Diagnostic and treatment modalities in nonunions of the femoral shaft. A review

Injury, Int. J. Care Injured 43 (2012) 980–988

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Review

Diagnostic and treatment modalities in nonunions of the femoral shaft. A review Ioannis D. Gelalis *, Angelos N. Politis, Christina M. Arnaoutoglou, Anastasios V. Korompilias, Emilios E. Pakos, Marios D. Vekris, Athanasios Karageorgos, Theodoros A. Xenakis Department of Orthopaedic Surgery and Traumatology, University of Ioannina, School of Medicine, Ioannina, Greece

A R T I C L E I N F O

A B S T R A C T

Article history: Accepted 15 June 2011

Nonunions of the femoral shaft represent a treatment challenge for the orthopaedic surgeon and a serious socioeconomic problem for the patient. Inadequate fracture stability, insufficient blood supply, bone loss or presence of infection are the main reasons for the development of a nonunion. Careful classification and exclusion of infection are crucial for the choice of the proper treatment alternative. Nail dynamization, primary intramedullary nailing or nail exchange, plate osteosynthesis and external fixation along with bone grafting, usage of bone substitutes and electrical stimulation can stimulate osseous union. A review of the aetiology, classification and treatment should prove helpful managing this serious complication. ß 2011 Elsevier Ltd. All rights reserved.

Keywords: Nonunion Femoral shaft Intramedullary nailing External fixation Plate osteosynthesis

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Identification and eligibility of relevant studies . . . . . . . . . Data extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Classification of nonunions. . . . . . . . . . . . . . . . . . . . . . . . . . Diagnostic modalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intramedullary nailing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nail dynamization . . . . . . . . . . . . . . . . . . . . . . . . . Primary intramedullary nailing or nail exchange Plate osteosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . External fixation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other treatment modalities . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Introduction Despite the advances in trauma care, improved surgical techniques, newer implants and the evolution of new adjuvants to healing, biologic agents, nonunions still occur and are often a

* Corresponding author at: Department of Orthopaedic Surgery and Traumatology, University of Ioannina, School of Medicine, 11 Pantazidi Street, 45221, Ioannina, Greece. Tel.: +30 2651008097; fax: +30 2651008069. E-mail address: [email protected] (I.D. Gelalis). 0020–1383/$ – see front matter ß 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.injury.2011.06.030

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result of a high energy initial trauma. Femoral nonunion represents a serious socioeconomic problem for the patient, associated with prolonged patient morbidity, gait abnormality, inability to return to work, re-operations and psycho-emotional impairment. It moreover stands for a treatment challenge for the orthopaedic surgeon, having to take factors into consideration such as different treatment modalities, deformity correction, treatment of infection and rapid rehabilitation of the patient. Winquist–Hansen classification of femoral shaft fractures system takes into consideration the extend of comminution and was established to determine the need for intramedullary nail

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locking and the post-operative weight bearing protocol, in order to avoid the settlement of a nonunion of the femoral shaft.1 Inappropriate mechanical environment of the fracture (inadequate fracture stability), insufficient blood supply (avascularity), bone loss or presence of an infection are the main reasons for the development of a nonunion. In some cases, despite the appropriate treatment, there is no evident reason. Special categories of patients are those with co-existence of an acute spinal cord injury. Nonoperative treatment of these patients leads to a 31% higher rate of femoral nonunion.2 Several different treatment modalities are available to the surgeon, including nail dynamization, plate osteosynthesis, external fixation, exchange plating and adjuvant alternatives such as electrical or ultrasound stimulation, bone grafting with autogenous or allogenic bone grafts and Bone Morphogenetic Proteins (BMPs).3 In cases were segmental defects are present, vascularized bone transfer and distraction osteogenesis can be used.4,5 Closed reamed intramedullary nailing combined with or without open bone grafting has been suggested by many authors as the treatment of choice for nonunions of the femoral shaft.6–9 The nonunion rate in femoral shaft fractures treated with intramedullary nailing ranges between 1% and 20% depending on the type of fracture and on the technique used.1,6–8,10,11 The success rate of nonunion treatment will decrease after repeated operations, primary because of repeated local, periosteal and vascular destruction, with reduced nutrition as a result.12 The reported success rate for other treatment modalities, such as exchange nailing, nail dynamization, external osteosynthesis and plate osteosynthesis, ranges between 47 and 100%.6,7,13–21 Materials and methods Identification and eligibility of relevant studies We considered all in vivo clinical studies that assessed the results of treatment of femoral nonunions. All types of studies (case series, case control, randomized controlled trials) were considered eligible for the review. Cadaveric, animal studies and morphologic articles were excluded. MEDLINE, OVID, and Springer databases were used for the literature search covering the period from January 1950 until December 2010. Only studies in the English language were included in the search. The search strategy was based on combinations of the following keywords: ‘‘nonunion’’; ‘‘femoral shaft’’; ‘‘intramedullary nailing’’; ‘‘external fixation’’; ‘‘plate osteosynthesis’’. Screening included titles; subtitles and abstracts. Additionally all references of the retrieved articles were also reviewed. Investigators were contacted and asked to supplement additional data and clarifications when key information was missing. Data extraction Two reviewers independently screened the titles and abstracts of all publications, which were obtained by the search strategy. All potentially eligible studies were obtained as full articles and were assessed independently for inclusion by the two reviewers. In doubtful or controversial cases, the reviewers discussed all identified discrepancies and reached consensus on all items. If consensus was not reached, they referred to the senior reviewer to solve the problem. We extracted data on characteristics of studies and patients, and results. Specifically, the following data were collected: type of study (case series, case control, randomized control trial), number of patients, classification of nonunion, age, gender, type of

