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1.
Nefrología (Madrid) ; 40(5): 506-513, sept.-oct. 2020. tab, graf
Artigo em Inglês | IBECS | ID: ibc-199031

RESUMO

INTRODUCTION: Sclerostin is an anti-anabolic protein synthesized by osteocytes that may cause osteoporosis by inhibiting bone formation. The aim of our study was to investigate the correlation between sclerostin and bone mineral density (BMD) reduction in renal transplant recipients (RTRs) with more than 1 year after transplantation. MATERIAL AND METHODS: This cross-sectional study was conducted on 80 patients (38 (47.5%) male/42 (52.5%) female) RTRs with a mean age of 44.68±10.39 years. Patients were compared with an age and sex-matched control group of 40 healthy individuals. BMD was measured by dual-energy X-ray absorptiometry. The levels of sclerostin were determined using enzyme-linked immunosorbent assay. RESULTS: The mean sclerostin was 3.77±0.3pg/mL in patients and 3.81±0.21pg/mL in healthy individuals. The mean T score of femoral trochanter (FT) (FT-T), femoral neck (FN) (FN-T), lumbar vertebrae (L1-4) (L1-4-T) were −0.81±0.86, −1.08±1.09 and −0.8±1.2, respectively. The mean Z score of FT (FT-Z), FN (FN-Z), L1-4 (L1-4-Z) were −0.6±0.73, −0.32±0.9 and −0.54±1.13, respectively. FT-Z and L1-4-Z were lower in patients than healthy subjects (p = 0.009, p = 0.021 respectively). Serum creatinine (p < 0.001), intact parathyroid hormone (p < 0.001) were higher and phosphate (p < 0.001), was lower in patients than healthy subjects. Patients with a log10 sclerostin of >3.84pg/mL had higher FT-T (p = 0.040), FT-Z, FN-T (p = 0.018), FN-Z (p = 0.006) than those with a log10 sclerostin of ≤3.84pg/mL. There was a significant correlation between log10 sclerostin and FN-T (r=−0.296, p = 0.009) and FN-Z (r=−0.269, p = 0.019). In linear regression analysis, high sclerostin was found to be correlated with male gender, lower FN-T and lower FN-Z independently of other risk factors. CONCLUSION: The levels of sclerostin can predict reduction of proximal femur BMD and development of mineral and bone disorder in RTRs. There was no difference in sclerostin levels between RTRs and healthy individuals


INTRODUCCIÓN: La esclerostina es una proteína con efecto antianabólico sintetizada por los osteocitos que puede causar osteoporosis al inhibir la formación de hueso. El objetivo de nuestro estudio fue investigar la correlación entre la esclerostina y la reducción de la densidad mineral ósea (DMO) en receptores de trasplante renal (RTR) más de un año después del trasplante. MATERIALES Y MÉTODOS: Este estudio transversal se realizó en 80 pacientes (38 [47,5%] varones/42 [52,5%] mujeres) RTR con una edad media de 44,68±10,39 años. Se comparó a los pacientes con un grupo de comparación emparejado por edad y sexo de 40 individuos sanos. La DMO se midió mediante absorciometría de rayos X de doble energía. Los niveles de esclerostina se determinaron utilizando un enzimoinmunoanálisis de adsorción. RESULTADOS: El nivel medio de esclerostina fue de 3,77±0,3pg/ml en pacientes y 3,81±0,21pg/ml en individuos sanos. La puntuación T media del trocánter femoral (TF) (T-TF), del cuello femoral (CF) (T-CF), las vértebras lumbares (L1-4) (T-L1-4) fue de −0,81±0,86, −1,08±1,09 y −0,8±1,2, respectivamente. La puntuación Z media del TF (Z-TF), CF (Z-CF), L1-4 (Z-L1-4) fue de -0,6±0,73, −0,32±0,9 y −0,54±1,13, respectivamente. Las puntuaciones Z-TF y Z-L1-4 fueron inferiores en los pacientes que en los sujetos sanos (p = 0,009 y p = 0,021, respectivamente). Los niveles de creatinina sérica (p < 0,001) y hormona paratiroidea intacta (p < 0,001) fueron superiores en los pacientes que en los sujetos sanos, y los niveles de fosfato (p < 0,001) fueron inferiores. Los pacientes con un log10 esclerostina >3,84pg/ml tuvieron puntuaciones T-TF (p = 0,040), Z-TF, T-CF (p = 0,018), Z-CF (p = 0,006) superiores a las de los pacientes con un log10 esclerostina ≤3,84pg/ml. Se observó una correlación significativa entre log10 esclerostina y T-CF (r=−0,296, p = 0,009) y Z-CF (r=−0,269, p = 0,019). En el análisis de regresión lineal, se observó que los niveles elevados de esclerostina estaban correlacionados con el sexo masculino, una puntuación T-CF inferior y una puntuación Z-CF inferior independientemente de otros factores de riesgo. CONCLUSIÓN: Los niveles de esclerostina pueden predecir la reducción de la DMO del fémur proximal y el desarrollo de un trastorno mineral y óseo en RTR. No se observaron diferencias en los niveles de esclerostina entre los RTR y los individuos sanos


