Clinical effectiveness and cost-effectiveness of bone morphogenetic proteins in the non-healing of fractures and spinal fusion: a systematic review. [Cost-benefit analysis of the use of rhBMP-2 in open tibial fractures: savings from a health insurer's perspective]. An ongoing research for evaluation of treatment with BMPs or AGFs in long bone non-union: protocol description and preliminary results. Healing of fresh tibial fractures with OP-1. A preliminary report. Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. Recombinant human BMP-2 and allograft compared with autogenous bone graft for reconstruction of diaphyseal tibial fractures with cortical defects. A randomized, controlled trial. Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. Preclinical and clinical evaluation of osteogenic protein-1 (BMP-7) in bony sites. Osteogenic activity of OP-1 bone morphogenetic protein (BMP-7) in a human fibular defect. A comparison of RhBMP-7 (OP-1) and autogenous graft for metaphyseal defects after osteotomy of the distal radius.
To assess the clinical effectiveness and cost-effectiveness of bone morphogenetic protein (BMP) for the treatment of spinal fusions and the healing of fractures compared with the current standards of care.
                Electronic databases, related journals and references from identified studies were searched in January 2006, with an updated search only for randomised controlled trials (RCTs) in November 2006.
                A systematic review of available data was conducted. The data from selected studies were then analysed and graded according to quality and processed to give a value to the efficacy of BMP. Existing models were modified or updated to evaluate the cost-effectiveness of BMP for open tibial fractures and spinal fusion.
                All selected trials were found to have several methodological weaknesses. Insufficient sample size in most trials, meant that patient baseline comparability between trial arms was not achieved and the statistical power to detect a moderate effect was low. Data did indicate that BMP increased fracture union among patients with acute tibial fractures and found that high-dose BMP is more effective than a lower dose for open tibial fractures. The healing rate in the BMP group was not found to be statistically significantly different from that in the autogenous bone grafting group for patients with tibial non-union fractures, but BMP reduced the number of secondary interventions in patients with acute tibial fractures compared with controls. There was very limited evidence that BMP in scaphoid non-union was safe and may help to accelerate non-union healing when used in conjunction with either autograft or allograft. There was evidence that BMP-2 is more effective than autogenous bone graft for radiographic fusion in patients with single-level degenerative disc disease. No significant difference was found when BMP-7 was compared with autograft for degenerative spondylolisthesis with spinal stenosis and spondylolysis. The use of BMP was associated with a reduced operating time, improvement in clinical outcomes and a shorter hospital stay as compared with autograft. The proportion of secondary interventions tended to be lower in the BMP group than the control, but not of statistical significance. Trial data on time to return to work postoperatively were sometimes difficult to interpret because of unclear or inappropriate data analysis methods. The incremental cost of BMP for open tibial fractures was estimated to be about 3.5 million pounds per year in the UK. The estimated incremental cost per quality-adjusted life-year (QALY) gained is 32,603 pounds. The probability that cost per QALY gained is less than 30,000 pounds for open tibial fracture is 35.5%. The cost-effectiveness ratio is sensitive to the price of BMP and the severity of open tibial fractures. The use of recombinant human bone morphogenetic protein for spinal fusion surgery may increase the cost to the UK NHS by about 1.3 million pounds per year. The estimated incremental cost per QALY gained was about 120,390 pounds. The probability that BMP is cost-effective (i.e. cost/QALY less than 30,000 pounds) was only 6.4%. From the societal perspective, the estimated total cost of using BMP for spinal fusion is about 4.2 million pounds per year in the UK.
                Additional BMP treatment plus conventional intervention is more effective than conventional intervention alone for union of acute open tibial fractures. The cost-effectiveness of additional BMP may be improved if the price of BMP is reduced or if BMP is mainly used in severe cases. BMP may eliminate the need for autogenous bone grafting so that costs and complications related to harvesting autograft can be avoided. In non-unions, there is no evidence that BMP is more or less effective than bone graft; however, it is currently used when bone graft and other treatments have failed. The use of BMP-2 in spinal fusion surgery seems to be more effective than autogenous bone graft in terms of radiographic spinal fusion among patients with single-level degenerative disc disease. There is a lack of evidence about the effectiveness of BMP for other spinal disorders including spondylolisthesis and spinal stenosis. There was limited evidence showing that BMP is associated with greater improvement in clinical outcomes. According to the results of economic evaluation, the use of BMP for spinal fusion is unlikely to be cost-effective. The following areas would benefit from further research: clinical trials of BMP that include formal economic evaluation, a multicentre RCT of fracture non-union and of interbody and/or posterolateral spinal fusion, trials of non-tibial acute long bone fractures, and RCTs comparing BMP-2, BMP-7 and controls. The purpose of the current study was to evaluate savings from the use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in open tibia fractures by faster fracture healing and reduction of secondary treatment costs from a health insurance perspective for Germany and to compare them to the upfront price of 2900 EUR of rhBMP-2.
