A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned

Bone morphogenetic protein-2 (BMP-2) is currently the only Food and Drug Administration (FDA)-approved osteoinductive growth factor used as a bone graft substitute. However, with increasing clinical use of BMP-2, a growing and well-documented side effect profile has emerged. This includes postoperative inflammation and associated adverse effects, ectopic bone formation, osteoclast-mediated bone resorption, and inappropriate adipogenesis. Several large-scale studies have confirmed the relative frequency of adverse events associated with the clinical use of BMP-2, including life-threatening cervical spine swelling. In fact, the FDA has issued a warning of the potential life-threatening complications of BMP-2. This review summarizes the known adverse effects of BMP-2, including controversial areas such as tumorigenesis. Next, select animal models that replicate BMP-2's adverse clinical effects are discussed. Finally, potential molecules to mitigate the adverse effects of BMP-2 are reviewed. In summary, BMP-2 is a potent osteoinductive cytokine that has indeed revolutionized the bone graft substitute market; however, it simultaneously has accrued a worrisome side effect profile. Better understanding of these adverse effects among both translational scientists and clinicians will help determine the most appropriate and safe use of BMP-2 in the clinical setting.

A Review of the Clinical Side Effects of Bone Morphogenetic Protein-2

The major Food and Drug Association-approved osteoinductive factors in wide clinical use are bone morphogenetic proteins (BMPs). Although BMPs can promote robust bone formation, they also induce adverse clinical effects, including cyst-like bone formation and significant soft tissue swelling. In this study, we evaluated multiple BMP2 doses in a rat femoral segmental defect model and in a minimally traumatic rat femoral onlay model to determine its dose-dependent effects. Results of our femoral segmental defect model established a low BMP2 concentration range (5 and 10 μg/mL, total dose 0.375 and 0.75 μg in 75 μg total volume) unable to induce defect fusion, a mid-range BMP2 concentration range able to fuse the defect without adverse effects (30 μg/mL, total dose 2.25 μg in 75 μg total volume), and a high BMP2 concentration range (150, 300, and 600 μg/mL, total dose 11.25, 22.5, and 45 μg in 75 μg total volume) able to fuse the defect, but with formation of cyst-like bony shells filled with histologically confirmed adipose tissue. In addition, compared to control, 4 mg/mL BMP2 also induced significant tissue inflammatory infiltrates and exudates in the femoral onlay model that was accompanied by increased numbers of osteoclast-like cells at 3, 7, and 14 days. Overall, we consistently reproduced BMP2 side effects of cyst-like bone and soft tissue swelling using high BMP2 concentration approaching the typical human 1500 μg/mL.

High doses of bone morphogenetic protein 2 induce structurally abnormal bone and inflammation in vivo.

Cortical bone trajectory for lumbar pedicle screws.

Context No national data exist to examine use of bone-morphogenetic proteins (BMPs) in spinal fusion surgery. Objective To determine the patterns of use and rates of complications and financial charges associated with BMP use in spinal fusion nationally. Design, Setting, and Patients Retrospective cohort study of 328 468 patients undergoing spinal fusion procedures from 2002-2006 identified from the Nationwide Inpatient Sample database, a 20% sample of US community hospitals. Main Outcome Measures The rates of use of BMP among patients undergoing spinal fusion procedures are examined along with complications, length of stay, and hospital charges associated with use of this fusion adjunct. Results The nationwide usage of BMP has increased from 0.69% of all fusions in 2002 to 24.89% of all fusions in 2006. Use of BMP varied by patient sex, race, and primary payer with increased use seen in women (56.26% with BMP vs 53.35% without BMP; odds ratio [OR], 1.12; 95% confidence interval, [CI], 1.09-1.16) and Medicare patients (29.62% with BMP vs 27.16% without BMP; OR, 1.43; 95% CI, 1.31-1.56) and decreased use in nonwhite patients (8.69% with BMP vs 10.23% without BMP; OR, 0.80; 95% CI, 0.75-0.85). When comparing immediate postoperative, in-hospital rates of complications for the year 2006 among patients undergoing spinal fusion by BMP use status, no differences were seen for lumbar, thoracic, or posterior cervical procedures. On univariate analysis and after multivariable adjustment, the use of BMP in anterior cervical fusion procedures was associated with a higher rate of complication occurrence (7.09% with BMP vs 4.68% without BMP; adjusted OR, 1.43; 95% CI, 1.12-1.70) with the primary increases seen in wound-related complications (1.22% with BMP vs 0.65% without BMP; adjusted OR, 1.67; 95% CI, 1.10- 2.53) and dysphagia or hoarseness (4.35% with BMP vs 2.45% without BMP; adjusted OR, 1.63; 95% CI, 1.30-2.05). Bone-morphogenetic protein use was associated with greater inpatient hospital charges across all categories of fusion. Increases between 11% and 41% of total hospital charges were reported, with the greatest percentage increase seen for anterior cervical fusion. Conclusion Bone-morphogenetic protein was used in approximately 25% of all spinal fusions nationally in 2006, with use associated with more frequent complications for anterior cervical fusions and with greater hospital charges for all categories of fusions.