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treatment method used, success of the treatment method, time to osseous union and complications. Our literature search identified 191 possible eligible studies. 111 studies (58.1%) were omitted due to the fact that they did not fulfil the inclusion criteria. Therefore 80 studies were eventually included in the analysis. Classification of nonunions The differences between delayed union and nonunion are mostly of degree. Union is considered delayed when healing has not advanced at the average rate for the location and type of fracture (usually 3–6 months). On the other hand a fracture of the shaft of a long bone should not be considered a nonunion until at least 6 months after the injury because often union requires more time, especially after some local complication, such as an infection.12 Classification of nonunions is based on radiographic and scintigraphic appearance of the fracture site, according to the criteria described by Mu¨ller and Weber/Cech.3,12,19,22 This classification is based on the viability at the bone fragments ends, with fractures divided into hypervascular, hypertrophic or viable and avascular, atrophic or non-viable sub-types. Hypertrophic nonunions are well vascularized and there has been an obvious attempt by the local environment to heal the fracture. Radionuclide scans show increased uptake of strondium85. The main problem in this type of nonunion is inadequate fracture stability or reduction. Correction of the aforementioned factor will usually lead to rapid healing of nonunion. Hypertrophic nonunions are subdivided into: a. ‘Elephant foot’ nonunions: These nonunions are rich in callus. b. ‘Horse hoof’ nonunions: Some callus and possibly signs of bone sclerosis are present and, c. Oligotrophic nonunions: Osteogenic activity of bone edges is poor, despite the intact blood supply, and there are radiographic signs of very moderate or no formation of callus at the nonunion site. In atrophic nonunions there has been a minimal attempt of healing as the formatted callus at the fracture site is little or absent. The quality of the bone ends is poor and their potential for repair is significantly diminished. In order this type of nonunion to heal, stability of the fracture site and axial alignment must be considered, together with enhancement of biologic regenerative activity of the bone ends. Radionuclide scans demonstrate cold or ischemic bone ends with poor uptake of strondium-85. Atrophic nonunions are subdivided into: a. Torsion wedge nonunions: An intermediate fragment with reduced or no blood supply is present. There is absence of callus formation at the fracture site. b. Comminuted nonunions: One or more necrotic intermediate fragments are present, without any sign of callus formation. c. Defect nonunions: The loss of a bone fragment makes healing of the fracture impossible. The bone ends may be viable or atrophic. d. Atrophic nonunions: Scar tissue is formed between the osteoporotic or atrophic bone ends. Based on the presence or absence of infection, nonunions can further be divided into the non-infected or infected categories. Diagnostic modalities A careful patient history, including the date of injury, details of the initial and subsequent treatment, patient’s nutritional status

