[Use of osteoanabolics in fracture nonunion]. / Anwendung von Osteologika bei gestörter Frakturheilung.

BACKGROUND: The treatment of fracture nonunion (pseudarthrosis) is often lengthy and debilitating for the patient. There are operative and conservative therapies available. RESEARCH QUESTION: Does the systemic use of osteoanabolic acting substances (osteoanabolics) lead to an acceleration of the delayed fracture healing and/or strengthening of the fracture? Which types of pseudarthrosis are suitable for this treatment option? MATERIALS AND METHODS: A literature review was carried out focusing on the systemic anabolic therapy options for the treatment of delayed healing of fractures or pseudarthrosis. Additionally, our own case studies are presented. RESULTS: Teriparatide and strontium ranelate have a positive effect on the healing of fractures in animal studies and in humans. There are also case studies on the use of both substances in delayed fracture healing or pseudarthrosis. The scientific knowledge regarding teriparatide is significantly more comprehensive. However, prospective randomized trials are lacking so far. CONCLUSION: The systemic use of anabolics can be a therapeutic option, especially for biological reactive pseudarthrosis. However, these are off-label treatments and contraindications should be especially well heeded. Because of the numerous positive results, from the point of view of teriparatide treatment, a multicentric, prospective randomized study on the treatment of aseptic pseudarthrosis should be initiated.

BMP-2 delivered from a self-crosslinkable CaP/hydrogel construct promotes bone regeneration in a critical-size segmental defect model of non-union in dogs.

OBJECTIVES: To determine whether the addition of recombinant human bone morphogenetic protein (rhBMP-2) to a self-crosslinkable cellulosic hydrogel/biphasic calcium phosphate (BCP) granules construct promotes bone healing in critical-size ulnar defects in dogs. METHODS: A standardized 2 cm long ulnar ostectomy was performed bilaterally in five dogs to compare bone healing with hydrogel/BCP constructs associated with or without rhBMP-2. Cancellous-bone autografts were used as positive controls in unilateral ulnar defects in five additional dogs. Radiographically, bone healing was evaluated at four, eight, 12, 16 and 20 weeks postoperatively. Histological qualitative analysis with microCT imaging and light and scanning electron microscopy were performed 20 weeks after implantation. RESULTS: All rhBMP-2-loaded constructs induced the formation of well-differentiated mineralized lamellar bone surrounding the BCP granules and bridging bone/implant interfaces as early as eight weeks after surgery. Bone regeneration appeared to develop earlier with the rhBMP-2 constructs than with the cancellous-bone autografts while similar results were obtained at 20 weeks. Constructs without any rhBMP-2 showed osteoconductive properties limited to the bone junctions and a lack of osteoinduction without bone ingrowth within the implantation site. In one dog, the leakage of the hydrogel loaded with rhBMP-2 induced an extensive heterotopic bone formation. CLINICAL SIGNIFICANCE: The addition of rhBMP-2 to a self-crosslinkable hydrogel/BCP construct could promote bone regeneration in a critical-size-defect model with similar performance to autologous bone grafts.

Augmentation of autologous bone graft by a combination of bone morphogenic protein and bisphosphonate increased both callus volume and strength.

BACKGROUND AND PURPOSE: Bone morphogenic proteins (BMPs) can be used in non-unions to replace autograft. BMPs induce osteoblasts and (less well known) also osteoclasts, which can in turn be controlled by a bisphosphonate. In the present study, our aim was to improve the biological effect of autologous bone graft by adding an anabolic BMP, with or without bisphosphonates, in an open-fracture model prone to non-union. METHODS: Rat femurs were osteotomized and fixed with an intramedullary K-wire. Autograft was placed at the osteotomy, mixed with either saline or BMP-7. After 2 weeks, the rats had a single injection of saline or of a bisphosphonate (zoledronate). The rats were killed after 6 weeks and the femurs were evaluated by radiography, micro-CT, histology, and 3-point bending test. RESULTS: All fractures healed. The callus volume was doubled in the BMP-treated femurs (p < 0.01) and increased almost 4-fold in the femurs treated with both BMP and systemic zoledronate (p < 0.01) compared to autograft. In mechanical testing, the autograft group reached approximately half the strength of the contralateral, non-osteotomized femur (p < 0.001). By adding BMP to the autograft, the strength was doubled (p < 0.001) and with both BMP and systemic zoledronate, the strength was increased 4-fold (p < 0.001) compared to autograft alone. INTERPRETATION: The combination of BMP and bisphosphonate as an adjunct to autograft is superior to autograft alone or combined with BMP. The combination may prove valuable in the treatment of non-unions.

Mechanical load modulates the stimulatory effect of BMP2 in a rat nonunion model.

