Use Of Bone Morphogenetic Protein Research Articles

Transforaminal lumbar interbody fusion subsidence: computed tomography analysis of incidence, associated risk factors, and impact on outcomes.

The aims of this study were to 1) define the incidence of transforaminal lumbar interbody fusion (TLIF) interbody subsidence; 2) determine the relative importance of preoperative and intraoperative patient- and instrumentation-specific risk factors predictive of postoperative subsidence using CT-based assessment; and 3) determine the impact of TLIF subsidence on postoperative complications and fusion rates. All adult patients who underwent one- or two-level TLIF for lumbar degenerative conditions at a multi-institutional academic center between 2017 and 2019 were retrospectively identified. Patients with traumatic injury, infection, malignancy, previous fusion at the index level, combined anterior-posterior procedures, surgery with greater than two TLIF levels, or incomplete follow-up were excluded. Interbody subsidence at the superior and inferior endplates of each TLIF level was directly measured on the endplate-facing surface of both coronal and sagittal CT scans obtained greater than 6 months postoperatively. Patients were grouped based on the maximum subsidence at each operative level classified as mild, moderate, or severe based on previously documented < 2-mm, 2- to 4-mm, and ≥ 4-mm thresholds, respectively. Univariate and regression analyses compared patient demographics, medical comorbidities, preoperative bone quality, surgical factors including interbody cage parameters, and fusion and complication rates across subsidence groups. A total of 67 patients with 85 unique fusion levels met the inclusion and exclusion criteria. Overall, 28% of levels exhibited moderate subsidence and 35% showed severe subsidence after TLIF with no significant difference in the superior and inferior endplate subsidence. Moderate (≥ 2-mm) and severe (≥ 4-mm) subsidence were significantly associated with decreases in cage surface area and Taillard index as well as interbody cages with polyetheretherketone (PEEK) material and sawtooth surface geometry. Severe subsidence was also significantly associated with taller preoperative disc spaces, decreased vertebral Hounsfield units (HU), the absence of bone morphogenetic protein (BMP) use, and smooth cage surfaces. Regression analysis revealed decreases in Taillard index, cage surface area, and HU, and the absence of BMP use predicted subsidence. Severe subsidence was found to be a predictor of pseudarthrosis but was not significantly associated with revision surgery. Patient-level risk factors for TLIF subsidence included decreased HU and increased preoperative disc height. Intraoperative risk factors for TLIF subsidence were decreased cage surface area, PEEK cage material, bullet cages, posterior cage positioning, smooth cage surfaces, and sawtooth surface designs. Severe subsidence predicted TLIF pseudarthrosis; however, the causality of this relationship remains unclear.

Accelerated fusion dynamics by recombinant human bone morphogenetic protein-2 following transforaminal lumbar interbody fusion, particularly in osteoporotic conditions

BACKGROUND CONTEXTEarly fusion is crucial in interbody procedures to minimize mechanical complications resulting from delayed union, especially for patients with osteoporosis. Bone morphogenetic proteins (BMPs) are used in spinal fusion procedures; however, limited evaluation exists regarding time-to-fusion for BMP use, particularly in patients with osteoporosis. PURPOSETo evaluate the difference in time-to-fusion after single-level transforaminal lumbar interbody fusion (TLIF) surgery between recombinant human bone morphogenetic protein-2 (rhBMP-2) usage and nonusage groups according to bone density. STUDY DESIGNRetrospective single-center cohort study. PATIENT SAMPLEThis study enrolled 132 patients (mean age, 65.25±8.66; male patients, 40.9%) who underwent single-level TLIF for degenerative disorders between February 2012 and December 2021, with pre and postoperative computed tomography (CT). OUTCOME MEASUREThe interbody fusion mass and bone graft status on postoperative CT scans was obtained annually, and time-to-fusion was recorded for each patient. METHODSThe patients were divided into 2 groups based on rhBMP-2 use during the interbody fusion procedure. Patients were further divided into osteoporosis, osteopenia, and normal groups based on preoperative L1 vertebral body attenuation values, using cutoffs of 90 and 120 Hounsfield units. It was strictly defined that fusion is considered complete when a trabecular bone bridge was formed, and therefore, the time-to-fusion was measured in years. Time-to-fusion was statistically compared between BMP group and non-BMP groups, followed by further comparison according to bone density. RESULTSThe time-to-fusion differed significantly between BMP and non-BMP groups, with half of the patients achieving fusion within 2.5 years in the BMP group compared with 4 years in the non-BMP group (p<.001). The fusion rate varied based on bone density, with the maximum difference observed in the osteoporosis group, when half of the patients achieved fusion within 3 years in the BMP group compared to 5 years in the non-BMP group (p<.001). Subgroup analysis was conducted, revealing no significant associations between time-to-fusion and factors known to influence the fusion process, including age, gender, medical history, smoking and alcohol use, and medication history, except for rh-BMP2 use and bone density. CONCLUSIONSRhBMP-2 usage significantly reduced time-to-fusion in single-level TLIF, especially in patients with osteoporosis. LEVEL OF EVIDENCELevel III.

