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Fracture nonunion in long bones: A literature review of risk factors and surgical management

Open AccessPublished:November 11, 2020DOI:https://doi.org/10.1016/j.injury.2020.11.029

      Highlights

      • The burden of a long bone nonunion is substantial with pain, loss of function and psychological distress commonly encountered.
      • Nonunion in clinical practice is most commonly associated with long bone fractures of the forearm, humerus, tibia, clavicle and femur.
      • The majority of nonunions can be effectively managed with conventional surgical techniques.

      Abstract

      Nonunion following a long bone fracture causes considerable morbidity when it occurs. Risk factors depend on specific fractures but there is a complex interplay of injury severity, comorbidities, patient medication and infection. The majority of nonunions occur after long bone fractures with the tibia, femur, forearm, humerus and clavicle predominating. Despite interest in the biological augmentation of fracture healing, the majority of nonunions can be effectively managed with conventional surgical techniques. In this review we present a review of risk factors for nonunion and the outcome following surgical management.

      Keywords

      Definition and classification

      Nonunion is thought to occur in approximately 2% of all fractures [
      • Mills L.A.
      • Aitken S.A.
      • Simpson A.H.R.W.
      The risk of non-union per fracture: current myths and revised figures from a population of over 4 million adults.
      ] but for diaphyseal fractures the incidence can be as high as 20% for certain injuries [
      • Zura R.
      • Xiong Z.
      • Einhorn T.
      • Watson J.T.
      • Ostrum R.F.
      • Prayson M.J.
      • et al.
      Epidemiology of fracture nonunion in 18 human bones.
      ]. The incidence of nonunion in the U.K. is estimated at 20 per 100,000 population with males of the working age being the most common group [
      • Mills L.A.
      • Simpson A.H.R.W.
      The relative incidence of fracture non-union in the Scottish population (5.17 million): a 5-year epidemiological study.
      ]. The burden of a long bone nonunion is substantial with pain, loss of function and psychological distress commonly encountered [
      • Lerner R.K.
      • Esterhai J.L.
      • Polomano R.C.
      • Cheatle M.D.
      • Heppenstall R.B.
      Quality of life assessment of patients with posttraumatic fracture nonunion, chronic refractory osteomyelitis, and lower-extremity amputation..
      ]. The financial implications can often be extensive for patients due to loss of potential earnings and with an estimated medical expense of up to £79,000 per case being reported [
      • Mills L.A.
      • Aitken S.A.
      • Simpson A.H.R.W.
      The risk of non-union per fracture: current myths and revised figures from a population of over 4 million adults.
      ,
      • Pati S.
      • Montgomery R.
      Management of complex tibial and femoral nonunion using the Ilizarov technique, and its cost implications..
      ]. Nonunion in clinical practice is most commonly associated with long bone fractures of the forearm, humerus, tibia, clavicle and femur [
      • Mills L.A.
      • Aitken S.A.
      • Simpson A.H.R.W.
      The risk of non-union per fracture: current myths and revised figures from a population of over 4 million adults.
      ,
      • Zura R.
      • Xiong Z.
      • Einhorn T.
      • Watson J.T.
      • Ostrum R.F.
      • Prayson M.J.
      • et al.
      Epidemiology of fracture nonunion in 18 human bones.
      ].
      A precise definition of nonunion is difficult. According to the US FDA definition, a fracture ununited 9 months after injury or one in which there is a failure of progression towards union over the previous three months, can be classified as a nonunion [

      Federal Register :: Guidance document for industry and CDRH staff for the preparation of investigational device exemptions and premarket approval applications for bone growth stimulator devices; draft; availability [Internet]. [cited 2020 Feb 13]. Available from: https://www.federalregister.gov/documents/1998/04/28/98-11158/guidance-document-for-industry-and-cdrh-staff-for-the-preparation-of-investigational-device.

      ]. However, 9 months is a long period of time for patients to wait for defining a nonunion. A specific duration of time to define nonunion must be related to the location of the fracture and the severity of the original injury, two factors which will have a profound influence on time to union. In general, lower energy closed fractures can be expected to progress to union in much shorter time than high energy open long bone fractures. Rather than relying on a specific time frame to define a nonunion it has been proposed that a more practical definition of nonunion is a fracture that will not unite without further intervention.
      Traditional classification and treatment of nonunion patterns was based on plain radiographs. A hypertrophic nonunion is characterised by abundant callus formation and is usually considered to have excessive motion but good biological potential for healing at the fracture site. An oligotrophic nonunion has poor callus formation and is considered to have viable fracture fragments but has a combination of excess motion but also impaired biological potential for healing at the fracture site. An atrophic nonunion has no callus formation with no biological capacity to heal without some biological stimulus as part of the treatment, most commonly in the form of a bone graft [
      • Simpson A.H.R.W.
      • Robiati L.
      • Jalal M.M.K.
      • Tsang S.T.J.
      Non-union: indications for external fixation.
      ]. These categories are no longer considered valid for a variety of reasons. Firstly, many fractures treated nonoperatively in the past are now treated by internal fixation and the classic radiographic patterns of hypertrophic and atrophic nonunions are less commonly seen. Secondly, histological studies of stiff atrophic and hypertrophic nonunions indicate no difference in the vascularity of the fracture site between the two types [
      • Reed A.A.C.
      • Joyner C.J.
      • Brownlow H.C.
      • Simpson A.H.R.W.
      Human atrophic fracture non-unions are not avascular.
      ].
      Current literature supports the view that the majority of long bone nonunions can be addressed with operative fixation to reduce the mechanical strain environment to promote union without the need for biological augmentation [
      • Perren S.M.
      Physical and biological aspects of fracture healing with special reference to internal fixation..
      ]. However, in certain nonunion cases careful consideration needs to be given to the biological factors affecting healing and risk factors in the host which may influence fracture healing. In this article we review the current evidence relating to the causes and results of conventional surgical management of long bone fracture nonunion.
      A structured review of the relevant literature indexed in PubMed was undertaken with keywords “nonunion” or “delayed union” combined with “diagnosis”, “definition”, “risk factors”, “clavicle”, “humerus”, “forearm”, “femur” and “tibia”. For the tibia and femur these were also combined with “exchange nailing” and “circular frame”. Focus was placed on the contemporary surgical management of long bone nonunion in order to aid clinical decision making. The results are presented with the focus on risk factors and surgical treatment of specific fractures.

