Bone morphogenetic proteins in orthopaedic trauma surgery

Fracture healing describes the normal post-traumatic physiologic process of bone regeneration. Commonly, this complicated process occurs without interruption, however, certain clinical situations exist that may benefit from the usage of bone healing enhancement agents. Bone morphogenetic proteins (BMPs) assist in the process of bone healing by recruiting bone-forming cells to the area of trauma. The usage of BMP currently has two FDA-approved indications: (1) treatment of acute tibial fractures treated with intramedullary fixation and (2) treatment of long bone non-union. Despite this limited scope, off-label BMP usage continues to push the envelope for new applications. Although proven to be clinically successful, BMP use must be balanced with the large costs associated with their application. Regardless, more prospective randomised clinical trials must be conducted to validate and expand the role of BMP in the setting of trauma.     

Use of bone morphogenetic proteins in traumatology

An estimated 5–10% of all fractures show impaired healing, leading to delayed union, or non-union. Chemical, or physical methods to accelerate bone healing are of great interest to the orthopaedic and trauma community. Research over the last 20 years has established that successful fracture healing is steered by specific growth factors. Of these, the bone morphogenetic proteins (BMPs) are probably the most important. The signalling pathway of these proteins is tightly regulated, overseeing a finely orchestrated cascade of events that occur after a fracture. The promising results of BMPs in preclinical studies have recently cleared the way for their use in specific fractures, or non-unions in clinical practice. The purpose of this work is to give a brief overview of BMPs and to review the clinical data currently available on the use of BMPs in fracture healing.     

Co-expression of BMPs and BMP-inhibitors in human fractures and non-unions

Bone morphogenetic proteins (BMPs) are increasingly being used clinically to enhance fracture repair and healing of non-unions. However, the potential efficacy of supraphysiological dosing for clinical results warrants further clarification of the BMP signaling pathway in human fracture healing. As BMP signaling can be fine-tuned at numerous levels, the role of BMP-inhibitors has become a major focus. The aim of the present study was to document co-expression of BMPs, pSmad 1/5/8, and BMP-inhibitors in human fracture callus and human non-unions. Using human tissue of fracture callus (n=14) and non-unions (n=4) we documented expression of BMPs (BMP2, BMP3 and BMP7), pSmad 1/5/8 and the BMP-inhibitors noggin, gremlin, chordin, Smad-6, Smad-7 and BAMBI. Co-expression of pSmad 1/5/8, BMPs and BMP-inhibitors was noted in the osteoblasts of fracture callus as well as of non-unions. Expression of BMP-inhibitors was generally stronger in non-unions than in fracture callus. The most pertinent differences were noted in the cartilaginous tissue components. Expression of BMP2 in chondrocytes was markedly decreased in non-unions compared to fracture callus and that of BMP7 was almost completely absent. Expression of BMP-inhibitors was almost the same in osteoblasts, chondrocytes and fibroblasts of fracture callus and well as in non-unions. Interestingly, although BMP ligands were present in the chondrocytes and fibroblasts of non-unions, they did not co-express pSmad 1/5/8 suggesting that BMP signaling may have been inhibited at some point before Smad 1/5/8 phosphorylation. These results suggest co-expression of BMP, pSmad 1/5/8 and BMP-inhibitors occurs in human fracture callus as well as non-unions but the relative expression of BMPs vs. BMP-inhibitors was different between these two tissue types. In contrast to our expectations, the expression of BMP inhibitors was comparable between fracture callus and non-unions, whereas the expression of BMPs was notably lower in the cartilaginous component of the non-unions in comparison to fracture callus. Based on these results, we believe that aberrations in the BMP-signaling pathway in the cartilaginous component of fracture healing could influence clinical fracture healing. An imbalance between the local presence of BMP and BMP-inhibitors may switch the direction towards healing or non-healing of a fracture.     