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Densidade Óssea , Transplante de Rim , Peptídeos e Proteínas de Sinalização Intercelular , Insuficiência Renal Crônica , Osso e Ossos/metabolismo , Proteínas Morfogenéticas Ósseas/efeitos adversos , Proteínas Morfogenéticas Ósseas/antagonistas & inibidores , Biomarcadores/sangue , Estudos Transversais , Modelos Lineares , Absorciometria de Fóton , Imunossupressores/uso terapêutico , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Ensaio de Imunoadsorção Enzimática/métodos , Proteínas Morfogenéticas Ósseas/administração & dosagem
2.
Spine J ; 19(10): 1640-1647, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31108234

RESUMO

BACKGROUND CONTEXT: Large observational studies on potential oncogenic effects of recombinant human bone morphogenetic protein (rhBMP) in spine fusion surgery are limited by relatively short follow-up times. PURPOSE: To study the possible association between rhBMP and cancer risk in a long-term follow-up study. STUDY DESIGN: A retrospective cohort study using a combination of the Washington State Comprehensive Hospital Abstract Reporting System, the Washington State Cancer Registry, State of Washington death certificates, and the Washington State Department of Licensing. PATIENT SAMPLE: Participants were adults age ≥21 years who underwent spine fusion surgery enhanced by rhBMP for degenerative spine disease between January 1, 2002 and December 31, 2010. A comparison group matching each patient receiving rhBMP with three patients not receiving rhBMP was created using the indicators of age, sex, and year of treatment. We excluded patients receiving spine fusion for vertebral fractures or infection, and those with a diagnosis of cancer before or at the index procedure. OUTCOME MEASURES: The primary outcome was the first diagnosis of any cancer as identified in the records of the state cancer registry or death certificate through the end of 2015. METHODS: We compared cancer risk between those receiving spine fusion with and without rhBMP using survival analysis. We calculated incidence rates (hazards) by computing the ratio of the number of events and total time at risk. Unadjusted hazard ratios (HR) and adjusted HR (aHR) and their respective 95% confidence intervals (CI) were calculated assuming a Cox proportional hazard regression model. We adjusted the model to include the site of surgery (lumbar vs. cervical) as a covariate as this differed in frequency between the two treatment groups. To assess whether rhBMP adversely affects the progression of cancer, we compared mortality between rhBMP users and nonusers in those who developed cancer. Research support toward this study was received from Medtronic Sofamor Danek USA. The investigators alone, and not Medtronic, were solely responsible for the design, conduct, analysis, and reporting of this study. RESULTS: We included 16,914 patients who had spine fusion, of whom 4,246 received rhBMP. During the study period, 1,342 patients were diagnosed with some form of cancer. The incidence rate was similar between the two groups: 11.2 per 1,000 person years in the rhBMP group and 10.4 per 1,000 person years in the non-rhBMP group, with an aHR of 0.96; 95% CI, 0.85 to 1.10. Similarly, rhBMP use was not associated with an increased risk of commonly occurring individual cancer types, nor with cancer specific mortality after a cancer diagnosis, aHR, 0.92; 95% CI, 0.69 to 1.22. CONCLUSIONS: Long-term follow-up confirms previous findings that rhBMP application treated with elective spinal fusion did not result in an increased cancer risk in a large population of US adults.


Assuntos
Proteínas Morfogenéticas Ósseas/efeitos adversos , Neoplasias/epidemiologia , Complicações Pós-Operatórias/epidemiologia , Fraturas da Coluna Vertebral/cirurgia , Fusão Vertebral/métodos , Adulto , Feminino , Humanos , Região Lombossacral/cirurgia , Masculino , Pessoa de Meia-Idade , Neoplasias/etiologia , Complicações Pós-Operatórias/etiologia , Proteínas Recombinantes/efeitos adversos , Fusão Vertebral/efeitos adversos
3.
Nephrol Dial Transplant ; 34(3): 408-414, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29846712

RESUMO

Canonical Wnt signalling activity is a major player in physiological and adaptive bone metabolism. Wnt signalling is regulated by soluble inhibitors, with sclerostin being the most widely studied. Sclerostin's main origin is the osteocyte and its major function is blockade of osteoblast differentiation and function. Therefore, sclerostin is a potent inhibitor of bone formation and mineralization. Consequently, blocking sclerostin via human monoclonal antibodies (such as romosozumab) represents a promising perspective for the treatment of (postmenopausal) osteoporosis. However, sclerostin's physiology and the effects of sclerostin monoclonal antibody treatment are not limited to the skeleton. Specifically, the potential roles of sclerostin in chronic kidney disease (CKD) and associated pathologies covered by the term chronic kidney disease and mineral bone disorder (CKD-MBD), which also includes accelerated cardiovascular calcification, warrant specific attention. CKD-MBD is a complex disease condition in which sclerostin antibodies may interfere at different levels and influence the multiform interplay of hyperparathyroidism, renal osteodystrophy and vascular calcification, but the clinical sequelae remain obscure. The present review summarizes the potential effects of sclerostin blockade in CKD-MBD. We will address and summarize the urgent research targets that are being identified and that need to be addressed before a valid risk-benefit ratio can be established in the clinical setting of CKD.


