REVIEW ARTICLE

Diaphyseal long bone nonunions — types, aetiology, economics,and treatment recommendations

Markus Rupp1 & Christoph Biehl1 & Matthäus Budak1 & Ulrich Thormann1 & Christian Heiss1 & Volker Alt1

Received: 8 May 2017 /Accepted: 12 December 2017# SICOT aisbl 2017

AbstractThe intention of the current article is to review the epidemiology with related socioeconomic costs, pathophysiology, andtreatment options for diaphyseal long bone delayed unions and nonunions. Diaphyseal nonunions in the tibia and in the femurare estimated to occur 4.6–8% after modern intramedullary nailing of closed fractures with an even much higher risk in openfractures. There is a high socioeconomic burden for long bone nonunions mainly driven by indirect costs, such as productivitylosses due to long treatment duration. The classic classification of Weber and Cech of the 1970s is based on the underlyingbiological aspect of the nonunion differentiating between Bvital^ (hypertrophic) and Bavital^ (hypo−/atrophic) nonunions, andcan still be considered to represent the basis for basic evaluation of nonunions. The Bdiamond concept^ units biomechanical andbiological aspects and provides the pre-requisites for successful bone healing in nonunions. For humeral diaphyseal shaftnonunions, excellent results for augmentation plating were reported. In atrophic humeral shaft nonunions, compression platingwith stimulation of bone healing by bone grafting or BMPs seem to be the best option. For femoral and tibial diaphyseal shaftfractures, dynamization of the nail is an atraumatic, effective, and cheap surgical possibility to achieve bony consolidation,particularly in delayed nonunions before 24 weeks after initial surgery. In established hypertrophic nonunions in the tibia andfemur, biomechanical stability should be addressed by augmentation plating or exchange nailing. Hypotrophic or atrophicnonunions require additional biological stimulation of bone healing for augmentation plating.

Keywords Fracture . Nonunion . Nailing . Plating . Bone grafting . Tibia . Femur . Humerus

Introduction

Historically, the definition of delayed union and nonunion isrelated to healing time. If a fracture does not heal within ausually adequate period of time, it is first considered as de-layed union. Despite the slow and delayed fracture healingprocess, union of the fracture is still possible without surgicalintervention. For nonunions, bone healing without surgicalintervention cannot be expected [1]. According to the UnitedStates Food and Drug Administration (FDA), a nonunion isestablished after a minimum of nine months after trauma withno visible progressive signs of healing for three months [2].

Epidemiology and socioeconomic cost

Nonunion rates of all fractures are estimated between 1.9%and 10% [3, 4]. It has been hypothesized that 100,000 frac-tures go on to nonunion each year in the United States [5]. Arecent study from Scotland found 4895 nonunion cases treatedas inpatients between 2005 and 2010, averaging 979 per year,with an overall incidence of 18.94 per 100,000 population perannum [6].

Nonunion rates vary significantly due to different anatomicregions, soft-tissue injury, and fracture fixation principles usedfor surgical treatment. Regarding humeral shaft fractures,which account for 0.5 to 3% of all fractures, nonunion ratesare reported to be higher after locked intramedullary nailing(up to 33%), compared to plate fixation, respectively [7, 8].Femoral shaft nonunions have been reported in about 8% inmodern antegrade nailing of femoral shaft fractures [9, 10].For tibial shaft fractures, an overall nonunion rate of 4.6%wasreported after intramedullary nailing for closed and open tibialshaft fractures [11]. Vallier et al. described a nonunion rate

* Volker Altvolker.alt@chiru.med.uni-giessen.de

1 Department of Trauma, Hand and Reconstructive Surgery,University Hospital Giessen-Marburg GmbH, Campus Giessen,Rudolf-Buchheim-Str. 7, 35385 Giessen, Germany

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after intramedullary nailing of 7.1% and 4.2% after plating ofdistal tibia shaft fractures with all nonunions occurring afteropen fractures [12]. Regarding the impact of soft tissue inju-ries on nonunion rates of tibial shaft fractures, Sanders et al.showed nonunion rates of 16% in Gustilo-Anderson type II,60% in Gustilo-Anderson type IIIA, and 80% in Gustilo-Anderson type IIIB fractures [13]. These findings were con-firmed by a review article from Court-Brown with 1106 casesand nonunion rates of 0–6.4% for Gustilo-Anderson type Iand II, and of 42.1–69.2% for Gustilo-Anderson type IIIBopen tibial fractures [14].