      Risk factors for nonunion

      Local factors

      Establishing key risk factors to predict nonunion has been the subject of much interest in orthopaedic literature. Despite an abundance of research on the topic, there is controversy in relation to the relative importance of specific risk factors. This reflects widespread variation in study design, definition of nonunion, heterogeneity of fracture types and patient populations [
      • Zura R.
      • Mehta S.
      • Della Rocca G.J.
      • Steen R.G.
      Biological risk factors for nonunion of bone fracture.
      ].
      Probably the most important local factor affecting bone healing is the energy of the injury causing the fracture and the associated soft tissue injury. Open injuries with associated soft tissue stripping have an intrinsic risk of poor healing as reported for clavicle [
      • Robinson C.M.
      Fractures of the clavicle in the adult.
      ] and tibia [
      • Bhandari M.
      • Tornetta P.
      • Sprague S.
      • Najibi S.
      • Petrisor B.
      • Griffith L.
      • et al.
      Predictors of reoperation following operative management of fractures of the tibial shaft..
      ,
      • Schemitsch E.H.
      • Bhandari M.
      • Guyatt G.
      • Sanders D.W.
      • Swiontkowski M.
      • Tornetta P.
      • et al.
      Prognostic factors for predicting outcomes after intramedullary nailing of the Tibia.
      ] but is likely to be relevant for most long bone fractures [
      • Court-Brown C.M.
      • Caesar B.
      Epidemiology of adult fractures: a review..
      ]. Bone loss as a result of open fracture is another risk factor associated with nonunion but this is not common and in one study was reported in 0.4% of all fractures requiring admission to a large tertiary trauma hospital [
      • Keating J.F.
      • Simpson A.H.R.W.
      • Robinson C.M.
      The management of fractures with bone loss..
      ]. Spontaneous healing can usually be expected with conventional fixation techniques if the defect is less than 2cm or involving no more than 50% circumference of the bone [
      • Keating J.F.
      • Simpson A.H.R.W.
      • Robinson C.M.
      The management of fractures with bone loss..
      ]. Although increasing displacement and the presence of comminution are often considered as risk factors for most long bone injuries, the evidence of this assumption rests largely on retrospective studies which are prone to bias [
      • Zura R.
      • Mehta S.
      • Della Rocca G.J.
      • Steen R.G.
      Biological risk factors for nonunion of bone fracture.
      ]. The association of multiple fractures with polytrauma is thought to be an independent predictor for poor bone healing, although not completely understood, a persistent systemic inflammatory response and the association with high energy injuries is likely to explain this finding [
      • Zura R.
      • Xiong Z.
      • Einhorn T.
      • Watson J.T.
      • Ostrum R.F.
      • Prayson M.J.
      • et al.
      Epidemiology of fracture nonunion in 18 human bones.
      ,
      • Metsemakers W.J.
      • Handojo K.
      • Reynders P.
      • Sermon A.
      • Vanderschot P.
      • Nijs S.
      Individual risk factors for deep infection and compromised fracture healing after intramedullary nailing of tibial shaft fractures: a single centre experience of 480 patients.
      ,
      • Hildebrand F.
      • Van Griensven M.
      • Huber-Lang M.
      • Flohe S.B.
      • Andruszkow H.
      • Marzi I.
      • et al.
      Is There an impact of concomitant injuries and timing of fixation of major fractures on fracture healing? A focused review of clinical and experimental evidence..
      ].
      While the energy of the injury causing the fracture is important, it is clearly not the only element. Most clavicle fractures occur as the result of what would be considered low energy trauma, but in completely displaced fractures the nonunion risk is approximately 15% following non-operative treatment [
      • Lenza M.
      • Buchbinder R.
      • Johnston R.V.
      • Ferrari B.A.
      • Faloppa F.
      Surgical versus conservative interventions for treating fractures of the middle third of the clavicle.
      ]. Similarly, many humeral diaphyseal fractures will occur as a consequence of low energy trauma but recent series report nonunion rates of up to 20% following non-operative treatment [
      • Harkin F.E.
      • Large R.J.
      Humeral shaft fractures: union outcomes in a large cohort.
      ,
      • Ali E.
      • Griffiths D.
      • Obi N.
      • Tytherleigh-Strong G.
      • Van Rensburg L.
      Nonoperative treatment of humeral shaft fractures revisited.
      ]. Perren's strain theory would suggest excessive motion interferes with fracture healing and it may reflect the difficulty of immobilisation of clavicle and certain humeral shaft fractures.
      In any fracture complicated by nonunion following fixation infection should always be considered. Diagnosis is not straightforward as there may be few or no clinical signs to confirm infection and inflammatory markers such as C reactive protein may be normal. Clinical suspicion should be raised in cases where there is a history of initial superficial wound infections, there is persistent pain or swelling of the affected limb. Radiographs may also demonstrate findings consistent with infection such as progressive osteolysis and early failure of fixation. It has been estimated that 5% of nonunions are associated with an occult infection. At the time of any revision surgery samples should be sent both for microbiological and histological examination to look for infection in all nonunion cases [

      Mills L., Tsang J., Hopper G., Keenan G., Simpson A.H.R.W.. The multifactorial aetiology of fracture nonunion and the importance of searching for latent infection. Bone Jt Res [Internet]. 2016 [cited 2020 Apr 23];5 Oct 1 (10):512–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27784669

      ].