https://jamanetwork.com/journals/jama/articlepdf/184181/joc90057_58_66.pdf

Prevalence, Complications, and Hospital Charges Associated With Use of Bone-Morphogenetic Proteins in Spinal Fusion Procedures

The use of bone morphogenetic protein-2 (rhBMP-2) in spinal fusion has increased dramatically since an FDA approval for its use in anterior lumbar fusion with the LT cage. There are several reports of its use in transforaminal lumbar interbody fusion, posterolateral fusion, and anterior cervical fusion. Reports on adverse effects of rhBMP-2 when used in spinal fusion are scarce in literature. An Institutional Review Board approved retrospective study was conducted in patients undergoing anterior spinal fusion and instrumentation following diskectomy at a single center. Forty-six consecutive patients were included. Twenty-two patients treated with rhBMP-2 and PEEK cages were compared to 24 in whom allograft spacers and demineralized bone matrix was used. Patients filled out Cervical Oswestry Scores, VAS for arm pain, neck pain, and had radiographs preoperatively as well at every follow up visit. Radiographic examination following surgery revealed end plate resorption in all patients in whom rhBMP-2 was used. This was followed by a period of new bone formation commencing at 6 weeks. In contrast, allograft patients showed a progressive blurring of end plate-allograft junction. Dysphagia was a common complication and it was significantly more frequent and more severe in patients in whom rhBMP-2 was used. Post operative swelling anterior to the vertebral body on lateral cervical spine X-ray was significantly larger in the rhBMP-2 group when measured from 1 to 6 weeks after which it was similar. These effects are possibly due to an early inflammatory response to rhBMP-2 and were observed to be dose related. With the parameters we used, there was no significant difference in the clinical outcome of patients in the two groups at 2 years. The cost of implants in patients treated with rhBMP-2 and PEEK spacers was more than three times the cost of allograft spacers and demineralized bone matrix in 1, 2, and 3-level cases. Despite providing consistently good fusion rates, we have abandoned using rhBMP-2 and PEEK cages for anterior cervical fusion, due to the side effects, high cost, and the availability of a suitable alternative.

/pdf/complications-of-anterior-cervical-discectomy-and-fusion-4xgm1yuz0z.pdf

Complications of anterior cervical discectomy and fusion using recombinant human bone morphogenetic protein-2

Study design All patients of spinal interbody fusion using polyetheretherketone (PEEK) cages and recombinant human bone morphogenetic protein (rhBMP)-2 performed over a 16-month period were reviewed. Objective To determine the suitability of PEEK cages when used in conjunction with rhBMP-2 in interbody spinal fusion. Summary of background data Bone morphogenetic proteins are increasingly being used in spinal fusion to promote osteogenesis. PEEK is a semicrystalline aromatic polymer that is used as a structural spacer to maintain the disc and foraminal height. Their use has led to increased and predictable rates of fusion. However, not many reports of the adverse effects of their use are available. Methods Fifty-nine consecutive patients of interbody spinal fusion in the cervical or lumbar spine using a PEEK cage and rhBMP-2 were followed for an average of 26 months after surgery. A clinical examination and a record of Oswestry Disability Index, Visual Analog Scale for pain, and a pain diagram were performed preoperatively and at every follow-up visit. All patients had plain radiographs carried out to assess fusion. Ten patients of lumbar spine fusion were additionally evaluated with a computed tomography scan. Results All cases demonstrated an appreciable amount of new bone formation by 6 to 9 months in the cervical spine and by 9 to 12 months in the lumbar spine. End plate resorption was visible radiologically in all cervical spine fusions and majority of lumbar fusions. Cage migration was observed to occur maximally in patients with transforaminal lumbar interbody fusion and posterior lumbar interbody fusion. Disc space subsidence was seen in both cervical and lumbar arthrodesis with the latter showing a lesser incidence, but with a greater degree of collapse. Conclusions PEEK cages and rhBMP-2 when used in spinal fusion give consistently good fusion rates. However, the early role of BMP in the resorptive phase may cause loosening, cage migration, and subsidence.