                Raw data from a previously published study (BESTT study) were used to conduct an economic calculation for secondary treatment costs for each patient from the standard care group and the 1.5 mg/ml rhBMP-2 group based on G-DRG 2005 prices from a health insurer's perspective for an observation period of 1 year for Germany.
                The use of rhBMP-2 leads to savings of 5697 EUR and 3183 EUR per patient for Gustilo-Anderson grade IIIB and all grade IIIA and B injuries, respectively. These savings offset the upfront price of 2900 EUR of rhBMP-2 and, therefore, net savings of 2797 EUR and 283 EUR for grade IIIB and all grade IIIA and B injuries can be achieved, respectively. These savings are mainly due to reduced sickness payments because of faster fracture healing in the rhBMP-2 group.
                The current study shows that the use of rhBMP-2 in Gustilo-Anderson grade IIIA and B open fractures leads--besides the better medical outcome for patients as shown previously in the BESTT study--to net savings from a health insurer's perspective. Treatment of long bone non-union (NU) continues to be a challenging task for the trauma surgeon often resulting in unsatisfactory results and long-term morbidity. Whilst autologous bone grafting remains the gold standard of treatment of these difficult cases, recently, due to the advances made in tissue engineering techniques, other alternatives have become available. In this study we report our preliminary results of treating long bone non-unions using either bone morphogenetic protein-7 (BMP-7) or platelet rich plasma (PRP) concentrations. Twenty-nine cases have entered this study thus far. Preliminary results indicate that BMP-7 is more efficacious that PRP as there was a significant failure rate of 6.2% versus 38.5% between BMP-7 and PRP, respectively. Osteogenic proteins (OP) are elements of a class of natural growth factors called Bone Morphogenetic Proteins (BMP). A specific member of this class is OP-1, a human recombinant protein that has osteogenic properties. The osteoinductive and osteoconductive properties of OP-1, with its specific collagen matrix, promote the generation of new functionally active, biologically and biomechanically mature bone. We carried out a clinical study to verify the potential of this protein in fresh tibial closed fractures, using OP-1 associated with osteosynthesis by means of a monolateral external fixator. The treatment of open fractures of the tibial shaft is often complicated by delayed union and nonunion. The objective of this study was to evaluate the safety and efficacy of the use of recombinant human bone morphogenetic protein-2 (rhBMP-2; dibotermin alfa) to accelerate healing of open tibial shaft fractures and to reduce the need for secondary intervention.
                In a prospective, randomized, controlled, single-blind study, 450 patients with an open tibial fracture were randomized to receive either the standard of care (intramedullary nail fixation and routine soft-tissue management [the control group]), the standard of care and an implant containing 0.75 mg/mL of rhBMP-2 (total dose of 6 mg), or the standard of care and an implant containing 1.50 mg/mL of rhBMP-2 (total dose of 12 mg). The rhBMP-2 implant (rhBMP-2 applied to an absorbable collagen sponge) was placed over the fracture at the time of definitive wound closure. Randomization was stratified by the severity of the open wound. The primary outcome measure was the proportion of patients requiring secondary intervention because of delayed union or nonunion within twelve months postoperatively.
                Four hundred and twenty-one (94%) of the patients were available for the twelve-month follow-up. The 1.50-mg/mL rhBMP-2 group had a 44% reduction in the risk of failure (i.e., secondary intervention because of delayed union; relative risk = 0.56; 95% confidence interval = 0.40 to 0.78; pairwise p = 0.0005), significantly fewer invasive interventions (e.g., bone-grafting and nail exchange; p = 0.0264), and significantly faster fracture-healing (p = 0.0022) than did the control patients. Significantly more patients treated with 1.50 mg/mL of rhBMP-2 had healing of the fracture at the postoperative visits from ten weeks through twelve months (p = 0.0008). Compared with the control patients, those treated with 1.50 mg/mL of rhBMP-2 also had significantly fewer hardware failures (p = 0.0174), fewer infections (in association with Gustilo-Anderson type-III injuries; p = 0.0219), and faster wound-healing (83% compared with 65% had wound-healing at six weeks; p =0.0010).
