Review ArticleComplications with the use of bone morphogenetic protein 2 (BMP-2) in spine surgery
Introduction
In 1965, Marshall Urist discovered the bone morphogenetic protein (BMP) [1], a class of growth factors belonging to the transforming growth factor-β family [2]. Numerous types of BMP molecules have been discovered; however, few have been involved in osteoblast differentiation and bone development [3].
Recombinant human bone morphogenetic protein 2 (rhBMP-2) (InFUSE; Medtronic Sofamor Danek, Memphis, TN, USA) is a commercially available form and currently approved by the U.S. Food and Drug Administration (FDA) for use in the anterior lumbar interbody fusion (ALIF) within a titanium tapered cage [4], [5].
Multiple studies on ALIFs by Burkus et al. reported excellent fusion rates, decreased operative time, lower blood loss, and shorter hospital stay with the use of rhBMP-2 compared with autologous iliac crest bone graft (ICBG) [4], [5], [6].
Besides its application in ALIF, all other uses of rhBMP-2 are considered off label [4], [6], [7], [8], [9], [10].
A meta-analysis looked at the benefits of rhBMP-2 in promoting posterolateral fusion. The authors reported significantly lower rates of fusion failures, shorter hospitalization, and less blood loss with the use of BMP-2 compared with autologous ICBG [11].
Even in smokers, Glassman reported the superiority of BMP-2 (95%) over autologous ICBG (76%) in promoting solid posterolateral lumbar fusion at a single level, after 2 years follow-up [12].
Similarly, other investigators reported 95% to 100% successful arthrodesis with the use of BMP-2 in posterior lumbar interbody fusion (PLIF) [7], [8], [13].
Additionally, the role of BMP-2 in promoting arthrodesis, as a substitute for ICBG in patients with multilevel spinal deformity, was investigated by Mulconrey et al. At 2-year follow-up, the investigators concluded that the use of rhBMP-2 eliminated the necessity for ICBG and yielded an excellent fusion rate [14].
Recent systematic reviews questioned the effectiveness and advantages of BMP-2 over ICBG as previously reported by the industry-sponsored trials. Reviews and investigations from the Yale University Open Data base Project, the Medtronic internal reports, the FDA reports, and a thorough literature search concluded that there are no clear advantages of BMP-2 use in spine fusion over bone graft, and even more serious adverse events were found to be associated with BMP-2 use; therefore, clear indications for BMP-2 use and its safety were precluded [15], [16].
Section snippets
Trends in usage and cost-related concerns
Cahill in 2009 retrospectively looked at patients who underwent spinal fusion between 2002 and 2006 and noted that the nationwide use of BMP has increased from 0.69% of all fusions in 2002 to 24.89% in 2006. With this tremendous increase in BMP usage, adverse events start being noted and reported. Additionally, with usage of BMP-2, greater inpatient hospital charges were noted across all categories of fusion ranging from 11% to 41% with greatest percentage increase seen for anterior cervical
Complications of rhBMP-2 use in lumbar spine surgery
The use of BMP-2 in the lumbar spine has raised some concerns and safety issues as adverse events start being documented adverse events were start being documented. Cahill reported the following complications with their respective means: vertebral osteolysis (44%), graft subsidence (27%) and graft migration (31%), formation of neutralizing antibodies against BMP-2 (26%), ectopic/heterotopic bone formation (7%), and hematoma formation (3%) [17].
On the other hand, concerns were raised by FDA with
Complications of rhBMP-2 use in cervical spine surgery
Systematic reviews looked at the complications associated with the use of rhBMP-2 in the cervical spine and reported 43% mean of osteolysis and graft subsidence. Also, dysphagia and soft-tissue swelling with respiratory difficulties occurred with a mean ranging between 5.8% and 17% [17], [32].
At the 2005 annual North American Spine Society meeting, numerous studies looked at the adverse events seen with BMP-2 use in anterior cervical decompression and fusion (ACDF). The investigators reported
Dosage considerations
The approved human concentration of 1.5 mg/mL, initially used in human clinical trials, was based on nonhuman primate data [22]. Currently, three sizes of the InFUSE Bone Graft component are available: small kit 2.8 mL, medium kit 5.6 mL, and large kit 8 mL with solution concentration of 1.5 mg/mL.
The dose-dependent effect of BMP-2 has been recently re-investigated in an in vivo rat model with femoral segmental defect. The results of this study established a low sub-therapeutic BMP-2
Carcinogenesis concerns
Many clinical and basic science investigations looked at the potential carcinogenic effect of BMP-2.
In certain tumors, the expressions of many BMP surface receptors were found to be highly expressed [51], [52], [53]. However, preclinical safety data regarding rhBMP-2 effects on human cancerous cell proliferation revealed no significant mutagenic consequence [54], [55].
Mines et al. retrospectively studied patients (>66 years) who underwent lumbar spinal fusion surgery with and without rhBMP-2
Carrier concerns
The effectiveness of BMP-2 is dependent on its bio-availability at the planned fusion site, and this largely depends on the structural and biomechanical properties of the carriers. The BMP molecules are relatively soluble, and if not maintained by an appropriate carrier, they will be cleared from the planned fusion site and their osteogenic effect will be wasted or they will diffuse into adjacent undesirable tissues and promote ectopic bony formation.
The available different types of BMP
Conclusion
In light of its early reported promising results in meeting the challenges of interbody and posterolateral fusion environments, the BMP-2 use, including its off-label applications, is certainly popular among spine surgeons.
More recent systemic data analyses failed to report convincing data to warrant rhBMP-2 use over ICBG; therefore, full disclosures of safety concerns with potential BMP recipients should be clearly stated. Despite the catastrophic complications reported, rhBMP-2 remains one of
References (70)
- et al.