      General factors

      Surgeons need to consider modifiable patient risk factors for nonunion as optimising these may improve the prospects of success with surgical intervention.
      Most orthopaedic surgeons would regard age as an independent predictor of nonunion (82% from a recent survey) [
      • Bhandari M.
      • Fong K.
      • Sprague S.
      • Williams D.
      • Petrisor B.
      Variability in the definition and perceived causes of delayed unions and nonunions: a cross-sectional, multinational survey of orthopaedic surgeons.
      ]. The evidence for this is poor and observational data from large epidemiological databases have found that nonunion incidence peaks around the age of 35 to 44 and decreases thereafter [
      • Mills L.A.
      • Aitken S.A.
      • Simpson A.H.R.W.
      The risk of non-union per fracture: current myths and revised figures from a population of over 4 million adults.
      ,
      • Zura R.
      • Braid-Forbes M.J.
      • Jeray K.
      • Mehta S.
      • Einhorn T.A.
      • Watson J.T.
      • et al.
      Bone fracture nonunion rate decreases with increasing age: a prospective inception cohort study.
      ]. This may reflect the fracture epidemiology in certain age groups. For example, elderly patients have a high incidence of low energy fractures in metaphyseal bone such as distal radial fractures which are recognised as having a low risk of nonunion. By contrast, younger patients will have a higher incidence of high energy fractures.
      Smoking is generally considered to have a negative effect on bone healing and this viewpoint is supported by most, but not all, studies which have evaluated this as a risk factor [
      • Hernigou J.
      • Schuind F.
      Tobacco and bone fractures: a review of the facts and issues that every orthopaedic surgeon should know..
      ]. The adverse effects of smoking on union rates have been found in the clavicle, humerus, tibia, and femoral shaft. Studies that did not show an association with smoking and nonunion were characterised by small patient cohorts. Large systematic reviews and studies based on large databases clearly demonstrate that smoking is a risk factor for nonunion. In their systematic review which included over 6000 patients Scolaro et al reported an odds ratio for bone nonunion at 2.32 for current smokers against non-smokers [
      • Scolaro J.A.
      • Schenker M.L.
      • Yannascoli S.
      • Baldwin K.
      • Mehta S.
      • Ahn J.
      Cigarette smoking increases complications following fracture: a systematic review..
      ].
      Diabetes is known to predispose to complications following foot and ankle trauma surgery [
      • Shibuya N.
      • Humphers J.M.
      • Fluhman B.L.
      • Jupiter D.C.
      Factors associated with nonunion, delayed union, and malunion in foot and ankle surgery in diabetic patients.
      ]. In a large database analysis of over 300,000 fractures, type II diabetes was identified as a risk factor for nonunion [
      • Zura R.
      • Xiong Z.
      • Einhorn T.
      • Watson J.T.
      • Ostrum R.F.
      • Prayson M.J.
      • et al.
      Epidemiology of fracture nonunion in 18 human bones.
      ]. The mechanism for this is uncertain but there are adverse metabolic consequences of diabetes on bone metabolism that are likely to be implicated [
      • Takahara S.
      • Lee S.Y.
      • Iwakura T.
      • Oe K.
      • Fukui T.
      • Okumachi E.
      • et al.
      Altered expression of microRNA during fracture healing in diabetic rats.
      ]. These include a toxic effect of hyperglycaemia on osteoblasts, an osmotic diuresis of calcium associated with glucosuria, functional hypoparathyroidism and in some patients renal osteodystrophy [
      • Jiao H.
      • Xiao E.
      • Graves D.T.
      ]. As might be expected the risk is probably higher in patients with poor diabetic control and this has been shown in one study where raised haemoglobin A1c levels, were associated with complications including wound breakdown, loss of fixation and an increased risk of nonunion [
      • Shibuya N.
      • Humphers J.M.
      • Fluhman B.L.
      • Jupiter D.C.
      Factors associated with nonunion, delayed union, and malunion in foot and ankle surgery in diabetic patients.
      ]. There is also evidence that it has a general negative effect on bone healing and approximately doubles the risk of long bone fracture nonunion [
      • Hernandez R.K.
      • Do T.P.
      • Critchlow C.W.
      • Dent R.E.
      • Jick S.S.
      Patient-related risk factors for fracture-healing complications in the United Kingdom general practice research database.
      ]. Better diabetic control may reduce the risk but in their large database study Zura et al found diabetes to be an independent risk factor irrespective of whether it was controlled or uncontrolled [
      • Zura R.
      • Mehta S.
      • Della Rocca G.J.
      • Steen R.G.
      Biological risk factors for nonunion of bone fracture.
      ].
      Obesity has been associated with nonunion for the humerus, femur and tibia in a number of studies [
      • Zura R.
      • Mehta S.
      • Della Rocca G.J.
      • Steen R.G.
      Biological risk factors for nonunion of bone fracture.
      ]. In studies of distal radial fractures [
      • Hall M.J.
      • Ostergaard P.J.
      • Dowlatshahi A.S.
      • Harper C.M.
      • Earp B.E.
      • Rozental T.D.
      The impact of obesity and smoking on outcomes after volar plate fixation of distal radius fractures.
      ] and ankle fractures [
      • Thorud J.C.
      • Mortensen S.
      • Thorud J.L.
      • Shibuya N.
      • Maldonado Y.M.
      • Jupiter D.C.
      Effect of obesity on bone healing after foot and ankle long bone fractures.
      ] it was not associated with an increased risk of nonunion. In a large database study of over 309,000 fracture patients, obesity was a risk factor for nonunion with an odds ratio of 1.19, so the effect would seem to be modest [
      • Zura R.
      • Xiong Z.
      • Einhorn T.
      • Watson J.T.
      • Ostrum R.F.
      • Prayson M.J.
      • et al.
      Epidemiology of fracture nonunion in 18 human bones.
      ]. The increased risk associated with obesity may be explained, to some extent by the difficulty in achieving an appropriate strain environment for fracture healing with non-operative treatment in obese patients where adequate immobilisation of the fracture is difficult to achieve. However, there is increasing recognition of metabolic changes associated with obesity which may affect fracture healing. These include decreasing osteoblast differentiation and bone formation, an increase in tissue pro-inflammatory cytokines promoting osteoclast activity and bone resorption, and a reduction in intestinal calcium absorption, thereby decreasing calcium availability for bone formation [
      • Streubel P.N.
      • Desai P.
      • Suk M.
      Comparison of RIA and conventional reamed nailing for treatment of femur shaft fractures.
      ]. Additionally, large body habitus is thought independently to influence fracture mobility and risk of nonunion with humeral shaft non-operative management [
      • Decomas A.
      • Kaye J.
      Risk factors associated with failure of treatment of humeral diaphyseal fractures after functional bracing.
      ]. It is possible that obesity effects the normal homeostasis of bone metabolism and fracture healing but this relationship is complex and remains incompletely understood [
      • Cao J.J.
      Effects of obesity on bone metabolism..
      ,
      • Savvidis C.
      • Tournis S.
      • Dede A.D.
      Obesity and bone metabolism..
      ].
      Numerous medications have been associated with increasing the risk of nonunion. Steroids although often considered to negatively influence bone healing have no evidence of a significant effect from a recent review [
      • Zura R.
      • Mehta S.
      • Della Rocca G.J.
      • Steen R.G.
      Biological risk factors for nonunion of bone fracture.
      ]. Non-steroidal analgesic consumption (NSAIDS) twelve months prior to a fracture have been associated with nonunion with an estimated odds ratio of 2.6 [
      • Hernandez R.K.
      • Do T.P.
      • Critchlow C.W.
      • Dent R.E.
      • Jick S.S.
      Patient-related risk factors for fracture-healing complications in the United Kingdom general practice research database.
      ]. Specifically for long bone fractures, NSAIDS following post intramedullary nailing of femoral shaft fractures was found to be strongly associated with nonunion and delayed healing [
      • Giannoudis P V.
      • MacDonald D.A.
      • Matthews S.J.
      • Smith R.M.
      • Furlong A.J.
      • De Boer P.
      Nonunion of the femoral diaphysis.
      ]. In an randomised controlled trial (RCT) designed to determine if 6 weeks of indomethacin was effective at reducing heterotopic ossification after acetabular fractures, a significant increase in nonunion was observed in the long bone fractures that these patients had also sustained [
      • Burd T.A.
      • Hughes M.S.
      • Anglen J.O.
      Heterotopic ossification prophylaxis with indomethacin increases the risk of long-bone nonunion.
      ]. However, a preclinical study in a rat model suggested that if NSAIDs were used for just for 48 hours post fracture, there was no detrimental effect [
      • Hjorthaug G.A.
      • Søreide E.
      • Nordsletten L.
      • Madsen J.E.
      • Reinholt F.P.
      • Niratisairak S.
      • et al.
      Short-term perioperative parecoxib is not detrimental to shaft fracture healing in a rat model.
      ].
      In the largest database study to analyse the effect of medications on union [
      • Zura R.
      • Xiong Z.
      • Einhorn T.
      • Watson J.T.
      • Ostrum R.F.
      • Prayson M.J.
      • et al.
      Epidemiology of fracture nonunion in 18 human bones.
      ] NSAIDS and opioid medications were both strongly associated with an increased risk of nonunion and weaker associations were noted with anti-convulsant medication and anti-coagulants. It is important to note that these associations may not be causal. In the case of NSAIDS and anti-convulsant therapy there are known effects on the cyclo-oxygenase pathways and bone metabolism respectively that might indicate a causal association. The association with opioid medication may simply reflect the greater likelihood that patients with nonunions will have a more prolonged treatment course possibly with multiple surgical interventions and will have a higher analgesic requirement than patients who heal uneventfully within expected timeframes. Comorbidities and chronic disease states including osteoporosis have been associated with poor bone healing although not universal to all long bone fractures with some contradictory findings in the literature [
      • Zura R.
      • Xiong Z.
      • Einhorn T.
      • Watson J.T.
      • Ostrum R.F.
      • Prayson M.J.
      • et al.
      Epidemiology of fracture nonunion in 18 human bones.
      ,
      • Zura R.
      • Mehta S.
      • Della Rocca G.J.
      • Steen R.G.
      Biological risk factors for nonunion of bone fracture.
      ]. There is better agreement for alcoholism and drug abuse although this is limited to the femoral neck and humerus [
      • Duckworth A.D.
      • Bennet S.J.
      • Aderinto J.
      • Keating J.F.
      Fixation of intracapsular fractures of the femoral neck in young patients: Risk factors for failure.
      ,
      • Foulk D.A.
      • Szabo R.M.
      Diaphyseal humerus fractures: natural history and occurrence of nonunion.
      ].
      The development of nonunion appears to be multifactorial with a complex interplay between the fracture, patient comorbidities, medications and social behaviours [
      • Zura R.
      • Xiong Z.
      • Einhorn T.
      • Watson J.T.
      • Ostrum R.F.
      • Prayson M.J.
      • et al.
      Epidemiology of fracture nonunion in 18 human bones.
      ,