Assuntos
Doenças Ósseas/tratamento farmacológico , Proteínas Morfogenéticas Ósseas/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Distúrbio Mineral e Ósseo na Doença Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/tratamento farmacológico , Calcificação Vascular/induzido quimicamente , Proteínas Adaptadoras de Transdução de Sinal , Marcadores Genéticos , Humanos , Prognóstico
4.
World Neurosurg ; 111: 55-59, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29229348

RESUMO

BACKGROUND: Bone morphogenetic protein (BMP) graft showed promising outcome during early phases of its use. However, unreported adverse events and off-label use shattered its safe profile and raised concerns regarding its indication. In 2008 the U.S. Food and Drug Administration prohibited its use in anterior cervical spine procedures due to the possibility of edema, hematoma, and need to intubate. At the molecular level, BMPs act as multifactorial growth factors playing a role in cartilage, heart, and bone formation. However, its unfavorable effect on bone overgrowth or heterotopic ossification post spine surgeries has been described. Reported cases in the literature were limited to epidural bone formation. CASE DESCRIPTION: We present a rare and interesting case of a 59-year-old female, in whom BMP caused intradural bone growth several years after an anterior lumbar interbody fusion surgery. CONCLUSION: Caution must be exercised while using BMPs because of inadvertent complications.


Assuntos
Proteínas Morfogenéticas Ósseas/efeitos adversos , Proteínas Morfogenéticas Ósseas/uso terapêutico , Vértebras Lombares/cirurgia , Fusão Vertebral/métodos , Desenvolvimento Ósseo , Dura-Máter/diagnóstico por imagem , Dura-Máter/patologia , Feminino , Humanos , Vértebras Lombares/diagnóstico por imagem , Pessoa de Meia-Idade , Debilidade Muscular/etiologia , Uso Off-Label , Tomografia Computadorizada por Raios X , Resultado do Tratamento
5.
Neurosurg Clin N Am ; 28(3): 331-334, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28600007

RESUMO

Bone morphogenic protein (BMP) provides excellent enhancement of fusion in many spinal surgeries. BMP should be a cautionary tale about the use of industry-sponsored research, perceived conflicts of interest, and holding the field of spinal surgery to the highest academic scrutiny and ethical standards. In the case of BMP, not having a transparent base of literature as it was approved led to delays in allowing this superior technology to help patients.


Assuntos
Proteínas Morfogenéticas Ósseas/efeitos adversos , Fusão Vertebral/métodos , Proteínas Morfogenéticas Ósseas/uso terapêutico , Conflito de Interesses , Aprovação de Drogas , Indústria Farmacêutica/ética , Humanos , Procedimentos Neurocirúrgicos , Apoio à Pesquisa como Assunto
6.
Int Orthop ; 41(6): 1073-1083, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28424852

RESUMO

PURPOSE: This paper documents the existing evidence on bone morphogenetic proteins (BMPs) use for the treatment of bone fractures, non-union, and osteonecrosis, through a review of the clinical literature, underlying potential and limitations in terms of cost effectiveness and risk of complications. METHODS: A systematic review was performed on the PubMed database using the following string: (bone morphogenetic proteins OR BMPs) and (bone repair OR bone regeneration) including papers from 2000 to 2016. The search focused on clinical trials dealing with BMPs application to favor bone regeneration in bone fractures, non-union, and osteonecrosis, in English language, with level of evidence I, II, III, and IV. Relevant data (type of study, number of patients, BMPs delivery material, dose, site, follow-up, outcome, and adverse events) were extracted and analyzed. RESULTS: Forty-four articles met the inclusion criteria: 10 randomized controlled trials (RCTs), 7 comparative studies, 18 case series, and 9 case reports. rhBMP-2 was documented mainly for the treatment of fractures, and rhBMP-7 mainly for non-unions and osteonecrosis. Mixed results were found among RCTs and comparative papers: 11 reported positive results for BMPs augmentation, 3 obtained no significant effects, and 2 showed negative results. The only study comparing the two BMPs showed a better outcome with rhBMP-2 for non-union treatment. CONCLUSION: Clinical evidence on BMPs use for the treatment of fractures, non-union, and osteonecrosis is still controversial, with the few available reports being mainly of low quality. While positive findings have been described in many studies, mixed results are still present in the literature in terms of efficacy and adverse events. The difficulties in drawing clear conclusions are also due to the studies heterogeneity, mainly in terms of different BMPs applied, with different concomitant treatments for each bone pathology. Therefore, further research with well-designed studies is needed in order to understand the real potential of this biological approach to favour bone healing.


Assuntos
Proteínas Morfogenéticas Ósseas/uso terapêutico , Regeneração Óssea/efeitos dos fármacos , Fraturas Ósseas/tratamento farmacológico , Fraturas não Consolidadas/tratamento farmacológico , Osteonecrose/tratamento farmacológico , Proteínas Morfogenéticas Ósseas/efeitos adversos , Osso e Ossos/fisiopatologia , Humanos
7.
J Pediatr Orthop ; 37(6): e375-e378, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27603194

