Giorgio Maria Calori

The use of bone-graft substitutes in large bone defects: any specific needs?

INTRODUCTION The gold standard for restoring bone defects is still considered to be autologous bone grafting. However, clinical benefits are not guaranteed and donor-site complications and morbidity is not infrequent. Research is on-going for the development of alternative bone substitutes of both biological and synthetic origin. The purpose of this study was to evaluate the type of materials used and their efficacy for the treatment of large bone defects in traumatology and orthopaedic surgery. MATERIALS AND METHOD A literature review was carried out of Embase and PubMed databases. Inclusion criteria were articles in English language focusing on the use of bone substitutes in trauma and orthopaedic surgery for the treatment of bone defects and included details on the structural, biological or biomechanical properties of the pure product. Furthermore, based on two clinical challenges, fracture non-union and impaction grafting we elaborated on the use of polytherapy for large bone defects as guided by the diamond concept. RESULTS All the products indicated in this manuscript possess osteoconductive activities but have different resorption times and biomechanical properties. Bone graft substitute materials are used for a wide range of clinical applications even when the level of clinical evidence is low. The size and location of the defect and the local biological and mechanical environment as well as the biomechanical characteristics of the material determine the type of device that can be implanted in a bone defect. CONCLUSION Proper assessment of the biological and mechanical environment and accurate patient selection are necessary to judge the extent of therapy the injury warrants. A sound understanding of various aspects of biomaterial properties and their relation and influence towards bone healing is of utmost importance. We suggest the application of polytherapy for the treatment of large bone defects and advocate the use of the diamond concept as a guideline.

Application of BMP-7 to tibial non-unions: A 3-year multicenter experience

SUMMARY The effective treatment of the often debilitating, longlasting and large-asset-consuming complication of fracture non-unions has been in the centre of scientific interest the last decades. The use of alternative bone substitutes to the gold standard of autologous graft includes the osteoinductive molecules named bone morphogenetic proteins (BMPs). A multicenter registry and database (bmpusergroup.co.uk) focused on the application of BMP-7/OP-1 was created in December 2005. We present the preliminary results, using the prospective case-series of aseptic tibial non-unions as an example. Sixty-eight patients fulfilled the inclusion criteria for this observational study, with a minimum follow-up of 12 months. The median duration of tibial non-union prior to BMP-7 application was 23 months (range 9-317 mo). Patients had undergone a median of 2 (range 0-11) revision procedures prior to the administration of BMP-7. In 41% the application of BMP-7 was combined with revision of the fixation at the non-union site. Non-union healing was verified in 61 (89.7%) in a median period of 6.5 months (range 3-15 mo). No adverse events or complications were associated with BMP-7 application. The safety and efficacy of BMP-7 was verified in our case series, and was comparable to the existing evidence. The establishment of multicenter networks and the systematic and long-term follow- up of these patients are expected to provide further information and significantly improve our understanding of this promising osteoinductive bone substitute.

Application of rhBMP-7 and platelet-rich plasma in the treatment of long bone non-unions: a prospective randomised clinical study on 120 patients.

The purpose of this prospective randomised clinical study was to compare the efficacy of recombinant bone morphogenetic protein 7 (rhBMP-7) and platelet-rich plasma (PRP) as bone-stimulating agents in the treatment of persistent fracture non-unions. One hundred and twenty patients were randomised into two treatment groups (group rhBMP-7 vs. group PRP). Sixty patients with sixty fracture non-unions were assigned to each group (median age: 44 years, range 19-65, for the rhBMP-7 group and 41 years, range 21-62, for the PRP group, respectively). In the rhBMP-7 group, there were 15 tibial non-unions, 10 femoral, 15 humeral, 12 ulnar, and 8 radial non-unions. In the PRP group, there were 19 tibial non-unions, 8 femoral, 16 humeral, 8 ulnar, and 9 radial non-unions. The median number of operations performed prior to our intervention was 2 (range 1-5) and 2 (range 1-5) with autologous bone graft being used in 23 and 21 cases for the rhBMP-7 and PRP groups, respectively. Both clinical and radiological union occurred in 52 (86.7%) cases of the rhBMP-7 group compared to 41 (68.3%) cases of the PRP group, with a lower median clinical and radiographic healing time observed in the rhBMP-7 group (3.5 months vs. 4 months and 8 months vs. 9 months, respectively). This study supports the view that in the treatment of persistent long bone non-unions, the application of rhBMP-7 as a bone-stimulating agent is superior compared to that of PRP with regard to their clinical and radiological efficacy.