      Mills L., Tsang J., Hopper G., Keenan G., Simpson A.H.R.W.. The multifactorial aetiology of fracture nonunion and the importance of searching for latent infection. Bone Jt Res [Internet]. 2016 [cited 2020 Apr 23];5 Oct 1 (10):512–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27784669

      ]. Despite the abundance of literature, accurate prediction of patients at increased risk of nonunion based on factors present from the time of injury remains challenging for all fractures. In the next section we consider the current literature on outcomes of conventional surgical management of aseptic diaphyseal nonunion.

      Current evidence of the management for long bone nonunion

      Clavicle

      Older studies by Neer and Rowe reported very low rates of clavicular nonunion with rates less than 1% [
      • Neer C.S.
      Nonunion of the clavicle.
      ]. More recent studies of displaced mid-shaft clavicle fractures in adults have recorded much higher rates of nonunion in approximately 15% of cases [
      • Amer K.
      • Smith B.
      • Thomson J.E.
      • Congiusta D.
      • Reilly M.C.
      • Sirkin M.S.
      • et al.
      Operative versus nonoperative outcomes of middle-third clavicle fractures: a systematic review and meta-analysis.
      ]. The majority tend to be symptomatic requiring operative intervention, but a fibrous union can be tolerated in the elderly or low demand patients.
      Over the past decade there have been over a dozen randomized controlled trials that compared operative fixation to non-operative management for displaced mid-shaft fractures with no cortical contact. The nonunion risk with plate fixation was 1.4% vs 14% with non-operative management [
      • Amer K.
      • Smith B.
      • Thomson J.E.
      • Congiusta D.
      • Reilly M.C.
      • Sirkin M.S.
      • et al.
      Operative versus nonoperative outcomes of middle-third clavicle fractures: a systematic review and meta-analysis.
      ]. Functional outcomes appear similar at long-term follow-up when union occurs and most malunions appear to be well tolerated [
      • Goudie E.B.
      • Clement N.D.
      • Murray I.R.
      • Lawrence C.R.
      • Wilson M.
      • Brooksbank A.J.
      • et al.
      The influence of shortening on clinical outcome in healed displaced midshaft clavicular fractures after nonoperative treatment.
      ]. Targeted fixation of displaced fractures destined for nonunion would be advantageous given routine plate fixation of all displaced fractures is not cost-effective and potentially results in over treatment [
      • Nicholson J.A.
      • Clement N.
      • Goudie E.
      • Robinson C.M.
      TRAUMA Routine fixation of displaced midshaft clavicle fractures is not cost-effective: a cost analysis from a randomized controlled trial.
      ]. Nonunion is more likely with increasing age, smoking and greater degrees of fracture displacement and comminution [
      • Murray I.R.
      • Foster C.J.
      • Eros A.
      • Robinson C.M.
      Risk factors for nonunion after nonoperative treatment of displaced midshaft fractures of the clavicle.
      ]. However these risk factors lack specificity and accurate prediction of patients who will go on to develop a nonunion is currently an unsolved problem [
      • Backus J.D.
      • Merriman D.J.
      • McAndrew C.M.
      • Gardner M.J.
      • Ricci W.M.
      Upright versus supine radiographs of clavicle fractures: does positioning matter?.
      ].
      In a recent Cochrane review of trials [
      • Lenza M.
      • Buchbinder R.
      • Johnston R.V.
      • Ferrari B.A.
      • Faloppa F.
      Surgical versus conservative interventions for treating fractures of the middle third of the clavicle.
      ] evaluating operative versus non-operative treatment of mid-shaft clavicle fractures, 14 studies with 1469 participants were included. The authors pointed out that that almost all of these studies had design features that carry a high risk of bias, which limited the strength of their findings. They were able to confirm that surgery did not appear to be associated with any functional benefit at one year and that the main source of treatment failure was mechanical failure (3.4%) in the surgery group and symptomatic nonunion (11.6%) in the conservative-treatment group.
      There is increasing evidence that delayed primary fixation in the first three months post-injury is a valid alternative without an apparent increase in complications [
      • Das A.
      • Rollins K.E.
      • Elliott K.
      • Johnston P.
      • Van-Rensburg L.
      • Tytherleigh-Strong G.M.
      • et al.
      Early versus delayed operative intervention in displaced clavicle fractures.
      ,
      • Sawalha S.
      • Guisasola I.
      Complications associated with plate fixation of acute midshaft clavicle fractures versus non-unions.
      ,
      • Nicholson J.A.
      • Gribbin H.
      • Clement N.D.
      • Robinson C.M.
      Open reduction and internal fixation of clavicular fractures after a delay of three months is associated with an increased risk of complications and revision surgery.
      ]. Delayed recovery following non-operative management may predict union and can be accurately judged on a patient reported QuickDASH score and other objective clinical features at six weeks post-injury [
      • Clement N.D.
      • Goudie E.B.
      • Brooksbank A.J.
      • Chesser T.J.S.
      • Robinson C.M.
      Smoking status and the disabilities of the arm shoulder and hand score are early predictors of symptomatic nonunion of displaced midshaft fractures of the clavicle.
      ,
      • Nicholson J.A.
      • Clement N.D.
      • Clelland A.D.
      • MacDonald D.
      • Simpson A.H.R.W.
      • Robinson C.M.
      Displaced midshaft clavicle fracture union can be accurately predicted with a delayed assessment at 6 weeks following injury: a prospective cohort study.
      ].
      For established nonunion after non-operative treatment plate fixation is considered the treatment of choice. Historical case series with plate fixation and bone grafting suggested a low rate of complications with union achieved in the majority of cases [
      • Pyper J.B.
      Non-union of fractures of the clavicle.
      ,
      • Manske D.J.
      • Szabo R.M.
      The operative treatment of mid-shaft clavicular non-unions.
      ,
      • Eskola A.
      • Valnionpää S.
      • Myllynen P.
      • Pätiälä H.
      • Rokkanen P.
      Surgery for ununited clavicular fracture.
      ,
      • Jupiter J.B.
      • Leffert R.D.
      Non-union of the clavicle. Associated complications and surgical management..
      ,
      • Davids P.H.P.
      • Luitse J.S.K.
      • Strating R.P.
      • Van Der Hart C.P.
      Operative treatment for delayed union and nonunion of midshaft clavicular fractures: AO reconstruction plate fixation and early mobilization.
      ,
      • Ikuta T.
      • Yuasa T.
      • Higashi T.
      Surgical treatment of fracture and pseudoarthrosis of clavicle using reconstruction plate.
      ,
      • Der Tavitian J.
      • Davison J.N.S.
      • Dias J.J.
      Clavicular fracture non-union surgical outcome and complications.
      ]. The largest case series to date (n=47) found a persistent nonunion at approximately 7% post-operatively [
      • Endrizzi D.P.
      • White R.R.
      • Babikian G.M.
      • Old A.B.
      Nonunion of the clavicle treated with plate fixation: a review of forty-seven consecutive cases.
      ] which reflects more recent literature [
      • Nicholson J.A.
      • Gribbin H.
      • Clement N.D.
      • Robinson C.M.
      Open reduction and internal fixation of clavicular fractures after a delay of three months is associated with an increased risk of complications and revision surgery.
      ]. Although bone grafting was traditionally used in clavicular fracture nonunion, more recent series suggest it is not required for the majority of cases [
      • Chen W.
      • Tang K.
      • Tao X.
      • Yuan C.
      • Zhou B.
      Clavicular non-union treated with fixation using locking compression plate without bone graft.
      ]. Resection of the sclerotic bone ends with compression plating has a high success rate as reported in several studies [
      • Nicholson J.A.
      • Gribbin H.
      • Clement N.D.
      • Robinson C.M.
      Open reduction and internal fixation of clavicular fractures after a delay of three months is associated with an increased risk of complications and revision surgery.
      ,
      • Chen W.
      • Tang K.
      • Tao X.
      • Yuan C.
      • Zhou B.
      Clavicular non-union treated with fixation using loc king compression plate without bone graft.
      ,
      • Stufkens S.A.
      • Kloen P.
      Treatment of midshaft clavicular delayed and non-unions with anteroinferior locking compression plating.
      ,
      • Martetschläger F.
      • Gaskill T.R.
      • Millett P.J.
      Management of clavicle nonunion and malunion.
      ] (Fig. 1).
      Fig 1
      Fig. 1Clavicle
      A .Atrophic clavicle fracture at six months post injury
      B. Successful union with compression plating without bone grafting. Radiograph at six months post-operative.