RESUMO

BACKGROUND: The use of bone morphogenetic protein (BMP) has been associated with a number of complications in adult patients. However, this association is less established in children. The aim of this study was to evaluate the safety of BMP use in children by determining the complication rates after BMP use at multiple institutions. METHODS: In a retrospective study (2000 to 2013), the medical records of all patients who received BMP at any of the 5 institutions were reviewed. Demographic information, preoperative data, and postoperative follow-up data were collected on those patients who were under the age of 18 at the time of surgery. RESULTS: A total of 312 pediatric patients underwent surgery with BMP application during the study period. The surgical procedures consisted of 228 spinal fusions, 39 pars repairs, 33 nonunion repair, and 12 other various procedures. Overall 21% (65/312) of patients who had BMP utilized had a complication. Fifty-five percent (36/65) of patients with a complication required a revision surgery. The average follow-up was 27 months (range, 3 to 96 mo); 80% of patients had a follow-up period of >12 months. The average age at the time of surgery was 13 years (range, 1 to 17 y). Males and females were almost equally represented in the study: 143 males (46%) and 168 females (54%). Of the patients who received BMP, 9% had minor complications and 13% had major complications. Wound dehiscence without infection was the most common minor complication and occurred in 59% (16/27) of patients with minor complications. Infection and implant failures were the most frequent major complications, occurring in 38% (15/39) and 33% (13/39) of patients with major complications, respectively. Five of 312 (2%) patients had neurological injury, 3 of which were only temporary. CONCLUSIONS: This multicenter study demonstrates a relatively high rate of complications after the use of BMP in children. However, further study is needed to attribute the complications directly to the use of BMP. LEVEL OF EVIDENCE: Level IV.


Assuntos
Proteínas Morfogenéticas Ósseas/efeitos adversos , Procedimentos Ortopédicos/estatística & dados numéricos , Complicações Pós-Operatórias/etiologia , Adolescente , Proteínas Morfogenéticas Ósseas/administração & dosagem , Criança , Feminino , Humanos , Masculino , Uso Off-Label , Período Pós-Operatório , Reoperação/estatística & dados numéricos , Estudos Retrospectivos
8.
Orthopedics ; 40(2): e229-e237, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-27992640

RESUMO

Complications associated with the use of recombinant human bone morphogenetic protein in the lumbar spine include retrograde ejaculation, ectopic bone formation, vertebral osteolysis and subsidence, postoperative radiculitis, and hematoma and seroma. These complications are controversial and remain widely debated. This article discusses the reported complications and possible implications for the practicing spine surgeon. Understanding the complications associated with the use of recombinant human bone morphogenetic protein and the associated controversies allows for informed decision making by both the patient and the surgeon. [Orthopedics. 2017; 40(2):e229-e237.].


Assuntos
Proteínas Morfogenéticas Ósseas/efeitos adversos , Vértebras Lombares/cirurgia , Complicações Pós-Operatórias/induzido quimicamente , Proteínas Recombinantes/efeitos adversos , Fusão Vertebral/efeitos adversos , Proteínas Morfogenéticas Ósseas/uso terapêutico , Hematoma/induzido quimicamente , Humanos , Ossificação Heterotópica/induzido quimicamente , Osteólise/induzido quimicamente , Radiculopatia/etiologia , Proteínas Recombinantes/uso terapêutico , Fusão Vertebral/métodos
9.
J Bone Joint Surg Am ; 98(13): 1064-72, 2016 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-27385679

RESUMO

BACKGROUND: Recombinant bone morphogenetic proteins (BMPs) are growth factors utilized in lumbar arthrodeses. Limited data from randomized trials suggest that BMP may increase cancer risk. We sought to evaluate cancer risk and mortality following the use of BMP in lumbar arthrodesis. METHODS: Within the linked Surveillance, Epidemiology, and End Results (SEER) Program-Medicare cohort, we conducted a case-cohort study of 7,278 individuals who were ≥65 years of age and had undergone a lumbar arthrodesis from 2004 to 2011. Of these patients, 3,627 were individuals in a 5% random subcohort of Medicare enrollees in SEER areas including 191 who developed cancer, and there were 3,651 individuals outside the subcohort who developed cancer. Weighted Cox proportional-hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for cancer on the basis of exposure to BMP. RESULTS: In the SEER-Medicare subcohort, 30.7% of individuals who underwent a lumbar arthrodesis received BMP. BMP was not associated with overall cancer risk in univariate analyses (HR, 0.92 [95% CI, 0.82 to 1.02]) or after adjustment for demographic characteristics, comorbidities, hospital size, history of cancer, and calendar year (adjusted HR, 0.94 [95% CI, 0.84 to 1.05]). Individual cancer types were also not significantly elevated (p > 0.05 for all) in BMP users compared with nonusers. In addition, BMP use was not associated with a new cancer in people who had cancer prior to undergoing lumbar arthrodesis (adjusted HR, 1.04 [95% CI, 0.71 to 1.52]) or with mortality after a cancer diagnosis (adjusted HR, 1.05 [95% CI, 0.93 to 1.19]). CONCLUSIONS: In a large population of elderly U.S. adults undergoing lumbar arthrodesis, BMP use was not associated with cancer risk or mortality. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.


Assuntos
Proteínas Morfogenéticas Ósseas/uso terapêutico , Vértebras Lombares/cirurgia , Neoplasias/etiologia , Fusão Vertebral/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Proteínas Morfogenéticas Ósseas/efeitos adversos , Estudos de Coortes , Bases de Dados Factuais , Feminino , Humanos , Masculino , Medicare , Risco , Medição de Risco , Programa de SEER , Doenças da Coluna Vertebral/cirurgia , Fusão Vertebral/métodos , Estados Unidos
10.
Gac Med Mex ; 152(3): 381-5, 2016.
Artigo em Espanhol | MEDLINE | ID: mdl-27335195

RESUMO

Since the introduction of bone morphogenetic proteins, their use has become an invaluable ally for the treatment of bone defects. These proteins are potent growth factors, related to angiogenic and osteogenic activity. The osteoinductive capacity of recombinant bone morphogenetic protein (rhBMP) in the formation of bone and cartilage has been confirmed in in vitro studies and evaluated in clinical trials. To obtain a therapeutic effect, administration is systemic, by injection over the physiological dose. Among the disadvantages, ectopic bone formation or high morbidity in cases of spinal fusion is observed. In this review, the roles of bone morphogenetic proteins in bone repair and clinical applications are analyzed. These findings represent advances in the study of bone regeneration and application of growth factors for more predictable results.