Bone morphogenetic protein in subaxial cervical arthrodesis: a meta-analysis of 5828 patients.

Use of bone morphogenetic protein (BMP)-an osteoinductive agent commonly used in lumbar arthrodesis-is off-label for cervical arthrodesis. This study aimed to identify the effect of BMP use on clinical and radiological outcomes in instrumented cervical arthrodesis. A comprehensive systematic review of the literature was performed to identify studies directly comparing outcomes between cervical arthrodeses with and without using BMP. Outcomes were analyzed separately for cases of anterior cervical discectomy and fusion (ACDF) and posterior cervical fusion (PCF). A total of 20 studies with 5828 patients (1948 with BMP and 3880 without BMP) were included. In the ACDF cases, BMP use was associated with higher fusion rates (98.9% vs 93.6%, risk difference [RD] 8%; risk ratio [RR] 1.12, p = 0.02), lower reoperation rates (2.2% vs 3.1%, RD 3%; RR 0.48, p = 0.04), and higher risk of dysphagia (24.7% vs 8.1%, RD 11%; RR 1.93, p = 0.02). No significant differences in the Neck Disability Index, neck pain, or arm pain scores were associated with the use of BMP. On subgroup meta-analysis of ACDF cases, older age (≥ 50 years) and higher BMP dose (≥ 0.9 mg/level) were associated with significantly higher fusion rates and relatively lower risk for dysphagia, whereas arthrodesis of fewer segments (< 2 levels) showed significantly higher dysphagia rates without a significant increase in fusion rates. In the PCF cases, the use of BMP was not associated with significant differences in fusion (p = 0.38) or reoperation (p = 0.61) rates but was associated with significantly higher blood loss during surgery (mean difference 146.7 ml, p ≤ 0.01). Use of BMP in ACDF offers higher rates of augmented fusion and lower rates of all-cause reoperation but with an increased risk of dysphagia. The benefit of fusion outweighs the risk of dysphagia with a higher BMP dose in older patients being operated on for < 2 levels. The use of BMP in PCF seems to have a less important effect on clinical and radiological outcomes.

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

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. 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. 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). 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.

Kielin/chordin-like protein enhances induction of osteoblast differentiation by Bone Morphogenetic Protein-2.

Bone morphogenetic proteins (BMPs) play a key role in embryonic differentiation for osteoblast and bone formation. Kielin/chordin-like protein (Kcp) is known to enhance the effects of BMP signaling. Here, we present ALP activity, gene expression, and calcification data demonstrating that Kcp affects the differentiation of C2C12 myoblasts into osteoblasts. We report that the presence of Kcp enhances the ability of BMP-2 to induce differentiation of C2C12 myoblasts into osteoblasts. Additionally, BMP-2-mediated stimulation of phosphorylated Smad1/5 was apparently enhanced in the presence of Kcp. The present findings may contribute to progression towards the clinical use of BMPs for treatment of bone fracture, osteoarthritis, and other similar conditions.

Bone morphogenetic proteins in spine surgery: a scientometric analysis to date.