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and associated medical problems is essential before beginning the diagnostic workup. The patient’s description of a painful and mobile fracture site may be the first sign in the detection of the nonunion. Potential risk factors such as smoking, use of nonsteroidal anti-inflammatory drugs and peripheral vascular disease should also be recognized. The physical examination must assess the presence or not of pain and/or motion in the area of the nonunion or pain in the adjacent joints.3 The patient should also be examined in the weight bearing position. Antalgic gait and/or the presence of ambulatory assistive equipment may be present. Static and dynamic functional alignment in the frontal, horizontal and sagittal planes must carefully be assessed, as well as range of motion of the adjacent joints. Neurovascular evaluation of the lower extremity is essential. The evaluation should include peripheral pulses, skin temperature and hair distribution. Arteriogram remains the gold standard for defining vascular injury, whereas Duplex ultrasonography can also be used.23 It is also important to determine the condition of the surrounding and adjacent to the deformity soft tissues. The diagnosis of infection is crucial. Thus, assessment of clinical signs such as malaise, fever and pus drainage is part of the initial examination. The radiographic evaluation must include anteroposterior, lateral and oblique projections with the beam centred on the deformity. In some cases internal and external oblique radiographs may be very informative to assess more accurately the healing process and the angular deformity. The adjacent joints must be included in the radiographs to allow precise localization of the anatomic axis of the joint. The diagnosis of a nonunion is based on the absence of bridging bone at the fracture site and persistence of the fracture line. Formation of callus should not be expected when principles of absolute stability are used in the osteosynthesis of a fracture, but only when principles of relative stability are used. Insecure fracture fixation or early weight bearing though can trigger the formation of exuberant callus. Stress views under fluoroscopy can determine the presence or absence of motion of the nonunion and define the planes of instability of the deformity. Plain tomography can also be useful in evaluation of the fracture healing or of the quality of the interface with an avascular fragment of the bone. Computerized tomography (CT) and magnetic resonance imaging (MRI) have replaced plain tomography, especially when internal fixation devices at the area of deformity are not present.24 CT scanning (Topogram) may be helpful in the exact measurement of the anatomic and mechanical axis of the limb. CT is more accurate than plain radiographs in the diagnosis of tibial nonunion.25 It has however limited specificity and surgeons must couple computed scanning and clinical findings to minimize the risk of making a false-positive diagnosis of nonunion.25 Infection should always be investigated in the presence of femoral nonunion. Laboratory tests include a complete blood test, erythrocyte sedimentation rate and C-reactive protein levels. Radionuclide, indium 111-labelled leucocyte scans and MRI can be used to evaluate the activity at the nonunion site or to evaluate the quality of the interface with an avascular butterfly fragment. Their role in detecting the presence of an acute or chronic bone or soft tissue infection is significant.26,27 The multiplanar imaging capability and high degree of contrast resolution of MRI allows accurate delineation of the limits of the infection.26 Tissue culture at the time of the secondary surgical procedure is needed for firm diagnosis of infection. Antibiotics should therefore be discontinued 10–14 days preoperatively. Specimens should be examined with Gram stain, aerobic, anaerobic and fungal cultures.

