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.

Postoperative Lumbar Fusion Bone Morphogenic Protein-Related Epidural Cyst Formation.

Bone morphogenetic protein is broadly used in spinal surgery to enhance fusion rates. Several complications have been associated with the use of bone morphogenetic protein, including postoperative radiculitis and pronounced bone resorption/osteolysis. Bone morphogenetic protein-related epidural cyst formation may represent another complication that has not been described aside from limited case reports. In this case series, we retrospectively reviewed imaging and clinical findings of 16 patients with epidural cysts on postoperative MR imaging following lumbar fusion. In 8 patients, mass effect on the thecal sac or lumbar nerve roots was noted. Of these, 6 patients developed new postoperative lumbosacral radiculopathy. During the study period, most patients were managed conservatively, and 1 patient required revision surgery with cyst resection. Concurrent imaging findings included reactive endplate edema and vertebral bone resorption/osteolysis. Epidural cysts had characteristic findings on MR imaging in this case series and may represent an important postoperative complication in patients following bone morphogenetic protein-augmented lumbar fusion.

Trends, payments, and costs associated with BMP use in Medicare beneficiaries undergoing spinal fusion.

BACKGROUND CONTEXT: Bone morphogenic protein (BMP) promotes bony fusion but increases costs. Recent trends in BMP use among Medicare patients have not been well-characterized. PURPOSE: To assess utilization trends, complication, payments, and costs associated with BMP use in spinal fusion in a Medicare-insured population. STUDY DESIGN/SETTING: Retrospective cohort study. PATIENT SAMPLE: Total of 316,070 patients who underwent spinal fusion in a 20% sample of Medicare-insured patients, 2006 to 2015. OUTCOME MEASURES: Utilization trends across time and geography, complications, payments, and costs. METHODS: Patients were stratified by fusion type and diagnosis. Multivariable logistic and linear regression were used to adjust for the effect of baseline characteristics on complications and total payments or cost, respectively. RESULTS: BMP was used in 60,249 cases (19.1%). BMP utilization rates decreased from 23.1% in 2006 to 12.0% in 2015, most significantly in anterior cervical (7.5%-3.1%), posterior cervical (17.0%-8.3%), and posterior lumbar fusions (31.5%-15.8%). There are significant state- and region-level geographic differences in BMP utilization. Across all years, states with the highest BMP use were Indiana (28.5%), Colorado (26.6%), and Nevada (25.7%). States with the lowest BMP use were Maine (2.3%), Vermont (8.2%), and Mississippi (10.4%). After multivariate risk adjustment, BMP use was associated with decreased overall complications in thoracic (odds ratios [OR] [95% confidence intervals [CI]): 0.89 [0.81-0.99]) and anterior lumbar fusions (OR [95% CI]: 0.89 [0.84-0.95]), as well as increased reoperation rates in anterior cervical (OR [95% CI]: 1.11 [1.04-1.19]), posterior cervical (OR (95% CI): 1.14 (1.04-1.25)), thoracic (OR (95% CI): 1.32 (1.23-1.41)), and posterior lumbar fusions (OR (95% CI): 1.11 (1.06-1.16)). BMP use was also associated with greater total costs, independent of fusion type, after multivariate risk adjustment (p<.0001). Payments, however, were comparable between groups in anterior and posterior cervical fusion with or without BMP. BMP use was associated with greater total payments in thoracic, anterior lumbar, and posterior lumbar fusions. Notably, the difference in payments was smaller than the associated cost increase in all fusion types. CONCLUSIONS: BMP use has declined across all fusion types over the last decade, after a peak in 2007. While BMP is associated with greater costs, reimbursement does not increase proportionally with BMP cost.

Off-label usage of RhBMP-2 in posterior cervical fusion is not associated with early increased complication rate and has similar clinical outcomes.

BACKGROUND CONTEXT: Arthrodesis is important for the success of posterior cervical fusion (PCF), however, there exists limited data regarding the safety and efficacy of bone morphogenic protein (BMP) in PCF. PURPOSE: The primary objective was to evaluate early postoperative complications associated with BMP in PCF and determine whether BMP leads to adverse early clinical outcomes. A secondary objective was to determine the optimal location for BMP sponge placement, within the facet joint (IF) or elsewhere, and the optimal dosage/level. DESIGN: Retrospective, consecutive case-control study. PATIENT SAMPLE: Seven hundred sixty-five patients who underwent PCF OUTCOME MEASURES: Patient-reported outcomes (PROs), complications, arthrodesis, optimum dose/level of BMP METHODS: Surgical data, including preoperative diagnosis, levels fused, type of bone graft, BMP dose (when used), and fusion technique were recorded. Complications were assessed by reviewing the medical record encompassing the first 6-weeks postoperative. These included medical, neurological, and wound-related complications and reoperation. Neurological complications were defined as any new weakness, radicular pain, or numbness. PROs were collected, including SF36, VAS, EQ-5D, and NDI scores. To determine the optimal dosage and location for BMP placement, a sub-analysis was performed. RESULTS: There were no significant differences between the BMP and no BMP group with regards to wound complications, neurological complications, or reoperation. There were no differences in PROs between BMP and no BMP. Placement of BMP for IF and at a dose of 0.87 mg/level minimized wound-related complications. The BMP group had a higher fusion rate compared to the no BMP group (96% vs. 91%, p=.02) when assessed 1 year post-operatively. CONCLUSION: BMP was not associated with a higher rate of early complications after PCF when the dose was minimized. Complications thought to be associated with BMP, such as compressive seroma, radiculitis, and wound-related complications were not seen at a higher rate. PROs at early follow-up were similar. Placement of BMP for IF and at lower doses than previously reported may minimize complications.