For the analysis of the socioeconomic burden of non-unions, direct costs of the treatment and indirect cost, suchas productivity losses, have to be taken into account.Antonova et al. described a median total care cost of US$25,556 for tibial shaft nonunions compared to US$ 11,686for those with union of tibial shaft fractures within 24 monthsafter fracture [15]. Khunda et al. calculated £ 26,000/patientfor the direct costs of the treatment of complex tibial nonunionwith the Taylor spatial frame in the United Kingdom [16].Another study from the United Kingdom estimated directtreatment costs between £ 7000 and £ 79,000 per case forthe National Health Service (NHS) [6].

However, indirect costs are the key driver for overall costsin fracture and nonunion patients. Hak et al. record indirectcosts to be 67–79% in the Canadian and 82.8–93% in theEuropean health care systems for the overall treatment costs[5].

Aetiology, classification and risk factors

Aetiology and risk factors

BThere is no difficulty, for example, in understanding that thematerials effused for the consolidation of a fracture can neverbe converted into a bony callus, if subjected to frequent mo-tion and disturbance^ — this determination is still as validtoday as it was when first published in the 5th edition ofAstley Coopers , Churchill, London, in 1842 [17]. Biomechanicalreasons, such as instability at the fracture site and shear stress,seem to be major risk factors for nonunion development.Furthermore, biological reasons, such as poor blood supplyand severe bone and soft tissue damage, are held responsiblefor disturbance in fracture healing including infections andlarge bone defects. Based on these findings, Weber andCech developed their classification oriented on surgical treat-ment of nonunions [1] (Fig.1a and b). At first, biological via-ble and reactive nonunions are divided due to radiologicalcriteria: hypertrophic nonunions, so called elephant foot non-unions, are characterized by exuberant callus formation due toinadequate biomechanical stability; in oligotrophic nonunions

immobilizing scaffolding due to fracture diastasis is not ableto create consolidation by callus formation. Horse’s hoof non-unions are characterized by less callus formation and can beregarded as a milder form of elephant foot nonunions, whichnei ther produce immovab le s tab i l i ty nor a l lowinterfragmentary mobility. Secondly, non-viable nonunionsare regarded as biologically non-reactive as they show nobiological activity on bone scans. This is mainly attributableto inadequate vascular supply to the fracture or nonunion site.In comminuted fractures, nonunions result from absence offracture healing between non-viable bone fragments, whereasthe main fragments are viable and not the primary reason fornonunion development. Third, defect nonunions are charac-terized by bone loss, mainly caused by the trauma itself or byinfection and subsequent sequester formation. Fourthly, atro-phic nonunions are the final stage of non-viable nonunionswith scar tissue in the former fracture gaps, osteoporosis,and atrophy of the main fragments close to the fracture site[1] (Fig. 2).

Hitherto, the Weber and Cech classification is the mostpopular classification system for nonunions. However, scien-tific evidence does not completely support the clinical andradiological findings described by Weber and Cech as severalsimilarities were reported in the histological analysis of atro-phic and hypertrophic nonunions. Fibrous, cartilaginous andconnective tissue were found in varying degree [18], whereasatrophic nonunions were histologically characterized as acel-lular and oligocellular compared to more cellular hypertrophicnonunions [18]. No difference in alkaline phosphatase (ALP)activity in cell cultures, low levels of osteocalcin in both tis-sues, but a different cell surface antigen profile of nonunionstromal cells for mesenchymal stem cell (MSC) relatedmarkers was found for atrophic (CD 105) and hypertrophic(CD13, CD29, CD44, CD90, CD105, and CD166) nonunions[18–20]. Using an animal model for atrophic nonunions, Reedet al. could show that the vessel density reaches the same levelas that of healing bone but at a later time-point [21]. Hofmannreported altered cell viability and down regulated gene expres-sion patterns for canonical Wnt-, IGF-, TGF-β-, and FGF-signaling pathways in osteoblasts of patients suffering fromhypertrophic nonunion compared to bone tissue samples ofhealthy individuals [22]. Being capable of degrading extracel-lular matrix proteins, matrix metalloproteinases (MMPs) playan important role in extracellular matrix remodeling in varioustissues of the organism. In enchondral fracture repair, a pivotalrole of MMPs for osteoclast independent cartilage callus deg-radation is described [23]. In line with impaired enchondralbone healing due to delaying cartilage callus removal byMMP inhibition, Fajardo et al. showed an up regulation ofMMP-7 and MMP-12 as well as binding and degrading ofbone morphogenetic protein (BMP)-2 by both MMPsin vitro [23, 24]. Levels of Dickkopf-1 protein, an antagonistof the Wnt signaling pathway and consequent suppressor of

