Meta-Analysis on Efficacy and Complications of Bone Morphogenetic Protein-2 for Posterior Fusion of Cervical Spine.

OBJECTIVE: Recombinant human bone morphogenetic protein-2 (rhBMP-2) is effective for promoting robust fusion for long-level cervical deformity and revision surgeries. However, only a few studies have reported its efficacy and complications in posterior cervical fusion (PCF). METHODS: Therefore we evaluated the efficacy and complications of rhBMP-2 application in PCF surgery by searching 3 electronic databases (PubMed, Cochrane Database, and EMBASE) for studies that evaluated the use of rhBMP-2 in PCF. Five studies (1 prospective and 4 retrospective) were included in the meta-analysis. RESULTS: The quality of each study was assessed, and data on pseudarthrosis, wound infection, neurologic, and immediate medical complications were extracted and analyzed. We found that the use of rhBMP-2 in PCF showed significant benefits in terms of pseudarthrosis and no significant increases in the risk for neurologic and immediate medical complications regardless of the dose. However, high-dose (>2.1 mg/level) rhBMP-2 was a risk factor for wound infection after PCF. CONCLUSIONS: Our meta-analysis of the currently available literature suggests that patients with PCF may benefit from BMP-2 usage without increasing the risk of complications. However, dose control and containment are important to ensure a low risk of complications.

Bone morphogenetic protein and cancer in spinal fusion: a propensity score-matched analysis.

OBJECTIVE: Bone morphogenetic protein (BMP) has been increasingly used in spinal surgery to promote arthrodesis. Because BMP stimulates cellular proliferation, its association with tumorigenesis is a concern. Previous research has generated conflicting conclusions on the risk of cancer in patients receiving BMP. The authors aimed to compare the incidence of solid organ and hematopoietic malignancies in patients undergoing spinal arthrodesis with or without BMP. METHODS: The PearlDiver Mariner Patient Claims Database was queried for patients undergoing thoracolumbar fusion between 2015 and 2021. Patients with preexisting malignancy were excluded. Data were analyzed for incidence of solid organ malignancy and hematopoietic malignancy diagnosed after spinal surgery. Propensity score matching using age, sex, tobacco usage, and year of surgery was performed between patients who did and those who did not receive BMP. RESULTS: Among patients without prior solid organ malignancy, BMP was used in 22,139 patients and not used in 306,249. In the propensity score-matched group, 3.1% of the BMP group developed solid organ malignancy following surgery compared with 3.5% in the non-BMP group. The relative risk (RR) of developing solid organ malignancy after BMP exposure was 0.89 (95% CI 0.81-0.98, p = 0.02). Among patients without prior hematopoietic malignancy, BMP was used in 23,505 patients and not used in 328,796 patients. In the propensity score-matched group, 0.4% of the BMP group developed hematopoietic malignancy compared with 0.6% of the non-BMP group. The RR of developing hematopoietic malignancy after BMP exposure was 0.71 (95% CI 0.55-0.93, p = 0.015). CONCLUSIONS: BMP use in thoracolumbar fusion was not associated with an increased risk of new malignancy, which further supports emerging data on the lack of an association between BMP use and increased malignancy.

Fusion rate of Escherichia coli-derived recombinant human bone morphogenetic protein-2 compared with local bone autograft in posterior lumbar interbody fusion for degenerative lumbar disorders.