                The rhBMP-2 implant was safe and, when 1.50 mg/mL was used, significantly superior to the standard of care in reducing the frequency of secondary interventions and the overall invasiveness of the procedures, accelerating fracture and wound-healing, and reducing the infection rate in patients with an open fracture of the tibia. Currently, the treatment of diaphyseal tibial fractures associated with substantial bone loss often involves autogenous bone-grafting as part of a staged reconstruction. Although this technique results in high healing rates, the donor-site morbidity and potentially limited supply of suitable autogenous bone in some patients are commonly recognized drawbacks. The purpose of the present study was to investigate the benefit and safety of the osteoinductive protein recombinant human bone morphogenetic protein-2 (rhBMP-2) when implanted on an absorbable collagen sponge in combination with freeze-dried cancellous allograft.
                Adult patients with a tibial diaphyseal fracture and a residual cortical defect were randomly assigned to receive either autogenous bone graft or allograft (cancellous bone chips) for staged reconstruction of the tibial defect. Patients in the allograft group also received an onlay application of rhBMP-2 on an absorbable collagen sponge. The clinical evaluation of fracture-healing included an assessment of pain with full weight-bearing and fracture-site tenderness. The Short Musculoskeletal Function Assessment (SMFA) was administered before and after treatment. Radiographs were used to document union, the presence of extracortical bridging callus, and incorporation of the bone-graft material.
                Fifteen patients were enrolled in each group. The mean length of the defect was 4 cm (range, 1 to 7 cm). Ten patients in the autograft group and thirteen patients in the rhBMP-2/allograft group had healing without further intervention. The mean estimated blood loss was significantly less in the rhBMP-2/allograft group. Improvement in the SMFA scores was comparable between the groups. No patient in the rhBMP-2/allograft group had development of antibodies to BMP-2; one patient had development of transient antibodies to bovine type-I collagen.
                The present study suggests that rhBMP-2/allograft is safe and as effective as traditional autogenous bone-grafting for the treatment of tibial fractures associated with extensive traumatic diaphyseal bone loss.
                Therapeutic Level II. See Instructions to Authors for a complete description of levels of evidence. The role of bone morphogenetic proteins (BMPs) in osseous repair has been demonstrated in numerous animal models. Recombinant human osteogenic protein-1 (rhOP-1 or BMP-7) has now been produced and was evaluated in a clinical trial conducted under a Food and Drug Administration approved Investigational Device Exemption to establish both the safety and efficacy of this BMP in the treatment of tibial nonunions. The study also compared the clinical and radiographic results with this osteogenic molecule and those achieved with fresh autogenous bone.
                One hundred and twenty-two patients (with 124 tibial nonunions) were enrolled in a controlled, prospective, randomized, partially blinded, multi-center clinical trial between February, 1992, and August, 1996, and were followed at frequent intervals over 24 months. Each patient was treated by insertion of an intramedullary rod, accompanied by rhOP-1 in a type I collagen carrier or by fresh bone autograft. Assessment criteria included the severity of pain at the fracture site, the ability to walk with full weight-bearing, the need for surgical re-treatment of the nonunion during the course of this study, plain radiographic evaluation of healing, and physician satisfaction with the clinical course. In addition, adverse events were recorded, and sera were screened for antibodies to OP-1 and type-I collagen at each outpatient visit.
                At 9 months following the operative procedures (the primary end-point of this study), 81% of the OP-1-treated nonunions (n = 63) and 85% of those receiving autogenous bone (n = 61) were judged by clinical criteria to have been treated successfully (p = 0.524). By radiographic criteria, at this same time point, 75% of those in the OP-1-treated group and 84% of the autograft-treated patients had healed fractures (p = 0.218). These clinical results continued at similar levels of success throughout 2 years of observation, and there was no statistically significant difference in outcome between the two groups of patients at this point (p = 0.939). All patients experienced adverse events. Forty-four percent of patients in each treatment group had serious events, none of which were related to their bone grafts. More than 20% of patients treated with autografts had chronic donor site pain following the procedure.