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fracture repair, were higher in atrophic nonunion stromal cellscompared to bone marrow stromal cells [18]. Furthermore, agenetic predisposition for nonunion development was eluci-dated by identifying polymorphisms in blood and bone callussamples of nonunion patients [25, 26].

Risk factors

Fracture personalities and patient variables are important riskfactors for nonunion development. Claes et al. could show theimpact of the fracture gap size for healing time and nonuniondevelopment in a sheep model with a critical fracture gap sizeof 2 mm in the tibia as well as in patients with tibia shaftfractures treated with external fixation. Fracture gaps largerthan 10 mm showed significantly decreased healing than frac-ture gaps smaller than 3 mm [27, 28]. The authors emphasized

the importance of fracture reduction and minimization of frac-ture gaps for undisturbed fracture healing for the surgical pro-cedure. Gaebler et al. showed a higher risk for delayed unionand nonunion in tibia shaft fractures after unreamedintramedullary nailing for fracture gaps larger than 3 mm aswell (OR, CI 95%: delayed union: 11.8 (5.6–24.7), nonunion:4.1 (0.96–17.8)) [29]. Drosos et al. could confirm the higherrisk for nonunion in fractures with gaps larger than 3 mm in aretrospective analysis of tibia shaft fractures afterintramedullary nailing (Hazard ratio 2.69, CI 95%, 1.68–4.31). [30]. The significance of fracture gaps

The Bclassical^ technical question in intramedullary nailingof long bone shaft fractures has been for decades: to ream ornot to ream? Reamed nailing is supposed to provide betterbiomechanical stability due to the use of thicker nails, whereasbenefits of unreamed nailing are seen in the conservation ofthe endosteal blood supply. Despite several meta-analyses,this question has not been finally answered. The above men-tioned SPRINT trial showed that reamed compared withunreamed nailing had a statistically decreased risk for negativeoutcomes in closed fractures [11]. However, this relationshipwas no longer significant when autodynamization anddynamization were removed from the composite outcome.Therefore, final evidence on the superiority of one of the tech-niques is yet to be provided.

Furthermore, specific patient variables and comorbiditiesare risk factors for nonunion development. Nonunion inci-dence is higher in men (OR, 95% CI) (1.21; 1.16–1.25).Morbidities, such as high body mass index (1.19; 1.12–1.25), smoking (1.20; 1.14–1.26), diabetes mellitus type I(1.40; 1.21–1.61) and II (1.15; 1.07–1.24), osteoarthritis andrheumatism (1.58; 1.38–1.82), osteoporosis (1.24; 1.14–1.34), vitamin D deficiency (1.14; 1.05–1.22), and renal in-sufficiency (1.11; 1.04–1.17), seem to promote nonunion de-velopment. Moreover, nonunions are found more frequent inpatients taking anticoagulants (1.58; 1.51–1.66), benzodiaze-pines (1.49; 1.36–1.62), insulin (1.21; 1.10–1.31), antibiotics(1.17; 1.13–1.21), diuretics (1.13; 1.07–1.18), NSAID, andopioids (1.84; 1.73–1.95) [32].

Treatment options

Asmentioned above, there are bothmechanical and biologicalunderlying factors for the development of nonunions. Basedon these observations, Giannoudis et al. introduced the so-called Bdiamond concept^ for successful bone healing empha-sizing the impact of the mechanical environment, osteogeniccells, scaffolds, and growth factors [33].

These four different aspects are discussed in the followingparagraphs with nail dynamization being a special property forintramedullary nailing.

Nail dynamization

In the 1970s, intramedullary locking nails for fixation of di-aphyseal bone fractures were established as the standard tech-nique in orthopaedic trauma care [34].