The correlation between sclerostin and bone mineral density in renal transplant recipients / Correlación entre la esclerostina y la densidad mineral ósea en receptores de trasplante renal

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

Complications, Costs, and Quality Outcomes of Patients Undergoing Cervical Deformity Surgery With Intraoperative BMP Use.

STUDY DESIGN: An epidemiological study using national administrative data from the MarketScan database. OBJECTIVE: The aim of this study was to identify the impact of bone morphogenetic protein (BMP) on postoperative outcomes in patients undergoing adult cervical deformity (ACD) surgery. SUMMARY OF BACKGROUND DATA: BMP has been shown to stimulate bone growth and improve fusion rates in spine surgery. However, the impact of BMP on reoperation rates and postoperative complication rate is controversial. METHODS: We queried the MarketScan database to identify patients who underwent ACD surgery from 2007 to 2015. Patients were stratified by BMP use in the index operation. Patients <18 years and those with any history of tumor or trauma were excluded. Baseline demographics and comorbidities, postoperative complication rates, and reoperation rates were analyzed. RESULTS: A total of 13,549 patients underwent primary ACD surgery, of which 1155 (8.5%) had intraoperative BMP use. The overall 90-day complication rate was 27.6% in the non-BMP cohort and 31.1% in the BMP cohort (P < 0.05). Patients in the BMP cohort had longer average length of stay (4.0 days vs. 3.7 days, P < 0.05) but lower revision surgery rates at 90 days (14.5% vs. 28.3%, P < 0.05), 6 months (14.9% vs. 28.6%, P < 0.05), 1 year (15.7% vs. 29.2%, P < 0.05), and 2 years (16.5% vs. 29.9%, P < 0.05) postoperatively. BMP use was associated with higher payments throughout the 2-year follow-up period ($107,975 vs. $97,620, P < 0.05). When controlling for baseline group differences, BMP use independently increased the odds of postoperative complication (odds ratio [OR] 1.22, 95% confidence interval [CI] 1.1-1.4) and reduced the odds of reoperation throughout 2 years of follow-up (OR 0.49, 95% CI 0.4-0.6). CONCLUSION: Intraoperative BMP use has benefits for fusion integrity in ACD surgery but is associated with increased postoperative complication rate. Spine surgeons should weigh these benefits and drawbacks to identify optimal candidates for BMP use in ACD surgery. LEVEL OF EVIDENCE: 3.

Longer follow-up continues to reveal no increased risk of cancer with the use of recombinant human bone morphogenetic protein in spine fusion.

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.

Sclerostin in chronic kidney disease-mineral bone disorder think first before you block it!

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.

Bone Morphogenetic Protein Usage in Anterior Lumbar Interbody Fusion: What Else Can Go Wrong?

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.

Bone Morphogenic Protein Use in Spinal Surgery.

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.

Clinical application of bone morphogenetic proteins for bone healing: a systematic review.

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.

Complications Associated With Bone Morphogenetic Protein in the Lumbar Spine.

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.].

Complication Rates After Bone Morphogenetic Protein (BMP) Use in Orthopaedic Surgery in Children: A Concise Multicenter Retrospective Cohort Study.

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.

Bone Morphogenetic Protein Use and Cancer Risk Among Patients Undergoing Lumbar Arthrodesis: A Case-Cohort Study Using the SEER-Medicare Database.

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.

[Bone morphogenetic proteins (BMP): clinical application for reconstruction of bone defects]. / Proteínas morfogenéticas óseas (BMP): aplicación clínica para reconstrucción de defectos en hueso.

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.

Survey of the Effectiveness of Internet Information on Patient Education for Bone Morphogenetic Protein.

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.

Exploratory meta-analysis on dose-related efficacy and morbidity of bone morphogenetic protein in spinal arthrodesis surgery.

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.

Local rhBMP-12 on an Absorbable Collagen Sponge as an Adjuvant Therapy for Rotator Cuff Repair - A Phase 1, Randomized, Standard of Care Control, Multicenter Study: Safety and Feasibility.

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.

A comprehensive assessment of the risk of bone morphogenetic protein use in spinal fusion surgery and postoperative cancer diagnosis.

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.