Clinical application of BMP 7 in long bone non-unions

Background

Non-unions of long bone fractures are a therapeutic and economic problem of increasing frequency. Aside from conservative treatment options such as ultrasound, impulse waves, and casts, the basic surgical options are autogenous cancellous bone grafting, rod dynamization, reamed nailing, plate fixation, and bone transport techniques. If these methods fail to work, there is a need for alternative treatment options.

Methods

Since May 2001, treatment with recombinant human bone morphogenic protein 7 (BMP 7 or osteogenic protein 1) in combination with a type-one collagen carrier has been the subject of increasing interest. BMP 7 induces the formation of new bone by stem cell differentiation, thereby initiating the reaction cascade of osteogenesis. Non-unions over 9 months and unsuccessful bone grafting constitute the indication for this treatment.

Results

We report our experience with 54 patients who had atrophic non-union of long bone fractures. Between May 2002 and May 2006, 57 units of BMP 7 were used. The localization of the non-unions included 21 in the femur, 26 in the tibia, 3 in the humerus and 7 in the forearm. In 36 cases, BMP 7 was used in combination with osteosynthesis revision and bone grafting; in 9 additional patients, BMP 7 was used with bone grafting alone. In 12 patients, BMP 7 was applied as a single procedure without any bone grafting or any change in osteosynthesis.

Conclusions

There were no perioperative or postoperative complications. Follow-up was obtained for a minimum of 6 months. 47 of the 57 (82%) implantations were successful, with bony healing confirmed by clinical and radiological evaluation. In summary, our results support BMP 7 as an additional innovative therapy for long bone non-unions.     

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.Several factors are known to increase the risk of developing a delayed union or non-union. General factors include malnutrition, infection, smoking, diabetes, and the use of drugs, e.g. NSAIDs, which can all lead to decreased bone formation and a hypotrophic/atrophic non-union. Also, local factors such as a devascularized periosteum in open fractures or after extensive surgical approaches might lead to hypotrophic/atrophic non-union (Calori et al. 2007, Perumal and Roberts 2007). Autograft is the gold standard for induction of callus formation in established hypotrophic/atrophic non-unions. Instead of autograft, recombinant bone morphogenic protein (BMP), which is commercially available as rhBMP-2 and -7, can be used alone or as an adjunct to either allograft or autograft to induce osteoblast recruitment and differentiation (Little et al. 2007). In randomized trials, BMP has been shown to be equivalent but not better than autograft regarding rate of healing (Jones et al. 2006, Ristniemi et al. 2007, Kanakaris et al. 2008). What is less well known is that BMPs also stimulate cells of the osteoclastic cell lineage, inducing bone resorption (Giannoudis et al. 2007). Bisphosphonates are a group of drugs that inactivate osteoclasts by inducing apoptosis (Rogers et al. 2011), thereby inhibiting bone resorption.In previous rat bone chamber studies using cancellous bone graft, the speed of remodeling and the volume of remodeled graft were found to be increased by BMP, but most of the newly formed bone was resorbed. By adding a bisphosphonate, locally (Belfrage et al. 2011) or systemically (Harding et al. 2008), the anabolic effect of the BMP was retained while the resorption was inhibited. The amount of remaining new-formed bone after remodeling increased several fold. The combination of BMP and bisphosphonates has also been used in a critical defect model (Little et al. 2005) and an open-fracture model (Doi et al. 2011), with similar results.We investigated whether BMP or BMP together with a systemic bisphosphonate can augment autograft in an osteotomy model designed to reflect the healing difficulties in open fractures. We hypothesized that by adding a bisphosphonate, the resorptive effect of BMP would be muted and the osteoinductive effect would be retained—and that this would result in stronger calluses.     

