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Pseudo-Pedicle Heterotopic Ossification From Use of Recombinant Human Bone Morphogenetic Protein 2 (rhBMP-2) in Transforaminal Lumbar Interbody Fusion Cages

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Author Affiliation | Disclosures

Authors’ Disclosure Statement: The authors report no actual or potential conflict of interest in relation to this article. 

Dr. Rosen and Dr. Kiester are Clinical Professors, Department of Orthopaedic Surgery, University of California Irvine School of Medicine, Orange, California. Dr. Lee is Senior Research Career Scientist, Veterans Affairs Rehabilitation Research and Development, Professor and Vice Chairman for Research and Academic Affairs, Department of Orthopaedic Surgery, and Professor, Department of Biomedical Engineering, Henry Samueli School of Engineering, University of California Irvine, Orange, California.

Address correspondence to: Charles D. Rosen, MD, Department of Orthopaedic Surgery, University of California Irvine (UCI) Medical Center, 101 City Drive S, Pavilion III, Orange, CA 92868 (tel, 714-456-1699; email, crosen@uci.edu).

Abstract

We conducted a study to determine the common characteristics of patients who developed radiculopathy symptoms and corresponding heterotopic ossification (HO) from transforaminal lumbar interbody fusions (TLIF) using recombinant human bone morphogenetic protein 2 (rhBMP-2). HO can arise from a disk space with rhBMP-2 use in TLIF. Formation of bone around nerve roots or the thecal sac can cause a radiculopathy with a consistent pattern of symptoms.

We identified 38 patients (26 males, 12 females) with a mean (SD) age of 50.8 (7.5) years who developed radiculopathy symptoms and corresponding HO from TLIF with rhBMP-2 in the disk space between 2002 and 2015. To document this complication and improve its recognition, we recorded common patterns of symptom development and radiologic findings: specifically, time from implantation of rhBMP-2 to symptom development, consistency with side of TLIF placement, and radiologic findings.

Radicular pain generally developed a mean (SD) of 3.8 (1.0) months after TLIF with rhBMP-2. Development of radiculopathy symptoms corresponded to consistent “pseudo-pedicle”-like HO. In all 38 patients, HO arising from the annulotomy site showed a distinct pseudo-pedicle pattern encompassing nerve roots and the thecal sac. In addition, development of radiculopathy symptoms and corresponding HO appear to be independent of amount of rhBMP-2. HO resulting from TLIF with rhBMP-2 in the disk space is a pain generator and a recognizable complication that can be diagnosed by assessment of symptoms and computed tomography characteristics.




Take-Home Points

  • Use of rhBMP-2 in TLIF cages can result in HO out of the cage into the spinal canal.
  • HO from rhBMP-2 in TLIF cages can result in a radiculopathy from compression or inflammatory reaction.
  • HO out of the cage into the spinal canal resulting from use of rhBMP-2 in TLIF cages can be adequately diagnosed only with CT.
  • HO can appear as a pedicle or pseudo-pedicle.
  • Consider potential HO when using rhBMP-2 in TLIF cages.

Bone morphogenetic proteins (BMPs), first isolated by Urist in 19641, are a family of growth factors that stimulate the cascade of bone formation. Recombinant human BMP (rhBMP), specifically rhBMP-2 and rhBMP-7 (also known as osteogenic protein 1 [OP-1]), was developed in the 1990s after the advent of gene splicing. Then, in 2002, the US Food and Drug Administration (FDA) approved use of rhBMP to stimulate fusion in the human spine. Specifically, rhBMP-2 (Medtronic) was approved for use in combination with a specific brand of interbody cage in 1-level anterior lumbar interbody fusion.2 Over the past decade, off-label use of rhBMP-2 to achieve osseous union has increased dramatically, particularly in spinal surgery: transforaminal lumbar interbody fusion (TLIF), posterior lumbar interbody fusion, and posterolateral lumbar fusion.3-9 However, this widespread off-label use for posterior spinal fusion began despite FDA data indicating that specific complications were underreported in the peer-reviewed literature.10,11 Although rhBMP-2 is very effective in increasing osteoblast formation and improving osteogenesis and subsequent bone healing in spinal surgery,12,13 its use in TLIF resulted in significant adverse side effects, including radiculopathy with and without neuroforaminal heterotopic ossification (HO); 14-24 complications in the FDA studies; 14,22,25-27 and osteolysis causing intervertebral cage subsidence, inflammatory radiculitis, genitourinary complications, infections, possible systemic effects, and significant HO complications.10,28-30 Of these, HO complications involved rhBMP leakage through the annulotomy to the disk space that led to HO. Specifically, rhBMP leaked directly out of the disk space and formed a pillar of bone that encased the nerve roots and dura, which led to occlusion of the foramen and symptoms of radiculopathy.10,28-30

