In vitro & in vivo assessment of a herbal formula used topically for bone fracture treatment.

AIM OF THE STUDY: A novel topical paste used for fracture healing (FH), consisting of the extracts of six herbs, Radix Dipsaci, Ramulus Sambucus Williamsii, Rhizoma Notoginseng, Flos Carthami, Rhizoma Rhei and Fructus Gardeniae, was developed according to the classical theory of traditional Chinese medicine. This study aimed to determine the effectiveness of this formula, and some of its important chemical components in the promotion of fracture healing. The transdermal transport of FH was also examined. MATERIALS AND METHODS: The osteogenic, angiogenic and nitric oxide suppressing effects of FH and its important chemical marker components were assessed by using osteoblastosacroma UMR-106 cells, human umbilical vein endothelial cells (HUVEC) and murine macrophage RAW264.7 cells, respectively. The bone healing effects of the FH paste and its transdermal absorption were determined using a rabbit fracture model. The callus sizes, bone specific alkaline phosphatase levels and biomechanical properties of the healed bone were assessed. RESULTS: FH significantly increased the cell proliferation in UMR-106 and HUVEC cells and inhibited the nitric oxide production in murine macrophage in dose-dependent manner. Its important chemical components asperosaponin VI, ginsenoside Rg1 and emodin were shown to be acting positively in the respective in vitro studies. FH paste significantly improved the bone healing in the rabbit fracture model, as was indicated by the increases in callus size at weeks 2-5, and the elevations in bone specific alkaline phosphatase activities at weeks 5-6. The analysis using LC/MS/MS also showed the presence of important chemical marker components of the FH formula in the plasma after 8 weeks of topical treatment. CONCLUSION: This study presents the first scientific evidence of the efficacy of a herbal paste in the promotion of fracture healing. There were evidences of transdermal transport of the chemical components, control the inflammation through nitric oxide inhibition, promotion of angiogenesis, and bone healing in the in vitro tests, as well as in the experimental animal.

Bone morphogenetic protein (BMP) for fracture healing in adults.

BACKGROUND: Delay in fracture healing is a complex clinical and economic issue for patients and health services. OBJECTIVES: To assess the incremental effectiveness and costs of bone morphogenetic protein (BMP) on fracture healing in acute fractures and nonunions compared with standards of care. SEARCH STRATEGY: We searched The Cochrane Library (2008, Issue 4), MEDLINE, and other major health and health economics databases (to October 2008). SELECTION CRITERIA: Randomised controlled trials (RCTs) and full or partial economic evaluations of BMP for fracture healing in skeletally mature adults. DATA COLLECTION AND ANALYSIS: All clinical and economic data were extracted by one author and checked by another. MAIN RESULTS: Eleven RCTs, all at high risk of bias, and four economic evaluations were included. Apart from one study, the times to fracture healing were comparable between the BMP and control groups. There was some evidence for increased healing rates, without requiring a secondary procedure, of BMP compared with usual care control in acute, mainly open, tibial fractures (risk ratio (RR) 1.19, 95% CI 0.99 to 1.43). The pooled RR for achieving union for nonunited fractures was 1.02 (95% CI 0.90 to 1.15). One study found no difference in union for patients who had corrective osteotomy for radial malunions. Data from three RCTs indicated that fewer secondary procedures were required for acute fracture patients treated with BMP versus controls (RR 0.65, 95% CI 0.50 to 0.83). Adverse events experienced were infection, hardware failure, pain, donor site morbidity, heterotopic bone formation and immunogenic reactions. The evidence on costs for BMP-2 for acute open tibia fractures is from one large RCT. This indicates that the direct medical costs associated with BMP would generally be higher than treatment with standard care, but this cost difference may decrease as fracture severity increases. Limited evidence suggests that the direct medical costs associated with BMP could be offset by faster healing and reduced time off work for patients with the most severe open tibia fractures. AUTHORS' CONCLUSIONS: 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.

Bone morphogenetic proteins in orthopaedic trauma: recent clinical findings with human bone morphogenetic protein-2 (rhBMP-2).

This article introduces papers based on presentations from a symposium entitled "Bone Morphogenic Protein Advisory Meeting in Orthopaedic Trauma", where recent clinical findings with human bone morphogenetic protein-2 (rhBMP-2) were reviewed. It also presents two case studies which illustrate the clinical problems with the potential morbidity of tibial fractures and the potential benefits of the use of rhBMP-2 at surgery. The article concludes with a summary of the symposium. Tibial shaft fracture repair is associated with a significant financial burden on the patient, the health care providers and the medical insurance companies. It is anticipated that the clinical advantages of rhBMP-2 could lead to cost savings both inside and outside the hospital setting.

Economic considerations for the use of recombinant human bone morphogenetic protein-2 in open tibial fractures in Europe: the German model.

The addition of recombinant human bone morphogenetic protein (rhBMP-2) to the standard of care, consisting of soft tissue management and intramedullary nailing, in the BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) study led to a significantly better outcome for the patient. Reductions in fracture healing time, secondary interventions for delayed fracture healing and infection rates were observed with 1.50 mg/mL rhBMP-2 compared with the standard of care alone. In Germany the approximate cost of applying one dose of recombinant human bone morphogenetic protein-2 (rhBMP-2) to an open tibial fracture is euro2970. The current German-Diagnosis-Related Group reimbursement system provides one flat rate per hospital stay or treatment case, and does not take into account the costs of rhBMP-2 application. Therefore there is no reimbursement for the price of rhBMP-2 for hospitals by health insurance companies. However, the above mentioned improvements in medical outcome could lead to important savings for health care systems, particularly for health insurance companies. A sound economic model to assess the cost-effectiveness and budget impact of rhBMP-2 is required. Using medical data from the BESTT study the differences in fracture healing time, in reduction of secondary interventions for fracture healing and infection treatment can be transferred into economic savings. It is anticipated that the overall savings that can be achieved by rhBMP-2 treatment in open tibia fractures, offset the upfront price of rhBMP-2 and lead to net savings for health insurance companies.

Recombinant human bone morphogenic protein-2 in fracture care.

Recombinant human bone morphogenic protein-2 (rhBMP-2) is an osteoinductive protein that is now available for the acute treatment of open tibial fracture. Data from preclinical and clinical trials support its role in fracture care. This article summarizes data from two randomized controlled clinical trials investigating the safety and efficacy of rhBMP-2 in patients with open tibial shaft fractures and tibial fractures with bone defects. Also included is a summary of an economic analysis that examined the cost impact of rhBMP-2 from a hospital and payor perspective.