BACKGROUND CONTEXT: The use of recombinant human bone morphogenetic proteins-2 (rhBMP-2) for spinal fusion has been reported to be effective. However, most studies have focused on posterolateral and anterior lumbar interbody fusion, and few have investigated posterior lumbar interbody fusion (PLIF). PURPOSE: This study aimed to determine the effectiveness and safety of the delivery of Escherichia coli-derived rhBMP-2 (E.BMP-2) with hydroxyapatite (HA) and ß-tricalcium phosphate (ß-TCP) poloxamer hydrogel composite carriers for PLIF. STUDY DESIGN: A retrospective study. PATIENT SAMPLE: Patients who underwent 1 to 3 levels of PLIF for lumbar degenerative disc disorders between 2015 and 2020 with a follow-up of ≥1 year were enrolled. In total, 254 patients (357 levels) were included in the analysis. The evaluation was performed at each segment level. In the E.BMP-2 group, 160 patients (221 levels) received autologous local bone with E.BMP-2 (maximum 0.5 mg/level), and in the control group, 94 patients (136 levels) received only local bone graft. OUTCOME MEASURES: The primary outcome of this study was to compare the X-ray and CT fusion rates between the two groups. Secondary outcomes included analysis of the patients' clinical outcomes and postoperative complications on CT scans. METHODS: Clinical evaluations were performed using a visual analog scale for back pain, the Oswestry Disability Index for disability, and physical and mental component summaries of the Short Form 36-Item Form Health Survey to assess functional effects and quality of life. The fusion was evaluated using radiography and CT. On radiography, solid fusion was defined when the difference between extension and flexion was less than 5°. On CT, solid fusion was defined when the upper and lower vertebral bodies were connected by the trabecular bone (bone bridge formation). In addition, complications such as osteolysis, cage subsidence, and screw loosening were investigated using CT. RESULTS: All clinical results for low back pain, disability, and quality of life in both groups were excellent and showed statistically significant improvements compared with baseline (p<.0001). According to the X-ray evaluations, fusion was achieved in 92.31% (204/221) of the patients in the E.BMP-2 group and 82.35% (112/136) of the patients in the control group (p=.0041). According to the CT evaluations, the fusion rates were 93.21% (206/221) and 88.24% (120/136) in the E.BMP-2 and control groups (p=.1048), respectively. Except for screw loosening, which had a significantly higher incidence in the control group (p=.0014), the rates of most postoperative complications were not significantly different between the groups. CONCLUSIONS: This study demonstrated that the adjunctive use of a low dose of E.BMP-2 with HA and ß-TCP hydrogel can effectively promote bone fusion, making it a promising option for patients with limited autograft availability or compromised bone quality in PLIF.

Application of rhBMP in spinal fusion surgery: any correlation of cancer incidence? A systematic review and meta-analysis.

PURPOSE: Safety concerns regarding the application of bone morphogenetic proteins (BMPs) have been highlighted in recent years. It is noted that both BMP and their receptors being identified as a trigger for cancer growth. Here, we aimed to determine the safety and efficacy of BMP for spinal fusion surgery. METHODS: We conducted this systematic review on topics of spinal fusion surgery with rhBMP application from three database (PubMed, EuropePMC, and Clinicaltrials.gov) with MeSH phrases such as "rh-BMP," "rhBMP," "spine surgery," "spinal arthrodesis," and "spinal fusion" were searched (using the Boolean operators "and" and "or"). Our research includes all articles, as long as published in English language. In the face of disagreement between the two reviewers, we discussed it together until all authors reached a consensus. The primary key outcome of our study is the incidence of cancer following rhBMP implantation. RESULTS: Our study included a total of 8 unique studies (n = 37,682). The mean follow-up varies among all studies, with the longest follow-up is 66 months. Our meta-analysis showed that exposure to rhBMP in spinal surgery did increase the risk of cancers (RR 1.85, 95%CI [1.05, 3.24], p = 0.03). CONCLUSIONS: Our study found that rhBMP was not associated with the increased risk of cancer incidence within the rhBMP cohort. Still, we did face several limitations, in which further studies are needed to confirm the result of our meta-analysis.

Mid-term efficacy and safety of Escherichia coli-derived rhBMP-2/hydroxyapatite carrier in lumbar posterolateral fusion: a randomized, multicenter study.

PURPOSE: This study aimed to evaluate the mid-term efficacy and safety of Escherichia coli-derived bone morphogenetic protein-2 (E.BMP-2)/hydroxyapatite (HA) in lumbar posterolateral fusion (PLF). METHODS: This multicenter, evaluator-blinded, observational study utilized prospectively collected clinical data. We enrolled 74 patients who underwent lumbar PLF and had previously participated in the BA06-CP01 clinical study, which compared the short-term outcomes of E.BMP-2 with an auto-iliac bone graft (AIBG). Radiographs and CT scans were analyzed to evaluate fusion grade at 12, 24, and 36 months. Visual analog scale (VAS), Oswestry disability index (ODI), and Short Form-36 (SF-36) scores were measured preoperatively and at 36 months after surgery. All adverse events in this study were assessed for its relationship with E.BMP-2. RESULTS: The fusion grade of the E.BMP-2 group (4.91 ± 0.41) was superior to that of the AIBG group (4.25 ± 1.26) in CT scans at 36 months after surgery (p = 0.007). Non-union cases were 4.3% in the E.BMP-2 and 16.7% in the AIBG. Both groups showed improvement in pain VAS, ODI, and SF-36 scores when compared to the baseline values, and there were no statistically significant differences between the two groups. No treatment-related serious adverse reactions were observed in either group. No neoplasm-related adverse events occurred in the E.BMP-2 group. CONCLUSIONS: The fusion quality of E.BMP-2/HA was superior to that of AIBG. E.BMP-2/HA showed comparable mid-term outcomes to that of AIBG in terms of efficacy and safety in one-level lumbar PLF surgery.