Despite this frequent finding of HO in the intervertebral space outside the target fusion area, use of rhBMP-2 with intervertebral cages increased so rapidly that rhBMP-2 was used more often than autologous bone.5,11,17,31 In this study, we reviewed the common characteristics of patients who developed HO and subsequent radiculopathy from TLIF with rhBMP.

Methods

After this study received Institutional Review Board approval, we retrospectively reviewed cases of radiculopathy symptoms that developed after TLIF with rhBMP between January 2002 and January 2015. During this period, 38 patients (26 males, 12 females) with a mean (SD) age of 50.8 (7.5) years and radiculopathy symptoms arising from TLIF with rhBMP-2 were identified to determine commonalities and defining characteristics that will help facilitate diagnosis.

Inclusion criteria were computed tomography (CT)–documented HO arising from the TLIF annulotomy site in continuity with bone in the disk space or ectopic bone forming a distinctive shell with contouring around the thecal sac or nerve roots, as well as recurrence or initial occurrence of radiculopathy with signs and symptoms corresponding to the CT site of aberrant bone growth in terms of laterality and particular nerve root(s) involved. Exclusion criteria were malplacement of interbody cage or pedicle screws, disk herniation, systemic neuropathic disease, and new or unresolved radiculopathy immediately after index surgery.

To improve recognition of this complication, we also documented the amount of BMP used, common patterns of radiculopathy symptom development, and radiologic findings. Type and timing of radiculopathy symptom onset and consistency with side of TLIF placement were documented as well. Radiculopathy symptoms included shooting pain in the legs, incontinence, sexual dysfunction, and severe paralysis. Radiologic findings were specific to bone formation from the disk space (detected with CT).

Results

All 38 selected patients had radiculopathy symptoms from HO out of the intervertebral space. The Table lists the patients’ overall characteristics. The left side had the most radiculopathy symptoms (31/38 patients), followed by the right side (5/38) and both sides (2/38). Radiculopathy symptoms began a mean (SD) of 3.8 (1.0) months (range, 2-6 months) after index surgery. The 38 patients had 4 characteristics in common:

1. Bone growing out of the annulotomy site for TLIF cage placement was present and in continuity with the disk space in 33 (87%) of the 38 cases. In the other 5 cases (13%), HO was present around the neural tissue, but not necessarily in continuity with the disk space. This bone appeared ectopic and not osteophytic and facet-related, as it formed a shell around either the nerve root or the thecal sac, contouring to the structure.

2. The common, novel finding on CT was a “pseudo-pedicle” (Figures 1A, 1B), which appeared as ectopic growth from the disk space—a solid piece of bone in the same direction as the anatomical pedicle. Confusing similarity to the anatomical pedicle is present on axial cuts and during surgery. The pseudo-pedicle varied in thickness and extent out of the disk space, but was always presented as a bar of bone arising from the annulotomy site. After arising from the disk space, the HO could disperse in any direction, further calcifying neural structures or the facet joints above or below. There was no apparent distinguishable repeating pattern, given the variable nature of arthritic facet changes, scoliotic deformities, size of annulotomies, amount of rhBMP used, and placement in cage and disk space or only in cage.

3. In 36 (95%) of the 38 cases, the initial interpretation of HO on magnetic resonance imaging (MRI) was of tissue other than bone, such as fibrous tissue, granulation tissue, recurrent disk herniation, or postoperative changes. However, this tissue was later determined to be bone from HO complications, which we confirmed with CT in all 38 cases. It is important to note that HO on MRI (Figures 2A, 2B) was initially interpreted by a radiologist as fibrous tissue, but same-level CT of the same case (Figures 3A, 3B) showed clear HO.