Posterolateral lumbar spine fusion with INFUSE bone graft
Spine J
(2007) - et al.
The perioperative cost of infuse bone graft in posterolateral lumbar spine fusion
Spine J
(2008) - et al.
Complications associated with single-level transforaminal lumbar interbody fusion
Spine J
(2009) - et al.
Histopathologic inflammatory response induced by recombinant bone morphogenetic protein-2 causing radiculopathy after transforaminal lumbar interbody fusion
Spine J
(2010) - et al.
Promoting fusion in minimally invasive lumbar interbody stabilization with low-dose bone morphogenic protein-2—but what is the cost?
Spine J
(2011) - et al.
Neurologic impairment from ectopic bone in the lumbar canal: a potential complication of off-label PLIF/TLIF use of bone morphogenetic protein-2 (BMP-2)
Spine J
(2008) - et al.
Vertebral osteolysis after posterior interbody lumbar fusion with recombinant human bone morphogenetic protein 2: a report of five cases
Spine J
(2007) - et al.
Retrograde ejaculation after anterior lumbar interbody fusion using rhBMP-2: a cohort controlled study
Spine J
(2011) - et al.
Retrograde ejaculation after anterior lumbar interbody fusion with and without bone morphogenetic protein-2 augmentation: a 10-year cohort controlled study
Spine J
(2012) Prospective nonrandomized comparison of an allograft with bone morphogenic protein versus an iliac-crest autograft in anterior cervical discectomy and fusion
Spine J
(2008)
Bone morphogenetic protein 2 exerts diverse effects on cell growth in vitro and is expressed in human pancreatic cancer in vivo
Gastroenterology
Does BMP-2 really cause cancer? A systematic review of the literature—NASS meeting 2012
Spine J
Bone: formation by autoinduction. 1965
Clin Orthop Relat Res
Purification and characterization of other distinct bone-inducing factors
Proc Natl Acad Sci U S A
Osteogenic activity of the fourteen types of human bone morphogenetic proteins (BMPs)
J Bone Joint Surg Am
Anterior lumbar interbody fusion using rhBMP-2 with tapered interbody cages
J Spinal Disord Tech
Clinical and radiographic outcomes of anterior lumbar interbody fusion using recombinant human bone morphogenetic protein-2
Spine
Influence of rhBMP-2 on the healing patterns associated with allograft interbody constructs in comparison with autograft
Spine
Contribution of recombinant human bone morphogenetic protein-2 to the rapid creation of interbody fusion when used in transforaminal lumbar interbody fusion: a preliminary report. Invited submission from the Joint Section Meeting on Disorders of the Spine and Peripheral Nerves, March 2004
J Neurosurg Spine
Safety of transforaminal lumbar interbody fusion and intervertebral recombinant human bone morphogenetic protein-2
J Neurosurg Spine
Minimally invasive transforaminal lumbar interbody fusion (TLIF): technical feasibility and initial results
J Spinal Disord Tech
Efficacy of autologous iliac crest bone graft and bone morphogenetic proteins for posterolateral fusion of lumbar spine: a meta-analysis of the results
Spine
The efficacy of rhBMP-2 for posterolateral lumbar fusion in smokers
Spine
Posterior lumbar interbody fusion using rhBMP-2
Eur Spine J
Bone morphogenetic protein (RhBMP-2) as a substitute for iliac crest bone graft in multilevel adult spinal deformity surgery: minimum two-year evaluation of fusion
Spine
Effectiveness and harms of recombinant human bone morphogenetic protein-2 in spine fusion: a systematic review and meta-analysis
Ann Intern Med
Safety and effectiveness of recombinant human bone morphogenetic protein-2 for spinal fusion: a meta-analysis of individual-participant data
Ann Intern Med
Prevalence, complications, and hospital charges associated with use of bone-morphogenetic proteins in spinal fusion procedures
JAMA
Economic evaluation of bone morphogenetic protein versus autogenous iliac crest bone graft in single-level anterior lumbar fusion: an evidence-based modeling approach
Spine
Use of recombinant human bone morphogenetic protein-2 to achieve posterolateral lumbar spine fusion in humans: a prospective, randomized clinical pilot trial: 2002 Volvo Award in clinical studies
Spine
The safety and efficacy of OP-1 (rhBMP-7) as a replacement for iliac crest autograft in posterolateral lumbar arthrodesis: a long-term (>4 years) pivotal study
Spine
Recombinant human bone morphogenetic protein-2-induced radiculitis in elective minimally invasive transforaminal lumbar interbody fusions: a series review
Spine
Perioperative complications with rhBMP-2 in transforaminal lumbar interbody fusion
Eur Spine J
Heterotopic bone formation with the use of rhBMP2 in posterior minimal access interbody fusion: a CT analysis
Spine
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FDA device/drug status: Approved (INFUSE® Bone Graft-P050053).
Author disclosures: CAT: Nothing to disclose. HSA: Royalties: U&I Inc. (About D/year, Paid directly to institution/employer); Stock Ownership: U&I Inc. (D shares, Paid directly to institution/employer), Spinal Kinteics (B shares, Paid directly to institution/employer), Advanced Biologics Inc. (B shares, Paid directly to institution/employer), Medyssey Inc. (B shares, Paid directly to institution/employer); Endowments: Rush University Medical Center (D/year, Paid directly to institution/employer); Grants: Spinalcyte Inc. (F, Paid directly to institution/employer).
The disclosure key can be found on the Table of Contents and at www.TheSpineJournalOnline.com.