Treatment Intramedullary nailing Nail dynamization Nail dynamization is usually the first treatment option in the cases of femoral shaft nonunion where the initial treatment was intramedullary nailing in a static locking mode. The method converts the fixation from static to dynamic and promotes callus remodelling, stimulates osteogenesis and induces fracture union by allowing the weight-bearing forces to transfer through the site of nonunion.28,29 Axial stability of the fracture is a crucial prerequisite for the effectiveness of the system. The reported union rate after nail dynamization in the published literature is approximately 50%.17,19,21,30 The main complication from nail dynamization is bone shortening that can lead to significant leglength discrepancy. Highly comminuted or oblique fractures are in higher risk of developing significant shortening. Timing of nail dynamization is of crucial importance for the final outcome. Wu et al. reported poor results of nail dynamization after 6 (5–10) months of 12 intramedullary nails used for femoral shaft fractures. Five of the 12 fractures led to union. The authors therefore suggested early cancellous bone grafting in cases of delayed union.31 Wu et al. reported dynamization of twenty-eight static femoral interlocking nails. At 4 months postoperatively, dynamization of a static interlocking nail was suggested for patients with sparse callus formation (oligotrophic or atrophic) at the fracture site. This procedure was performed between 4 and 12 months (median, 6 months) postoperatively. Fourteen patients (58%) achieved a solid union with a union period of 5.2  2.0 months after dynamization. Twenty-one percent of patients (5 of 24) had more than 2 cm of femoral shortening; all occurred in cases of nonunion. All 10 cases of nonunion were treated with cancellous bone grafting with or without lengthening and achieved satisfactory outcomes. The authors conclude that dynamization is suggested for patients without segmental bony defects. After dynamization, patients must be regularly followed. If progressive shortening of more than 1 cm is noted or if shortening is noted after 7 months and the fracture site is still ununited, cancellous bone grafting should be performed as soon as possible.21 Primary intramedullary nailing or nail exchange The treatment of choice for the majority of femoral nonunions is intramedullary nailing (Fig. 1).6–9,32 As has been reported from many authors, the treatment of a nonunion can be accomplished by closed or limited open methods, thus minimally disturbing the periosteal blood supply and preserving conditions needed for early healing.32–34 The advantage of this method is that the intramedullary nail acts as a load-sharing device, which allows physiologic compression of the nonunion. The fixation is mainly based on elastic three point contact in a longitudinal direction32 and offers excellent stability promoting early weight-bearing. Motion of the nonunion site is reduced but not eliminated. Interlocking nailing has extended the indications for intramedullary nailing to the total diaphyseal and metaphyseal shaft providing excellent stabilization and early functional rehabilitation.6 The late effects of stress shielding from plate fixation and refractures through screw hole stress risers are not seen using intramedullary nailing.35,36 Reaming causes considerable vascular damage to the blood circulation of the endosteum.34,37 Based on the vascular anatomy of the endosteum, the essential damage is mainly caused by the first reaming.34 On the other hand, reaming particles represent a strong osteoinductive substance and are considered of great importance in fracture healing when vital tissue is presented at the nonunion site. At devitalized zones of the endosteum the reaming particles can become necrotic particles and must be considered in

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Fig. 1. A. Patient 24 years old with a mid-shaft fracture treated with plate osteosynthesis. Development of aseptic pseudarthrosis 8 months postoperatively. B. Conversion of the treatment method to intramedullary nailing. C. Progression of osseous union 12 months after the insertion of the intramedullary nail. D. X-ray of the patient 3 years postoperatively. The patient was symptom-free, with complete absence of pain at the fracture site and full return to his normal activitities.

view of possible bacterial contamination, when an open technique is performed. El Moumni et al. investigated the incidence of nonunion in 129 femoral shaft fractures treated with unreamed intramedullary stabilisation. Non-union occurred in two patients (1.9%). The authors concluded that the incidence of non-union following unreamed intramedullary nailing is low and comparable with the best results of reamed nailing in the literature.38 The primary contraindication for this operative technique is a prior history of deep soft tissue infection and osteomyelitis. Previous infection makes intramedullary nailing potentially more dangerous for reactivation or extension of the infection into the medullary canal.39 Relative contraindications can be large bone defects, which require vascularized or nonvascularized bone transport, cases where extensive dissection is required to restore length and alignment40 and a low-grade infection. Management of femoral nonunions with intramedullary nail fixation is reported highly succesfull (Fig. 2).6,7,32,41,42 Wu and Chen43 compared the results of 16 patients treated by closed intramedullary nailing technique and 19 patients by an open technique. The closed technique consisted of replacement of a

larger size reamed nail. The open method consisted of local debridement, maintaining local stability, and upper tibial cancellous bone grafting. Union occured in 100% of the patients, as the union period for the closed technique was significantly shorter than with the open technique. Kempf et al. evaluated retrospectively the results of 27 noninfected femoral nonunions treated with locked intramedullary nailing. Twenty five of 27 (92.6%) nonunions healed after a first operation in a mean time of 15.7 weeks and the remaining two femurs healed following renailing.7 Wu et al.9 compared the results of different methods for the treatment of 84 femoral nonunions. A locked Grosse-Kempf nail was used in 37 cases, a Kuntscher nail in 20, a plate in 16, and a Huckstep nail in 11 cases. The authors concluded that locked nailing and Kuntsher nailing were superior in union rates (32/37 and 18/20 respectively), with fewer complications, less operative time and blood loss. A study by Webb et al.7 reported an overall union rate of 96% in a total of 105 patients, 61 with delayed union and 44 with nonunion of the femoral shaft treated by intramedullary reamed nailing. Oh et al. treated fifteen femoral nonunions with dynamically locked reamed nailing with no open bone grafting for a defects less than

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Fig. 2. A. Patient 24 years old with breakage of the plate osteosynthesis, due to development of nonunion of a mid-shaft femoral fracture 3 years after the primary operation. B. After removal of the plate, intramedullary nailing was performed. C. Achievement of complete osseous union 3 years after the revision procedure. D. X-ray of the patient after removal of the intramedullary nail.