      Humerus

      The classic Sarmiento technique of functional bracing of humeral shaft fractures suggested nonunion is extremely rare occurring in only 2% of closed fractures and 6% in open injuries [
      • Sarmiento A.
      • Kinman P.B.
      • Galvin E.G.
      • Schmitt R.H.
      • Phillips J.G.
      Functional bracing of fractures of the shaft of the humerus.
      ,
      • Sarmiento A.
      • Zagorski J.B.
      • Zych G.A.
      • Latta L.L.
      • Capps C.A.
      Functional bracing for the treatment of fractures of the humeral diaphysis.
      ]. As with clavicle fractures more recent series have reported nonunion rates of approximately 20% for humeral shaft fractures managed non-operatively [
      • Harkin F.E.
      • Large R.J.
      Humeral shaft fractures: union outcomes in a large cohort.
      ,
      • Ali E.
      • Griffiths D.
      • Obi N.
      • Tytherleigh-Strong G.
      • Van Rensburg L.
      Nonoperative treatment of humeral shaft fractures revisited.
      ]. Angular deformity and comminution does not appear to predict nonunion but displaced proximal third fractures are known to have an increased risk [
      • Updegrove G.F.
      • Mourad W.
      • Abboud J.A.
      Humeral shaft fractures.
      ]. Purely transverse fractures have also been reported to have a higher incidence of nonunion, potentially because the fracture surface available for healing is small. Recent evidence suggests that fracture mobility at six weeks post non-operative management has good accuracy to predict nonunion with 82% sensitivity and 99% specificity when present [

      Driesman A.S., Fisher N., Karia R., Konda S., Egol K.A.. Fracture site mobility at 6 weeks after humeral shaft fracture predicts nonunion without surgery. 2017 [cited 2020 Feb 9]; Available from: www.jorthotrauma.com

      ]. Additionally the use of callus radiograph grading, similar to that of the tibia, has been shown to aid with prediction at six weeks post-injury [
      • Oliver W.M.
      • Smith T.J.
      • Nicholson J.A.
      • Molyneux S.G.
      • White T.O.
      • Clement N.D.
      • et al.
      The Radiographic Union Score for HUmeral fractures (RUSHU) predicts humeral shaft nonunion.
      ]. Trials comparing non-operative treatment of humeral shaft fractures with plating have reported lower nonunion rates with plate fixation but in longer term follow-up there does not appear to be any benefit in the functional outcome [
      • Matsunaga F.T.
      • Tamaoki M.J.S.
      • Matsumoto M.H.
      • Netto N.A.
      • Faloppa F.
      • Belloti J.C.
      Minimally invasive osteosynthesis with a bridge plate versus a functional brace for humeral shaft fractures: a randomized controlled trial.
      ,
      • Mahdi S.
      • Khameneh H.
      • Abbasian M.
      • Abrishamkarzadeh H.
      • Bagheri S.
      • Abdollahimajd F.
      • et al.
      Humeral shaft fracture: a randomized controlled trial of nonoperative versus operative management (plate fixation).
      ].
      The most popular treatment of humeral nonunion has been compression plating, with or without bone grafting. The majority of humeral shaft nonunions are considered to be atrophic in pattern and therefore plating with additional bone grafting has been the most popular treatment. Although generally considered to be a successful procedure, post-operative complications can be encountered with a persistent nonunion rate of 16% [
      • Wiss D.A.
      • Garlich JM.
      Healing the index humeral shaft nonunion.
      ], post-operative infection of 11% [
      • Abalo A.
      • Dosseh E.D.
      • Adabra K.
      • Walla A.
      • James Y.E.
      • Dossim A.
      Open reduction and internal fixation of humeral non-unions: radiological and functional results.
      ] and radial nerve palsy rate in 17% [
      • Crosby L.A.
      • Norris B.L.
      • Dao K.D.
      • McGuire M.H.
      Humeral shaft nonunions treated with fibular allograft and compression plating.
      ] in certain case series. A meta-analysis of humeral nonunions identified 36 studies of 672 patients treated with plate fixation and bone grafting with a reported union rate of 98% [
      • Peters R.M.
      • Claessen F.M.A.P.
      • Doornberg J.N.
      • Kolovich G.P.
      • Diercks R.L.
      • Van Den Bekerom M.P.J.
      Union rate after operative treatment of humeral shaft nonunion - a systematic review..
      ]. This was superior to the results of intramedullary nailing with bone grafting (88% union rate, 164 cases) or without bone grafting (66% union rate, 71 cases). Only two studies reported the results of plating without bone grafting with a 95% union rate, but these studies combined only had 19 cases. For aseptic diaphyseal humeral nonunion, plating with bone grafting remains the treatment of choice based on current evidence.