                rhOP-1 (BMP-7), implanted with a type I collagen carrier, was a safe and effective treatment for tibial nonunions. This molecule provided clinical and radiographic results comparable with those achieved with bone autograft, without donor site morbidity. Osteogenic proteins (OPs), also referred to as bone morphogenetic proteins (BMPs), are a family of bone-matrix polypeptides isolated from a variety of mammalian species. Implantation of osteogenic proteins induces a sequence of cellular events that leads to the formation of new bone. In preclinical studies, the implantation of recombinantly produced human osteogenic protein-1 (OP-1, also referred to as BMP-7) into surgically created, critical-size diaphyseal segmental defects resulted in the regeneration of new bone that was fully functional biologically and biomechanically. Injection of an OP-1 solution into a fresh fracture model accelerated the bone repair process compared with control fracture healing. This was the result of greater and earlier new bone formation. Further study has demonstrated that OP-1 can be used as a bone graft substitute to promote spinal fusion, aid in the incorporation of metal implants, and improve the performance of autograft and allograft bone. Clinical study of OP-1 implanted in conjunction with a bovine bone-derived type 1 collagen carrier for the treatment of tibial nonunion fractures has shown healing characteristics similar to that obtained with autogenous iliac crest bone graft. Advantages of OP-1 included no donor site complications, less blood loss, and a shorter operative time. We performed a prospective, randomised double-blind study in 24 patients undergoing high tibial osteotomy to evaluate the effectiveness of human recombinant osteogenic protein (OP-1) on a collagen type-I carrier in a critically-sized fibular defect. The study had two phases, each evaluated by clinical, radiological and DEXA methods during the first postoperative year. The first concerned the validation of the model of the fibular defect, using positive (demineralised bone) and negative (untreated) controls. The second phase concerned the osteogenic potential of OP-1 on collagen type-I v collagen type-I alone. The results of the first phase established the critically-sized nature of the defect. In the untreated group no bony changes were observed while, in the demineralised bone group, formation of new bone was visible from six weeks onwards. The results of the second phase showed no significant formation of new bone in the presence of collagen alone, while in the OP-1 group, all patients except one showed formation of new bone from six weeks onwards. This proved the osteogenic activity of OP-1 in a validated critically-sized human defect. SUMMARY AIM: The aim of the study was to demonstrate whether RhBMP-7 is an effective alternative to autogenous bone graft in the healing of metaphyseal defects in the distal radius following corrective osteotomies for symptomatic malunion after distal radial fractures.
                Thirty patients were entered into the study and were randomised to receive either RhBMP-7 or autogenous bone graft harvested from the ipsilateral iliac crest. Stabilisation of the osteotomy was either carried out with non- bridging external fixation or the pi-plate. Clinical, radiographic and functional review were carried out at regular intervals up to 1 year.
                The first 10 patients were treated using non-bridging external fixation of the osteotomy. Two of the 4 patients treated with RhBMP-7 developed excessive osteolysis around the osteotomy site resulting in loss of the corrected position and non-union of the osteotomy. The other 2 patients healed at 13 weeks. The 6 patients treated with autogenous bone graft all healed at an average of 7 weeks, without any complications. It was postulated that the osteolysis was related to instability of the osteotomy site, and the use of external fixation was abandoned and replaced with internal fixation with a dorsal pi-plate. In the pi-plate group of patients, 10 were treated with autogenous bone graft and 10 with RhBMP-7. The bone graft patients healed at 7 weeks compared to 18 weeks for the RhBMP-7 patients, which was statistically significant (p = 0.019). The patients who received bone graft had complete filling of the metaphyseal defect radiologically. Five patients treated with RhBMP-7 healed at the volar cortex with a dorsal defect remaining at 1 year. Two patients developed non-union radiologically. Ten patients (3 in the RhBMP-7 and 7 in the bone graft groups) required plate removal for soft tissue complications.
                RhBMP-7 does not confer the same stability as bone graft, allowing shear forces across the osteotomy site when used in conjunction with non-bridging external fixation, reducing the capacity for healing and resulting in osteolysis. Using the RhBMP-7 with a pi-plate resulted in healing of the osteotomy, but at a slower rate than autogenous bone graft.
This review highlights a paucity of data on the use of BMP in fracture healing as well as considerable industry involvement in currently available evidence. There is limited evidence to suggest that BMP may be more effective than controls for acute tibial fracture healing, however, the use of BMP for treating nonunion remains unclear. The limited available economic evidence indicates that BMP treatment for acute open tibial fractures may be more favourable economically when used in patients with the most severe fractures.