Efficacy and safety of recombinant human bone morphogenetic protein-2 (rhBMP-2) combined with autologous bone for the treatment of long bone nonunion: A report of a prospective case series.

INTRODUCTION: Recombinant human Bone morphogenetic proteins have been used for the treatment of nonunions with promising results. We have been investigating both experimentally and clinically the efficacy of the rhBMP-2 with the macro / micro-porous hydroxyapatite carrier granules on the potency on the reconstruction of long bone defect. The purpose of this study was to prospectively evaluate the efficacy and safety of this specific rhBMP-2 with HA carrier granules mixed with autologous cancellous bone in patients with nonunion and bone defect resulted from the fracture related infection. MATERIALS AND METHODS: This was a retrospective review of a prospective cohort at a university hospital. Patients diagnosed with nonunion under the definition of the United States Food and Drug Administration with bone defect after long bone fractures were enrolled from January 2020 to February 2021. We included patients with atrophic and oligotrophic nonunion, and hypertrophic nonunion with malalignment that needed to be corrected. The other patient group was consisted of segmental bone defect resulted from FRI. The maximum amount of rhBMP-2 allowed in this clinical study was 6 mg and was added to autologous bone at a 1:1 ratio. Autologous bone was added to the mixture if the volume of mixed graft was insufficient to fill the bone defect. Patients were followed 3, 6, and 12 months post-operatively. Each visit, a radiograph was taken for assessment. Visual analog scale (VAS), questionnaire for quality of life (SF-12 physical component summary [PCS], mental component summary [MCS]), and weight-bearing status were collected for functional outcome assessment. Drug safety was assessed by examining BMP-2 antibodies. RESULTS: Of the 24 enrolled patients (mean age: 57 years), 15 (62.5 %), 2 (8.33 %), and 7 (29.17 %) presented atrophic nonunion, hypertrophic nonunion with deformity, and bone defect after fracture related infection, respectively. Thirteen patients had nonunion in the femur, 9 in the tibia, and 1 in the humerus and radius. The average amount of harvested autologous bone was 9.25 g and 4.96 mg of rhBMP-2. All 24 patients achieved union after 1-year follow up. The union rate was 95.83 % and 100 % at 6 and 12 months postoperatively, respectively. Preoperative SF-12 PCS (mean: 34.71) improved at 6 and 12 months postoperatively, respectively. Preoperative SF-12 MCS (mean: 42.89) improved 12 months postoperatively (49.13, p = 0.0338). Change of VAS was statistically significant 3 months postoperatively (p = 0.0012). No adverse effects or development of BMP-2 antibodies were observed. CONCLUSION: BMP-2 combined with autogenous bone resulted in excellent radiographical and functional outcomes in a relatively small prospective series of patients with nonunion and bone defect, without adverse effects. Further investigations are necessary to support our finding and optimize treatment strategies in nonunion patients.

Midterm Outcomes of Multimodal Approach to Treating Severe Scoliosis in Patients With Osteogenesis Imperfecta.

INTRODUCTION: The surgical management of severe scoliosis in patients with osteogenesis imperfecta (OI) is challenging because of curve rigidity, small stature, and inherent bone fragility. This study evaluated the midterm outcomes of our multimodal approach to address these issues, integrating perioperative bisphosphonate therapy, preoperative/intraoperative traction, various osteotomies, segmental pedicle screw instrumentation with cement augmentation, and bone morphogenetic protein-2 application. METHODS: A single-center retrospective review of 30 patients (average age 14.1 ± 2.2 years; 18 were female) diagnosed with OI and scoliosis was conducted. These patients underwent posterior spinal fusion between 2008 and 2020 and completed a minimum follow-up of 2 years. We measured radiographic parameters at each visit and reviewed the incidence of complications. A mixed-effects model was used to evaluate changes in radiographic parameters from preoperative measurements to the first and latest follow-ups. RESULTS: The patient cohort consisted of 2 individuals with type I OI, 20 with type III, 6 with type IV, and 2 with other types (types V and VIII). Surgical intervention led to a notable improvement in the major curve magnitude from 76° to 36°, with no notable correction loss. In addition, the minor curve, apical vertical translation, lowest instrumented vertebra tilt, and pelvic obliquity were also improved. In the sagittal plane, thoracic kyphosis and lumbar lordosis remained unchanged while thoracolumbar kyphosis markedly improved. Two patients experienced proximal junctional kyphosis with screw pullout, one of whom required revision surgery. One patient developed a superficial infection that was successfully treated with oral antibiotics. No instances of neurologic deficits or cement extravasation were observed. DISCUSSION: This study demonstrated the effectiveness and safety of our multimodal approach to treating scoliosis in patients with OI, achieving a 53% major curve correction with minimal complications over 2-year follow-up. These findings provide notable insights into managing scoliosis in this population. LEVEL OF EVIDENCE: Level IV (case series).