      Forearm

      Skeletally mature patients with displaced diaphyseal forearm fractures will usually undergo plate fixation to minimise the risk of malunion associated with non-operative management. Open injuries with segmental defects are thought to be at increased risk of poor bone healing [
      • Ring D.
      • Allende C.
      • Jafarnia K.
      • Allende B.T.
      • Jupiter J.B.
      Ununited diaphyseal forearm fractures with segmental defects: plate fixation and autogenous cancellous bone-grafting.
      ]. Successful union following plate fixation is thought to occur in the majority of cases with a reported union rates between 95 – 100% in most series with conventional plating techniques [
      • Anderson L.D.
      • Sisk T.D.
      • Tooms R.E.
      • Park W.I.
      Compression plate fixation in acute diaphyseal fractures of the radius and ulna.
      ,
      • Hadden W.A.
      • Reschauer R.
      • Seggl W.
      Results of AO plate fixation of forearm shaft fractures in adults.
      ,
      • Chapman M.W.
      • Gordon E.
      • Zissimos A.G.
      Compression-plate fixation of acute fractures of the diaphyses of the radius and ulna.
      ]. Failure of forearm fractures to unite is most commonly due to poor surgical technique with technical errors in plating [
      • Marcheix P.S.
      • Delclaux S.
      • Ehlinger M.
      • Scheibling B.
      • Dalmay F.
      • Hardy J.
      • et al.
      Pre- and postoperative complications of adult forearm fractures treated with plate fixation.
      ]. Revision surgery for nonunion is generally successful in dealing with the problem. In three clinical case series [
      • dos Reis F.B.
      • Faloppa F.
      • Fernandes H.J.A.
      • Albertoni W.M.
      • Stahel P.F.
      Outcome of diaphyseal forearm fracture-nonunions treated by autologous bone grafting and compression plating.
      ,
      • Kloen P.
      • Wiggers J.K.
      • Buijze G.A.
      Treatment of diaphyseal non-unions of the ulna and radius.
      ,
      • Regan D.K.
      • Crespo A.M.
      • Konda S.R.
      • Egol K.A.
      Functional outcomes of compression plating and bone grafting for operative treatment of nonunions about the forearm.
      ] reporting the results of plating for forearm nonunion there were 101 cases and only 3 persistent nonunions. These studies included 21 isolated radial nonunions, 42 ulnar nonunions and 38 nonunions involving both bones. Standard techniques using 3.5mm dynamic compression plating were used in most cases, generally augmented by bone grafting for cases judged to have oligotrophic or atrophic nonunion. Ring et al reported plating and bone grafting of 35 cases of forearm nonunions with segmental bone defects [
      • Ring D.
      • Allende C.
      • Jafarnia K.
      • Allende B.T.
      • Jupiter J.B.
      Ununited diaphyseal forearm fractures with segmental defects: plate fixation and autogenous cancellous bone-grafting.
      ]. All fractures united within 6 months. In their series, they reported rather variable functional outcomes reflecting a cohort of patients with more complex fractures which had originally been open or had been complicated by infection.
      In conclusion, forearm nonunion can be successfully treated by plate fixation in the majority of cases, irrespective of whether the nonunion involves radius, ulnar or both bones. Based on the published literature, additional bone grafting is advisable in any patients with bone loss or an atrophic pattern of nonunion.

      Tibia

      Nonunion following a tibial diaphyseal fracture is found in approximately 9% of cases when considering the spectrum of both closed and open injuries [
      • Mills L.A.
      • Aitken S.A.
      • Simpson A.H.R.W.
      The risk of non-union per fracture: current myths and revised figures from a population of over 4 million adults.
      ,
      • Court-Brown C.
      • McQueen M.
      • Quaba A.
      • Christie J.
      Locked intramedullary nailing of open tibial fractures.
      ,
      • Rupp M.
      • Biehl C.
      • Budak M.
      • Thormann U.
      • Heiss C.
      • Alt V.
      Diaphyseal long bone nonunions — types, aetiology, economics, and treatment recommendations..
      ,
      • Connelly C.L.
      • Bucknall V.
      • Jenkins P.J.
      • Court-Brown C.M.
      • McQueen M.M.
      • Biant L.C.
      Outcome at 12 to 22 years of 1502 tibial shaft fractures.
      ]. As expected open fractures have a higher incidence of nonunion and the risk correlates to the severity of the injury as classified by Gustilo and Anderson grading [
      • Court-Brown C.
      • McQueen M.
      • Quaba A.
      • Christie J.
      Locked intramedullary nailing of open tibial fractures.
      ]. Type IIIB open fractures have a high requirement of surgical reintervention to achieve union [
      • Rupp M.
      • Biehl C.
      • Budak M.
      • Thormann U.
      • Heiss C.
      • Alt V.
      Diaphyseal long bone nonunions — types, aetiology, economics, and treatment recommendations..
      ].
      In modern orthopaedic practice, intramedullary nailing is the most popular initial management of unstable tibial diaphyseal fractures. When aseptic nonunion occurs, exchange nailing is a straightforward treatment with a high success rate. Although static versus dynamic screw configuration is not thought to influence success, a combined procedure with a fibular osteotomy has been found to reduce time to union [
      • Abadie B.
      • Leas D.
      • Cannada L.
      • Malm P.
      • Morwood M.
      • Howes C.
      • et al.
      Does screw configuration or fibular osteotomy decrease healing time in exchange Tibial nailing?.
      ] (Fig. 2). The need for exchange nailing is generally rare and in a large series of over 1500 tibia fractures, it was required in only 5% of all cases [
      • Connelly C.L.
      • Bucknall V.
      • Jenkins P.J.
      • Court-Brown C.M.
      • McQueen M.M.
      • Biant L.C.
      Outcome at 12 to 22 years of 1502 tibial shaft fractures.
      ]. The indications and timing for exchange nailing must take into account the severity of the original injury. Most closed tibial diaphyseal fractures will heal between 12 and 16 weeks following injury. Absence of radiographic evidence of progression to union by 16 weeks is therefore a relative indication for exchange nailing. Open fractures, particularly type IIIA and IIIB, can be expected to unite in longer time frames, often taking longer than 20 weeks [
      • Court-Brown C.M.
      • Keating J.F.
      • Christie J.
      • McQueen M.M.
      Exchange intramedullary nailing. Its use in aseptic tibial nonunion.
      ].
      Fig 2
      Fig. 2Tibia
      A. Closed tibia fracture managed with IM nailing
      B. Tibia with nonunion and low grade infection at nine months post injury
      C. Successful union with exchange nailing, fibula corticotomy and anitiboitc cover. Radiograph at six months post-operative.
      For uncomplicated nonunion without infection or bone loss in closed diaphyseal fractures the success rate of exchange nailing is high. Court-Brown et al reported on 33 cases of exchange nails for tibial nonunion with 100% success achieving union in closed, type 1, 2, and 3A open fractures [
      • Court-Brown C.M.
      • Keating J.F.
      • Christie J.
      • McQueen M.M.
      Exchange intramedullary nailing. Its use in aseptic tibial nonunion.
      ]. This has been replicated by two other independent centres with similar size cohorts with a success rate of approximately 95% [
      • Zelle B.A.
      • Gruen G.S.
      • Klatt B.
      • Haemmerle M.J.
      • Rosenblum W.J.
      • Prayson M.J.
      Exchange reamed nailing for aseptic nonunion of the tibia.
      ,
      • Kostic I.
      • Mitkovic M.
      • Mitkovic M.
      The diaphyseal aseptic tibial nonunions after failed previous treatment options managed with the reamed intramedullary locking nail.
      ]. The largest cohort in the literature of aseptic tibial nonunion was recently published by Hierholzer, they prospectively followed 188 patients and found 88% united after a single exchange nailing [
      • Hierholzer C.
      • Friederichs J.
      • Glowalla C.
      • Woltmann A.
      • Bühren V.
      • von Rüden C.
      Reamed intramedullary exchange nailing in the operative treatment of aseptic tibial shaft nonunion.
      ]. It is also thought that exchange nailing is superior to dynamization in the presence of comminution or persistent fracture gap from the initial procedure [
      • Litrenta J.
      • Tornetta P.
      • Mehta S.
      • Jones C.
      • O'Toole R.V.
      • Bhandari M.
      • et al.
      Determination of radiographic healing: an assessment of consistency using RUST and modified RUST in metadiaphyseal fractures.
      ].
      Tsang reported more variable outcomes however and found a 63% success rate of achieving union with a single tibial nail exchange procedure in 96 patients [
      • Tsang S.T.J.
      • Mills L.A.
      • Frantzias J.
      • Baren J.P.
      • Keating J.F.
      • Simpson A.H.R.W.
      Exchange nailing for nonunion of diaphyseal fractures of the tibia.
      ]. Their series included 31 infected nonunions and type III open tibial shaft fractures. For aseptic nonunions the success rate of an exchange nailing was 70%. Fracture union was ultimately achieved in 89 of 96 patients (92.7%) with one or more exchange nailing procedures. Risk factors for failure of exchange nailing included presence of infection, bone gap of more than 5mm, and an atrophic pattern.
      The authors therefore advise that patients should be made aware that their nonunion is unlikely to unite with a single exchange nailing procedure, in the context of known infection or a sclerotic fracture [
      • Tsang S.T.J.
      • Mills L.A.
      • Frantzias J.
      • Baren J.P.
      • Keating J.F.
      • Simpson A.H.R.W.
      Exchange nailing for nonunion of diaphyseal fractures of the tibia.
      ]. If none of the 4 cortices have periosteal new bone formation near to the fracture site, it appears that repeated exchange nailing is unlikely to be successful and a different technique should be considered. Alternative strategies for an established septic nonunion include fine wire circular external fixation frame application combined with open debridement of the fracture, with or without acute shortening and ipsilateral corticotomy. This technique has been reported to have high union rates but has the morbidity associated with a prolonged frame time for patients [
      • Shahid M.
      • Hussain A.
      • Bridgeman P.
      • Bose D.
      Clinical outcomes of the Ilizarov method after an infected tibial non union.
      ,
      • Megas P.
      • Saridis A.
      • Kouzelis A.
      • Kallivokas A.
      • Mylonas S.
      • Tyllianakis M.
      The treatment of infected nonunion of the tibia following intramedullary nailing by the Ilizarov method.
      ,
      • Bose D.
      • Kugan R.
      • Stubbs D.
      • McNally M.
      Management of infected nonunion of the long bones by a multidisciplinary team.
      ,
      • Barker K.L.
      • Lamb S.E.
      • Simpson A.H.R.W.
      Functional recovery in patients with nonunion treated with the Ilizarov technique.
      ]. Monolateral external fixator rather than the traditional circular frame may also be a reasonable alternative to undertake distraction osteogenesis [
      • Rohilla R.
      • Sharma P.K.
      • Wadhwani J.
      • Beniwal R.
      • Singh R.
      • Devgan A.
      • et al.
      Prospective randomized comparison of quality of regenerate in distraction osteogenesis of ring versus monolateral fixator in patients with infected nonunion of the tibia using digital radiographs and CT.
      ]. A two staged exchange nailing procedure similar to that of a prosthetic joint infection is also an option [
      • Brinker M.R.
      • O'connor D.P.
      Exchange nailing of ununited fractures.
      ].
      For uncomplicated aseptic tibial diaphyseal nonunion exchange nailing is the treatment of choice. For cases associated with bone loss and infection, more complex reconstructive techniques are often required. In the presence of known infection with a periosteal reaction adjacent to the fracture, repeated exchange nailing with antibiotic cover is still a feasible treatment option. If there is densely atrophic bone with no periosteal reaction adjacent to the fracture, then excision of the dead bone and limb reconstructive techniques with fine wire circular external fixation is the preferred option.