50% of the diameter and immediate weight bearing achieving solid union in 93% of the cases.44 There is an ongoing debate on the effect of exchange nailing in the treatment of femoral nonunions. Hak et al. investigated the success of exchange reamed femoral nailing in the treatment of femoral nonunion after intramedullary nailing and analysed the factors that may contribute to failure of exchange reamed femoral nailing. Twenty-three patients were identified whose radiographs failed to show progression of healing for four months after treatment with a reamed IM femoral nail and were treated by exchange reamed femoral nailing. The diameter of the new nail was one to three millimetres larger than that of the previous nail. Overall, exchange reamed femoral nailing was successful in eighteen cases (78.3%). Tobacco use was found to have a detrimental impact on the success of exchange reamed nailing. The authors concluded that exchange reamed intramedullary nailing has low morbidity, may obviate the need for additional bone grafting, and allows full weight-bearing and active rehabilitation.45 On the contrary, Park et al. compared the results between exchange nailing and augmentation plating with a nail left in situ for nonisthmal femoral shaft nonunion after femoral nailing. Eighteen patients with 18 nonisthmal femoral nonunions were retrospectively reviewed. Seven patients with 7 fractures treated for nonisthmal femoral shaft nonunions after femoral nailing with exchange nailing and 11 patients with 11 fractures with augmentation plating combined with bone grafting. Five nonunions in the exchange nailing group failed to achieve union (72% failure rate), whereas all 11 pseudarthroses in the augmentation plating group obtained osseous union. The authors concluded that augmentation plating with autogenous bone grafting might be a better option than exchange nailing for nonisthmal femoral nonunions.46 Steinberg et al. evaluated the efficacy of the expandable nailing system for treating femur and tibia shaft nonunions. Sixteen

femoral nonunions were treated with the pre-mentioned method. All but one nonunions healed after 16 weeks (range, 8–40 weeks) and the authors recommended expandable nail systems for femur and tibia shaft nonunions and the use of reamed debris in order to decrease the use of autogenous bone graft. The expandable nail offers the theoretical advantages of improved load sharing and rotational control without the need for interlocking screws.47 During the last years there is a tendency of combining intramedullary nailing with bone grafting with high union rates.43,48 Nevertheless, despite achievement of union at a high rate, delayed union or persistence of nonunion still occurs. Plate osteosynthesis Plating techniques are also effective in the treatment of femoral shaft nonunions after intramedullary fracture fixation (Fig. 3). Muller and Rosen first described the use of the plate compression principle in the treatment of femoral nonunions.22,49 Despite the disadvantages of higher blood loss, higher rates of infection and higher nonunion rates than with exchange nailing, plate osteosynthesis has been proven effective for the treatment of femoral nonunions.18,50 The indications for plating osteosynthesis include hypertrophic nonunions, proximal and distal metadiaphyseal nonunions3 where the application of intramedullary nailing is difficult. In oligotrophic or atrophic nonunions the method can be combined with bone grafting. If the need for exposure of the nonunion should arise, as with a significant fixed deformity, the theoretical advantages of exchange nailing over plate fixation may be negated.14 Drawbacks of the technique include restricted weight bearing immobilization due to the danger of plate failure, increased blood loss, increased risk of infection and devascularization of the nonunion site that can further decrease the blood supply to the area.3

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Fig. 3. A. Patient 30 years old with a comminuted femoral diaphyseal fracture. B. X-ray of the patient 12 months after the primary procedure showing progression of the osseous healing. C. Removal of the intramedullary nail 18 months after the primary procedure reveals an established nonunion. D. Achievement of osseous union 12 months after plate osteosynthesis.