Tooth movement toward alveolar bone grafting with rhBMP-2 in a child with unilateral cleft lip and palate: Case report with long-term follow-up.

The secondary alveolar bone grafting procedure is typically recommended during the late mixed dentition phase, prior to the eruption of the permanent canine, in patients with cleft lip and palate. The anatomical and functional adaptations observed in the grafted area allow spontaneous migration and eruption of the adjacent maxillary canine. An alveolar bone graft can be performed using autogenous bone or recombinant human bone morphogenetic protein-2 (rhBMP-2). Employing rhBMP-2 in a collagen membrane eliminates the need for a donor site, thus reducing surgical morbidity. This paper aims to present a case involving complete orthodontic rehabilitation with a three-year follow-up of a male patient with a unilateral complete cleft lip and palate, posterior and anterior crossbite, where grafting was performed with rhBMP-2 at a single centre. Orthodontic intervention began at 8 years of age with rapid maxillary expansion, followed by facemask therapy. The alveolar bone grafting procedure was performed using rhBMP-2 in a collagen membrane, according to the surgical protocol developed by the Oslo team. Comprehensive orthodontic treatment started 15 months post bone grafting, during which the maxillary permanent lateral incisor distal to the alveolar cleft was successfully moved mesially into the grafted region. This intervention resulted in adequate occlusal and periodontal outcomes. The alveolar graft with rhBMP-2 produced adequate and stable alveolar bone formation, facilitating tooth eruption, orthodontic movement, and stability at the cleft site.

Comparison of transforaminal and posterior lumbar interbody fusion outcomes in patients receiving a novel allograft versus rhBMP-2: a radiographic and patient-reported outcomes analysis.

OBJECTIVE: Recombinant human bone morphogenetic protein-2 (rhBMP-2) has been demonstrated to achieve the highest rates of arthrodesis in multilevel lumbar fusion but is also associated with possible perioperative morbidity. A novel allograft (OSTEOAMP) is a differentiated allograft that retains growth factors supporting bone healing. The authors sought to compare the clinical and radiographic outcomes of rhBMP-2 and the novel allograft in lumbar interbody arthrodesis to determine if the latter may be a safer and equally effective alternative to rhBMP-2 for single- and multilevel posterior or transforaminal lumbar interbody fusion (PLIF or TLIF). METHODS: Patients who underwent single- or multilevel TLIF or PLIF using either OSTEOAMP or rhBMP-2 at the authors' institution over a 2-year period were prospectively followed for 12 months. Healthcare utilization, safety measures, patient satisfaction, physical disability (measured on the Oswestry Disability Index [ODI]), back and leg pain (on the numeric rating scale [NRS]), quality of life (on the EQ-5D scale), and return to work (RTW) were prospectively recorded. For purposes of this study, this consecutive series was retrospectively analyzed and pseudarthrosis rates were assessed at 2 years of follow-up. All patients (100%) had both 12-month patient-reported outcome follow-up and 24-month clinical and radiographic follow-up. RESULTS: One thousand one hundred fifty-four patients (654 treated with OSTEOAMP, 500 with rhBMP-2) were prospectively enrolled in the institutional registry. After propensity score matching, there were no significant baseline differences between 330 novel allograft and 330 rhBMP-2 cases. Perioperative morbidity and 90-day hospital readmission (3.3% vs 2.4%, p = 0.485) did not significantly differ between the novel allograft and the rhBMP-2 cases. At the 2-year follow-up, symptomatic pseudarthrosis requiring revision surgery occurred in 8 patients (2.4%) with OSTEOAMP and 6 patients (1.8%) with rhBMP-2 (p = 0.589). The overall fusion rate at 2 years was similar between groups (p = 0.213). Both groups showed significant and equivalent improvement in patient-reported outcome measures (PROMs) from baseline to 12-month follow-up, with no significant difference in 1-year mean NRS leg pain score (2.5 vs 2.7), ODI (25 vs 26), quality-adjusted life years (0.73 vs 0.73), satisfaction (83% vs 80%), or RTW (6.6 vs 7 weeks). CONCLUSIONS: In the authors' institutional experience, OSTEOAMP is a clinically viable substitute for rhBMP-2 for single- and multilevel lumbar fusion. This novel allograft provides clinically effective arthrodesis and improvements in PROMs comparable to rhBMP-2 with a similar safety profile. Additional indications and outcome assessment in longitudinal studies are needed to further characterize this allogeneic graft.