INTRODUCTION: Local application of bone morphogenetic proteins (BMPs) at the fracture site is known to stimulate bone regeneration. However, recent studies illustrate that the BMP-initiated mineralization may be enhanced by additional mechanical stimulation. Therefore, bone healing was monitored in vivo in order to investigate the effect of mechanical loading on the initiation and maturation of mineralization after cytokine treatment. We hypothesized that the mechanical stimulation would further enhance the efficacy of BMP2 treatment. METHOD: Female Sprague-Dawley rats underwent a 5-mm defect, stabilized with an external fixator. Type I collagen scaffolds containing 50 µg of BMP2 diluted in a solvent or solvent only were placed into the defects. The BMP2-treated specimens and control specimens were then each divided into two groups: one that underwent mechanical loading and a nonloaded group. In vivo loading began immediately after surgery and continued once per week for the entire 6-week experimental period. For all groups, the newly formed callus tissue was quantitatively evaluated first by in vivo microcomputed tomography at 2, 4, and 6 weeks and further by histologic or histomorphometric analysis at 6 weeks postoperation. RESULTS: Mechanical stimulation with BMP2 treatment significantly enhanced mineralized tissue volume and mineral content at 2 weeks. Histological analysis demonstrated a significantly greater area of fibrous connective tissue including bone marrow in the stimulated group, suggesting reconstitution of the endosteal canal and more advanced bone remodeling present in the mechanical loaded group. Both groups receiving BMP2 underwent massive bone formation, achieving bony bridging after only 2 weeks, while both control groups, receiving solvent only, revealed a persisting nonunion, filled with fibrous connective tissue, prolapsed muscle tissue, and a sealed medullary canal at week 6. CONCLUSION: Mechanical loading further enhanced the efficacy of BMP2 application evidenced by increased mineralized tissue volume and mineralization at the stage of bony callus bridging. These data suggest that already a minimal amount of mechanical stimulation through load bearing or exercise may be a promising adjunct stimulus to enhance the efficacy of cytokine treatment in segmental defects. Further studies are required to elucidate the mechanistic interplay between mechanical and biological stimuli.

Prevention of atrophic nonunion by the systemic administration of parathyroid hormone (PTH 1-34) in an experimental animal model.

OBJECTIVES: Recombinant human parathyroid hormone (PTH 1-34) has been previously shown to enhance fracture healing in animal models. Here, we sought to determine whether the systemic administration of PTH 1-34 is effective in preventing atrophic fracture nonunion in a murine, surgical nonunion model. METHODS: We used an established reproducible long-bone murine fracture nonunion model by generating a midshaft femur fracture, followed by fracture distraction using an intramedullary pin and custom metallic clip to maintain a fracture gap of 1.7 mm. Mice were randomized to receive either daily intraperitoneal injections of 30 µg/kg PTH 1-34 for 14 days or saline injections. At 6 weeks after the procedure, radiographic and histologic assessment of fracture healing was performed. RESULTS: At 6 weeks after surgery, the group treated with PTH showed higher rates of bony union (50% vs 8%; P < 0.05) as assessed by radiographic analysis. Mean gap size was also significantly lower in the PTH group (1.42 vs 0.36 mm in the control group; P < 0.05). Histologic analysis of atrophic nonunions in the control group revealed a persistent fracture gap with intervening fibrous tissue. In contrast, healed subjects in the PTH-treated group had cortical bridging with mature bone and relatively little callus, which is consistent with primary intramembranous ossification. CONCLUSIONS: Daily systemic administration of recombinant PTH 1-34 increased the rate of union in a mouse atrophic nonunion model. This may have important implications for the potential clinical role of PTH 1-34 in the treatment of atrophic fracture nonunions.

[Results of nonunion treatment with bone morphogenetic protein 7 (BMP-7)]. / Ergebnisse der Pseudarthrosenbehandlung mit "bone morphogenetic protein 7" (BMP-7).

BACKGROUND: Complex patterns of impaired bone healing can result in a severe economic and social burden for the patient. Herein we describe the local application of recombinant human bone morphogenetic protein 7 (BMP-7). The goal of this prospective study is to review the indications, application and validation of this therapy. MATERIAL AND METHOD: From June 2002 to June 2008, we applied 101 BMP-7 treatments in 101 nonunions of 98 patients. The average age of the patients was 50 years (18-88 years). The gender composition was 29 women (30%) and 69 men (70%). Before BMP-7 application, patients had already underwent surgical treatement an average of 3.3 times (median 3, 1- to 13-times). We used BMP-7 "off-label" in all long bones. RESULTS: In 93 cases (92%), we observed proper bone healing. The average healing time was 4.8 months (range 1.5-11 months). The average time from injury to BMP-7 application was 18.4 months (3-84 months). In 65 cases, BMP-7 application was combined with re-osteosynthesis and autologous bone grafting. Serious side effects were not observed. CONCLUSIONS: BMP-7 should not be used as general treatment of nonunion in all patients, but appears to be effective for the treatment of complex cases. In clinical practice, the decision to proceed with off-label use of BMP-7 should be made on a case-by-case basis.

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.

Recombinant human bone morphogenetic protein-7 for treatment of long bone non-union: an observational, retrospective, non-randomized study of 105 patients.

Autogenous bone-grafting is frequently used in the treatment of fracture non-union. The donor-site morbidity and potentially limited supply of suitable autogenous bone are commonly recognized drawbacks. Recent studies advocated the benefit and safety of recombinant human bone morphogenetic protein-7 (rhBMP-7) in several anatomical sites. An observational, retrospective, non-randomized study on the use of BMP-7 in treating non-union in various sites has been carried out by the BMP-7 Italian Observational Study (BIOS) Group. The clinical series included 105 patients. Additional grafts were used based on the surgeon's decision. Radiographic and clinical assessments were carried out at progressive time intervals on two groups: BMP-7+autograft (A) or BMP-7 (B). The mean follow-up was 29.2 months. The last assessment showed an 88.8% success rate with an average healing time of 7.9 months. At >/=9 months there was overlapping between the unions recorded in the two groups (PA-PB=1.5%; CI 95%: -0.149; 0.119). This is an observational study that illustrates the efficacy of BMP-7 with and without bone grafting for the treatment of long bone non-unions.