Browsing by Subject "Bone Morphogenetic Protein 2"
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Item Open Access Arterial pole progenitors interpret opposing FGF/BMP signals to proliferate or differentiate.(Development, 2010-09) Hutson, MR; Zeng, XL; Kim, AJ; Antoon, E; Harward, S; Kirby, MLDuring heart development, a subpopulation of cells in the heart field maintains cardiac potential over several days of development and forms the myocardium and smooth muscle of the arterial pole. Using clonal and explant culture experiments, we show that these cells are a stem cell population that can differentiate into myocardium, smooth muscle and endothelial cells. The multipotent stem cells proliferate or differentiate into different cardiovascular cell fates through activation or inhibition of FGF and BMP signaling pathways. BMP promoted myocardial differentiation but not proliferation. FGF signaling promoted proliferation and induced smooth muscle differentiation, but inhibited myocardial differentiation. Blocking the Ras/Erk intracellular pathway promoted myocardial differentiation, while the PLCgamma and PI3K pathways regulated proliferation. In vivo, inhibition of both pathways resulted in predictable arterial pole defects. These studies suggest that myocardial differentiation of arterial pole progenitors requires BMP signaling combined with downregulation of the FGF/Ras/Erk pathway. The FGF pathway maintains the pool of proliferating stem cells and later promotes smooth muscle differentiation.Item Open Access Cost-Utility Analysis of rhBMP-2 Use in Adult Spinal Deformity Surgery.(Spine, 2020-07) Jain, Amit; Yeramaneni, Samrat; Kebaish, Khaled M; Raad, Micheal; Gum, Jeffrey L; Klineberg, Eric O; Hassanzadeh, Hamid; Kelly, Michael P; Passias, Peter G; Ames, Christopher P; Smith, Justin S; Shaffrey, Christopher I; Bess, Shay; Lafage, Virginie; Glassman, Steve; Carreon, Leah Y; Hostin, Richard A; International Spine Study GroupStudy design
Economic modeling of data from a multicenter, prospective registry.Objective
The aim of this study was to analyze the cost utility of recombinant human bone morphogenetic protein-2 (BMP) in adult spinal deformity (ASD) surgery.Summary of background data
ASD surgery is expensive and presents risk of major complications. BMP is frequently used off-label to reduce the risk of pseudarthrosis.Methods
Of 522 ASD patients with fusion of five or more spinal levels, 367 (70%) had at least 2-year follow-up. Total direct cost was calculated by adding direct costs of the index surgery and any subsequent reoperations or readmissions. Cumulative quality-adjusted life years (QALYs) gained were calculated from the change in preoperative to final follow-up SF-6D health utility score. A decision-analysis model comparing BMP versus no-BMP was developed with pseudarthrosis as the primary outcome. Costs and benefits were discounted at 3%. Probabilistic sensitivity analysis was performed using mixed first-order and second-order Monte Carlo simulations. One-way sensitivity analyses were performed by varying cost, probability, and QALY estimates (Alpha = 0.05).Results
BMP was used in the index surgery for 267 patients (73%). The mean (±standard deviation) direct cost of BMP for the index surgery was $14,000 ± $6400. Forty patients (11%) underwent revision surgery for symptomatic pseudarthrosis (BMP group, 8.6%; no-BMP group, 17%; P = 0.022). The mean 2-year direct cost was significantly higher for patients with pseudarthrosis ($138,000 ± $17,000) than for patients without pseudarthrosis ($61,000 ± $25,000) (P < 0.001). Simulation analysis revealed that BMP was associated with positive incremental utility in 67% of patients and considered favorable at a willingness-to-pay threshold of $150,000/QALY in >52% of patients.Conclusion
BMP use was associated with reduction in revisions for symptomatic pseudarthrosis in ASD surgery. Cost-utility analysis suggests that BMP use may be favored in ASD surgery; however, this determination requires further research.Level of evidence
2.Item Open Access Does recombinant human bone morphogenetic protein-2 use in adult spinal deformity increase complications and are complications associated with location of rhBMP-2 use? A prospective, multicenter study of 279 consecutive patients.(Spine, 2014-02) Bess, Shay; Line, Breton G; Lafage, Virginie; Schwab, Frank; Shaffrey, Christopher I; Hart, Robert A; Boachie-Adjei, Oheneba; Akbarnia, Behrooz A; Ames, Christopher P; Burton, Douglas C; Deverin, Vedat; Fu, Kai-Ming G; Gupta, Munish; Hostin, Richard; Kebaish, Khaled; Klineberg, Eric; Mundis, Gregory; O'Brien, Michael; Shelokov, Alexis; Smith, Justin S; International Spine Study Group ISSGStudy design