Do Nonsteroidal Anti-Inflammatory Drugs Affect Bone Healing? A Critical Analysis

Nonsteroidal anti-inflammatory drugs (NSAIDs) play an essential part in our approach to control pain in the posttraumatic setting. Over the last decades, several studies suggested that NSAIDs interfere with bone healing while others contradict these findings. Although their analgesic potency is well proven, clinicians remain puzzled over the potential safety issues. We have systematically reviewed the available literature, analyzing and presenting the available in vitro animal and clinical studies on this field. Our comprehensive review reveals the great diversity of the presented data in all groups of studies. Animal and in vitro studies present so conflicting data that even studies with identical parameters have opposing results. Basic science research defining the exact mechanism with which NSAIDs could interfere with bone cells and also the conduction of well-randomized prospective clinical trials are warranted. In the absence of robust clinical or scientific evidence, clinicians should treat NSAIDs as a risk factor for bone healing impairment, and their administration should be avoided in high-risk patients.

Risk factors contributing to fracture non-unions

Many studies have been carried out on the matter of pseudoarthrosis since the 1920s, where pseudoarthrosis is defined to occur when consolidation cannot be completed wi thout new biological or mechanical st imulation. Since then, several authors have contr ibuted their knowledge of osteogenetic mechanisms, placing the emphasis on the risk factors of a non-union. In genera[ terms the risk factors contr ibut ing to non-union can be separated into genera[ and local factors (Table 1 ). The purpose of this study is to ident i fy and report on the di f ferent factors which have been implicated in the pathogenesis of non-union of fractures.

Classification of non-union: Need for a new scoring system?

SUMMARY A new scoring system is proposed in order to assist surgeons with the complex analysis associated with non-union surgery. Patients with non-union are rarely easily compared with one another and this has frustrated research in this field. We have therefore attributed values to clinical features based on clinical experience and research evidence, so that patients of similar complexity can be compared with one another. When greater experience with this scoring system has been gained it will be further refined and validated. We propose that surgeons with a sub specialist interest in non-union surgery use this system in reporting results, and that non- specialist surgeons use it to inform their decision to treat the fracture themselves, or refer to a sub specialist.

Application of bone morphogenetic proteins to femoral non-unions: a 4-year multicentre experience

Fracture non-unions often complicate orthopaedic trauma. BMPs (bone morphogenetic proteins) are currently considered the most appealing osteoinductive agents. Applications of BMP-7 since January 2004 were prospectively recorded in a multicentre registry of aseptic femoral non-unions. The study included 30 patients who had undergone a median of 1 revision operation before BMP-7 application and who were followed up for a median 24 months. In 23/30 cases the application of BMP-7 was combined with revision of the fixation, and in 12 it was combined also with autograft. Non-union healing was verified in 26/30 cases in a median period of 6 months. No adverse events were associated with BMP-7 application. Our case series supports the safety and efficacy of BMP-7 in femoral non-unions. Multicentre networks and systematic, long-term follow-up of patients may improve understanding of this promising osteoinductive bone substitute.

Bone morphogenetic proteins and tissue engineering: future directions.

As long as bone repair and regeneration is considered as a complex clinical condition, the administration of more than one factor involved in fracture healing might be necessary. The effectiveness or not of bone morphogenetic proteins (BMPs) in association with other growth factors and with mesenchymal stem cells in bone regeneration for fracture healing and bone allograft integration is of great interest to the scientific community. In this study we point out possible future developments in BMPs, concerning research and clinical applications.

Treatment of long bone non-unions with polytherapy: Indications and clinical results

The incidence of long bone non-unions has been estimated to range between 5 and 10%. Autologous bone graft usually harvested from the iliac crest continues to be the gold standard for biological enhancement of atrophic non-unions. However, its use has been hampered by minor and major donor site complications. Moreover despite possessing the properties of osteogenecity, osteoconductivity and some osteoinductivity the overall results of treatment have not been consistent with disappointing success rates at times. The concept of polytherapy for the treatment of non-unions, namely the simultaneous application of the three fundamental elements of the diamond concept, osteoprogenitor cells, growth factor and osteoconductive scaffold, appears to be an attractive alternative but more studies are desirable to validate this strategy.

Autograft versus BMPs for the treatment of non-unions: What is the evidence?

Autograft is considered the gold standard in non-union treatment. However, it is associated with significant morbidity and limited biological activity. The introduction of bone morphogenetic proteins (BMPs) has added a valuable tool to the surgeons possibilities. The initial expectations of the effectiveness of BMPs were high, but over the years the union rate of BMPs was shown to be comparable with autograft. In this overview, both treatment modalities are compared. The off-label use of BMPs, the combination of BMPs and autograft, and the economic perspective of BMP use are summarized. In their current formulation, BMPs are an effective alternative for autograft in selected cases. The beneficial effect outweighs the economic costs. Widening of the indication to other long bone non-unions and new formulations are expected in the nearby future.