Bone morphogenetic proteins (BMPs) are part of the transforming growth factor-beta superfamily and are involved in bone formation and repair. In spine surgery, recombinant human BMP (rhBMP) is used as an alternative to autografts for spinal fusions. This study aimed to evaluate bibliometric parameters and citations of the literature on BMPs to provide an overview of how the field has evolved. A comprehensive search of the literature was conducted using Elsevier's Scopus database to capture all the published and indexed studies relevant to BMPs from 1955 to the present. A discrete set of validated bibliometric parameters was extracted and analyzed. All statistical analyses were performed using R 4.1.1. The 100 most cited articles were published between 1994 and 2018 by 472 unique authors in 40 sources (e.g., journals and books). On average, there were 279 citations per publication and 17.69 citations per publication per year. The United States had the publications with the most citations (n = 23,761), followed by Hong Kong (n = 580) and the United Kingdom (n = 490). The three institutions in the United States with the greatest number of publications in the field were Emory University (n = 14), Hughston Clinic (n = 9), Hospital for Special Surgery (n = 6), and University of California (n = 6). The authors evaluated and characterized the 100 most cited articles about BMP. Most of the publications were clinical in nature and focused on BMP's application in spine surgery. While early scientific efforts focused on basic science research to advance the understanding of BMP's mechanism of action in promoting bone formation, the majority of the more recent publications are clinically focused. It will be beneficial to conduct more controlled clinical trials to compare the outcomes of BMP use with other methods.

Medical Malpractice Litigation Due to Off-Label Use of Bone Morphogenetic Protein.

Retrospective cohort study. To analyze the incidence and characteristics of malpractice lawsuits pertaining to the off-label use of Bone morphogenetic protein (BMP). BMP continues to be a popular alternative to the use of autologous bone graft during spinal fusion procedures. However, ~85% of BMP is used in an off-label manner, which may expose surgeons to claims of malpractice. Westlaw and VerdictSearch were queried for malpractice claims filed between 2000 and 2022 using the keywords "bone graft" and "spine." Case inclusion criteria were defined as a plaintiff's basis of litigation resting on a claim of medical malpractice due to off-label use of BMP. Additional collected data included the date of the case hearing, plaintiff's sex and age, defendants named in the lawsuit, verdict ruling, location of the filed claim, payment or settlement amount, sustained injuries, and additional allegations. Of 971 claims reviewed, 89 cases were due to off-label BMP use. The posterior approach was identified as the most common approach among the 89 cases. Of the 30 cases naming a surgeon defendant, 50% included allegations of insufficient informed consent. The most frequent adverse events were ectopic bone growth resulting in chronic pain or nerve damage. Zero cases involved heterotopic ossification, wound dehiscence, graft subsidence, hematoma, bladder retention, or retrograde ejaculation. A clear understanding that on-label BMP use is specific to single-level, anterior or anterolateral approaches between L2-S1 with vendor-specific cages is crucial for mitigating malpractice disputes. Though off-label use of BMP may incite litigation, the findings suggest court rulings are favorable for defendants as zero cases, resulting in plaintiff verdicts. Nevertheless, surgeons should balance the potential benefits of off-label use of BMP with the increased risk of litigation, and it may be advisable to disclose the use of BMP, whether on-label or off-label, in the informed consent.

Advances in bone regeneration with growth factors for spinal fusion: A literature review

Bone tissue is regenerated via the spatiotemporal involvement of various cytokines. Among them, the bone morphogenetic protein (BMP), which plays a vital role in the bone regeneration process, has been applied clinically for the treatment of refractory orthopedic conditions.Although BMP therapy using a collagen carrier has shown efficiency in bone regeneration over the last two decades, a major challenge—considerable side effects associated with the acute release of high doses of BMPs—has also been revealed. To improve BMP efficiency, the development of new carriers and biologics that can be used in conjunction with BMPs is currently underway.In this review, we describe the current status and future prospects of bone regeneration therapy, with a focus on BMPs. Furthermore, we outline the characteristics and molecular signaling pathways involving BMPs, clinical applications of BMPs in orthopedics, clinical results of BMP use in human spinal surgeries, drugs combined with BMPs to provide synergistic effects, and novel BMP carriers.