Development of a femoral non-union model in the mouse

OBJECTIVES: Advancements in our knowledge of fracture healing have occurred in large part by the understanding of this process on a microscopic level. The ability to develop experimental non-union models in animals will assist in the investigation of this problem and are likely to lead to novel treatments. We report on a technique for developing experimental non-unions in mice. METHODS: Femoral fractures were created in 48 CD1 mice, 24 mice underwent standard closed femoral fractures, and 24 mice underwent creation of a femoral non-union through an open osteotomy and fracture devascularisation method. All fractures were subsequently rodded. Histological examinations of the fractures were then conducted at eight time points post-operatively. RESULTS: The control group showed normal fracture healing with histological evidence of bony fracture bridging by 28 days and mature bony remodelling at 63 days. The non-union group showed delayed fracture healing at all time points and no evidence of bony healing at 63 days. CONCLUSION: This is the first report of a reliable method to develop fracture non-union in mice. We believe this technique will be critical to further the investigation of fracture non-union in normal mice and provides the great advantage of using the plethora of transgenic and knockout mouse models to analyse non-union at the cell and molecular level.     

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.     

Pseudarthrosen

Non-unions are a relevant medical and socio-economic problem. Hyper-, oligo- and atrophic non-unions as well as septic and aseptic non-unions are differentiated. Correct classification is essential for the selected therapy. The “diamond concept” describes five pillars, on which bone healing is based and that have to be considered in the treatment of non-unions: osteogenic cells (mesenchymal stem cells), osteoinduction (growth factors), osteoconduction (scaffolds), mechanical stability, and vascularization. Factors that predispose to non-union also influence fracture healing. The gold standard of therapy are still resection of the non-union, decortication and autologous bone grafting. No advantage could be proven for any of the numerous procedures in monotherapy. But the combination of various procedures – polytherapy – seems to be promising. The aim is to optimize these concepts.     

Collective review: bioactive implants coated with poly(D,L-lactide) and growth factors IGF-I, TGF-beta1, or BMP-2 for stimulation of fracture healing

Demographic data reveal that due to the increasing aging of the population, complications with the musculoskeletal system will increase in the next years. One major problem in orthopedic and trauma surgery are the delayed healing or non-unions of long bone fractures. The exogenous application of growth factors can stimulate the bone healing to reduce these complications. Beside the choice of the optimal growth factor the application system is important. Therefore, we developed a new bioactive coating method for implants, which is based on a biodegradable poly(D,L-lactide) (coating thickness: 10 mum).This coating allows the incorporation of growth factors and the controlled release of these factors during the healing process without the need for further devices. The effect of different growth factors (IGF-I, TGF-beta1, and BMP-2) locally released from coated intramedullary implants on fracture healing was investigated with biomechanical and histological analysis in rats. All investigated growth factors stimulated the fracture healing as assessed with biomechanical tests and histological analysis. The local application of combined IGF-I and TGF-beta1 had the most stimulating effect on fracture healing, followed by the effect of BMP-2, IGF-I, and TGF-beta1 alone. Bioactive coating of biomechanical well-established implants can on the one hand stabilize the fracture and on the other hand stimulate healing processes to increase healing and to reduce the rate of complications.     

Clinical applications of BMP-7: the UK perspective

Treatment of fracture non-union is a challenging situation in skeletal surgery. Since the discovery of bone morphogenetic proteins (BMPs) by Urist preclinical research as well as clinical trials has shown the efficacy of these molecules in bone healing enhancement. Recombinant bone morphogenetic protein became available in UK during August 2001. We evaluated the type of indications and the efficacy of BMP-7 in a variety of clinical conditions including persistent fracture non-unions, augmentation of periprosthetic fracture treatment and osteotomies, enhancement of fracture healing following acetalular reconstruction, distraction osteogenesis, free fibular graft and arthrodesis of joints. Out of 653 cases, the overall success rate was 82% (535 cases). No local or systemic adverse effects were encountered. The role of BMP's as a bone stimulating agent is safe, well established and could be considered as a power adjunct in the surgeon's armamentarium for the treatment of these challenging clinical conditions.     