The reported union rates with plate osteosynthesis are high and similar to those obtained with intramedullary nailing techniques.13,14 Plate augmentation with retaining the previous used intramedullary nail has also achieved excellent union rates.15,51 Bellabarba et al. concluded that plating of nonunited femoral fractures originally treated with intramedullary nailing is effective in achieving union in a timely fashion, with minimal complication.14 Prasarn et al. sought to determine whether management of infected femoral nonunions with a single-staged protocol utilising internal fixation (DCS plates, blade plates and intamedullary nails) led in a high union rate, resolution of infection and a good functional outcome.52 11 patients underwent a single-staged protocol that includes an antibiotic ‘‘holiday’’, then treating the infected nonunion with surgical debridement and hardware removal, local and systemic antibiotics, revision open reduction and internal fixation, and use of supplemental bone grafting. All patients did unite and resolve their infections. External fixation The circular external fixators (Ilizarov-type fixators) have also been used for the treatment of femoral nonunions. The principal role of this type of fixation lies mainly in the management of infected nonunions,53,54 whilst its use in aseptic nonunions is limited.55 The advantages of the Ilizarov fixation system include wide and

percutaneous application with minimal blood loss, correction of the deformity in three planes, correction of leg length discrepancy by distraction osteogenesis and bone transportation, access to soft tissue defects and bone in cases of infection, stable fixation using different construct designs which allow early motion and weight bearing. The disadvantages of this method include its limited use on non-complaint and psychological impaired patients, cost of the apparatus, long learning curve, and those related to external fixation devices such as prolonged use pin tract infection and risk of neurovascular injury at the time of wire insertion. Neurovascular injury is especially a problem with transfixion pins, but less of a problem with wire than with large-diameter pin fixation. The augmentation of intramedullary nailing with the Ilizarov technique and retention of the nail has also been reported with high union rates in cases where other treatment options have failed.56 Ilizarov treatment has also been proposed for femoral malunion or nonunion associated with fatigue fracture of an intramedullary nail. The method was used in three cases of femoral healing problems and resulted in good consolidation with minimal invasive surgery and limited morbidity.57 Other treatment modalities Other treatment options are used either alone or, more commonly, combined with the surgical options previously

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described. These include the usage of bone grafts, bone substitutes, newer biological factors such as BMPs, low intensity pulsed ultrasound and electrical stimulation. Bone grafting techniques have been used as adjuncts combined with surgical techniques usually with nailing47,48,58,59 or plating14,15. Autologous bone graft can be obtained either from the iliac crest58,60 or from the reaming products in cases of intramedullary nailing.47,48 Endoscopic techniques for the application of bone graft at the site of nonunion in cases where bone grafting is used as the only treatment have been reported.60 Rigid plate fixation and copious autologous bone grafting from the iliac crest has been reported highly successful, with 100% rate of union, in the treatment of supracondylar nonunions of the femur.61 Open reduction and internal fixation supplemented with deep-frozen allograft struts and autogenous iliac bone grafts is considered an effective treatment method for nonunion of the distal part of the femur.62 Percutaneous autologous bone marrow transplantation can be considered for uninfected hypervascular nonunions following intramedullary nail fixation.63 An autograft complex enriched with autologous platelet gel has a possible potential in the treatment of recalcitrant nonunions of the lower extremity after failed prior autografting.64 In considering treatment of patients with prior failure of autografting, repeating the standard autografting procedure includes the risk of another failure. The source of autograft is also decreased after repeated harvests. Under these circumstances, more complicated and extensive procedures like distraction osteogenesis and vascularized bone grafting could be considered. Lately, the use of a pedicled vascularized bone graft from the medial supracondylar region of the femur has been proposed as a technique with a good indication for intractable femoral nonunion without significant bone defects of the distal half of the femur.5 Recombinant BMP-2 (rhBMP-2) and BMP-7 (rhOP-1) have been evaluated in numerous preclinical models and successful healing in long bone defects has been reported.65–67 Currently rhBMP-7 has been approved by the United States Food and Drug Administration (FDA) for use in long bone defects and has received a humanitarian device exemption for recalcitrant long bone nonunions, whilst rhBMP-2 is approved for use in open tibial fractures.68 Combining autologous bone graft and rhBMP-7 as a bone stimulating agent in the treatment of long bone fracture aseptic atrophic nonunions, resulted in a nonunion healing rate of 100% in a series of 45 patients.69 RhBMP-2 has also been successfully used in a case with double femoral nonunion in a 49 year old patient.70 Kanakaris et al. assessed in a multicenter trial the efficacy of application of bone morphogenetic proteins to femoral nonunions. Applications of BMP-7 since January 2004 were prospectively recorded in a multicentre registry of aseptic femoral nonunions. The study included 30 patients who had undergone a median of 1 revision operation before BMP-7 application. Nonunion healing was verified in 26/30 cases in a median period of 6 months and no adverse events were associated with BMP-7 application. Multicentre networks and systematic, long-term follow-up of patients in specific studies about the efficacy of BMPs in the treatment of femoral nonunions will shed light towards that direction.71 Electromagnetic stimulation has also been used, mainly in the past, and has been proposed to promote healing in fracture nonunion.72 Electrical stimulation involves the generation of an electrical or electromagnetic current through the ununited fracture. Such currents, which are present in physiologically healing bone, provide stimuli that favour a healing response to bone cells. These stimuli include the enhancement of transmembrane and intracellular calcium-mediated signal transduction and an increased synthesis of paracrine and autocrine growth factors