After improved bone healing due to dynamization ofintramedullary nails was reported in fracture and delayedunion animal models [35, 36], dynamization of intramedullarynails was subsequently recommended as the standard proce-dure after intramedullary nailing of long bone shaft fractures[37, 38]. The underlying principle of dynamization is based on

an enhancement of the micromovement at the fracture siteresulting in stimulation of healing [39].

The major risk for dynamization is a possible loss of reduc-tion with successive leg length or rotation discrepancies, par-ticularly in patients with highly comminuted fractures [40,41]. Therefore, it should only be performed after regainingsufficient stability of the fracture gap against possible loss ofreduction several weeks after initial nailing.

Unstable atrophic nonunions were outlined as risk factorsfor dynamization, whereas unstable hypertrophic nonunionsare regarded as suitable for nail dynamization [42]. Open frac-tures correlate with failure of dynamization and the callusdiameter seems to be a predictive parameter for thedynamization procedure. A high callus to diaphysis ratio, ascan be observed in hypertrophic delayed unions and non-union, is considered a sign of high biological healing poten-tial. If fracture healing is achieved by dynamization, cost sav-ings of more than US$ 10,000 per case compared to exchangenailing treatment were estimated [43].

If dynamization is taken into consideration, perfecttiming for this intervention has not been determined, yet.Dynamization too early, after one week of rigid fracturefixation, shows impaired bone formation, while latedynamization, after three or four weeks, improves fracturehealing in an external fixator animal model [44, 45].Vaughn et al. could not show any evidence between timeof dynamization and success rates of dynamization in fem-oral and tibial shaft fractures [43]. Regarding the technicalprocedure, there seems to be some evidence that bone unionrates are significantly higher in patients with delayed unionwhen dynamization was carried out by preserving a screwin a dynamic locking hole (93.3%) compared to those withall screws removed at one end of the nail (58.3%) [46].Furthermore, the group treated with all screws removedfor dynamization showed a higher bone union rate for earlydynamization after ten to 24 weeks (83%) compared topatients treated with late dynamization after 24 weeks(33%) (Fig. 2). Interestingly, no difference between earlierdynamization and dynamization after 24 weeks was ob-served in the patients with a preserved screw in the dynamiclocking hole. The working group of Litrenta showed nodifference in time of failed or successful dynamization inintramedullary nailing of aseptic tibial nonunion. They re-ported a union rate of 83% for dynamization and showedthat a gap defined as a minimum of 5 mm distraction in anarea of no cortical contact was a statistically negative factorfor dynamization [47].

As the humerus is a non-weight bearing bone, dynamizationof nails in humeral diaphyseal shaft fractures is not a soundoption. Experimental studies could show a relatively positiverelation between compression and bone healing. For distrac-tion, as it occurs rather than compression in the hanging upperextremities, reports have been inconsistent [48].

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In summary, being a quickly performed, cost saving minorsurgery, dynamization can be recommended as first line sur-gical therapy. Comminuted fractures and fracture gaps are riskfactors for secondary loss of reduction after dynamization andmust definitely be considered. Hitherto, the best timing fordynamization is not clear, but dynamization of delayed unionis more promising than dynamization of established femoraland tibial diaphyseal nonunions.

Exchange nailing

The concept of reamed exchange nailing relies on the im-provement of biomechanical stability by the use of a nail be-ing at least one millimeter thicker in its diameter and on anBinternal bone grafting^ by the reaming procedure with sub-sequent transport of mesenchymal stem cells into the non-union site [49, 50].

Furthermore, longer nails with good filling of the entireintramedullary canal and the use of more locking screws alsocontribute to a biomechanical more stable construct [49]. Thelatest developments of implants transferred the angle stablelocking concept in plate fixation to nails resulting in angle-stable locking nails. Studies of the mechanical efficacy ofthose systems are inconsistent. Mechanical stiffness seems todepend more on the number of locking screws rather than onthe angle-stable locking technique [51].

Regarding aseptic nonunion treatment, reamed exchangenailing in aseptic tibial shafts can achieve high rates (97%) ofnonunion healing [52]. In exchange nailing procedures, no sta-tistically significant difference of time to union in statically-locked (7.3 months) versus dynamically-locked (7.9 months)exchange nails was found. Furthermore, Abadie et al. figuredout that patients with fibular osteotomy proceeded to union2.9 months faster than those without fibular osteotomy, and thistrended toward significance (P = 0.067) [53]. Because the fib-ula has no statistically significant impact on the stability ofdiaphyseal tibial fractures treated with intramedullary nailing,it seems to be a feasible method to enable earlier union (Fig. 3).