Autologous rib graft for posterior cervical fusion in pediatric patients: efficacy and safety in the early postoperative period.

OBJECTIVE: The objective was to describe the indications, technique, and initial outcomes of autologous rib graft with recombinant human bone morphogenetic protein (rhBMP) in pediatric patients undergoing posterior cervical fusion. METHODS: A retrospective study was performed of all pediatric patients who underwent autologous rib grafting with extra-small rhBMP-2 for posterior craniocervical or cervical arthrodesis at a single institution between May 2020 and July 2023. Patients with less than 3 months of postoperative follow-up and no postoperative CT data were excluded. Primary outcomes included presence of fusion on CT, 30-day perioperative complications, and rib harvest complications. RESULTS: Twenty-eight sequential patients met inclusion criteria. Thirteen were male, 15 were female, and the average age was 9 years. There were no surgical site infections or instances of postoperative seroma or unplanned return to the operating room. All patients had solid fusion on postoperative CT at 3 months. The average follow-up was 14.5 months, with a range of 4 months to 3 years. There were no complications associated with the rib harvest, including no instances of harvest site pain, and all patient incisions healed well. CONCLUSIONS: The authors' preliminary results demonstrate that autologous rib graft with extra-small rhBMP-2 is an effective strategy to achieve a high rate of fusion in pediatric patients undergoing posterior instrumented craniocervical or cervical fusion. In this series, the authors found an acceptable safety profile, without seroma, surgical site infection, unplanned return to the operating room, or rib harvest complications.

Efficacy of hydroxyapatite and fibrin sealant as carriers for bone morphogenetic protein-2 in maxillary sinus floor augmentation: a retrospective study.

The aim of this retrospective study was to assess the efficacy of recombinant human bone morphogenetic protein-2 (rhBMP-2) with hydroxyapatite (HA) granules and fibrin sealant (FS) in maxillary sinus floor augmentation (MSFA), with a focus on the volume change. Fifty-two of 137 patients who underwent MSFA with rhBMP-2/HA grafting between June 2016 and December 2022 met the study inclusion criteria; 25 had received rhBMP-2/HA without FS and 27 had received rhBMP-2/HA with FS. Computed tomography (CT) images were obtained preoperatively, immediately following the operation, and at 6 months postoperative. These images were three-dimensionally reconstructed to measure the volumetric and height changes following MSFA. The mean ± standard deviation percentage of volumetric change at 6 months was 48.75 ± 37.44% in the group with FS and 29.77 ± 13.42% in the group without FS (P = 0.019). The vertical height measured at a specific site of the grafted area showed a mean percentage change at 6 months of 4.05 ± 12.08% in the group with FS and 6.07 ± 10.15% in the group without FS (P = 0.518). The additional use of FS as a carrier for rhBMP-2/HA in MSFA was found to improve surgical convenience and bone regeneration ability.

Use of Recombinant Human Bone Morphogenetic Protein-2 After Anterior Cervical Corpectomy and Fusion for the Treatment of Vertebral Osteomyelitis.

OBJECTIVE: To report the operative outcomes after treating vertebral osteomyelitis patients with an anterior cervical corpectomy and fusion procedure using recombinant human bone morphogenetic protein-2 (rhBMP-2) as graft material. METHODS: A retrospective review of electronic medical records of 26 adult patients who underwent an anterior cervical corpectomy and fusion procedure for cervical osteomyelitis using rhBMP-2 at the University of Puerto Rico University District Hospital was performed. Indication, preoperative laboratory results, levels of corpectomy, preoperative American Spinal Injury Association Impairment Scale (ASIA) score, complications, fusion evaluation at 12 months, and ASIA score at 12 months were reviewed. RESULTS: For the cohort of patients, mean age was 47 ± 13 years and 65% were male. Spinal instability was present in 54%. The levels of corpectomy were: 1 level in 2 cases, 2 levels in 15 cases, 3 levels in 8 cases, and 5 levels in 1 case. Four patients had complications and, of these, 2 experienced dysphagia. The fusion rate was 100% and no reoperations were performed. An improvement in ASIA score was seen for 54% patients at 12-month follow-up. CONCLUSIONS: This study demonstrates a fusion rate of 100% with no reoperations reported. Recombinant human bone morphogenetic protein-2 could be considered and further researched as grafting material for anterior cervical corpectomy and fusion procedures in cervical osteomyelitis patients.