Multicenter, prospective analysis of consecutive patients with adult spinal deformity (ASD).Objective
Evaluate complications associated with recombinant human bone morphogenetic protein-2 (rhBMP-2) use in ASD.Summary of background data
Off-label rhBMP-2 use is common; however, underreporting of rhBMP-2 associated complications has been recently scrutinized.Methods
Patients with ASD consecutively enrolled into a prospective, multicenter database were evaluated for type and timing of acute perioperative complications.Inclusion criteria
age 18 years and older, ASD, spinal arthrodesis of more than 4 levels, and 3 or more months of follow-up. Patients were divided into those receiving rhBMP-2 (BMP) or no rhBMP-2 (NOBMP). BMP divided into location of use: posterior (PBMP), interbody (IBMP), and interbody + posterior spine (I + PBMP). Correlations between acute perioperative complications and rhBMP-2 use including total dose, dose/level, and location of use were evaluated.Results
A total of 279 patients (mean age: 57 yr; mean spinal levels fused: 12.0; and mean follow-up: 28.8 mo) met inclusion criteria. BMP (n = 172; average posterior dose = 2.5 mg/level, average interbody dose = 5 mg/level) had similar age, smoking history, previous spine surgery, total spinal levels fused, estimated blood loss, and duration of hospital stay as NOBMP (n = 107; P > 0.05). BMP had greater Charlson Comorbidity Index (1.9 vs. 1.2), greater scoliosis (43° vs. 38°), longer operative time (488.2 vs. 414.6 min), more osteotomies per patient (4.0 vs. 1.6), and greater percentage of anteroposterior fusion (APSF; 20.9% vs. 8.4%) than NOBMP, respectively (P < 0.05). BMP had more total complications per patient (1.4 vs. 0.6) and more minor complications per patient (0.9 vs. 0.2) than NOBMP, respectively (P < 0.05). NOBMP had more complications requiring surgery per patient than BMP (0.3 vs. 0.2; P < 0.05). Major, neurological, wound, and infectious complications were similar for NOBMP, BMP, PBMP, IBMP, and I + PBMP (P > 0.05). Multivariate analysis demonstrated small to nonexistent correlations between rhBMP-2 use and complications.Conclusion
RhBMP-2 use and location of rhBMP-2 use in ASD surgery, at reported doses, do not increase acute major, neurological, or wound complications. Research is needed for higher rhBMP-2 dosing and long-term follow-up.Level of evidence
2.Item Open Access Editorial. Anterior cervical fusion and rhBMP-2: a prospective study is needed to assess optimal dosing and delivery.(Neurosurgical focus, 2021-06) Buell, Thomas J; Shaffrey, Christopher IOBJECTIVE The use of recombinant human bone morphogenetic protein 2 (rhBMP-2) in routine anterior cervical fusion (ACF) is controversial. Early reports described high complication rates. A variety of dosing regimens ranging from 0.6 to 2.1 mg per level fused have been reported. The authors hypothesized that the high amounts of rhBMP-2 used in these studies led to the high complication rates observed; therefore, they set out to evaluate the safety and efficacy of low-dose rhBMP-2 for use in ACFs. METHODS Patient inclusion criteria were 1) age 18 to 70 years; 2) initial stand-alone ACF construct; 3) fusion augmentation with rhBMP-2; and 4) at least 1 year of radiographic follow-up. A successful fusion was defined by either 1) lateral flexion-extension radiographs with less than 1 mm of movement across the fused spinous processes, or 2) bone bridging at least half of the fusion area originally achieved by surgery on fine-cut CT. Patient demographics, perioperative data, and postoperative complications were recorded. RESULTS A total of 198 patients met the inclusion criteria and were included for analysis. Sixty-two patients (31%) were smokers. The median number of levels fused was 2 (IQR 1.25). The mean dose of rhBMP-2 was 0.50 ± 0.09 mg per level. Twenty-two (11%) patients experienced dysphagia. Eleven (6%) patients experienced cervical swelling. Two (1%) patients returned to the operating room (OR) for postoperative hematoma. One (0.5%) patient returned to the OR for seroma. Two (1%) patients experienced pseudarthrosis requiring a posterior fusion. Three (2%) patients experienced a new postoperative neurological deficit that had recovered by last the follow-up. Overall, 190 (96%) patients experienced solid arthrodesis over an average of 15 months of follow-up. There was no difference in fusion rates between patients who were either smokers or nonsmokers (p = 0.7073). CONCLUSIONS The use of low-dose rhBMP-2 safely and effectively augmented anterior cervical arthrodesis. The low-dose protocol assessed in this study appeared to significantly reduce complications associated with rhBMP-2 use in ACF compared with the literature. The authors have determined that using low-dose rhBMP-2 in patients who are smokers, those with multilevel ACFs, or others at high risk of developing pseudarthrosis is recommended.Item Open Access Editorial: Recombinant human bone morphogenetic protein-2.