55. Bone morphogenetic protein (BMP) use in adult spinal deformity surgery is associated with reduced implant failures and lower cost/QALY at mean four years postoperative

<h3>BACKGROUND CONTEXT</h3> Despite studies reporting the efficacy of BMP to promote surgical spinal fusion, hospital systems and third-party payors continue to deny use of BMP, claiming high cost and lack of long term follow up. <h3>PURPOSE</h3> Perform a propensity score matched analysis of complications and cost-effectiveness for surgically treated adult spinal deformity (ASD) patients receiving BMP vs no BMP. <h3>STUDY DESIGN/SETTING</h3> Prospective, multicenter, propensity score matched analysis. <h3>PATIENT SAMPLE</h3> ASD patients enrolled into a prospective multicenter study. <h3>OUTCOME MEASURES</h3> Numeric rating scale (NRS) back and leg pain, Scoliosis Research Society-22r questionnaire (SRS-22r), Short Form-36v2 questionnaire (SF-36), Oswestry Disability Index (ODI), cost of care, cost/QALY, postoperative complications. <h3>METHODS</h3> Surgically treated ASD patients prospectively enrolled into a multicenter study from 2009-2018 were assessed for receiving BMP or NOBMP (iliac crest bone graft and allograft only) at the time of surgery. BMP and NOBMP cohorts were propensity score matched (PSM) for age, BMI, frailty, total levels fused, fusion to the pelvis, osteotomies, interbody fusion and supplemental rod use. Postoperative alignment, complications, rod fractures, patient-reported outcomes (PROMs), cost of care (based on DRG reimbursements adjusted to 2021 US dollars), were evaluated at minimum 3-year follow-up, and cost/QALY calculated at 1-,2-, and minimum 3-year follow-up. <h3>RESULTS</h3> Of 888 patients, 483 (mean 4.2 years follow-up, range 2.9 to 8.8) were evaluated. Mean BMP dosage was 27.6 mg total (range 1 to 200), 2.2 mg/level posterior (range 0 to 25) and 1.7 mg/level interbody (range 0 to 18). BMP (n=407) had similar demographics, osteotomies, total and interbody levels fused, preop PROMs, follow-up duration, and pre- and postoperative spinal alignment as NOBMP (n=76; p>0.05). BMP had fewer implant failures (0.17/patient vs 0.33/patient; p 0.05). At last follow-up, BMP had better SF-36 social function (46.7 vs 43.9) and SF-36 mental component scores (51.5. vs 47.8) than NOBMP (p <0.05, respectively). BMP had lower mean total cost of care/patient ($78,679.61 vs $103,388.78) and lower cost/QALY ($22,455.48 vs $32,947.68) at last follow-up vs NOBMP, respectively (p < 0.05). Revision surgery rates were similar for BMP vs NOBMP (0.32 vs 0.42/patient, p=0.11); however, costs of revision surgery were less for BMP ($11,114.33) vs NOBMP ($22,912.53, p <0.05). <h3>CONCLUSIONS</h3> Propensity score matched analysis demonstrated BMP use in ASD surgery at mean 4-year follow-up was associated with decreased implant fracture rates, lower treatment costs and better cost/QALY than NOBMP. Hospital systems, administrators and third-party payors should consider that the initial cost of BMP use at index surgery may be offset by decreased total cost of care and improve cost/QALY for ASD patients. <h3>FDA DEVICE/DRUG STATUS</h3> Bone morphogenetic protein: Investigational.

Discovery of a novel class of benzimidazoles as highly effective agonists of bone morphogenetic protein (BMP) receptor signaling

Increasing or restoring Bone Morphogenetic Protein receptor signaling is an effective therapy for conditions such as bone fracture and pulmonary arterial hypertension. However, direct use of recombinant BMPs has encountered significant obstacles. Moreover, synthetic, full agonists of BMP receptor signaling have yet to be identified. Here, we report the discovery of a novel class of indolyl-benzimidazoles, synthesized using a one-pot synthetic methodology, which appear to mimic the biochemical and functional activity of BMPs. The first-in-series compounds, SY-LB-35 and SY-LB-57, stimulated significant increases in cell number and cell viability in the C2C12 myoblast cell line. Cell cycle analysis revealed that these compounds induced a shift toward proliferative phases. SY-LB-35 and SY-LB-57 stimulated canonical Smad and non-canonical PI3K/Akt, ERK, p38 and JNK intracellular signaling pathways, similar to BMP2-stimulated responses. Importantly, increases in Smad phosphorylation and cell viability were dependent on type I BMP receptor activity. Thus, these compounds robustly activate intracellular signaling in a BMP receptor-dependent manner and may signify the first known, full agonists of BMP receptor signaling. Moreover, discovery of small molecule activators of BMP pathways, which can be efficiently formulated and targeted to diseased or damaged areas, could potentially substitute recombinant BMPs for treatment of BMP-related pathologies.

