal exposure. Spine (Phila Pa 1976) 2003;28:1023–6.Spine. 2010; 35 (author reply E623): E622Crossref PubMed Scopus (2) Google Scholar]. In this letter, they indicated that 6.4% of the rhBMP-2-exposed male patients in the RCT developed RE compared with 1.5% of the control group. However, 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 [3Smoljanovic T. Siric F. Bojanic I. Six-year outcomes of anterior lumbar interbody arthrodesis with use of interbody fusion cages and recombinant human bone morphogenetic protein-2.J Bone Joint Surg Am. 2010; 92 (author reply 2615–6): 2614-2615PubMed Google Scholar, 13Smoljanovic T. Bojanic I. Cimic M. Re: Boden SD, Zdeblick TA, Sandhu HS, et al. The use of rhBMP-2 in interbody fusion cages. Definitive evidence of osteoinduction in humans: a preliminary report. Spine 2000; 25:376–81.Spine. 2010; 35 (author reply E1011): E1010-E1011Crossref Scopus (3) Google Scholar, 14Smoljanovic T. Bojanic I. Rakovac M. Re: Sasso RC, Burkus JK, LeHuec JC. Retrograde ejaculation after anterior lumbar interbody fusion: transperitoneal versus retroperitoneal exposure. Spine (Phila Pa 1976) 2003;28:1023–6.Spine. 2010; 35 (author reply E623): E622Crossref PubMed Scopus (2) Google Scholar]. In our opinion, this categorical denial was not credible. Over time, there has been a cumulative reporting of multiple independent authors regarding adverse effects of rhBMP-2. The present study by Carragee et al. [[2]Carragee E.J. Mitsunaga K.A. Hurwitz E.L. Scuderi G.J. Retrograde ejaculation after anterior lumbar interbody fusion using rhBMP-2: a cohort controlled study.Spine J. 2011; 11: 511-516Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar] adds further data to this growing field, and we are hoping that remaining issues related to the adverse effects of rhBMP-2 use for spinal interbody fusions will be clarified in the near future as well. This episode, however, is disturbing. It took us several years to get even the minimum clarification from Burkus et al. that eventually appeared in letter format in 2010. This belated information, that the RE rate was higher in an RCT comparing rhBMP-2 versus controls, illuminated otherwise confusing 8-year old FDA data. This revelation also spurred the investigation by Carragee et al. [[2]Carragee E.J. Mitsunaga K.A. Hurwitz E.L. Scuderi G.J. Retrograde ejaculation after anterior lumbar interbody fusion using rhBMP-2: a cohort controlled study.Spine J. 2011; 11: 511-516Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar] reported here. We hope that an improved system can be implemented to verify or rapidly resolve future discrepancies between the FDA (or other administrative data) and data in published articles from the same studies. Retrograde ejaculation after anterior lumbar interbody fusion using rhBMP-2: a cohort controlled studyThe Spine JournalVol. 11Issue 6PreviewThe commercially available growth factor recombinant bone morphogenic protein-2 (rhBMP-2) used in spinal fusion has been associated with numerous adverse reactions, including inflammatory reactions in soft tissue, heterotopic bone formation, radiculitis, osteolysis, and cage or graft subsidence. The original Food and Drug Administration Summary of 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. Full-Text PDF Yet another reason for improving approval and surveillance processes for health technologiesThe Spine JournalVol. 11Issue 8PreviewAs Caragee et al. [1] recently demonstrated, exposure to recombinant human bone morphogenetic protein-2 during anterior spinal fusion surgery is associated with a higher risk of retrograde ejaculation and infertility among male patients. Safety concerns on this product were raised in 2002 [2,3], but the reporting of industry-sponsored studies was engineered to camouflage this fact, and authors linked to the manufacturer dismissed these concerns [4,5]. As a result, physicians and patients were never warned about this complication. Full-Text PDF Adverse events and bone morphogenetic protein-2The Spine JournalVol. 11Issue 8PreviewRecently, a number of adverse events have been reported in the use of recombinant bone morphogenetic protein-2 (BMP-2) in spinal fusion [1–4]. We have been studying new bone formation after delivery of physiologic levels of BMP-2 using a cell therapy approach and have found this to rely on very selective neurogenic inflammation. We would like to suggest that this is actually a normal physiologic event in bone formation and fracture repair rather than an adverse event associated with delivery of this protein. Full-Text PDF