Assuntos
Doenças Ósseas/terapia , Proteínas Morfogenéticas Ósseas/administração & dosagem , Regeneração Óssea/efeitos dos fármacos , Doenças Ósseas/patologia , Proteínas Morfogenéticas Ósseas/efeitos adversos , Humanos , Injeções , Ossificação Heterotópica/induzido quimicamente , Osteogênese/efeitos dos fármacos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Fusão Vertebral/métodos
12.
World Neurosurg ; 87: 613-8, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26546998

RESUMO

OBJECTIVE: In light of recent reports of potential short- and long-term complications of bone morphogenetic protein (BMP) and increasing "off-label" use among spine surgeons, we wished to analyze online information on BMP and its controversial uses, as patients frequently search the Internet for medical information, even though the quality and accuracy of available information are highly variable. METHODS: Between December 2014 and January 2015, we conducted a Google search to identify the 50 most accessed websites providing BMP information using the search phrase "bone morphogenetic protein." Websites were classified based on authorship. Each website was examined for the provision of appropriate patient inclusion and exclusion criteria, surgical and nonsurgical treatment alternatives, purported benefits, disclosure of common and potential complications, peer-reviewed literature citations, and discussion of off-label use. RESULTS: Two percent of websites were authored by private medical groups, 2% by academic medical groups, 10% by insurance companies, 16% by biomedical industries, 4% by news sources, 0% by lawyers, and 66% by others. Sixty-two percent referenced peer-reviewed literature. Benefits and complications were reported in 44% and 26% of websites, respectively. Surgical and nonsurgical treatment alternatives were mentioned in 16% and 4% of websites, respectively. Discussion of off-label BMP use occurred in 18% of websites. CONCLUSIONS: Our study showed the ineffectiveness of the Internet in reporting quality information on BMP use. We found that websites authored by insurance companies provide an acceptable foundation for patient education. This, however, cannot replace the need for a thorough dialogue between doctor and patient about risks, benefits, and indications.


Assuntos
Proteínas Morfogenéticas Ósseas/uso terapêutico , Internet/estatística & dados numéricos , Educação de Pacientes como Assunto/estatística & dados numéricos , Proteínas Morfogenéticas Ósseas/efeitos adversos , Transplante Ósseo , Humanos , Disseminação de Informação , Uso Off-Label , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Medição de Risco , Ferramenta de Busca , Coluna Vertebral/cirurgia , Inquéritos e Questionários
13.
J Neurosurg Spine ; 24(3): 457-75, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26613283

RESUMO

OBJECT: Bone morphogenetic protein (BMP) is frequently used for spinal arthrodesis procedures in an "off-label" fashion. Whereas complications related to BMP usage are well recognized, the role of dosage is less clear. The objective of this meta-analysis was to assess dose-dependent effectiveness (i.e., bone fusion) and morbidity of BMP used in common spinal arthrodesis procedures. A quantitative exploratory meta-analysis was conducted on studies reporting fusion and complication rates following anterior cervical discectomy and fusion (ACDF), posterior cervical fusion (PCF), anterior lumbar interbody fusion (ALIF), transforaminal lumbar interbody fusion (TLIF), posterior lumbar interbody fusion (PLIF), and posterolateral lumbar fusion (PLF) supplemented with BMP. METHODS: A literature search was performed to identify studies on BMP in spinal fusion procedures reporting fusion and/or complication rates. From the included studies, a database for each spinal fusion procedure, including patient demographic information, dose of BMP per level, and data regarding fusion rate and complication rates, was created. The incidence of fusion and complication rates was calculated and analyzed as a function of BMP dose. The methodological quality of all included studies was assessed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Data were analyzed using a random-effects model. Event rates are shown as percentages, with a 95% CI. RESULTS: Forty-eight articles met the inclusion criteria: ACDF (n = 7), PCF (n = 6), ALIF (n = 9), TLIF/PLIF (n = 17), and PLF (n = 9), resulting in a total of 5890 patients. In ACDF, the lowest BMP concentration analyzed (0.2-0.6 mg/level) resulted in a fusion rate similar to the highest dose (1.1-2.1 mg/level), while permitting complication rates comparable to ACDF performed without BMP. The addition of BMP to multilevel constructs significantly (p < 0.001) increased the fusion rate (98.4% [CI 95.4%-99.4%]) versus the control group fusion rate (85.8% [CI 77.4%-91.4%]). Studies on PCF were of poor quality and suggest that BMP doses of ≤ 2.1 mg/level resulted in similar fusion rates as higher doses. Use of BMP in ALIF increased fusion rates from 79.1% (CI 57.6%-91.3%) in the control cohort to 96.9% (CI 92.3%-98.8%) in the BMP-treated group (p < 0.01). The rate of complications showed a positive correlation with the BMP dose used. Use of BMP in TLIF had only a minimal impact on fusion rates (95.0% [CI 92.8%-96.5%] vs 93.0% [CI 78.1%-98.0%] in control patients). In PLF, use of ≥ 8.5 mg BMP per level led to a significant increase of fusion rate (95.2%; CI 90.1%-97.8%) compared with the control group (75.3%; CI 64.1%-84.0%, p < 0.001). BMP did not alter the rate of complications when used in PLF. CONCLUSIONS: The BMP doses used for various spinal arthrodesis procedures differed greatly between studies. This study provides BMP dosing recommendations for the most common spine procedures.