Restoring implant fixation strength in osteoporotic bone with a hydrogel locally delivering zoledronic acid and bone morphogenetic protein 2. A longitudinal in vivo microCT study in rats.

Osteoporosis poses a major public health challenge, and it is characterized by low bone mass, deterioration of the microarchitecture of bone tissue, causing a consequent increase in bone fragility and susceptibility to fractures and complicating bone fixation, particularly screw implantation. In the present study, our aim was to improve implant stability in osteoporotic bone using a thermoresponsive hyaluronan hydrogel (HA-pNIPAM) to locally deliver the bisphosphonate zoledronic acid (ZOL) to prevent bone resorption and bone morphogenetic protein 2 (BMP2) to induce bone formation. Adult female Wistar rats (n = 36) were divided into 2 treatment groups: one group of SHAM-operated animals and another group that received an ovariectomy (OVX) to induce an osteoporotic state. All animals received a polyetheretherketone (PEEK) screw in the proximal tibia. In addition, subgroups of SHAM or OVX animals received either the HA-pNIPAM hydrogel without or with ZOL/BMP2, placed into the defect site prior to screw implantation. Periprosthetic bone and implant fixation were monitored using longitudinal in vivo microCT scanning post-operatively and at 3, 6, 9, 14, 20 and 28 days. Histological assessment was performed post-mortem. Our data showed that pure hydrogel has no impact of implant fixation The ZOL/BMP2-hydrogel significantly increased bone-implant contact and peri-implant bone fraction, primarily through reduced resorption. STATEMENT OF CLINICAL SIGNIFICANCE: Local delivery of ZOL and BMP2 using a biocompatible hydrogel improved implant stability in osteoporotic bone. This approach could constitute a potent alternative to systemic drug administration and may be useful in avoiding implant loosening in clinical settings.

Bone regeneration in critical-size defects of the mandible using biomechanically adapted CAD/CAM hybrid scaffolds: An in vivo study in miniature pigs.

The study aimed to analyze bone regeneration in critical-size defects using hybrid scaffolds biomechanically adapted to the specific defect and adding the growth factor rhBMP-2. For this animal study, ten minipigs underwent bilateral defects in the corpus mandibulae and were subsequently treated with novel cylindrical hybrid scaffolds. These scaffolds were designed digitally to suit the biomechanical requirements of the mandibular defect, utilizing finite element analysis. The scaffolds comprised zirconium dioxide-tricalcium phosphate (ZrO2-TCP) support struts and TCP foam ceramics. One scaffold in each animal was loaded with rhBMP-2 (100 µg/cm³), while the other served as an unloaded negative control. Fluorescent dyes were administered every 2 weeks, and computed tomography (CT) scans were conducted every 4 weeks. Euthanasia was performed after 3 months, and samples were collected for examination using micro-CT and histological evaluation of both hard and soft tissue. Intravital CT examinations revealed minor changes in radiographic density from 4 to 12 weeks postoperatively. In the group treated with rhBMP-2, radiographic density shifted from 2513 ± 128 (mean ± SD) to 2606 ± 115 Hounsfield units (HU), while the group without rhBMP-2 showed a change from 2430 ± 131 to 2601 ± 67 HU. Prior to implantation, the radiological density of samples measured 1508 ± 30 mg HA/cm³, whereas post-mortem densities were 1346 ± 71 mg HA/cm³ in the rhBMP-2 group and 1282 ± 91 mg HA/cm³ in the control group (p = 0.045), as indicated by micro-CT measurements. The histological assessment demonstrated successful ossification in all specimens. The newly formed bone area proportion was significantly greater in the rhBMP-2 group (48 ± 10%) compared with the control group without rhBMP-2 (42 ± 9%, p = 0.03). The mean area proportion of remaining TCP foam was 23 ± 8% with rhBMP-2 and 24 ± 10% without rhBMP-2. Successful bone regeneration was accomplished by implanting hybrid scaffolds into critical-size mandibular defects. Loading these scaffolds with rhBMP-2 led to enhanced bone regeneration and a uniform distribution of new bone formation within the hybrid scaffolds. Further studies are required to determine the adaptability of hybrid scaffolds for larger and potentially segmental defects in the maxillofacial region.