      Femur

      Reamed intramedullary nailing for femoral diaphyseal fractures has resulted in a low nonunion rate of 2% [
      • Furlong A.J.
      • Giannoudis P.V.
      • DeBoer P.
      • Matthews S.J.
      • MacDonald D.A.
      • Smith R.M.
      Exchange nailing for femoral shaft aseptic non-union.
      ,
      • Tsang S.T.J.
      • Mills L.A.
      • Baren J.
      • Frantzias J.
      • Keating J.F.
      • Simpson A.H.R.W.
      Exchange nailing for femoral diaphyseal fracture non-unions: risk factors for failure.
      ]. However, when it occurs it causes significant morbidity and cost [
      • Kanakaris N.K.
      • Giannoudis P.V.
      The health economics of the treatment of long-bone non-unions.
      ]. The risk of nonunion increases with open fractures, bone loss, poor biology or co-existent infection, which is present in a third of cases [
      • Simpson A.H.
      • Tsang J.S.T.
      Current treatment of infected non-union after intramedullary nailing.
      ]. With regards to the technical aspect of the principal procedure, diaphyseal fractures with a nail diameter of less than 70% of the isthmus width has been correlated with need for exchange nailing [
      • Millar M.J.
      • Wilkinson A.
      • Navarre P.
      • Steiner J.
      • Vohora A.
      • Hardidge A.
      • et al.
      Nail fit: does nail diameter to canal ratio predict the need for exchange nailing in the setting of aseptic, hypertrophic femoral nonunions.
      ].
      For uncomplicated aseptic nonunion of the femoral diaphysis exchange nailing is the most common surgical method of treatment [
      • Giannoudis P V.
      • MacDonald D.A.
      • Matthews S.J.
      • Smith R.M.
      • Furlong A.J.
      • De Boer P.
      Nonunion of the femoral diaphysis.
      ] (Fig. 3). The decision to perform exchange nailing is similar to that of the tibia as outlined in the previous section [
      • Bhandari M.
      • Guyatt G.
      • Walter S.D.
      • Tornetta P.
      • Schemitsch E.H.
      • Swiontkowski M.
      • et al.
      Randomized trial of reamed and unreamed intramedullary nailing of tibial shaft fractures.
      ]. Tsang showed in a series of 40 patients that underwent exchange nailing, with or without bone grafting, successful union was achieved in 96.2% of aseptic cases and 81.8% of infected nonunions [
      • Tsang S.T.J.
      • Mills L.A.
      • Baren J.
      • Frantzias J.
      • Keating J.F.
      • Simpson A.H.R.W.
      Exchange nailing for femoral diaphyseal fracture non-unions: risk factors for failure.
      ]. However, in those with infection approximately, half required an additional surgical procedure. Other independent centres have reported a 96%-82% union rates following a single exchange nail for aseptic nonunion [
      • Furlong A.J.
      • Giannoudis P.V.
      • DeBoer P.
      • Matthews S.J.
      • MacDonald D.A.
      • Smith R.M.
      Exchange nailing for femoral shaft aseptic non-union.
      ,
      • Hierholzer C.
      • Glowalla C.
      • Herrler M.
      • von Rüden C.
      • Hungerer S.
      • Bühren V.
      • et al.
      Reamed intramedullary exchange nailing: treatment of choice of aseptic femoral shaft nonunion.
      ]. The principal risk factors for failure of exchange nailing include smoking and infection [
      • Tsang S.T.J.
      • Mills L.A.
      • Baren J.
      • Frantzias J.
      • Keating J.F.
      • Simpson A.H.R.W.
      Exchange nailing for femoral diaphyseal fracture non-unions: risk factors for failure.
      ]. Additionally, an atrophic pattern, open fracture, associated ipsilateral upper limb injury and lack of immediate weight-bearing after index procedure have also been associated [
      • Hak D.J.
      • Lee S.S.
      • Goulet J.A.
      Success of exchange reamed intramedullary nailing for femoral shaft nonunion or delayed union.
      ,
      • Shroeder J.E.
      • Mosheiff R.
      • Khoury A.
      • Liebergall M.
      • Weil Y.A.
      The outcome of closed, intramedullary exchange nailing with reamed insertion in the treatment of femoral shaft nonunions.
      ].
      Fig 3
      Fig. 3Femur
      A. Open femur managed with anterograde nailing
      B. Femur with aseptic nonunion at nine months after open fracture
      C. Successful union with exchange nailing. Radiograph at six months post-operative.
      Dynamization is occasionally attempted as a less invasive method to achieve union in femoral diaphyseal fractures with an axial stable fracture configuration. A recent review suggested this has significantly inferior success to achieve union when compared to exchange nailing [
      • Vaughn J.
      • Gotha H.
      • Cohen E.
      • Fantry A.J.
      • Feller R.J.
      • Van Meter J.
      • et al.
      Nail dynamization for delayed union and nonunion in femur and tibia fractures.
      ,
      • Vaughn J.E.
      • Shah R.V.
      • Samman T.
      • Stirton J.
      • Liu J.
      • Ebraheim N.A.
      Systematic review of dynamization vs exchange nailing for delayed/non-union femoral fractures.
      ]. Bone grafting as a sole procedure without revision of the construct is also thought to be insufficient [
      • Giannoudis P V.
      • MacDonald D.A.
      • Matthews S.J.
      • Smith R.M.
      • Furlong A.J.
      • De Boer P.
      Nonunion of the femoral diaphysis.
      ,
      • Medlock G.
      • Stevenson I.M.
      • Johnstone A.J.
      Uniting the un-united: should established non-unions of femoral shaft fractures initially treated with IM nails be treated by plate augmentation instead of exchange IM nailing? A systematic review..
      ]. A recent development is augmentation of the femoral shaft with a plate to reduce strain and promote union rather than formal exchange nailing [
      • Verma R.
      • Sharma P.
      • Gaur S.
      Augmentation plating in management of failed femoral nailing.
      ,
      • Park K.C.
      • Oh C.W.
      • Kim J.W.
      • Park K.H.
      • Oh J.K.
      • Park I.H.
      • et al.
      Minimally invasive plate augmentation in the treatment of long-bone non-unions.
      ,
      • Uliana C.S.
      • Bidolegui F.
      • Kojima K.
      • Giordano V.
      Augmentation plating leaving the nail in situ is an excellent option for treating femoral shaft nonunion after IM nailing: a multicentre study.
      ]. A systematic review suggested that plate augmentation (n=191) was a valid alternative to exchange nailing (n=257) (
      • Medlock G.
      • Stevenson I.M.
      • Johnstone A.J.
      Uniting the un-united: should established non-unions of femoral shaft fractures initially treated with IM nails be treated by plate augmentation instead of exchange IM nailing? A systematic review..
      ). Combination of nail exchange with an additional compression plate has also been found to be a useful solution in complex revision cases for failed constructs or nonunion [
      • Benz D.
      • Tarrant S.M.
      • Balogh Z.J.
      Proximal femur fracture non-union with or without implant failure: a revision technique with clinical outcomes.
      ].
      Similar to that of the tibia, in the presence of established infected nonunion exchange nailing alone requires caution. A staged approach with removal of hard ware, debridement of the fracture site, local and systemic antibiotics followed by delayed definitive fixation has been proposed but can cause prolonged patient morbidity [
      • Bose D.
      • Kugan R.
      • Stubbs D.
      • McNally M.
      Management of infected nonunion of the long bones by a multidisciplinary team.
      ]. Exchange nailing with local and systemic antibiotic cover is a reasonable option in certain cases but patients should be warned they may need more than one exchange nailing procedure [
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      • McNally M.A.
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      ]. Novel IM nails with antibiotic coating are likely to be a useful addition in the management of septic nonunion post IM nailing [
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      ].