by osteoblasts. Current evidence justifies neither enthusiastic dissemination nor confident rejection of this therapeutic modality. Appropriately sized and methodologically sound trials are needed to resolve the current uncertainty, since no clear benefit in improving the rate of union in patients with nonunion has been proven.73,74 In a recent review of the evidence regarding the use of electromagnetic stimulation in the management of established non-union in long bone fractures by Griffin et al. though, there was a consensus that the available evidence supports the use of electromagnetic stimulation in the treatment of nonunion of the tibia.75 At the beginning of the 1980s in Brazil, Duarte was the first to develop and clinically use biophysical treatment with lowintensity pulsed ultrasound system (LIPUS) to stimulate bone osteogenesis.76 Histologic studies show that LIPUS influences all major cell types involved in bone healing, including osteoblasts, osteoclasts, chondrocytes and mesenchymal stem cells. The method appears as an effective and safe home treatment of aseptic and septic delayed-unions and nonunions, with a healing rate ranging from 70% to 93% in different, non-randomized, studies.77 LIPUS showed a union rate of 75% in 72 long bone fractures with delayed union or nonunion.78 Nevertheless the lack of controlled trials sets the role of LIPUS for healing of nonunions under investigation. Conclusions Femoral nonunion represents a serious socioeconomic problem for the patient, associated with prolonged patient morbidity, gait abnormality, inability to return to work, re-operations and psycho emotional impairment. Careful selection of the used treatment method should be based on the individual characteristics of each patient. Correct and careful surgical technique is crucial for a satisfactory result. Further research is required in the fields of newer adjuvant to healing methods that will promote osseous union. Crowley et al. in a recent review recognized that despite the fact that plating has reached near equivocal rates of success, exchange nailing for the treatment of a femoral nonunion remains the gold standard of treatment. The authors concluded that where exchange nailing fails, the use of plates and external fixators has been shown to provide useful adjuncts to the nail and that the use of bone graft should be considered for each case of hypotrophic nonunion.79 Our proposed treatment algorithm will not differ from the prementioned conclusions. To the writers’ opinion, nail dynamization is the first treatment option in cases of a femoral shaft nonunion where the initial treatment was intramedullary nailing in a static locking mode. If the first ostheosynthesis method is not intramedullary nailing, conversion of the osteosynthesis to intramedullary nailing is proposed. Nail exchange is the method of choice after failure of primary intramedullary nailing. Plate osteosynthesis is a method with promising results that should be kept in the second line of treatment and can be used as augmentation technique over a previous used intramedullary nail, with or without bone grafting. External fixators (Ilizarov-type fixators) can also be preserved in the second line of treatment and should mostly be targeted against septic cases of femoral nonunions or where gradual correction of deformity is required. Bone grafting techniques can be used as adjuncts combined with surgical techniques, mostly after the initial procedure has failed. Bone morphogenetic proteins are currently considered the most appealing osteoinductive agents. Thorough evaluation of these apparently expensive agents is needed before expansion of their usage in clinical practice. Electromagnetic stimulation and lowintensity pulsed ultrasound systems can be used as treatment