Bone Morphogenetic Protein in Anterior Lumbar Interbody Fusions: A Propensity-Matched Medicare Outcome Analysis.

Bone morphogenetic protein (BMP) is a costly agent commonly used in spine surgery. Its effectiveness and complication profile have never been studied in a large, propensity-matched population following its approval by the Food and Drug Administration for use in single-level anterior lumbar interbody fusion (ALIF) surgeries. To investigate the rate of symptomatic pseudarthrosis or need for revision surgery after single-level stand-alone ALIFs with and without the use of BMP. Medicare Standard Analytic files derived from Medicare parts A and B were used to identify adult patients who underwent single-level ALIF procedures with and without use of BMP between 2004 and 2014. Patients were propensity matched based on their age, gender, and history of diabetes mellitus, hypertension, chronic kidney disease, body mass index greater than 30 kg/m2, smoking, rheumatoid arthritis, and osteoporosis. Sensitivity analysis using adjusted multivariate logistic regression models was also performed. The primary outcomes were the rates of symptomatic pseudarthrosis or need for revision surgery. The propensity-matched population analyzed in this study contained 22,380 patients undergoing single-level ALIF (8971 [40.6%] with BMP and 13,139 [59.4%] without BMP). Both patient groups were balanced at baseline. The rate of symptomatic pseudarthrosis in the propensity-matched analysis was higher in the BMP group (1.9% vs 1.4%, P < 0.05). BMP use during single-level ALIFs was associated with 44% increased odds of developing pseudarthrosis (OR 1.44, 95% CI 1.16-1.76). However, there was no statistically significant difference in the rate of revision surgery between groups (3.7% vs 3.5%, P = 0.49). BMP use in single-level ALIFs may be associated with increased risk of symptomatic pseudarthrosis. Large prospective pragmatic trials are needed to corroborate our findings.

Stimulation of bone regeneration using bone morphogenetic proteins: modern concepts

It is known that the restoration of fractures or bone defects after trauma is one of the urgent problems of modern orthopedics and traumatology. Bone morphogenetic proteins (BMPs) are a group of growth and differentiation factors that are a large subfamily of the transforming growth factor- (TGF-) superfamily. To date, more than 20 types of different BMPs have been identified based on structural similarities, and it has been found that some of them, like BMP-2, -4, -6, -7, and -9, have the most pronounced osteogenic properties. BMPs induce migration, proliferation, and differentiation of undifferentiated mesenchymal stem cells to form osteoblasts and chondroblasts. BMPs have significant inductive effects on various stages of the bone healing process, such as inflammation, angiogenesis, callus formation, and bone remodeling. It is known that recombinant (rh) rhBMP-2 and rhBMP-7 (approved for clinical use in humans by the USA Food and Drug Administration (FDA)), together with the use of bone grafts, they are used to activate reparative osteogenesis in injuries and to replace bone defects in spinal surgery. Therefore, due to its unique properties, the use of BMPs in bone tissue regeneration is one of the most promising and rapidly developing directions in practical medicine. This review discusses the most important concepts regarding the use of BMPs in stimulating bone regeneration, including their mechanisms of action, modes of use, efficacy, and their advantages and disadvantages.

Mechanisms of maternal high-fat diet-induced brain and behavior changes

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.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.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.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.

Changes in Recombinant Human Bone Morphogenetic Protein-2 Use in Posterior Fusion Over the Past Two Decades.