Evaluation of the efficacy and safety of Escherichia coli-derived recombinant human bone morphogenetic protein-2 in transforaminal lumbar interbody fusion to treat degenerative spinal disease: a protocol of prospective, randomized controlled, assessor-blinded, open-label, multicenter trial.

BACKGROUND: Recombinant human bone morphogenetic protein-2 (rhBMP-2) has been widely used as an alternative bone graft in spine fusion surgery. However, clinical outcome such as effects and complications has not yet been revealed for transforaminal lumbar interbody fusion (TLIF). Although previous studies have reported some results, the evidence is weak. Therefore, the purpose of this trial is to evaluate the effectiveness and safety of Escherichia coli-derived rhBMP-2 combined with hydroxyapatite (HA) in TLIF. METHODS: This trial is designed as a prospective, assessor-blinded, open-label, multicenter, randomized controlled study. Participants will be recruited from six tertiary teaching hospitals. All randomized participants will be undergoing one- or two-level TLIF with rhBMP-2 (77 participants) as the active experimental group or with an auto-iliac bone graft (77 participants) as the control group. The primary interbody fusion rate outcome will be evaluated using computed tomography (CT) 12 months after surgery. The secondary outcomes will be as follows: clinical outcomes (visual analog scale score, EuroQol-5-dimensions-5-level score, Oswestry Disability Index score, and some surgery-related variables) and adverse effects (radiculitis, heterotrophic ossification, endplate resorption, and osteolysis). Radiological outcomes will be evaluated using simple radiography or CT. All outcomes will be measured, collected, and evaluated before surgery and at 12, 24, and 52 weeks postoperatively. DISCUSSION: This study will be the primary of its kind to evaluate the effectiveness and safety of E. coli-derived rhBMP-2 with HA in one- or two-level TLIF. It is designed to evaluate the equivalence of the results between rhBMP-2 with HA and auto-iliac bone graft using an appropriate sample size, assessor-blinded analyses, and prospective registration to avoid bias. This study will set up clear conclusions for using E. coli-derived rhBMP-2 with HA in TLIF. TRIAL REGISTRATION: This study protocol was registered at Korea Clinical Research Information Service ( https://cris.nih.go.kr ; number identifier: KCT0005610) on 19 November 2020. And protocol version is v1.1, January 2022.

Dose Adjustment Associated Complications of Bone Morphogenetic Protein: A Longitudinal Assessment.

OBJECTIVE: Bone morphogenetic protein (BMP) is a growth factor that aids in osteoinduction and promotes bone fusion. There is a lack of literature regarding recombinant human BMP-2 (rhBMP-2) dosage in different spine surgeries. This study aims to investigate the trends in rhBMP-2 dosage and the associated complications in spinal arthrodesis. METHODS: A retrospective study was conducted investigating spinal arthrodesis using rhBMP-2. Variables including age, procedure type, rhBMP-2 size, complications, and postoperative imaging were collected. Cases were grouped into the following surgical procedures: anterior lumbar interbody fusion/extreme lateral interbody fusion (ALIF/XLIF), posterior lumbar interbody fusion/transforaminal lumbar interbody fusion (PLIF/TLIF), posterolateral fusion (PLF), anterior cervical discectomy and fusion (ACDF), and posterior cervical fusion (PCF). RESULTS: A total of 1209 patients who received rhBMP-2 from 2006 to 2020 were studied. Of these, 230 were categorized as ALIF/XLIF, 336 as PLIF/TLIF, 243 as PLF, 203 as ACDF, and 197 as PCF. PCF (P < 0.001), PLIF/TLIF (P < 0.001), and PLF (P < 0.001) demonstrated a significant decrease in the rhBMP-2 dose used per level, with major transitions seen in 2018, 2011, and 2013, respectively. In our sample, 129 complications following spinal arthrodesis were noted. A significant relation between rhBMP-2 size and complication rates (χ2= 73.73, P = 0.0029) was noted. rhBMP-2 dosage per level was a predictor of complication following spinal arthrodesis (odds ratio = 1.302 [1.05-1.55], P < 0.001). CONCLUSIONS: BMP is an effective compound in fusing adjacent spine segments. However, it carries some regional complications. We demonstrate a decreasing trend in the dose/vertebral level. A decrease rhBMP-2 dose per level correlated with a decrease in complication rates.

The minimally effective dose of bone morphogenetic protein in posterior lumbar interbody fusion: a systematic review and meta-analysis.