Biomimetic Hematoma as a Novel Delivery Vehicle for rhBMP-2 to Potentiate the Healing of Nonunions and Bone Defects.

SUMMARY: The management of bone defects and nonunions creates unique clinical challenges. Current treatment alternatives are often insufficient and frequently require multiple surgeries. One promising option is bone morphogenetic protein-2 (BMP-2), which is the most potent inducer of osteogenesis. However, its use is associated with many side effects, related to the delivery and high doses necessary. To address this need, we developed an ex vivo biomimetic hematoma (BH), replicating naturally healing fracture hematoma, using whole blood and the natural coagulants calcium and thrombin. It is an autologous carrier able to deliver reduced doses of rhBMP-2 to enhance bone healing for complex fractures. More than 50 challenging cases involving recalcitrant nonunions and bone defects have already been treated using the BH delivering reduced doses of rhBMP-2, to evaluate both the safety and efficacy. Preliminary data suggest the BH is currently the only clinically used carrier able to effectively deliver reduced doses (∼70% less) of rhBMP-2 with high efficiency, rapidly and robustly initiating the bone repair cascade to successfully reconstruct complex bone injuries without side effects. The presented case provides a clear demonstration of this technology's ability to significantly alter the clinical outcome in extremely challenging scenarios where other treatment options have failed or are considered unsuitable. A favorable safety profile would portend considerable promise for BH as an alternative to bone grafts and substitutes. Although further studies regarding its clinical efficacy are still warranted, this novel approach nevertheless has tremendous potential as a favorable treatment option for bone defects, open fractures, and recalcitrant nonunions.

The Effect of Bone Morphogenetic Protein-2 (BMP-2) on Volumetric and Histometric Outcomes for Peri-Implant Defects in the Animal Model: A Systematic Review and Meta-Analysis.

Purpose: To study the effect of BMP-2 on the volumetric and histometric changes in peri-implant defect treatments in animal models. Materials and Methods: An electronic search of four databases and a manual search of peer-reviewed journals for relevant articles were performed. Animal studies with data that compared the volumetric and/or histometric outcomes of peri-implant defect treatment with and without the use of BMP-2 were included. Meta-analyses were performed to analyze the weighted mean difference (WMD) and confidence interval (CI) for the recorded variables. Results: After completing the search process, 21 randomized controlled trials were included. The results of the meta-analyses showed that the WMD of bone-to-implant contact (%BIC) with 4 to 8 weeks and 12 to 24 weeks of follow-up was 15.50% (95% CI = 3.28% to 27.72%, P = .01) and 16.17% (95% CI = 11.17% to 21.16%, P < .00001), respectively, favoring the BMP-2 group. The WMD for the percentage of defect fill with 4 to 8 weeks and 12 to 24 weeks of follow-up was 15.88% (95% CI = 3.90% to 27.86%, P = .009) and 10.48% (95% CI = 0.95% to 20.02%, P = .03), respectively, favoring the BMP-2 group. The WMD for the vertical bone gain with 8 to 16 weeks of follow-up was 1.63 mm (95% CI = 0.58 to 2.67 mm, P = .002), also favoring the BMP-2 group. Conclusion: This review demonstrated that the use of BMP-2 in treating peri-implant defects showed better clinical and histometric outcomes than defects not treated with BMP-2 in animal models.

An effectiveness and economic analyses of tricalcium phosphate combined with iliac bone graft versus RhBMP-2 in single-level XLIF surgery in Thailand.