锁定钢板治疗髓内固定失败致无菌性骨不连

目的 评价锁定钢板治疗因髓内钉固定失败而造成的无菌性骨不连的疗效.方法 2004年1月至2006年12月,因髓内钉固定失败而造成的四肢长骨无菌性骨小连患者38例,男26例,女12例;年龄9-70岁,平均39.2岁;骨不连时间6-84个月,平均16.2个月.按骨不连骨折端形态Judet分类法分型:肥大型9例,营养不良型10例,萎缩型19例,其中15例形成假关节.骨不连的部位:股骨20例,胫骨15例,肱骨3例,其中21例(占55.3%)位于长骨干骺端附近.该组病例均采用锁定钢板固定以及联合骨移植进行治疗.结果 患者均获得随访,随访时间6～20个月,平均11.6个月.骨不连均愈合,愈合时间4～8个月,平均5.3个月.3例(7.9%)出现切口表面感染,经治疗后均痊愈;1例(2.6%)切口延迟愈合;1例(2.6%)出现肢体短缩约2 cm.无一例发生骨折畸形愈合.末次随访时关节活动度较术前显著改善,其中30例(78.9%)功能优良,7例(18.4%)可,1例(2.6%)差.结论 对于髓内钉固定失败而造成的无菌性骨不连,采用锁定钢板进行固定是一种疗效确切的治疗方法,尤其是针对干骺端附近的骨不连.锁定钢板联合骨移植治疗能提供可靠的固定稳定性和骨诱导、骨传导作用.     

Bone morphogenetic proteins in clinical applications

The role of bone morphogenetic proteins (BMPs) in bone healing has been shown in numerous animal models. To date, at least 20 BMPs have been identified, some of which have been shown in vitro to stimulate the process of stem cell differentiation into osteoblasts in human and animal models. Having realized the osteoinductive properties of BMPs and having identified their genetic sequences, recombinant gene technology has been used to produce BMPs for clinical application - most commonly, as alternatives or adjuncts in the treatment of cases in which fracture healing is compromised. BMP-2 and BMP-7 are approved for clinical use in open fractures of long bones, non-unions and spinal fusion. However, despite significant evidence of their potential benefit to bone repair and regeneration in animal and preclinical studies, there is, to date, a dearth of convincing clinical trials. The purpose of this paper is to give a brief overview of BMPs and to critically review the clinical data currently available on the use of BMP-2 and BMP-7 in fracture healing.     

Use of extracorporeal shock-wave therapy (ESWT) in the treatment of non-unions

Presently, extracorporeal shock-wave therapy (ESWT) is not yet a standard therapeutic technique in orthopaedics. The mechanism for the analgesic effect or the effect of shock waves on osseous defects are still unknown. With the help of a review of the literature, indications and success rates for ESWT in the treatment of non-unions are outlined, while adequate impulse and energy rates are defined according to the present state of knowledge. Non-union is defined as an absent healing process after a duration of 6 months. The aim of this study is to rate the published data. A total of 52 papers referring to ESWT of the locomotor system are reviewed, with a focus on the 635 patients from 10 publications who underwent ESWT to treat non-unions. Validation was performed for each paper dealing with this topic according to the internationally accepted system of the American Association of Spine Surgery as types A-E. Conclusions regarding possible applications in therapy were taken only from high-quality publications of types A and B. This advice can be regarded as scientifically as well as economically sound. The investigations concerning non-union hardly live up to scientific standards. No serious complications were observed. Because of the complication rate in operative treatment of non-unions, ESWT seems to be justifiable. The techniques of ESWT, energy density levels and impulse rates will be described. Atrophic non-unions seem to represent a poorer starting point in comparison with hypertrophic non-unions. Most investigations showed a consolidation of the non-union during a period of 3 months following ESWT, so that in case of treatment failure, operative treatment in the form of a re-osteosynthesis would only be delayed for this period of time. The advantages of ESWT are its non-invasiveness and low rate of complications. The primary aim of further research should be the evaluation of adequate energy density levels and impulse rates for various indications in accordance with evidence-based medicine. Long-term results need to become available before ESWT can be compared with established methods.     