      Biological augments

      Biological augmentation of nonunion needs to be considered with a mobile atrophic pattern of nonunion or where there is bone loss. Autologous bone grafting remains the preferred option as it has osteoconductive, osteoinductive and osteogenic properties. It is still the most commonly used method of biological augmentation. The main drawback is the well-documented morbidity associated with harvesting bone graft from the iliac crest. As an alternative bone graft can be obtained from the medullary canal of long bones using the RIA (reamer/irrigator/aspirator) which enables bone graft to be collected during reaming of a long bone [
      • Dimitriou R.
      • Mataliotakis G.I.
      • Angoules A.G.
      • Kanakaris N.K.
      • Giannoudis P.V.
      Complications following autologous bone graft harvesting from the iliac crest and using the RIA: a systematic review.
      ]. The results of using bone graft harvested in this way are comparable to standard autologous bone grafting [
      • Sagi H.C.
      • Young M.L.
      • Gerstenfeld L.
      • Einhorn T.A.
      • Tornetta P.
      Qualitative and quantitative differences between (with a Reamer/Irrigator/Aspirator) and the iliac crest of the same patient.
      ]. More recently in a pre-clinical model, similar results to bone grafting have been reported with autologous bone marrow aspirate suggesting this could be a less morbid adjunct to healing [
      • Lim Z.X.H.
      • Rai B.
      • Tan T.C.
      • Ramruttun A.K.
      • Hui J.H.
      • Nurcombe V.
      • et al.
      Autologous bone marrow clot as an alternative to autograft for bone defect healing.
      ].
      There has also been much interest in synthetic alternatives. Urist identified osteoinductive properties of demineralised bone matrix and discovered this property was due to the presence of bone morphogenetic proteins [
      • Urist M.R.
      • Strates B.S.
      Bone morphogenetic protein.
      ]. However, their precise mechanism of action is not fully understood and continues to be studied [
      • Wang C.
      • Zheng G.F.
      • Xu X.F.
      MicroRnA-186 improves fracture healing through activating the bone morphogenetic protein signalling pathway by inhibiting sMAD6 in a mouse model of femoral fracture.
      ]. A number of these proteins, notably BMP-2 and BMP-7, were subsequently marketed as alternatives to autologous bone grafting but these materials have fallen in popularity. A recent review found the current evidence of BMP use for long bone fractures, mainly in open tibias, had conflicting results of benefit and currently is not routinely used in clinical practice in the U.K. [
      • Kostenuik P.
      • Mirza F.M.
      Fracture healing physiology and the quest for therapies for delayed healing and nonunion.
      ]. Several other pharmacological bone inducing agents exists but currently the evidence of their cost-effectiveness and clinical role is yet to be clearly established [
      • Kostenuik P.
      • Mirza F.M.
      Fracture healing physiology and the quest for therapies for delayed healing and nonunion.
      ].

      Summary

      Nonunion remains a challenge to predict and common risk factors need to be evaluated critically for a specific fracture. Risk factors such as smoking, alcohol intake, non-steroidal use and diabetic control are amenable to modification and this may improve the prognosis for treatment. Infection as a contributory cause should be considered particularly after open fracture or in fractures initially treated surgically which fail to heal. When nonunion is encountered there is good evidence available to guide decision making and successful union can usually be achieved with conventional trauma fixation techniques in the majority of cases. Biological augmentation of fracture healing is not necessary in most cases but needs to be considered in higher risk cases with a mobile atrophic pattern.

      Declaration of Competing Interest

      There are no conflicts of interest to declare for any of the authors involved in this study.

      Appendix. Supplementary materials

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