Assuntos
Artrodese/métodos , Proteínas Morfogenéticas Ósseas/uso terapêutico , Doenças da Coluna Vertebral/cirurgia , Fusão Vertebral/métodos , Proteínas Morfogenéticas Ósseas/efeitos adversos , Relação Dose-Resposta a Droga , Humanos , Uso Off-Label , Complicações Pós-Operatórias
14.
Am J Sports Med ; 43(8): 1994-2004, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26033972

RESUMO

BACKGROUND: Recombinant human bone morphogenetic protein-12 (rhBMP-12) has been shown to induce tendon and ligament formation in rats and to improve tendon healing; however, the safety and feasibility of implanting rhBMP-12/absorbable collagen sponge (ACS) in humans are not known. PURPOSE: To investigate the safety and feasibility of rhBMP-12 on an ACS as an adjuvant therapy in open rotator cuff repair. STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: This study consisted of 20 patients with full-thickness rotator cuff tears. Patients were randomized either to standard of care (SOC) treatment (open rotator cuff repair) or to receive 0.015 mg/mL rhBMP-12/ACS and SOC treatment during their open rotator cuff repair (rhBMP-12/ACS group) at a rate of 1/4 SOC/rhBMP-12/ACS. The feasibility of implanting the product and the safety of the product were evaluated during the 1-year follow-up period. The evaluation involved up to 10 postoperative visits, which included physical examinations, radiographs, computed tomography (CT) scans, magnetic resonance imaging (MRI) scans with an emphasis on heterotopic ossification (HO), pharmacokinetics, immunogenicity, laboratory evaluations, and local and systemic adverse events at specified time points. RESULTS: Small amounts of HO were seen on follow-up CT scans in 10 of 16 patients in the rhBMP-12/ACS group and in 2 of 3 patients in the SOC group. HO did not increase at 26 weeks and was not associated with any adverse events or unsatisfactory clinical outcomes. Pharmacokinetics demonstrated that circulating levels of rhBMP-12 were not detectable after administration. Five of 16 patients showed a postoperative immunogenic response but did not show any correlating adverse events. Complete healing of the rotator cuff was observed in 14 of 16 patients; 2 of 16 imaging results could not be analyzed because of artifacts in the rhBMP-12 group on MRI scans. In the SOC group, 1 of 4 patients showed a retear at 12 weeks after surgery. CONCLUSION: The use of rhBMP-12/ACS has been shown to be feasible and safe in a concentration of 0.015 mg/mL when used in open rotator cuff repair. Higher dose concentrations of rhBMP-12 should be evaluated in the future to evaluate their safety and potential to increase rotator cuff healing after open surgical repair.


Assuntos
Proteínas Morfogenéticas Ósseas/administração & dosagem , Fatores de Diferenciação de Crescimento/administração & dosagem , Lesões do Manguito Rotador , Manguito Rotador/cirurgia , Animais , Proteínas Morfogenéticas Ósseas/efeitos adversos , Proteínas Morfogenéticas Ósseas/farmacocinética , Colágeno , Estudos de Viabilidade , Fatores de Diferenciação de Crescimento/efeitos adversos , Fatores de Diferenciação de Crescimento/farmacocinética , Humanos , Masculino , Ossificação Heterotópica , Período Pós-Operatório , Ratos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/farmacocinética , Manguito Rotador/patologia , Padrão de Cuidado , Tampões de Gaze Cirúrgicos , Cicatrização
15.
J Neurosurg Spine ; 23(1): 86-93, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25860517

RESUMO

The risk of postoperative cancer following the use of recombinant human bone morphogenetic protein (BMP)-2 in spinal fusion is one potential complication that has received significant interest. Until recently, there has been little clinical evidence to support the assertion of potential cancer induction after BMP use in spinal surgery. This report aims to summarize the findings from clinical data available to date from the Yale University Open Data Access (YODA) project as well as more recently published large database studies regarding the association of BMP use in spinal fusion and the risk of postoperative cancer. A detailed review was based on online databases, primary studies, FDA reports, and bibliographies of key articles for studies that assessed the efficacy and safety of BMP in spinal fusion. In an analysis of the YODA project, one meta-analysis detected a statistically significant increase in cancer occurrence at 24 months but not at 48 months, and the other meta-analysis did not detect a significant increase in postoperative cancer occurrence. Analysis of 3 large health care data sets (Medicare, MarketScan, and PearlDiver) revealed that none were able to detect a significant increase in risk of malignant cancers when BMP was used compared with controls. The potential risk of postoperative cancer formation following the use of BMP in spinal fusion must be interpreted on an individual basis for each patient by the surgeon. There is no conclusive evidence that application of the common formulations of BMP during spinal surgery results in the formation of cancer locally or at a distant site.