4. The radiculopathy symptoms caused by HO were independent of the amount of rhBMP-2 used in TLIF. Of the 38 patients, 19 had 1 rhBMP-2 sponge placed in the cage, 12 had a small kit sponge (1.05 mg), 5 had 1 sponge placed in the cage and 1 sponge placed directly in the disk space before cage placement (no notation of precise size or amount of rhBMP-2), and 2 had 1 sponge placed in the cage (no notation of rhBMP-2 amount). The data showed that HO can occur with even a small amount of rhBMP-2.

Bone formation with rhBMP-2 is robust and beneficial, but HO-related complications are significant, and identifiable on assessment of radiculopathy symptoms and CT characteristics.

Discussion

We identified 38 patients with a recognizable and consistent pattern of complications of off-label use of rhBMP-2 in TLIF performed at our institution between 2002 and 2015. This pattern included consistent radiculopathy symptoms with corresponding HO at the annulotomy site in continuity with bone in the disk space or ectopic bone forming a distinctive shell around the thecal sac or nerve roots, as well as showing a distinct pseudo-pedicle pattern encompassing nerve roots and the thecal sac. Our finding differs from other findings of similar complication characteristics, but with much larger variations without consistency within the patient population.19,20,22,24 Specifically, previous studies found an association between off-label rhBMP-2 use in the posterior spine and radiculopathy with and without neuroforaminal HO. However, our study found consistent radiculopathy symptoms with pseudo-pedicle-like HO complications in all its 38 patients a mean (SD) of 3.8 (1.0) months after surgery.

In this study, consistent radiculopathy symptoms with pseudo-pedicle-like HO complications were independent of the amount of rhBMP-2 used, as some complications occurred with use of small pack rhBMP-2 with TLIF. It is well understood that high doses of rhBMP-2 may be required to improve fusion rates, but to our knowledge an optimal dosing strategy for TLIF has not been reported, particularly with respect to potential complications.8,20,31-33 For anterior lumbar interbody fusion surgery, the FDA-approved use of rhBMP-2 appears to have a significantly decreased risk of neuroforaminal HO complications. This may be attributable to the protective presence of the intact posterior annulus and longitudinal ligament for this procedure.20,33 For TLIF, it has been suggested that rhBMP-2 should be placed only along the anterior annulus with a posterior strut and morselized bone allograft barricade,33 and that fibrin glue should be used to limit BMP diffusion through the annulotomy site31 to prevent this complication.

Our study results suggest that radiculopathy symptoms with pseudo-pedicle-like HO complications appear to be caused by leakage of rhBMP-2 from the disk space through the annulotomy site. This was often initially interpreted incorrectly on MRI in the first year after surgery as being fibrous or granulation tissue, or even postoperative changes that the heterotopic tissue was bone was obvious only on CT. Even then the tissue may be incorrectly identified, as the encasing nerve roots in bone are similar to the scar tissue having no compressive effect. HO may compress, but it also has an inflammatory component that the scars lack. Additionally, the HO from the disk space, caused by leakage of the BMP placed in or around the fusion cage, can create a pseudo-pedicle of varying size and extent. This was present in all 38 of our cases.

This retrospective case series had its limitations. Its clinical and radiographic findings were not blinded. Confounding variables cannot be isolated for causal relationships, if any, to the complication in a case series such as this.

Bone formation with rhBMP-2 is robust and beneficial, but HO-related complications are significant, and identifiable on assessment of radiculopathy symptoms and CT characteristics.

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Key Info

Key Info

Figures/Tables

Table. Transforaminal Lumbar Interbody Fusion With Recombinant Human Bone Morphogenetic Protein 2: Onset Time for Radiculopathy Symptoms, Surgery Level, Side of Pseudo-Pedicle Bone Formation, and Subsequent Complications