Complications in the use of rhBMP-2 in PEEK cages for interbody spinal fusions.

We carried out a prospective study to determine whether the addition of a recombinant human bone morphogenetic protein (rhBMP-2) to a machined allograft spacer would improve the rate of intervertebral body fusion in the spine. We studied 77 patients who were to undergo an interbody fusion with allograft and instrumentation. The first 36 patients received allograft with adjuvant rhBMP-2 (allograft/rhBMP-2 group), and the next 41, allograft and demineralised bone matrix (allograft/demineralised bone matrix group). Each patient was assessed clinically and radiologically both pre-operatively and at each follow-up visit using standard methods. Follow-up continued for two years. Every patient in the allograft/rhBMP-2 group had fused by six months. However, early graft lucency and significant (> 10%) subsidence were seen radiologically in 27 of 55 levels in this group. The mean graft height subsidence was 27% (13% to 42%) for anterior lumbar interbody fusion, 24% (13% to 40%) for transforaminal lumbar interbody fusion, and 53% (40% to 58%) for anterior cervical discectomy and fusion. Those who had undergone fusion using allograft and demineralised bone matrix lost only a mean of 4.6% (0% to 15%) of their graft height. Although a high rate of fusion (100%) was achieved with rhBMP-2, significant subsidence occurred in more than half of the levels (23 of 37) in the lumbar spine and 33% (6 of 18) in the cervical spine. A 98% fusion rate (62 of 63 levels) was achieved without rhBMP-2 and without the associated graft subsidence. Consequently, we no longer use rhBMP-2 with allograft in our practice if the allograft has to provide significant structural support.

/pdf/interbody-fusion-with-allograft-and-rhbmp-2-leads-to-2i7fc7iruo.pdf

Interbody fusion with allograft and rhBMP-2 leads to consistent fusion but early subsidence

Objectives:To present a novel internal fixation device for stabilizing unstable pelvic fractures using supra-acetabular spinal pedicle screws and a subcutaneous connecting rod (INFIX).Setting:Level I trauma center.Design:Case series.Patients:Twenty-four patients with rotational or vertically unstabl

Treatment of unstable pelvic ring injuries with an internal anterior fixator and posterior fixation: initial clinical series

Study Design. Single-center retrospective study. Objective. The aim of the study was to compare the surgical experience, clinical outcomes, and effect on body weight between obese and morbidly obese patients undergoing lumbar spine fusion surgery. Summary of Background Data. Obese and morbidly obese patients undergoing spinal fusion surgery are a challenge to the operating surgeon. Only few reports are available on the perioperative data in this group of patients. Further, it is unknown if the degree of obesity has an effect on the surgical experience and clinical outcomes including body weight. Methods. A retrospective study of 63 patients undergoing lumbar spinal fusion was carried out. The main inclusion criteria were a body mass index (BMI) equal to or greater than 30. Information recorded included surgical set-up time, surgical time, blood loss, American Association of Anesthesiologists score, and surgical complications. At follow-up, the Oswestry Disability Index and visual analog scale for back and leg pain were recorded along with a pain diagram and radiographic evaluation. Results. The obese group had lower American Association of Anesthesiologists scores. The surgical time was dependent on the number of levels fused and was independent of the BMI. Blood loss during surgery was marginally greater in the obese patients. Neither group showed significant change in weight and BMI. Clinical outcomes showed improvement in visual analog scale for back and leg pain with some improvement in Oswestry scores and were independent of the BMI of the patient. The incidence of postoperative complications was significant in 45% of morbidly obese and 44% of obese patients. Conclusion. Obese and morbidly obese patients have multiple comorbidities, and the spinal surgeon should be prepared to encounter perioperative complexities. Operative times are longer in comparison with normal weight patients with a higher incidence of postoperative complications. No weight loss occurs after spinal surgery.

Rahul Vaidya

Papers

Complications of anterior cervical discectomy and fusion using recombinant human bone morphogenetic protein-2

Complications in the use of rhBMP-2 in PEEK cages for interbody spinal fusions.

Interbody fusion with allograft and rhBMP-2 leads to consistent fusion but early subsidence

Treatment of unstable pelvic ring injuries with an internal anterior fixator and posterior fixation: initial clinical series

Lumbar spine fusion in obese and morbidly obese patients.