In femur shaft nonunions, a success rate of 86% healed non-unions four months after revision surgery has been shown [54].Hak et al. reported an overall success rate of 78.9% in ex-changed reamed nailing of femur shaft nonunions, whereby riskfactors such as smoking reduced the success rate to 66% [55].According to Tsang et al., infection, bone gaps of more than5 mm, and an atrophic pattern of nonunion were statisticallysignificant risk factors for failure of exchange nailing in tibiashaft fracture. Only 11 out of 31 infected nonunions (35.4%)healed after one exchange nail procedure [56]. In humeral shaftnonunions, inconsistent results of exchange nailing have beenreported. Lin et al. reported in 22 patients out of 23 (95.6%)bony union after revision exchange nailing. Nonunions wereaddressed with open reduction, additional K-wire fixation, andeither antegrade or retrograde nailing in 19 cases [57]. McKeeet al. compared exchange nailing with open reduction, platefixation, and autogenous bone grafting. Four out of ten (40%)exchange nail procedures resulted in bony consolidation,whereas in nine out of nine cases consolidation was achievedby plate fixation and autologous bone graft application [58]. Aconsolidation rate of 46.1% (6/13) after exchange nailing forhumeral shaft nonunions is described by Flinkkilä [59]. A re-cent review on union rates after surgical treatment of humeralshaft nonunions showed the highest healing rate of 98% inpatients who underwent plate fixation with autologous bonegrafting (ABG) compared to plate fixation without bonegrafting (95%). In contrast to plate fixation, union rates werelower in revision surgery with intramedullary nailing: 88% forintramedullary nailing with ABG (n = 164) and 66% forintramedullary nailing without ABG (n = 78). External fixationalso yielded a high healing rate of 98%, but was associated withthe highest complication rate [8].

Bone grafts and bone morphogenetic proteins

In the case of atrophic nonviable nonunions, biological issuessuch as poor vascular supply are considered to be the mainreason of nonunion development. Besides improvement of the

a db cFig. 2 X-rays series of a delayed union treated with dynamization of thenail after surgical treatment of an AO type 42 A1 fracture with closedreduction and internal fixation (CRIF) by locked reamed intramedullarynailing a X-rays at 6 weeks after CRIF with a locked reamed tibia nail,pain-adapted full load was allowed. b X-rays 12 weeks after CRIF and

after full weight-bearing of 6 weekswith absence of fracture gap bridging.Decision for dynamization was made and carried out after 12 weeks. cX-rays 4 weeks after dynamization with removal of both proximal staticlocking bolts, d X-rays after 12 weeks after dynamization with consoli-dation of the fracture

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mechanical stability, the purpose of the surgical therapy is toaddress and to improve the biological environment accordingto the Bdiamond concept^ [33].

Autogenous bone grafting provides all required properties forbone formation: osteogenesis, osteoconduction andosteoinduction, and is associated with low costs, absence ofdisease transmission or rejection of the graft [60, 61]. Classicalharvest sites for cancellous autogenous bone grafting are theiliac crest, proximal tibia, distal tibia, and the distal radius.

General limitations of autogenous bone grafting are limitedavailability and donor site morbidity, such as chronic donorsite pain, wound complications, such as seroma or infections,sensory loss, and scarring [62, 63].

For cortical bone grafts of the iliac crest, slower revascu-larization, bone resorption, and transformation are describeddue to a lower amount of available and biological active cellsin the graft [64]. Vascularized bone graft techniques wereestablished to overcome these limitations, with freevascularized fibula bone grafts being the most frequently usedtechnique [65].

The reamer-irrigator-aspirator (RIA) is an alternative meth-od for the harvesting of autogenous cancellous bone graftmaterial from the intramedullary canal of the femur by anintramedullary reaming system and high union rates were re-ported for RIA bone grafts in the treatment of nonunions [66].A recent study showed significantly lower complications ratesin donor site morbidity compared to the iliac crest [67].