(Journal of neurosurgery. Spine, 2013-02) Shaffrey, Christopher I; Smith, Justin SItem Open Access Long-Segment Fusion for Adult Spinal Deformity Correction Using Low-Dose Recombinant Human Bone Morphogenetic Protein-2: A Retrospective Review of Fusion Rates.(Neurosurgery, 2016-08) Schmitt, Paul J; Kelleher, John P; Ailon, Tamir; Heller, Joshua E; Kasliwal, Manish K; Shaffrey, Christopher I; Smith, Justin SBackground
Although use of very high-dose recombinant human bone morphogenetic protein-2 (rhBMP-2) has been reported to markedly improve fusion rates in adult spinal deformity (ASD) surgery, most centers use much lower doses due to cost constraints. How effective these lower doses are for fusion enhancement remains unclear.Objective
To assess fusion rates using relatively low-dose rhBMP-2 for ASD surgery.Methods
This was a retrospective review of consecutive ASD patients that underwent thoracic to sacral fusion. Patients that achieved 2-year follow-up were analyzed. Impact of patient and surgical factors on fusion rate was assessed, and fusion rates were compared with historical cohorts.Results
Of 219 patients, 172 (78.5%) achieved 2-year follow-up and were analyzed. Using an average rhBMP-2 dose of 3.1 mg/level (average total dose = 35.9 mg/case), the 2-year fusion rate was 73.8%. Cancellous allograft, local autograft, and very limited iliac crest bone graft (<20 mL, obtained during iliac bolt placement) were also used. On multivariate analysis, female sex was associated with a higher fusion rate, whereas age, comorbidity score, deformity type, and 3-column osteotomy were not. There were no complications directly attributable to rhBMP-2.Conclusion
Fusion rates for ASD using low-dose rhBMP-2 were comparable to those reported for iliac crest bone graft but lower than for high-dose rhBMP-2. Importantly, there were substantial differences between patients in the present series and those in the historical comparison groups that could not be fully adjusted for based on available data. Prospective evaluation of rhBMP-2 dosing for ASD surgery is warranted to define the most appropriate dose that balances benefits, risks, and costs.Abbreviations
ASD, adult spinal deformityICBG, iliac crest bone graftOR, odds ratiorhBMP-2, recombinant human bone morphogenetic protein-2RR, risk ratioTCO, 3-column osteotomy.Item Open Access Predictors of Revision Surgical Procedure Excluding Wound Complications in Adult Spinal Deformity and Impact on Patient-Reported Outcomes and Satisfaction: A Two-Year Follow-up.(The Journal of bone and joint surgery. American volume, 2016-04) Passias, Peter G; Soroceanu, Alexandra; Yang, Sun; Schwab, Frank; Ames, Christopher; Boniello, Anthony; Smith, Justin; Shaffrey, Christopher; Boachie-Adjei, Oheneba; Mundis, Gregory; Burton, Douglas; Klineberg, Eric; Hart, Robert; Hamilton, D Kojo; Sciubba, Daniel M; Bess, Shay; Lafage, VirginieBackground
The surgical procedure to treat adult spinal deformity is challenging, with high rates of complications, including revision procedures performed to repair instrumentation failure or unplanned surgical complications. This study quantifies the incidence of, identifies predictors for, and determines health-related quality-of-life changes associated with revision procedures to treat adult spinal deformity.Methods
We analyzed a multicenter database of patients who underwent a surgical procedure for adult spinal deformity, which was defined as having an age of eighteen years or older and scoliosis of ≥20°, sagittal vertical axis of ≥5 cm, pelvic tilt of ≥25°, and/or thoracic kyphosis of >60°. We focused on demographic, radiographic, health-related quality-of-life, and operative data at the two-year follow-up. Patients with primary infections were excluded. Predictive and confounding variables for revisions were identified using univariate analysis and multivariate logistic regression modeling.Results