BackgroundIn 2011, studies suggested that complications and cancer rates associated with bone morphogenetic protein (BMP) were greater than previously reported. However, later studies reported complication rates similar to prior literature and no increased cancer rate. We evaluated the pattern of clinical utilization of BMP in posteriorly based lumbar fusion by comparing two periods: 2002-2004 and 2017-2019.MethodsPatients who received BMP from 2002-2004 (Early) and 2017-2019 (Late) from a single multi-surgeon institution who had a lumbar fusion were identified. One hundred patients from each cohort were randomly selected. Mean total BMP used at each level and the proportion of BMP placed in the interbody space versus posterolateral gutters were evaluated.ResultsIn the transforaminal lumbar intebody fusion (TLIF) cohort, the total BMP dose in the Late group (6.15 mg) was nearly half of that used in the Early group (12.04 mg, p<0.000). The amount of BMP used in the posterolateral gutters remained similar (Early: 4.01 mg vs Late: 3.38 mg, p=0.222). The amount of BMP used in the interbody space was less in the Late group (2.76 mg) compared to the Early group (8.03 mg, p<0.000). In the posterior spinal fusion (PSF) cohort, the total BMP dose remained similar between the Early (11.96 mg) and the Late groups (10.82 mg, p=0.007).ConclusionChange in the use of BMP in TLIF cases was driven by the complications reported in the literature with no change in outcome. A similar impetus was not seen for PSF.

Bone Morphogenetic Protein in Scaphoid Nonunion: A Systematic Review.

Background Scaphoid nonunion can lead to carpal collapse and osteoarthritis, a painfully debilitating problem. Bone morphogenetic protein (BMP) has been successfully implemented to augment bone healing in other circumstances, but its use in scaphoid nonunion has yielded conflicting results. Case Description The purpose of this study is to assess the outcomes and complications of scaphoid nonunion treated surgically with BMP. Literature Review A literature review of all available journal articles citing the use of BMP in scaphoid nonunion surgery from 2002 to 2019 was conducted. We included studies that used BMP as an adjunct to surgical treatment for scaphoid nonunions in both the primary and revision settings with computed tomography determination of union. Demographic information, dose of BMP, tobacco use, outcomes, and complications were recorded. A total of 21 cases were included from four different studies meeting inclusion criteria. Clinical Relevance The union rates were 90.5% overall, 100% for primary surgeries, and 77.8% for revision surgeries. Five patients (24%) experienced 11 complications, including four cases (19%) of heterotrophic ossification. Use of BMP in scaphoid nonunion surgery resulted in a 90.5% overall union rate but was also associated with complications such as heterotopic ossification. All included studies used BMP to augment bone graft, screw or wire fixation, or a combination of methods. The efficacy of BMP in scaphoid nonunion is unclear, and a sufficiently powered, randomized controlled trial is needed to determine optimal fixation methods, dosing, and morbidity of the use of BMP. Level of Evidence This is a Level IC, therapeutic interventional study.

Bone morphogenetic proteins: A strategic review

Bone morphogenetic proteins (BMPs) are the cytokines which play a pivotal role in embryonic patterning and initial skeletal development and also have a potent effect on bone and cartilage growth. BMPs have promising prospects for repair of bone and cartilage, therapeutic utility in orthopaedic and dento-alveolar reconstruction,working as powerful bone-inducing components in diverse tissue-engineering products. Considering the increasing amount of work in the field of BMPs, there are prospects of a brilliant future in the field of regenerative medicine of bone and cartilage with the use of BMPs. This review focuses on its historical background, structure, functions,mechanism of the bone formation, carriers and its clinical applications. Keywords:Bone morphogenetic proteins, BMP’s, Autoinduction, Bone formation, Signalling molecules, Transforming growth factor ?, Bone induction cascade