PtSympton Onset, moSurgery Level(s)Side(s)Complication(s)
13L3-L5 (2)BothRadiculopathy, pseudo-pedicle, urine
23L4-L5 (2)RRadiculopathy, pseudo-pedicle
34L5-S1 (1)RRadiculopathy, pseudo-pedicle
45L5-S1 (1)LRadiculopathy, pseudo-pedicle
54L4-S1 (2)LRadiculopathy, pseudo-pedicle, subsidence
65L5-S1 (1)LRadiculopathy, pseudo-pedicle
74L5-S1 (1)LRadiculopathy, pseudo-pedicle
84L5-S1 (1)LRadiculopathy, pseudo-pedicle
93L5-S1 (1)LRadiculopathy, pseudo-pedicle
102L5-S1 (1)LRadiculopathy, pseudo-pedicle
112L5-S1 (1)LRadiculopathy, pseudo-pedicle, subsidence, neurologic
126L5-S1 (1)LRadiculopathy, pseudo-pedicle
133L5-S1 (1)LRadiculopathy, pseudo-pedicle, neurologic
142L2-L3 (1)RRadiculopathy, pseudo-pedicle
154L5-S1 (1)LRadiculopathy, pseudo-pedicle
163L4-L5 (1)LRadiculopathy, pseudo-pedicle
173L2-L3, L4-L5 (2)LRadiculopathy, pseudo-pedicle
183L4-L5, L2-L3 (1)LRadiculopathy, pseudo-pedicle, nonunion
194L4-L5 (1)RRadiculopathy, pseudo-pedicle
205L4-L5 (1)LRadiculopathy, pseudo-pedicle
215L5-S1 (1)RRadiculopathy, pseudo-pedicle
223L3-L4, L5-S1 (2)BothRadiculopathy, pseudo-pedicle
234L4-L5 (1)LRadiculopathy, pseudo-pedicle
246L5-S1 (1)LRadiculopathy, pseudo-pedicle
254L5-S1 (1)LRadiculopathy, pseudo-pedicle
263L5-S1 (1)LRadiculopathy, pseudo-pedicle, urine, bowel
274L5-S1 (1)LRadiculopathy, pseudo-pedicle
284L4-L5 (1)LRadiculopathy, pseudo-pedicle
296L5-S1 (1)LRadiculopathy, pseudo-pedicle
303L5-S1 (1)LRadiculopathy, pseudo-pedicle
313L5-S1 (1)LRadiculopathy, pseudo-pedicle
324L5-S1 (1)LRadiculopathy, pseudo-pedicle
333L5-S1 (1)LRadiculopathy, pseudo-pedicle
344L5-S1 (1)LRadiculopathy, pseudo-pedicle
354L5-S1 (1)LRadiculopathy, pseudo-pedicle
363L5-S1 (1)LRadiculopathy, pseudo-pedicle
374L4-L5 (1)LRadiculopathy, pseudo-pedicle
384L4-L5 (1)LRadiculopathy, pseudo-pedicle

References

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4. Boden SD, Zdeblick TA, Sandhu HS, Heim SE. The use of rhBMP-2 in interbody fusion cages. Definitive evidence of osteoinduction in humans: a preliminary report. Spine. 2000;25(3):376-381.

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17. Joseph V, Rampersaud YR. Heterotopic bone formation with the use of rhBMP2 in posterior minimal access interbody fusion: a CT analysis. Spine. 2007;32(25):2885-2890.

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19. Mroz TE, Wang JC, Hashimoto R, Norvell DC. Complications related to osteobiologics use in spine surgery: a systematic review. Spine. 2010;35(9 suppl):S86-S104.

20. Muchow RD, Hsu WK, Anderson PA. Histopathologic inflammatory response induced by recombinant bone morphogenetic protein-2 causing radiculopathy after transforaminal lumbar interbody fusion. Spine J. 2010;10(9):e1-e6.

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22. Rihn JA, Patel R, Makda J, et al. Complications associated with single-level transforaminal lumbar interbody fusion. Spine J. 2009;9(8):623-629.

23. Vaidya R, Sethi A, Bartol S, Jacobson M, Coe C, Craig JG. Complications in the use of rhBMP-2 in PEEK cages for interbody spinal fusions. J Spinal Disord Tech. 2008;21(8):557-562.

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26. Vaccaro AR, Patel T, Fischgrund J, et al. A pilot study evaluating the safety and efficacy of OP-1 putty (rhBMP-7) as a replacement for iliac crest autograft in posterolateral lumbar arthrodesis for degenerative spondylolisthesis. Spine. 2004;29(17):1885-1892.

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33. Zhang H, Sucato DJ, Welch RD. Recombinant human bone morphogenic protein-2-enhanced anterior spine fusion without bone encroachment into the spinal canal: a histomorphometric study in a thoracoscopically instrumented porcine model. Spine. 2005;30(5):512-518.

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