BACKGROUND CONTENT: The risks and benefits of recombinant human bone morphogenetic protein-2 (BMP) in posterior lumbar interbody fusion (PLIF) and transforaminal lumbar interbody fusion (TLIF) have been widely reported. However, the BMP dose associated with such reports varied widely. Additionally, data on the location of BMP placement on complications and fusion are lacking. PURPOSE: To determine the minimally effective dose (MED) of BMP which results in optimal fusion rates while minimizing complications; to determine the effects of the location of BMP placement has on fusion rates and complications. STUDY DESIGN: Systematic review and meta-analysis. STUDY SAMPLE: Adult patients undergoing PLIF/TLIF for degenerative indications. OUTCOME MEASURES: Rates of radiculitis, fusion, osteolysis, heterotopic bone formation, and new cancer diagnosis. METHODS: PubMed, Embase, and Cochrane Database were used to identify studies published between January 1, 2011 and April 30, 2019 reporting BMP usage in adult patients who underwent PLIF/TLIF degenerative indications. A qualitative and quantitative synthesis was performed to evaluate the MED of BMP and the effect of location of BMP placement on fusion and complications. Complications were defined as osteolysis, heterotopic bone growth, radiculitis, and rate of new cancer diagnosis. Complications and fusion outcomes were each pooled according to commercially available BMP doses. Additionally, complications and fusion outcomes were pooled according to 4 location groups (interbody cage only, interbody cage + posterolateral gutter [PLG], cage + interspace, and interspace + PLG). Heterogeneity was assessed with Q and I2 statistics. RESULTS: Twenty-two articles, totaling 2,729 patients were included. Sixteen studies reported fusion and 15 reported complications. Among fusion studies, the mean BMP/level ranged from 1.28 to 12 mg/level. Among complication studies, the mean BMP/level ranged from 6.7 to 23.6 mg/level. The pooled overall fusion rate was 94.0% (91.4-95.8 confidence intervals). There was no significant difference in fusion and complication rates between different BMP doses. Thirteen studies included data on the location of BMP placement with 1,823 patients. At each BMP location, the fusion rate was not significantly different across the dose ranges (1.28-12 mg/level). We found the fusion rate to be marginally higher in the interspace + PLG group compared to the other groups. When BMP was placed in the interbody cage there was a mild increase in the rate of osteolysis compared to other placement locations. CONCLUSIONS: Fusion and complication rates did not differ significantly between different doses of BMP with the lowest MED for fusion as low as 1.28 mg/level. The location of BMP placement does not significantly affect fusion or complication rates.

Bone morphogenetic protein-2 promotes osteosarcoma growth by promoting epithelial-mesenchymal transition (EMT) through the Wnt/ß-catenin signaling pathway.

The correlation between BMP-2 and osteosarcoma growth has gained increased interest in the recent years, however, there is still no consensus. In this study, we tested the effects of BMP-2 on osteosarcoma cells through both in vitro and in vivo experiments. The effect of BMP-2 on the proliferation, migration and invasion of osteosarcoma cells was tested in vitro. Subcutaneous and intratibial tumor models were used for the in vivo experiments in nude mice. The effects of BMP-2 on EMT of osteosarcoma cells and the Wnt/ß-catenin signaling pathway were also tested using a variety of biochemical methods. In vitro tests did not show a significant effect of BMP-2 on tumor cell proliferation. However, BMP-2 increased the mobility of tumor cells and the invasion assay demonstrated that BMP-2 promoted invasion of osteosarcoma cells in vitro. In vivo animal study showed that BMP-2 dramatically enhanced tumor growth. We also found that BMP-2 induced EMT of osteosarcoma cells. The expression levels of Axin2 and Dkk-1 were both down regulated by BMP-2 treatment, while ß-catenin, c-myc and Cyclin-D1 were all upregulated. The expression of Wnt3α and p-GSK-3ß were also significantly upregulated indicating that the Wnt/ß-catenin signaling pathway was activated during the EMT of osteosarcoma driven by BMP-2. From this study, we can conclude that BMP-2 significantly promotes growth of osteosarcoma cells (143B, MG63), and enhances mobility and invasiveness of tumor cells as demonstrated in vitro. The underlying mechanism might be that BMP-2 promotes EMT of osteosarcoma through the Wnt/ß-catenin signaling pathway. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1638-1648, 2019.

Postoperative Seroma Formation After Posterior Cervical Fusion with Use of RhBMP-2: A Report of Two Cases.

CASE: We present 2 cases of postoperative seroma formation following posterior cervical fusion with the use of recombinant human bone morphogenetic protein-2 (rhBMP-2). CONCLUSION: Although some who advocate for the off-label use of rhBMP-2 in patients undergoing posterior cervical spine fusion believe it to be safe, relatively little has been published regarding complication rates. We believe that rhBMP-2 carries a risk of seroma formation in patients who undergo posterior cervical fusion, which necessitates the use of a postoperative drain. Surgeons should have a low threshold for obtaining postoperative magnetic resonance imaging in a symptomatic patient.