STUDY DESIGN: Retrospective study. OBJECTIVES: To perform effectiveness and economic analyses using data from a retrospective study of patients who underwent XLIF surgery using tricalcium phosphate combined with iliac bone graft (TCP + IBG) or BMP-2 in Thailand. METHODS: Data were collected from retrospective review of the medical charts and the spine registry of Siriraj Hospital, Bangkok, Thailand. The patients were divided into two groups (TCP + IBG group and BMP-2 group). Demographic, perioperative data, radiographic, clinical results, and quality of life related to health were collected and analyzed at 2-year follow-up. All economic data were collected during the perioperative period and presented as total charge, bone graft, implant/instrumentation, operative service, surgical supply, transfusion, medication, anesthesia, laboratory, and physical therapy. RESULTS: Twenty-five TCP + IBG and 30 BMP-2 patients with spondylolisthesis and spinal stenosis as primary diagnosis were included. There were no significant differences in all demographic parameters (gender, age, underlying disease, diagnosis, and level of spine) between these two groups. During the perioperative period, the TCP + IBG group had more mean blood loss and more postoperative complications compared to the BMP-2 group. At 2 years of follow-up, there were no significant differences between the radiographic and clinical outcomes of the TCP + IBG and BMP-2 groups. The fusion rate for TCP + IBG and BMP-2 at 2 years of follow-up was 80% and 96.7%, respectively, and no statistically significant differences were observed. All clinical outcomes (Utility, Oswestry Disability Index, and EuroQol Visual Analog Scale) at 2-year follow-up improved significantly compared to preoperative outcomes, but there were no significant differences between the TCP + IBG and BMP-2 groups, either at preoperatively or at 2-year follow-up. The total charge of TCP + IBG was statistically significantly lower than that of BMP-2. Furthermore, the charges of TCP + IBG and BMP-2 during the perioperative period in Thailand were up to three times less than those in the United States. CONCLUSIONS: Using TCP + IBG as a standalone bone substitution for XLIF surgery with additional posterior instrumentation resulted in significantly lower direct medical charge compared to those using BMP-2 in the perioperative period. However, we could not detect a difference in the long-term radiographic and clinical outcomes of patients with TCP + IBG and BMP-2. These suggest that TCP + IBG may be a valuable alterative bone graft, especially in low- and middle-income countries.

Current Trends in Recombinant Human Bone Morphogenetic Protein 2 (rhBMP2) Usage for Spinal Fusion Surgery.

(1) Background: Since first approved by the FDA, on-label and off-label usage of recombinant human bone morphogenetic protein 2 (rhBMP2) for spinal fusion surgeries has become widespread. While many studies have investigated the safety and efficacy of its use, as well as its economic impact, few have looked at the current trends in its on- and off-label use. The goal of this study is to evaluate the current trends of on- and off-label rhBMP2 use for spinal fusion surgery. (2) Methods: A deidentified survey was created and electronically distributed to members of two international spine societies. Surgeons were asked to report their demographic information, surgical experience, and current usage of rhBMP2. They were then presented with five spinal fusion procedures and asked to report if they use rhBMP2 for these indications in their current practice. Responses were stratified between rhBMP2 users vs. non-users and on-label vs. off-label use. Data were analyzed using chi-square with Fisher's exact test for categorical data. (3) Results: A total of 146 respondents completed the survey with a response rate of 20.5%. There was no difference in overall rhBMP2 usage based on specialty, experience, or number of cases per year. Fellowship-trained surgeons and those who practice in the United States were more likely to use rhBMP2. Surgeons who were trained in the Southeast and Midwest regions reported the highest usage rates. rhBMP2 use was more common among fellowship-trained and US surgeons for ALIFs; non-US surgeons for multilevel anterior cervical discectomy and fusions; and fellowship-trained and orthopedic spine surgeons for lateral lumbar interbody fusions. Non-US surgeons were more likely to use rhBMP2 for off-label indications compared to surgeons from the US. (4) Conclusions: While various demographics of surgeons report different rates of rhBMP2 use, off-label use remains relatively commonplace amongst practicing spine surgeons.

The Use of Bone Morphogenetic Protein 2 (BMP-2) in Spine Surgery Is It Valuable?

BACKGROUND: Bone morphogenetic protein 2 (BMP-2) is one of the most widely used biologics in spine surgery. Its osteoinductive properties have been shown since its inception to improve fusion rates. Despite the positive effects on promoting fusion, there remains concerns regarding the significant costs associated with its use. The goal of this review was to investigate the value of BMP-2 in spine surgery. METHODS: A literature search was performed on various studies that report on the cost effectiveness and the value of BMP-2 in spine surgery. The value of BMP-2 was analyzed in two distinct settings: comparison to the gold standard iliac crest autograft and demineralized bone matrix. The value of BMP-2 was further analyzed in the setting of spinal deformity surgery. RESULTS: The findings of our review determined that BMP-2 offers significant improvement in outcomes related to improvement of fusion rates and minimization of pseudoarthrosis and reoperations related to pseudoarthrosis and donor site morbidity from harvesting iliac crest bone graft. However, BMP-2 has been found to be significantly more expensive in comparison to iliac crest bone graft and other bone graft substitutes, which detracts from its positive value. In deformity surgery, BMP-2 is associated with improvement in fusion rates as well as reducing the rate of reoperations and pseudoarthrosis. These positive outcomes, however, are associated with an expensive upfront cost for BMP-2. CONCLUSIONS: In terms of value, BMP-2 is associated with improvement in quality outcomes related to a reduction in pseudoarthrosis and reoperations. It also leads to improved outcomes with a reduction in donor site morbidity associated with iliac crest bone graft harvest. However, the value of BMP-2 is negatively affected because of its significant costs. As a result, higher expense thresholds are needed to increase quality adjusted life years in patients who receive BMP-2. Further research investigating ways to minimize the costs associated with BMP-2 use can further improve its value in spine surgery.