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alternatives/or subsidiary methods in the treatment of aseptic nonunions. The authors recommend that every patient should be treated at an individual basis, taking under consideration factors such as age, biologic healing potential, concomitant diseases and smoking history. Since there seems to be no universal treatment protocol we recommend: a. Nail dynamization or conversion to intramedullary nailing/nail exchange as the first treatment option. b. Plate osteosynthesis or use of external fixators should be preserved in the second line of treatment. c. Adjuvant treatment modalities should be used as subsidiary methods and cannot compensate for a mechanically unstable osteosynthesis. Conflict of interest statement The authors declare that they have not received from any organization any personal or financial benefit that could influence to the work published in this article. Acknowledgements The authors would like to thank G. Gouvas and Ch. Garnavos for their assistance in providing photographic documentation. References 1. Winquist RA, Hansen ST, Clawson DK. Closed intramedullary nailing for femoral fractures: a report of five hundred and twenty cases. J Bone Joint Surg Am 1984;66:529–39. 2. Garland DE, Rieser TV, Singer DI. Treatment of femoral shaft fractures associated with acute spinal cord injuries. Clin Orthop Relat Res 1985;197:191–5. 3. Lynch JR, Taitsman LA, Barei DP, Nork SE. Femoral nonunion: risk factors and treatment ortions. J Am Acad Orthop Surg 2008;16:88–97. 4. Lai D, Chen CM, Chiu FY, Chang MC, Chen TH. Reconstruction of juxta-articular huge defects of distal femur with vascularized fibular bone graft and Ilizarov’s distraction osteogenesis. J Trauma 2007;62:166–73. 5. Yoshida A, Yajima H, Murata K, Maegawa N, Kobata Y, Kawamura K, et al. Pedicled vascularized bone graft from the medial supracondylar region of the femur for treatment of femur nonunion. J Reconstr Microsurg 2009;25: 165–70. 6. Kempf I, Grosse A, Rigaut P. The treatment of noninfected pseudarthrosis of the femur and tibia with locked intramedullary nailing. Clin Orthop Relat Res 1986;212:142–54. 7. Webb LX, Winquist RA, Hansen ST. Intramedullary nailing and reaming for delayed union or nonunion of the femoral shaft. Clin Orthop Relat Res 1986;212: 133–41. 8. Wu CC, Chen W. Treatment of femoral shaft aseptic nonunions: comparison between closed and open bone grafting techniques. J Trauma 1997;43:112–6. 9. Wu CC, Shin C. Treatment of 84 cases of femoral nonunion. Acta Orthop Scand 1992;63:57–60. 10. Canadian Orthopaedic Trauma Society. Nonunion following intramedullary nailing of the femur with and without reaming. Results of a multicenter randomized clinical trial. J Bone Joint Surg Am 2003;85-A:2093–6. 11. Wolinsky PR, McCarty E, Shryr Y, Johnson K. Reamed intramedullary nailing of the femur: 551 cases. J Trauma 1999;46:392–9. 12. Cleveland BK. Delayed union and nonunion of fractures. In: Terry S Canale, James H Beaty, editors. Campbell’s operative orthopaedics, vol. 3., 11th ed. Philadelphia, Pennsylvania, USA: Mosby Elsevier Science; 2008. p. 3529–30 [chapter 56]. 13. Abdel Aa AM, Farouk OA, Elsaved A, Said HG. The use of a locked plate in the treatment of ununited femoral shaft fractures. J Trauma 2004;57:832–6. 14. Bellabarba C, Ricci WM, Bolhofner BR. Results of indirect reduction and plating of femoral shaft nonunions after intramedullary nailing. J Orthop Trauma 2001;15:254–63. 15. Choi YS, Kim KS. Plate augmentation leaving the nail in situ and bone grafting for non-union of femoral shaft fractures. Int Orthop 2005;29:287–90. 16. Furlong AJ, Giannoudis PV, DeBoer P, Matthews SJ, MacDonald DA, Smith RM. Exchange nailing for femoral shaft aseptic non-union. Injury 1999;30:245–9. 17. Pihlajama¨ki HK, Salminen ST, Bo¨stman OM. The treatment of nonunions following intramedullary nailing of femoral shaft fractures. J Orthop Trauma 2002;16:394–402. 18. Ring D, Jupiter JB, Sanders RA, Quintero J, Santoro VM, Ganz R, et al. Complex nonunion of fractures of the femoral shaft treated by wave-plate osteosynthesis. J Bone Joint Surg Br 1997;79:289–94.

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