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

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.

Comparison of transforaminal lumbar interbody fusion outcomes in patients receiving rhBMP-2 versus autograft.

BACKGROUND CONTEXT: Recombinant human bone morphogenetic protein 2 (rhBMP-2) plays a pivotal role in complex spine surgery. Despite its limited approval, the off-label use of rhBMP-2 is prevalent, particularly in transforaminal lumbar interbody fusions (TLIFs). PURPOSE: To determine the effectiveness and safety of rhBMP-2 use in TLIF procedures versus autograft. STUDY DESIGN: Retrospective cohort study. PATIENT SAMPLE: Patients older than 18 years undergoing spine surgery for lumbar degenerative spine disease at a single academic institution. OUTCOME MEASURES: Clinical outcome was determined according to patient records. Radiographic outcome was determined according to plain X-rays and computed tomography (CT). METHODS: A retrospective study from 1997 to 2014 was conducted on 191 adults undergoing anterior-posterior instrumented spinal fusion with TLIF at a single academic institution. Patient data were gathered from operative notes, follow-up clinic notes, and imaging studies to determine complications and fusion rates. One hundred eighty-seven patients fit the criteria, which included patients with a minimum of one TLIF, and had a minimum 2-year radiographic and clinical follow-up. Patients were further classified into a BMP group (n=83) or non-BMP group (n=104). Three logistic regression models were run using rhBMP-2 exposure as the independent variable. The respective outcome variables were TLIF-related complications (radiculitis, seroma, osteolysis, and ectopic bone), surgical complications, and all complications. RESULTS: Bone morphogenetic protein (n=83) and non-BMP (n=104) groups had similar baseline demographics (sex, diabetes, pre-existing cancer). On average, the BMP and non-BMP groups were similarly aged (51.9 vs. 47.9 years, p>.05), but the BMP group had a shorter follow-up time (3.03 vs. 4.06 years; p<.001) and fewer smokers (8 vs. 21 patients; p<.048). The fusion rate for the BMP and non-BMP groups was 92.7% and 92.3%, respectively. The pseudoarthrosis rate was 7.5% (14 of 187 patients). Radiculitis was observed in seven patients in the BMP group (8.4%) and two patients in the non-BMP group (1.9%). Seroma was observed in two patients in the BMP group (2.4%) and none in the non-BMP group. No deep infections were observed in the BMP group, and in one patient in the non-BMP group (0.96%). Although patients exposed to BMP were at a significantlygreater risk of developing radiculitis and seroma (odds ratio [OR]=4.53, confidence interval [CI]=1.42-14.5), BMP exposure was not a significant predictor of surgical complications (OR=0.32, CI=0.10-1.00) or overall complications (OR=1.11, CI=0.53-2.34). The outcome of TLIF-related complications was too rare and the confidence interval too wide for practical significance of the first model. CONCLUSION: Evidence supports the hypothesis that off-label use of rhBMP-2 in TLIF procedures is relatively effective for achieving bone fusion at rates similar to patients receiving autograft. Patients exhibited similar complication rates between the two groups, with the BMP group exhibiting slightly higher rates of radiculitis and seroma.

Bone morphogenic protein-2 use in revision total hip arthroplasty with acetabular defects.

INTRODUCTION: The restoration of acetabular bone stock during revision hip arthroplasty remains a challenge. There have been no clinical series reporting the efficacy of bone morphogenic protein-2 (rhBMP-2) in the revision hip setting. METHODS: We retrospectively reviewed the radiographs and records of 15 patients who received rhBMP-2 mixed with allograft bone chips (+BMP), and 14 who received allograft bone chips alone (-BMP) for their acetabular defect during revision total hip arthroplasty with a mean two-year follow up. Radiographs were evaluated for acetabular defect size, superior cup migration, and changes in the lateral cup abduction angle. Modified Harris hip scores were used for evaluation of clinical outcomes. RESULTS: Patients in the +BMP group compared to the -BMP group had significantly larger amounts of cancellous bone chips used (72.1 ± 35.5 cc vs. 38.6 ± 14.1 cc; p = 0.003). Mean rhBMP-2 used per case was 7.4 ± 3.1 mg in the +BMP group. Three patients in the -BMP group had cup migration which was not observed in the +BMP group. Mean Harris hip scores (HHS) improved post-operatively in both groups (40.1 ± 20.9 to 71.9 ± 19, p < .0001). No local adverse reaction was noted in the +BMP group. CONCLUSION: rhBMP-2 had modest clinical benefit in the setting of revision THA. Cost of this synthetic biologic versus the added clinical benefit should be carefully considered when being used in the revision hip setting.