Segmental defect healing in the presence or absence of recombinant human BMP2: Novel insights from a rat model.

This study defined and compared the course of native, impaired and growth factor-stimulated bone regeneration in a rat femoral defect model. A mid-diaphyseal defect with rigid internal fixation was surgically created in the right femur of male Fischer rats and serially analyzed over 36 weeks. Native bone regeneration was modeled using a sub-critical, 1 mm size defect, which healed uneventfully. Critical size defects of 5 mm were used to analyze impaired bone regeneration. In a third group, the 5 mm defects were filled with 11 µg of recombinant human bone morphogenetic protein 2 (rhBMP2) impregnated onto an absorbable collagen sponge, modeling its clinical use. Native bone regeneration was characterized by endochondral ossification with progressive remodeling to ultimately resemble intact femora. An endochondral response was also observed under conditions of impaired bone regeneration, but by week 8 medullary capping occurred with fibrofatty consolidation of the tissue within the defect, resembling an atrophic non-union. rhBMP2 treatment was associated with prolonged inflammatory cytokine expression and rapid intramembranous bone formation occurring with reduced expression of cartilage-associated collagens. Between weeks 4 and 36, rhBMP2-treated bones demonstrated decreased trabecular number and increased trabecular separation, which resulted in inferior mechanical properties compared with bones that healed naturally. Clinical Significance: Recombinant human bone morphogenetic protein 2 (rhBMP2) is used clinically to promote healing of long bones. Our data suggest that it drives intramembraneous ossification producing an inferior regenerate that deteriorates with time. Clinical outcomes would be improved by technologies favoring endochondral regenerative ossification.

Concentration-Dependent Efficacy of Recombinant Human Bone Morphogenetic Protein-2 Using a HA/ß-TCP Hydrogel Carrier in a Mini-Pig Vertebral Oblique Lateral Interbody Fusion Model.

Bone morphogenetic protein-2 (BMP-2) is used in the treatment of degenerative spinal disease and vertebral fractures, spine fusion, dental surgery, and facial surgery. However, high doses are associated with side effects such as inflammation and osteophytes. In this study, we performed spinal fusion surgery on mini-pigs using BMP-2 and a HA/ß-TCP hydrogel carrier, and evaluated the degree of fusion and osteophyte growth according to time and dosage. Increasing the dose of BMP-2 led to a significantly higher fusion rate than was observed in the control group, and there was no significant difference between the 8-week and 16-week samples. We also found that the HA + ß-TCP hydrogel combination helped maintain the rate of BMP-2 release. In conclusion, the BMP-2-loaded HA/ß-TCP hydrogel carrier used in this study overcame the drawback of potentially causing side effects when used at high concentrations by enabling the sustained release of BMP-2. This method is also highly efficient, since it provides mineral matter to accelerate the fusion rate of the spine and improve bone quality.

Long-Term Assessment of Bone Regeneration in Nonunion Fractures Treated with Compression-Resistant Matrix and Recombinant Human Bone Morphogenetic Protein-2 in Dogs.

OBJECTIVE: The aim of this study was to assess bone density, bone architecture and clinical function of canine nonunion distal appendicular long bone fractures with a defect treated with fixation, compression-resistant matrix and recombinant human bone morphogenetic protein-2 (rhBMP-2). STUDY DESIGN: Prospective cohort study with dogs at least 1-year post treatment. Computed tomography was performed and quantitative measurements from previous fracture sites were compared with measurements from contralateral limbs. Subjective evaluation included gait assessment and palpation. RESULTS: Six patients met the inclusion criteria. The rhBMP-2 treated bone exhibited higher density at the periphery and lower density in the centre, similar to the contralateral limb. All patients were weight bearing on the treated limb and all fractures were healed. CONCLUSION: The rhBMP-2-treated bone underwent restoration of normal architecture and density. Acceptable limb function was present in all patients. The results of this study can serve as a basis for long-term response in treating nonunion fractures in veterinary patients.