Human atrophic fracture non-unions are not avascular.

A small proportion of fractures progress to non-union. Non-unions are routinely classified into two groups either hypertrophic or atrophic according to their radiological appearance. It is a common preconception that non-unions with a hypertrophic appearance on X-ray are biologically active and vascular with potential to heal given the correct stable environment. Atrophic non-unions are considered to be avascular and inert and will not heal even under the correct stable environment. Non-unions are either infected or aseptic. In the present study, we tested the hypothesis that aseptic atrophic non-unions are less vascular than aseptic hypertrophic non-unions and healing fractures. Biopsies were taken from the fracture gap of patients with healing fractures, hypertrophic non-unions and atrophic non-unions. A dual labelling technique was used with antibodies against CD31 (JC70) and Collagen IV. Blood vessels were quantified using a Chalkley point eyepiece graticule. There was no statistically significant difference in the median vessel count between the three fracture groups. These findings do not support the hypothesis that established atrophic fracture non-union are less vascular than hypertrophic non-unions or healing fractures.     

Implantatassoziierte Frakturen

Only scant information is currently available on the treatment of implant-related and periprosthetic fractures of the humerus. Although the incidence of these fractures is low, an increase is expected in the future. Treatment is challenging since patients are often elderly and bone quality is poor. Conservative treatment often leads to delayed healing and non-union. Treatment goals include reliable implant fixation, sufficient stability to enable bony healing and stable osseointegration of the prosthesis for pain-free and useful joint function. Whereas long-stem revision surgery is performed in cases of loose stems and poor bone quality, overlapping osteosynthesis with angle stable plating systems and cerclages can be used in cases of good bone quality. With implant-related fractures at the junction between rigid bone due to an implant and flexible bone, revision surgery using long angle-stable plates or overlapping plates additional to the remaining implants can be accomplished. New intramedullary implants (long proximal humerus nails) can be successfully used either in primary osteosynthesis or in cases of revision and can achieve sufficient stability for early functional aftercare.     

A scoping review of operative and non-invasive management in the treatment of non-unions

IntroductionNon-union occurs when a fracture fails to adequately heal, and requires additional intervention to achieve union. The purpose of this scoping review is to provide a high-level overview of the existing non-union management literature. This review aims to highlight the current literature on non-union management, as well as identify key areas that require future research to provide a better understanding of potential non-union management strategies.MethodsThis study utilized the scoping review framework from Arksey and O'Malley All relevant literature on non-union management was systematically searched for within the OVID Medline, OVID Embase, and Web of Science databases. As a scoping review, this study aimed to identify the high-level trends in non-union literature. This was assessed through a visual and numerical summary of the general themes in non-union literature, as well as the timeline in which these trends have occurred.ResultsThe literature search identified 8081 articles, of which 2210 articles were included. There is a large body of evidence for various surgical treatment options for non-union. The literature suggests healing rates between 80 and 100 percent for commonly utilized surgical procedures, such as plating with bone graft for long bones. Despite these beneficial healing rates, the requirement of a surgery creates a large socioeconomic burden. The possibility for bone growth stimulator (BGS) options to achieve non-union healing rates in a similar realm as surgical options suggests that the use of a BGS may be a beneficial option prior to surgical intervention, as this would potentially reduce the number of patients who would otherwise require surgery.ConclusionA large body of evidence exists on non-union management, which is largely comprised of case series and reports. The most commonly assessed non-unions include the tibia, wrist, and femur. Bone grafting, plating, and nailing are the most investigated treatment options. BGS are a non-operative treatment options for non-union that provide similar healing rates to surgical options in certain indications within initial observational data. BGS are a potential option for non-operative management of non-unions to reduce socioeconomic burdens of surgical intervention, with a need for further high-quality investigation in this therapeutic area.     