Assuntos
Proteínas Morfogenéticas Ósseas/efeitos adversos , Neoplasias/induzido quimicamente , Medição de Risco , Fusão Vertebral , Humanos
16.
Spine J ; 15(4): 692-9, 2015 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-25523380

RESUMO

BACKGROUND CONTEXT: Use of bone morphogenetic protein (BMP) as an adjunct to spinal fusion surgery proliferated after Food and Drug Administration (FDA) approval in 2002. Major safety concerns emerged in 2008. PURPOSE: The purpose of this study was to examine whether published concerns about the safety of BMP altered clinical practice. STUDY DESIGN/SETTING: The study design involved the analysis of the National Inpatient Sample from 2002 through 2012. PATIENT SAMPLE: Adults (older than 20 years) undergoing an elective fusion operation for common degenerative diagnoses were identified using codes from the International Classification of Diseases, ninth revision, Clinical Modification. OUTCOME MEASURES: Outcome measures were proportion of cervical and lumbar fusion operations, over time, that involved BMP. METHODS: We aggregated the data into a monthly time series and reported the proportion of cervical and lumbar fusion operations, over time, that involved BMP. Autoregressive Integrated Moving Average, a regression model for time series data, was used to test whether there was a statistically significant change in the overall rate of BMP use after an FDA Public Health Notification in 2008. RESULTS: Use of BMP in spinal fusion procedures increased rapidly until 2008, involving up to 45.2% of lumbar and 13.5% of cervical fusions. Bone morphogenetic protein use significantly decreased after the 2008 FDA Public Health Notification and revelations of financial payments to surgeons involved in the pivotal FDA-approved trials. For lumbar fusion, the average annual increase was 7.9 percentage points per year from 2002 to 2008, followed by an average annual decrease of 11.7 percentage points thereafter (p≤.001). Use of BMP in cervical fusion increased 2.0% per year until the FDA Public Health Notification, followed by a 2.8% per year decrease (p=.035). CONCLUSIONS: Use of BMP in spinal fusion surgery declined subsequent to published safety concerns and revelations of financial conflicts of interest for investigators involved in the pivotal clinical trials.


Assuntos
Proteínas Morfogenéticas Ósseas/uso terapêutico , Vértebras Cervicais/cirurgia , Vértebras Lombares/cirurgia , Doenças da Coluna Vertebral/cirurgia , Fusão Vertebral/métodos , Proteínas Morfogenéticas Ósseas/efeitos adversos , Humanos , Fusão Vertebral/tendências , Resultado do Tratamento , Estados Unidos
17.
Yale J Biol Med ; 87(4): 549-61, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25506287

RESUMO

Bone morphogenetic proteins have been in use in spinal surgery since 2002. These proteins are members of the TGF-beta superfamily and guide mesenchymal stem cells to differentiate into osteoblasts to form bone in targeted tissues. Since the first commercial BMP became available in 2002, a host of research has supported BMPs and they have been rapidly incorporated in spinal surgeries in the United States. However, recent controversy has arisen surrounding the ethical conduct of the research supporting the use of BMPs. Yale University Open Data Access (YODA) recently teamed up with Medtronic to offer a meta-analysis of the effectiveness of BMPs in spinal surgery. This review focuses on the history of BMPs and examines the YODA research to guide spine surgeons in their use of BMP in spinal surgery.


Assuntos
Proteínas Morfogenéticas Ósseas/uso terapêutico , Coluna Vertebral/patologia , Proteínas Morfogenéticas Ósseas/efeitos adversos , Diretrizes para o Planejamento em Saúde , Humanos , Fusão Vertebral , Coluna Vertebral/efeitos dos fármacos
18.
J Neurosurg Pediatr ; 14(6): 635-43, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25303159

RESUMO

OBJECT: Use of recombinant human bone morphogenetic protein-2 has risen steadily since its approval by the FDA for use in anterior lumbar interbody fusion in 2002. The FDA has not approved the use of bone morphogenetic protein (BMP) in children. Age less than 18 years or lack of evidence of epiphyseal closure are considered by the manufacturer to be contraindications to BMP use. In light of this, the authors performed a query of the database of one of the nation's largest health insurance companies to determine the rate of BMP use and complications in pediatric patients undergoing spinal fusion. METHODS: The authors used the PearlDiver Technologies private payer database containing all records from United Health-Care from 2005 to 2011 to query all cases of pediatric spinal fusion with or without BMP use. A review of the literature was also performed to examine the complications associated with BMP use in pediatric spinal fusion. RESULTS: A total of 4658 patients underwent spinal fusion. The majority was female (65.4%), and the vast majority was age 10-19 years (94.98%) and underwent thoracolumbar fusion (93.13%). Bone morphogenetic protein was used in 1752 spinal fusions (37.61%). There was no difference in the rate of BMP use when comparing male and female patients or age 10 years or older versus less than 10 years. Anterior cervical fusions were significantly less likely to use BMP (7.3%). Complications occurred in 9.82% of patients treated with versus 9.88% of patients treated without BMP. The complication rate was nearly identical in male versus female patients and in patients older versus younger than 10 years. Comparison of systemic, wound-related, CNS, and other complications showed no difference between groups treated with and without BMP. The reoperation rate was also nearly identical. CONCLUSIONS: Bone morphogenetic protein is used in a higher than expected percentage of pediatric spinal fusions. The rate of acute complications in these operations does not appear to be different in patients treated with versus those treated without BMP. Caution must be exercised in interpreting these data due to the many limitations of the administrative database as a data source, including the short length of follow-up.