Two hundred and forty-three patients were included in this study; of these patients, forty (16.5%) underwent a revision surgical procedure (15% of these at six weeks, 38% between six weeks and one year, and 48% between one and two years). Screw or cage-related implant complications were the most common indications for revision, followed by proximal junctional kyphosis and rod failure. Positive predictors for a revision surgical procedure included total body mass, with an odds ratio of 1.33 (95% confidence interval, 1.04 to 1.70) per 10-kg increase, and preoperative sagittal vertical axis, with an odds ratio of 1.15 (95% confidence interval, 1.04 to 1.28) per 2-cm increase. Factors associated with lower risk of revision included use of bone morphogenetic protein-2 (BMP-2) (odds ratio, 0.16 [95% confidence interval, 0.05 to 0.47]) and greater diameter rods (odds ratio, 0.51 [95% confidence interval, 0.29 to 0.89]). Body mass index, although initially considered a potential predictor for a revision surgical procedure, was not significantly different between primary and revision cohorts on univariate analysis and was therefore not input into the multivariate model. All patients improved in two-year health-related quality-of-life scores; revision subjects had lower overall improvement (Scoliosis Research Society [SRS] score; p = 0.016) from baseline. Revision status did not predict two-year patient satisfaction (p = 0.726), as measured by the SRS Satisfaction domain (SRS-22r).Conclusions
Patients with greater preoperative sagittal vertical axis and high total body mass are at a higher risk for a revision surgical procedure following procedures to treat adult spinal deformity. Larger diameter rods and BMP-2 were associated with decreased revision odds. Revisions did not impact patient satisfaction at two years.Level of evidence
Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.Item Open Access Safety, efficacy, and dosing of recombinant human bone morphogenetic protein-2 for posterior cervical and cervicothoracic instrumented fusion with a minimum 2-year follow-up.(Neurosurgery, 2011-07) Hamilton, D Kojo; Smith, Justin S; Reames, Davis L; Williams, Brian J; Chernavvsky, Daniel R; Shaffrey, Christopher IBackground
Considerable attention has focused on concerns of increased complications with recombinant human bone morphogenetic protein-2 (rhBMP-2) use for anterior cervical fusion, but few reports have assessed its use for posterior cervical fusions.Objective
To assess the safety, efficacy, and dosing of rhBMP-2 as an adjunct for instrumented posterior cervical arthrodesis.Methods
All patients treated by the senior author with posterior cervical or cervicothoracic instrumented fusion using rhBMP-2 from 2003 to 2008 with a minimum of 2 years of follow-up were included. Diagnosis, levels fused, rhBMP-2 dose, complications, and fusion were assessed.Results
Fifty-three patients with a mean age of 55.7 years (range, 2-89 years) and an average follow-up of 40 months (range, 25-80 months) met inclusion criteria. Surgical indications included basilar invagination (n = 6), fracture (n = 6), atlantoaxial instability (n = 16), kyphosis/kyphoscoliosis (n = 22), osteomyelitis (n = 1), spondylolisthesis (n = 1), and cyst (n = 1). Fifteen patients had confirmed rheumatoid disease. The average rhBMP-2 dose was 1.8 mg per level, with a total of 282 levels treated (average, 5.3 levels; SD, 2.8 levels). Among 53 patients, only 2 complications (3.8%) were identified: a superficial wound infection and an adjacent-level degeneration. No cases of dysphagia or neck swelling requiring treatment were identified. At the last follow-up, all patients had achieved fusion.Conclusion
Despite many of the patients in the present series having complex pathology and/or rheumatoid arthritis, a 100% fusion rate was achieved. Collectively, these data suggest that use of rhBMP-2 as an adjunct for posterior cervical fusion is safe and effective at an average dose of 1.8 mg per level.Item Open Access The use of allograft and recombinant human bone morphogenetic protein for instrumented atlantoaxial fusions.(World neurosurgery, 2014-12) Hood, Brian; Hamilton, D Kojo; Smith, Justin S; Dididze, Marine; Shaffrey, Christopher; Levi, Allan DBackground
Iliac crest autograft is the historic gold standard for bone grafting, but is associated with a significant patient morbidity. Fusion rates of C1-C2 up to 88.9% using allograft and 96.7% using autologous iliac crest bone graft can be achieved when combined with rigid screw fixation. We sought to determine our fusion rate when combining allograft with recombinant human bone morphogenetic protein-2 (rh-BMP2) and rigid screw fixation.Methods