Failure of reamed nailing in humeral non-union: an analysis of 26 patients

The use of an intramedullary nail in the treatment of humeral non-unions remains controversial. This study evaluated the treatment of humeral delayed and non-unions with reamed nailing and compression. In a retrospective analysis of prospectively gathered data from 26 cases all treated with the Telescopic Locking Nail (TLN), the healing rate after the first intervention for non-union was 58%. After one or more re-interventions combined with an external cancellous bone graft at some time during follow-up, 90% of the 21 patients with complete follow-up eventually healed after a mean of 22 months. A total of 49 procedures with a mean of 1.9 per patient were needed. After a mean follow-up of 65 (range 24-88) months, we conducted a study to assess the functional results in the shoulder and elbow. Twelve patients were suitable for inclusion. We used the Neer and Morrey score for shoulder and elbow function, respectively. For the Neer score the median was 91 points and for the Morrey score 94 points. The outcome suggests that simple reamed nailing of humeral non-union is insufficient. Reamed interlocked nailing is feasible, provided that the primary intervention for non-union is combined with an external cancellous bone graft.     

Reindeer BMP extract in the healing of critical-size bone defects in the radius of the rabbit

Background?Native BMP extracts from reindeer effectively induce ectopic new bone formation in vivo, but their bone healing properties have not yet been evaluated. We investigated the effect of reindeer BMP extracts on the healing of long bone defects.

Methods?The implants tested contained 5?mg or 10?mg of unsterilized BMP extract from reindeer and 10?mg of gamma-sterilized BMP extract administered with collagen carrier (Lyostypt, B. Braun, Germany). 70 μg of rhBMP-2 with collagen carrier (InductOs; Wyeth Europa) served as positive control, and collagen implants (Lyostypt) and untreated defects served as negative controls. New Zealand White rabbits with 1.5?cm of critical-size radius bone defects were used, with 8 weeks of follow-up.

Results?Radiographic analysis showed bone formation (BF) to be higher in all groups containing BMPs than in the untreated controls. BF was also higher in the rhBMP-2 group, and marginally higher in the group treated with 10?mg of unsterilized reindeer BMP extract (p = 0.06) as compared to the collagen controls. Bone union (BU) was better in the unsterilized BMP extract groups and rhBMP-2 group than in the untreated controls. BU was also better in the implants with 10?mg of unsterilized reindeer BMP extract and rhBMP-2 than in the collagen-treated implants. The mean area of new bone at the site of the defect proved to be higher in all implants containing BMP than in the untreated defects. It was also higher in the groups with 10?mg of unsterilized reindeer BMP extract and rhBMP-2 than in the collagen-treated controls. Mechanical tests showed torsional stiffness of the bones to be higher in the group with 10?mg of unsterilized BMP extract than in the collagen group. The mean cross-sectional bone area measured by pQCT densitometry was higher in the rhBMP-2 group than in the collagen group. The mean bone density at the defect area was higher in the group with 10?mg of unsterilized BMP than in the rhBMP-2 group.

Interpretation?We conclude that both reindeer BMP extract and rhBMP-2 induced improved healing of the rabbit radius bone defects at the doses used. Gamma sterilization of reindeer BMP extract reduced osteoinductivity slightly, but not significantly.     

Ultraschall und Stoßwelle in der Pseudarthrosentherapie

Disorders of bone healing and non-union occur in 5–10% of all fractures. Surgical treatment is the gold standard for treatment of non-unions, although it is associated with high perioperative complication rates ranging from 32% to 73%; therefore, less invasive and more protective treatment options would be desirable. These include biophysical treatment options for non-union, such as ultrasound and shock wave treatment. In the past both non-surgical treatment options achieved good to very good bone consolidation rates taking the indication criteria into consideration, whereby different influencing factors could be identified. Due to the lack of inclusion in the statutory catalogue of services, reimbursement by statutory health insurances is currently a problem in Germany; therefore, further studies are necessary in order to establish and validate biophysical treatment as a supplementary option besides the operative gold standard.