A comparison of radiographic and clinical outcomes of anterior lumbar interbody fusion performed with either a cellular bone allograft containing multipotent adult progenitor cells or recombinant human bone morphogenetic protein-2.

BACKGROUND: Both the map3 Cellular Allogeneic Bone Graft® and recombinant human bone morphogenetic protein 2 (rhBMP-2, Infuse®) were developed to provide an alternative to iliac crest autograft, thus eliminating the morbidity associated with its harvest. The recent literature concerning adverse events associated with the use of rhBMP-2, however, highlights the need for a safe and effective alternative. The multipotent adult progenitor cells (MAPC) found in map3 allograft may provide this alternative. The purpose of this study is to report 1-year outcomes of patients treated via anterior lumbar interbody fusion (ALIF) using either map3 Cellular Allogeneic Bone Graft or rhBMP-2 for bony fusion. METHODS: This was a retrospective evaluation of 41 patients treated via ALIF with either map3 or rhBMP-2 in a polyetheretherketone cage with posterior stabilization at 1, 2, or 3 consecutive levels (L3-S1). Patients were equally divided between treatment groups. The Oswestry Disability Index (ODI) and visual analog scores (VAS) for pain were documented as part of the standard of care. An independent radiologist assessed bridging of bone, disc height, and lordosis. Primary outcome measures included radiographic analysis of fusion by plain film and CTs. Secondary clinical outcomes included visual analogue scale for neck and arm pain and low back disability index scores. RESULTS: The overall fusion rate was 91%, with no significant difference between groups. Improvements in ODI and VAS were observed among all patients (p < 0.001), with no significant difference between groups for ODI (p = 0.966) or VAS (p = 0.251). There was no significant difference in terms of changes to disc height and lordosis between groups (p < 0.05). The rhBMP-2 group had increased post-operative complications when compared to the map3 group, but the low numbers precluded statistical analysis. CONCLUSION: Improvements in radiographic and clinical findings were observed in both treatment groups one-year postoperatively. Map3 allograft demonstrated equivalent fusion rates to rhBMP-2. A review of surgical supply costs at the treatment facility favored map3 allograft for the treatment of patients with DDD undergoing an ALIF in 1-3 levels compared to rhBMP-2. Further studies to evaluate long-term outcomes and post-operative complications are required.

Recombinant human bone morphogenetic protein-2 versus iliac crest bone graft in anterior cervical discectomy and fusion: Dysphagia and dysphonia rates in the early postoperative period with review of the literature.

Recombinant human bone morphogenetic protein-2 (rhBMP-2) is a growth factor utilized to stimulate bone development in several clinical scenarios. Although the U.S. Food and Drug Administration approved this therapeutic modality for only two applications, it is frequently used off-label in anterior cervical discectomy and fusion (ACDF) procedures as an alternative to iliac crest bone graft (ICBG), the prior standard of care. This usage has been a source of controversy in the medical community due to evidence of increased rates of postoperative edema and dysphagia. This retrospective cohort study investigates two groups of 200 patients having undergone ACDF, one using rhBMP-2 and the other using ICBG, to evaluate the incidence of complications in the early postoperative period. A significant reduction in average length of stay was found in the rhBMP-2 cohort (1.40days) compared to the ICBG cohort (1.85days) as well as a significantly increased rate of dysphagia (25.5% in rhBMP-2 vs. 15% in ICBG; p=0.01). An increased rate of dysphonia was observed among patients undergoing revision surgery (25.0%) compared to primary surgery (1.6%), but stratification by number of levels, gender, and smoking status yielded no differences in complication rates. Our evaluation of two large cohorts along with review of the literature on the topic sheds light on potential benefits and risks of rhBMP-2 in ACDF procedures. Further investigation is warranted to determine if clinical gains outweigh the potential harms of rhBMP-2 use in this setting.

Heterotopic ossification related to the use of recombinant human BMP-2 in osteonecrosis of femoral head.