Bone Morphogenic Protein for Upper Extremity Fractures: A Systematic Review.

BACKGROUND: This review discusses success, time to healing, and complications of bone morphogenic proteins (BMPs) 7 and 2 in treating upper extremity nonunions. METHODS: Systematic review identified 26 of 479 studies that met inclusion criteria. Publications described application of BMPs to acute and chronic upper extremity delayed unions/nonunions. Unions, complications, patient demographics, and fracture/healing patterns were pooled and analyzed. RESULTS: Nonunions treated with BMP-7 (n=302) involved the humerus (64%), forearm (22%), clavicle (11%), and hand/wrist (3%), with prior surgical correction attempted in 84%. Nonunions treated with BMP-2 (n=96) involved the humerus (58%), hand/wrist (27%), forearm (14%), and clavicle (1%), with prior surgical correction attempted in all. Most nonunions (80%) were present for over 12 months before BMP application. Union rates of BMP-7 varied according to site: hand/wrist (95%), humerus (74%), forearm (29%), and clavicle (6.2%) nonunions achieved union as defined by study authors in 232 days (confidence interval=96-369, Q<0.001) on average. While not significant across studies, BMP-2 union rates were 71% of hand/wrist and 75% of humerus nonunions. Comparison of the BMPs demonstrates different proportions of success in humerus and hand/wrist fractures (P<.001) but not forearm fractures (P<.77) and longer time to radiographic union with BMP-7 (P<.011). CONCLUSIONS: Most hand/wrist and humerus nonunions treated with BMP-7 and BMP-2 achieved union, with significant similarity among BMP-7 studies not observed in BMP-2 studies. Nonunions treated with BMP-7 have longer healing times yet similar complication rates compared with BMP-2. Overall, BMPs are an effective adjunct to fracture healing with acceptable complication profile.

Bone Morphogenetic Protein 2 Plus Leukocyte and Platelet-Rich Fibrin for the Treatment of MRONJ.

Leukocyte and platelet-rich fibrin is known to contain high concentrations of growth factors and when associated with rhBMP-2, it may increase bone remodeling due to its osteoinductive property. The aim of this case is to report the outcome of surgical treatment of medication-related osteonecrosis of the jaw with prototype plate installation and the use of leukocyte and platelet-rich fibrin in association with rhBMP-2 in a 78-year-old female patient under therapy with alendronate. The present Studies describes that the combination of this treatment presented complete healing of osteonecrosis and represents a promising treatment option to be used for medication-related osteonecrosis of the jaw.

Cefazolin/BMP-2-Loaded Mesoporous Silica Nanoparticles for the Repair of Open Fractures with Bone Defects.

The study aimed to explore the feasibility of a nanodrug delivery system to treat open fractures with bone defects. We developed a cefazolin (Cef)/bone morphogenetic protein 2 (BMP-2)@mesoporous silica nanoparticle (MSN) delivery system; meanwhile, Cef/MBP-2@ poly(lactic-co-glycolic acid) (PLGA) was also developed as control. For the purpose of determining the osteogenic and anti-inflammatory actions of the nanodelivery system, we cultured bone marrow mesenchymal stem cells (BMSCs) and constructed a bone defect mouse model to evaluate its clinical efficacy. After physicochemical property testing, we determined that MSN had good stability and did not easily accumulate or precipitate and it could effectively prolong the Cef's half-life by nearly eight times. In BMSCs, we found that compared with the PLGA delivery system, MSNs better penetrated into the bone tissue, thus effectively increasing BMSCs' proliferation and migration ability to facilitate bone defect repair. Furthermore, the MSN delivery system could improve BMSCs' mineralization indexes (alkaline phosphatase [ALP], osteocalcin [OCN], and collagen I [Col I]) to effectively improve its osteogenic ability. Moreover, the MSN delivery system could inhibit inflammation in bone defect mice, which was mainly reflected in its ability to reduce the release of IL-1ß and IL-4 and increase IL-10 levels; it could also effectively reduce apoptosis of CD4+ and CD8+ T cells, thus improving their immune function. Furthermore, the percentage of new bones, bone mineral density, trabecular volume, and trabecular numbers in the fracture region were improved in mice treated with MSN, which allowed better repair of bone defects. Hence, Cef/BMP-2@MSN may be feasible for open fractures with bone defects.