Assuntos
Proteínas Morfogenéticas Ósseas/efeitos adversos , Fusão Vertebral , Adolescente , Proteínas Morfogenéticas Ósseas/administração & dosagem , Criança , Bases de Dados Factuais , Feminino , Humanos , Classificação Internacional de Doenças , Masculino , Período Pós-Operatório , Reoperação , Adulto Jovem
19.
Expert Opin Drug Saf ; 13(11): 1525-34, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25283875

RESUMO

INTRODUCTION: Bone morphogenetic proteins are multi-functional growth factors, which play an important role in embryonic development and cellular functions. Among several molecules in this family, BMP-2 and BMP-7 are currently being used in the clinical setting. Main clinical targets include the treatment of non-union, open fractures and spinal fusion. Their use has not been without complications, one of which might be a carcinogenic effect. AREAS COVERED: The authors offer a comprehensive review of the existing literature on the clinical studies analysing the role of bone morphogenetic proteins (BMPs) on carcinogenesis. The authors analyse the available literature and describe potential signalling pathways that can be affected as per available experimental in vitro and in vivo models. EXPERT OPINION: The available experimental data and clinical evidence are rather inadequate to allow any safe scientific conclusions. Clinical studies provide incomplete evidence to support the hypothesis that BMPs are carcinogenic. The available literature has several limitations including incomplete documentation, unreported data and inhered bias as a large number of trials have been funded by the industry. The need of well-structured studies is essential to address these safety concerns.


Assuntos
Proteínas Morfogenéticas Ósseas/efeitos adversos , Transformação Celular Neoplásica/induzido quimicamente , Neoplasias/induzido quimicamente , Animais , Regeneração Óssea/efeitos dos fármacos , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Consolidação da Fratura/efeitos dos fármacos , Humanos , Neoplasias/diagnóstico , Neoplasias/metabolismo , Segurança do Paciente , Medição de Risco , Fatores de Risco , Transdução de Sinais/efeitos dos fármacos
20.
J Bone Joint Surg Am ; 96(17): 1409-16, 2014 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-25187578

RESUMO

BACKGROUND: Usage of recombinant human bone morphogenetic protein (rhBMP) in anterior cervical discectomy and fusion (ACDF) procedures is controversial. Studies suggest increased rates of dysphagia, hematoma or seroma, and severe airway compromise in anterior cervical spine procedures using rhBMP. The purpose of the present study was to determine and describe national utilization trends and complication rates associated with rhBMP usage in anterior cervical spine procedures. METHODS: The MarketScan database from 2006 to 2010 was retrospectively queried to identify 91,543 patients who underwent ACDF with or without cervical corpectomy. Patient selection and outcomes were ascertained with use of ICD-9-CM (International Classification of Diseases, Ninth Revision, Clinical Modification) and CPT (Current Procedural Terminology) coding. A total of 3197 patients were treated with rhBMP intraoperatively. Mean follow-up was 588 days (interquartile range [IQR], 205 to 886 days) in the non-treated cohort and 591 days (IQR, 203 to 925 days) in the rhBMP-treated cohort. Multivariate logistic regression as well as propensity score analysis were used to evaluate the association of rhBMP usage with postoperative complications. RESULTS: In propensity score-adjusted models, rhBMP usage was associated with an increased risk of any complication (odds ratio [OR] = 1.34, 95% confidence interval [CI] = 1.2 to 1.5) and specific complications such as hematoma or seroma (OR = 1.8, 95% CI = 1.4 to 2.3), dysphagia (OR = 1.3, 95% CI = 1.1 to 1.5), and any pulmonary complication (OR = 1.5, 95% CI = 1.2 to 1.8) within thirty days postoperatively. There were no significant differences in the rates of readmission, in-hospital mortality, referral to pain management, new malignancy, or reoperation between the two cohorts. Usage of rhBMP was associated with a mean increase of $5545 (19%) in total payments to the hospital and primary physician (p < 0.001). CONCLUSIONS: We found an increased overall rate of postoperative complications in patients receiving rhBMP for cervical spinal fusion procedures compared with patients not receiving rhBMP. Hematoma or seroma, pulmonary complications, and dysphagia were also more common in the rhBMP cohort. Usage of rhBMP in a case was associated with $311 greater payments to the surgeon and $4213 greater payments to the hospital. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.


Assuntos
Proteínas Morfogenéticas Ósseas/efeitos adversos , Vértebras Cervicais/efeitos dos fármacos , Vértebras Cervicais/cirurgia , Discotomia/métodos , Fusão Vertebral/métodos , Adulto , Idoso , Proteínas Morfogenéticas Ósseas/uso terapêutico , Vértebras Cervicais/fisiopatologia , Terapia Combinada , Bases de Dados Factuais , Discotomia/efeitos adversos , Feminino , Seguimentos , Humanos , Modelos Logísticos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/fisiopatologia , Curva ROC , Proteínas Recombinantes/uso terapêutico , Doenças da Coluna Vertebral/tratamento farmacológico , Doenças da Coluna Vertebral/cirurgia , Fusão Vertebral/efeitos adversos , Resultado do Tratamento
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