Clinical effectiveness and cost-effectiveness of bone morphogenetic proteins in the non-healing of fractures and spinal fusion: a systematic review. Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. Acceleration of tibial fracture-healing by non-invasive, low-intensity pulsed ultrasound. [Cost-benefit analysis of the use of rhBMP-2 in open tibial fractures: savings from a health insurer's perspective]. Recombinant human BMP-2 and allograft compared with autogenous bone graft for reconstruction of diaphyseal tibial fractures with cortical defects. A randomized, controlled trial. Pulsed magnetic field therapy for tibial non-union. Interim results of a double-blind trial. Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. Should insertion of intramedullary nails for tibial fractures be with or without reaming? A prospective, randomized study with 3.8 years' follow-up. Complex tibial fracture outcomes following treatment with low-intensity pulsed ultrasound.
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 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. Sixty-seven closed or grade-I open fractures of the tibial shaft were examined in a prospective, randomized, double-blind evaluation of use of a new ultrasound stimulating device as an adjunct to conventional treatment with a cast. Thirty-three fractures were treated with the active device and thirty-four, with a placebo control device. At the end of the treatment, there was a statistically significant decrease in the time to clinical healing (86 +/- 5.8 days in the active-treatment group compared with 114 +/- 10.4 days in the control group) (p = 0.01) and also a significant decrease in the time to over-all (clinical and radiographic) healing (96 +/- 4.9 days in the active-treatment group compared with 154 +/- 13.7 days in the control group) (p = 0.0001). The patients' compliance with the use of the device was excellent, and there were no serious complications related to its use. This study confirms earlier animal and clinical studies that demonstrated the efficacy of low-intensity ultrasound stimulation in the acceleration of the normal fracture-repair process. 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. 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. Patients with tibial fractures which had remained un-united for at least 52 weeks were randomly allocated to either active or dummy pulsed magnetic field stimulators and treated in full leg plasters for 24 weeks with a non-weightbearing conservative regimen, as is usual with such techniques. Fractures in 5 of the 9 patients with working machines united and fractures in 5 of the 7 patients with dummy machines also united. These early results of this double-blind trial are compatible with a difference in success rate at 24 weeks on active treatment of + 33% to -61% (95% confidence limits) compared with the success rate on the dummy stimulators. The high proportion of fractures uniting in the control group suggests that conservative management of non-union is effective and this may explain much of the success attributed to pulsed magnetic field therapy. 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. To determine if any differences exist in healing and complications between reamed and unreamed nailing in patients with tibial shaft fractures.
                Prospective, randomized.
                Level 1 trauma center.
                Forty-five patients with displaced closed and open Gustilo type I-IIIA fractures of the central two thirds of the tibia.
                Stabilization of tibial fractures either with a slotted, stainless steel reamed nail or a solid, titanium unreamed nail.
                Nonunions, time to fracture healing, and rate of malunions.
                The average time to fracture healing was 16.7 weeks in the reamed group and 25.7 weeks in the unreamed group. The difference was statistically significant (P = 0.004). There were three nonunions, all in the unreamed nail group. Two of these fractures healed after dynamization by removing static interlocking screws. The third nonunion did not heal despite exchange reamed nailing 2 years after the primary surgery and dynamization with a fibular osteotomy after an additional 1 year. There were two malunions in the reamed group and four malunions in the unreamed group. There were no differences for all other outcome measurements.
                Unreamed nailing in patients with tibial shaft fractures may be associated with higher rates of secondary operations and malunions compared with reamed nailing. The time to fracture healing was significantly longer with unreamed nails. A clinical study was conducted to investigate the effect of low-intensity pulsed ultrasound (US) stimulation (LIPUS) on the healing of complex tibial fractures. Thirty complex tibial fractures were randomly assigned to the treatment with LIPUS (n = 16) or by a dummy machine (sham-exposed: n = 14). The fractures were immobilized by either internal or external fixations according to the clinical indications. LIPUS was given 20 min/day for 90 days. Fracture healing was monitored by clinical, radiological, densitometric and biochemical assessments. The LIPUS-treated group showed statistically significantly better healing, as demonstrated by all assessments. Complications were minimal in the LIPUS group. There were two cases of delayed union, with one in each group. There were two cases of infection in the control group. The delayed-union cases were subsequently treated by LIPUS and the infection cases were treated with standard protocol. Fracture healing in these patients was again treated by LIPUS.
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.