Despite the wide use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in bone defect, its application in treating osteonecrosis of femoral head (ONFH) is yet to be elucidated. The heterotopic ossification (HO) after rhBMP-2 usage in some orthopedic surgeries has been reported previously; however, only a few studies describe this complication in the treatment of ONFH.The present study investigated whether the rhBMP-2 application would increase the risk of HO formation in selected ONFH patients with nonvascularized bone grafting surgery and enhance the surgical results of nonvascularized bone grafting as compared to patients who did not receive intraoperative rhBMP-2.A retrospective analysis was performed on 94 patients (141 hips) who, with Association Research Circulation Osseous (ARCO) stages IIb, IIc, and IIIa ONFH, underwent nonvascularized bone grafting surgery. The first 46 patients (66 hips) received intraoperative rhBMP-2. The postoperative radiographic results (X-ray and CT scan) and Harris hip score (HHS) were reviewed in each patient to record the incidence of HO formation and evaluate the clinical efficacy of rhBMP-2, respectively.HO formation frequently occurred in patients receiving intraoperative rhBMP-2 (8/66 hips) than those not receiving the protein (1/75 hips) (P = .02). HHS improved from preoperatively at the final follow-up (P < .01) in the BMP-positive group, with a survival rate of 83.3%. In the BMP-negative group, the HHS improved from preoperatively at the end of the follow-up (P < .01), and the survival rate was 72.0%.rhBMP-2 has osteoinductive property and might serve as an adjuvant therapy in the surgical treatment of ONFH. However, the incidence of HO formation might increase when used in high doses.

Efficacy of Escherichia coli-derived recombinant human bone morphogenetic protein-2 in posterolateral lumbar fusion: an open, active-controlled, randomized, multicenter trial.

BACKGROUND CONTEXT: The efficacy and safety of recombinant human bone morphogenetic protein-2 (rhBMP-2) as a bone graft substitute in spinal fusion has been widely researched. However, no study of the efficacy and safety of Escherichia coli-derived rhBMP-2 (E.BMP-2) with a hydroxyapatite (HA) carrier has been proposed. PURPOSE: This study aimed to compare the efficacy and safety of fusion materials between E.BMP-2 and autogenous iliac bone graft in posterolateral fusion (PLF). STUDY DESIGN/SETTING: An open, active-controlled, randomized, multicenter trial was carried out. PATIENT SAMPLE: This study included 93 patients who underwent single-level lumbar or lumbosacral PLF. OUTCOME MEASURES: The primary outcome measure was computed tomography (CT)-based fusion rate at 12 and 24 weeks. Secondary outcome measures were fusion grade by radiographs and CT at 12 and 24 weeks and changes in Oswestry Disability Index (ODI), Short Form-36 (SF-36) Health Survey, and visual analogue scale (VAS). METHODS: Patients who underwent 1-level PLF (between L1 and S1) for severe spinal stenosis or grade 1 spondylolisthesis were randomized to receive E.BMP-2 with an HA carrier (E.BMP-2 group) or autogenous iliac bone graft (AIBG group). Thin-section CT (<2 mm), VAS, ODI, and SF-36 were obtained pre- and postoperatively at 12 and 24 weeks. Outcome measures were compared between the groups. RESULTS: A total of 100 patients were enrolled in this trial. Among them, 93 patients underwent planned surgery. Preoperative demographic and clinical data showed no difference between groups. CT-based fusion rates were 100.0% (41/41) for the E.BMP-2 group and 90.2% (46/51) for the AIBG group (p=.062) at 12 weeks and 100.0% (41/41) and 94.1% (48/51) (p=.251) at 24 weeks, respectively. Fusion grade based on radiographs and CT showed non-inferiority of the E.BMP-2 group compared with the AIBG group. All clinical parameters improved postoperatively. However, there was no difference in changes in VAS, ODI, or SF-36 between the groups. No serious adverse event related to E.BMP-2 was found. CONCLUSIONS: The fusion rate of E.BMP-2 was comparable with that of AIBG following PLF. Good clinical efficacy and safety of E.BMP-2 in spinal fusion were also revealed. It was also suggested that HA shows suitability as a carrier for E.BMP-2. Thus, E.BMP-2 with an HA carrier can be an alternative bone graft material in spinal fusion.

Cyst-Like Osteolytic Formations in Recombinant Human Bone Morphogenetic Protein-2 (rhBMP-2) Augmented Sheep Spinal Fusion.

Multiple case reports using recombinant human bone morphogenetic protein-2 (rhBMP-2) have reported complications. However, the local adverse effects of rhBMP-2 application are not well documented. In this report we show that, in addition to promoting lumbar spinal fusion through potent osteogenic effects, rhBMP-2 augmentation promotes local cyst-like osteolytic formations in sheep trabecular bones that have undergone anterior lumbar interbody fusion. Three months after operation, conventional computed tomography showed that the trabecular bones of the rhBMP-2 application groups could fuse, whereas no fusion was observed in the control group. Micro-computed tomography analysis revealed that the core implant area's bone volume fraction and bone mineral density increased proportionately with rhBMP-2 dose. Multiple cyst-like bone voids were observed in peri-implant areas when using rhBMP-2 applications, and these sites showed significant bone mineral density decreases in relation to the unaffected regions. Biomechanically, these areas decreased in strength by 32% in comparison with noncystic areas. Histologically, rhBMP-2-affected void sites had an increased amount of fatty marrow, thinner trabecular bones, and significantly more adiponectin- and cathepsin K-positive cells. Despite promoting successful fusion, rhBMP-2 use in clinical applications may result in local adverse structural alterations and compromised biomechanical changes to the bone.