We reviewed our experience using allograft, bone morphogenetic protein (rh-BMP2) and screw fixation of C1-C2 in 52 patients and examined indications, surgical technique, fusion rates, and complications. In 28 patients, corticocancellous allograft pieces were laid along decorticated bone after a C2 neurectomy was performed. In 24 patients, unicortical iliac crest allograft was precision-cut to fit between the C1 lamina and C2 spinous processes.Results
Fifty-two C1-C2 fusions were performed with allograft, rh-BMP2, and rigid screw fixation. There were 25 female and 27 male patients ranging in age from 6 to 92 years (mean, 65.8 years). Operative indications included trauma (56%), degenerative disease (21%), rheumatoid arthritis (15%), congenital anomalies (6%), and synovial cyst (2%). The mean follow-up was 23.9 ± 2.1 months (range, 2-55 months). The mean dose of rh-BMP2 used for all patients was 4.5 mg (range, 2.2-12 mg). In patients who achieved sufficient follow-up, 100% achieved solid fusion: 45/50 Lenke A, 5/50 Lenke B. There were no known complications attributable to the use of rh-BMP2.Conclusions
The use of small doses of rh-BMP2 added to allograft in addition to rigid screw fixation is a safe and highly effective means of promoting a solid fusion of the atlantoaxial complex and spares the patient the morbidity of iliac crest harvest.Item Open Access Use of rhBMP-2 for adult spinal deformity surgery: patterns of usage and changes over the past decade.(Neurosurgical focus, 2021-06) Bannwarth, Mathieu; Smith, Justin S; Bess, Shay; Klineberg, Eric O; Ames, Christopher P; Mundis, Gregory M; Kim, Han Jo; Lafage, Renaud; Gupta, Munish C; Burton, Douglas C; Shaffrey, Christopher I; Schwab, Frank J; Lafage, Virginie; International Spine Study Group (ISSG)Objective
Recombinant human bone morphogenetic protein-2 (rhBMP-2) has been shown to increase fusion rates; however, cost, limited FDA approval, and possible complications impact its use. Decisions regarding rhBMP-2 use and changes over time have not been well defined. In this study, the authors aimed to assess changes in rhBMP-2 use for adult spinal deformity (ASD) surgery over the past decade.Methods
A retrospective review of the International Spine Study Group prospective multicenter database was performed to identify ASD patients treated surgically from 2008 to 2018. For assessment of rhBMP-2 use over time, 3 periods were created: 2008-2011, 2012-2015, and 2016-2018.Results
Of the patients identified, 1180 met inclusion criteria, with a mean age 60 years and 30% of patients requiring revision surgery; rhBMP-2 was used in 73.9% of patients overall. The mean rhBMP-2 dose per patient was 23.6 mg. Patients receiving rhBMP-2 were older (61 vs 58 years, p < 0.001) and had more comorbidities (Charlson Comorbidity Index 1.9 vs 1.4, p < 0.001), a higher rate of the Scoliosis Research Society-Schwab pelvic tilt modifier (> 0; 68% vs 62%, p = 0.026), a greater deformity correction (change in pelvic incidence minus lumbar lordosis 15° vs 12°, p = 0.01), and more levels fused (8.9 vs 7.9, p = 0.003). Over the 3 time periods, the overall rate of rhBMP-2 use increased and then stabilized (62.5% vs 79% vs 77%). Stratified analysis showed that after an overall increase in rhBMP-2 use, only patients who were younger than 50 years, those who were smokers, those who received a three-column osteotomy (3CO), and patients who underwent revision sustained an increased rate of rhBMP-2 use between the later two periods. No similar increases were noted for older patients, nonsmokers, primary surgery patients, and patients without a 3CO. The total rhBMP-2 dose decreased over time (26.6 mg vs 24.8 mg vs 20.7 mg, p < 0.001). After matching patients by preoperative alignment, 215 patients were included, and a significantly lower rate of complications leading to revision surgery was observed within the 2012-2015 period compared with the 2008-2011 (21.4% vs 13.0%, p = 0.029) period, while rhBMP-2 was increasingly used (80.5% vs 66.0%, p = 0.001). There was a trend toward a lower rate of pseudarthrosis for patients in the 2012-2015 period, but this difference did not reach statistical significance (7% vs 4.2%, p = 0.283).Conclusions
The authors found that rhBMP-2 was used in the majority of ASD patients and was more commonly used in those with greater deformity correction. Additionally, over the last 10 years, rhBMP-2 was increasingly used for ASD patients, but the dose has decreased.