BMP and TGFβ use and release in bone regeneration

A fracture that does not unite in nine months is defined as nonunion. Nonunion is common in fragmented fractures and large bone defects where vascularization is impaired. The distal third of the tibia, the scaphoid bone or the talus fractures are furthermore prone to nonunion. Open fractures and spinal fusion cases also need special monitoring for healing. Bone tissue regeneration can be attained by autografts, allografts, xenografts and synthetic materials, however their limited availability and the increased surgical time as well as the donor site morbidity of autograft use, and lower probability of success, increased costs and disease transmission and immunological reaction probability of allografts oblige us to find better solutions and new grafts to overcome the cons. A proper biomaterial for regeneration should be osteoinductive, osteoconductive, biocompatible and mechanically suitable. Cytokine therapy, where growth factors are introduced either exogenously or triggered endogenously, is one of the commonly used method in bone tissue engineering. Transforming growth factor β (TGFβ) superfamily, which can be divided structurally into two groups as bone morphogenetic proteins (BMPs), growth differentiation factors (GDFs) and TGFβ, activin, Nodal branch, Mullerian hormone, are known to be produced by osteoblasts and other bone cells and present already in bone matrix abundantly, to take roles in bone homeostasis. BMP family, as the biggest subfamily of TGFβ superfamily, is also reported to be the most effective growth factors in bone and development, which makes them one of the most popular cytokines used in bone regeneration. Complications depending on the excess use of growth factors, and pleiotropic functions of BMPs are however the main reasons of why they should be approached with care. In this review, the Smad dependent signaling pathways of TGFβ and BMP families and their relations and the applications in preclinical and clinical studies will be briefly summarized.

Biologics and Minimally Invasive Approach to TLIFs: What Is the Risk of Radiculitis?

Bone morphogenetic protein (BMP) and allograft containing mesenchymal stem cells (live cell) are popular biologic substitutes for iliac crest autograft used in transforaminal lumbar interbody fusion (TLIF). Use of these agents in the pathogenesis of postoperative radiculitis remains controversial. Recent studies have independently linked minimally invasive (MIS) TLIF with increased radiculitis risk compared to open TLIF. The purpose of this study was to assess the rate of postoperative radiculitis in open and MIS TLIF patients along with its relationship to concurrent biologic adjuvant use. Patients ≥18 years undergoing single-level TLIF from June 2012 to December 2018 with minimum 1-year follow-up were included. Outcome measures were rate of radiculitis, intra- and postoperative complications, revision surgery; length of stay (LOS), and estimated blood loss (EBL). There were 397 patients: 223 with open TLIFs, 174 with MIS TLIFs. One hundred and fifty-nine surgeries used bone morphogenetic protein (BMP), 26 live cell, 212 neither. Open TLIF: higher mean EBL, LOS, and Charlson Comorbidity Index (CCI) than MIS. Postoperative radiculitis in 37 patients (9.32% overall): 16 cases MIS BMP (15.69% of their cohort), 6 MIS without BMP (8.33%), 5 open BMP (8.77%), 10 open without BMP (6.02%). MIS TLIF versus open TLIF: no differences in 1-year reoperation rates, infection/wound complication, pseudarthrosis, or postoperative complication rate. BMP versus non-BMP: no differences in reoperation rates, infection/wound complication, pseudarthrosis, or postoperative complication rate. Multivariate logistic regression found that neither BMP (P = .109) nor MIS (P = .314) was an independent predictor for postoperative radiculitis when controlled for age, gender, body mass index, and CCI. Using paired open and MIS groups (N = 168 each) with propensity score matching, these variables were still not independently associated with radiculitis (P = .174 BMP, P = .398 MIS). However, the combination of MIS with BMP was associated with increased radiculitis risk in both the entire patient cohort (odds ratio [OR]: 2.259 [1.117-4.569], P = .023, N = 397) and PSM cohorts (OR: 2.196 [1.045-4.616], P = .038, N = 336) compared to other combinations of surgical approach and biologic use. Neither the MIS approach nor BMP use is an independent risk factor for post-TLIF radiculitis. However, risk of radiculitis significantly increases when they are used in tandem. This should be considered when selecting biological adjuvants for MIS TLIF. 3.

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

An epidemiological study using national administrative data from the MarketScan database. 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. 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. 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. 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). 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. 3.

Cost-Utility Analysis of rhBMP-2 Use in Adult Spinal Deformity Surgery.

Economic modeling of data from a multicenter, prospective registry. 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. ASD surgery is expensive and presents risk of major complications. BMP is frequently used off-label to reduce the risk of pseudarthrosis. 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). 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. 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. 2.