Bone morphogenetic protein use in spine surgery in the United States: how have we responded to the warnings?

BACKGROUND CONTEXT: Recombinant human bone morphogenetic protein-2 (rhBMP-2) has been widely adopted as a fusion adjunct in spine surgery since its approval in 2002. A number of concerns regarding adverse effects and potentially devastating complications of rhBMP-2 use led to a Food and Drug Administration (FDA) advisory issued in 2008 cautioning its use, and a separate warning about its potential complications was published by The Spine Journal in 2011. PURPOSE: To compare trends of rhBMP-2 use in spine surgery after the FDA advisory in 2008 and The Spine Journal warning in 2011. STUDY DESIGN: Retrospective cross-sectional study using a national database. PATIENT SAMPLE: All patients from 2002 to 2013 who underwent spinal fusion surgery at an institution participating in the Nationwide Inpatient Sample (NIS). OUTCOME MEASURES: Proportion of spinal fusion surgeries using rhBMP-2. METHODS: We queried the NIS from 2002 to 2013 and used International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) procedure codes to identify spinal fusion procedures and those that used rhBMP-2. Procedures were subdivided into primary and revision fusions, and by region of the spine. Cervical and lumbosacral fusions were further stratified into anterior and posterior approaches. The percentage of cases using BMP was plotted across time. A linear regression was fit to the data from quarter 3 of 2008 (FDA advisory) through quarter 1 of 2011, and a separate regression was fit to the data from quarter 2 of 2011 (The Spine Journal warning) onward. The slopes of these regression lines were statistically compared to determine differences in trends. No funding was received to conduct this study, and no authors had any relevant conflicts of interest. RESULTS: A total of 4,167,079 patients in the NIS underwent spinal fusion between 2002 and 2013. We found a greater decrease in rhBMP-2 use after The Spine Journal warning compared with the FDA advisory for all fusion procedures (p=.006), primary fusions (p=.006), and revision fusions (p=.004). Lumbosacral procedures also experienced a larger decline in rhBMP-2 use after The Spine Journal article as compared with the FDA warning (p=.0008). This pattern was observed for both anterior and posterior lumbosacral fusions (p≤.0001 for both). Anterior cervical fusion was the only procedure that demonstrated a decline in rhBMP-2 use after the FDA advisory that was statistically greater than after The Spine Journal article (p=.02). CONCLUSIONS: Warnings sanctioned through the spine literature may have a greater influence on practice of the spine surgery community as compared with advisories issued by the FDA.Comprehensive guidelines regarding safe and effective use of rhBMP-2 must be established.

Bone Morphogenetic Proteins in Anterior Cervical Fusion: A Systematic Review and Meta-Analysis.

OBJECTIVE: Bone morphogenetic proteins (BMPs) have been commonly used as a graft substitute in spinal fusion. Although the U.S. Food and Drug Administration issued a warning on life-threatening complications of recombinant human BMPs (rhBMPs) in cervical spine fusion in 2008, their off-label use has been continued. This investigation aimed to review the evidence for the use of rhBMP-2 and rhBMP-7 in anterior cervical spine fusions. METHODS: A comprehensive search was performed through Ovid (MEDLINE), PubMed, and Embase. The risk of bias assessment was according to the recommended criteria by the Cochrane Back and Neck group and MINORS (Methodological Index for Non-Randomized Studies). A wide array of radiographic and clinical outcomes including the adverse events were collated. RESULTS: Eighteen articles (1 randomized and 17 nonrandomized) were eligible for inclusion. The fusion rate was higher with use of rhBMP in most studies and our meta-analysis of the pooled data from 4782 patients confirmed this finding (odds ratio, 5.45; P < 0.00001). Altogether, the rhBMP and control groups were comparable in patient-reported outcomes. However, most studies tended to show a significantly higher incidence of overall complication rate, dysphagia/dysphonia, cervical swelling, readmission, wound complications, neurologic complications, and ossification. CONCLUSIONS: Application of rhBMPs in cervical spine fusion yields a significantly higher fusion rate with similar patient-reported outcomes, yet increased risk of life-threatening complications. Thus, we do not recommend the use of rhBMP in anterior cervical fusions.