Allograft is available in many forms: cancellous, cortical,corticocancellous, osteochondral, and whole-bone segments.Major drawback is its lack of osteogenic potential as all cellsare removed during the production. Therefore, allografts pri-marily serve as structural scaffold exhibiting osteoconductivepotential [60, 68]. After cases of transmission of blood bornediseases such as HIV were reported in the 1980s and 1990s,screening methods as well as new methods of processing andpreparation of bone grafts were established. Between 1990and 2000more than 1,000,000 bone allografts were implantedwithout a reported evidence of HIV or hepatitis transmissionin the US [69]. The risk of viral transmission associated withblood is reported for hepatitis B as one in 63,000, for hepatitis

Fig. 3 X-rays series of anonunion treated with exchangenailing 11 months after surgicaltreatment of an AO type 42 C2fracture with CRIF by lockedreamed intramedullary nailing. aNo bony consolidation wasobserved 7 months after CRIF. bCoronal CTsections show the gap9 months after initial surgery,nonunion. c Postoperativecontrols after exchange nailing ofthe tibia with a dynamically-locked tibial nail and fibulaosteotomy 11 months after initialsurgery. d 6 weeks postoperativecontrols after exchange nailingshow beginning bony consolida-tion. e 3 months after revisionsurgery advanced consolidationwas documented. f 6 months afterexchange nailing X-rays showcomplete fracture consolidation

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C it is one in 100,000 and for HIV less than one in 1,000,000[70]. A further drawback of bone allograft implantation islocal infection of the allograft. The main reason for infectionis contamination of the graft. Contamination rates up to 10%and an overall infection rate of implanted allograft bone be-tween 5 and 12.2% are reported [71, 72].

In 1965, M. Urist was the first to describe theosteoinductive potential of demineralized bone matrix(DBM) and to discover the underlying BMPs, which belongto the transforming growth factor-β (TGF-β) protein super-family [73, 74].

In 2001, the FDA approved recombinant human (rh)BMP-2 (dibotermin alfa, Inductos® Medtronic, Minneapolis, MN)for the treatment of acute tibia fractures in adults, as an adjunctto standard care using open fracture reduction andintramedullary unreamed nail fixation and for single levellumbar interbody spine fusion as a substitute for autogenousbone graft in adults. RhBMP-7 (eptotermin alfa, Osigraft®Olympus Biotech, Hopkinton, MA) was approved by theFDA in 2002 for the treatment of tibia nonunion of at leastnine months duration, secondary to trauma, in skeletally ma-ture patients, in cases where previous treatment with autografthas failed or use of autograft was unfeasible. The trial ofFriedlaender et al. showed comparable clinical success ratesbetween rhBMP-7 (81%) and autogenous bone graft (85%) asan adjunct to intramedullary nailing in 124 tibial shaft non-unions after an observation period of nine months. This trialhad a non-inferiority study design to demonstrate safety andefficacy and was not intended to show superiority of rhBMP-7over autogenous bone grafting.

Currently, there is still a lack of sound randomized con-trolled trials on the effects of BMPs compared to standard ofcare treatment in nonunions, mainly attributable to the re-quired large sample size with several hundreds of patientsand associated high costs for such a clinical study.

However, the general concept of stimulation of bonehealing by BMPs [75] was confirmed in several case reportsand case series for nonunions of long bones of the upper [76,77] and lower extremity [78, 79] with good success rates.

Recently, Olympus Biotech shut down its activities forrhBMP-7 and rhBMP-2 currently remains the only commer-cially available BMP.

Cell therapy

The initial phase of bone healing is characterized by the onsetof inflammation. MSCs, endothelial cells and immune cellsmigrate toward the fractured bone region. Osteoprogenitorcells, originating from the periosteum, the bone marrow, andthe surrounding tissue react to the signals sent by thehaematoma and migrate into the fracture area [80]. Hence, itis not surprising that low levels of progenitor cells at nonunionsites and in bonemarrow of nonunion patients [81] as well as a

systemic mesenchymal and osteogenic cell pool defect wereobserved [82]. To improve the cellular environment in a dis-turbed bone healing process, the application of bone marrowwas proposed due to its osteogenic potential, which was firstobserved by Gougeon in the nineteenth century [83]. Later,Friedenstein et al. showed that new bone was formed byfibroblast-like bone marrow cells in vitro after necrosis ofhematopoietic cells, which led to the first isolation of MSCsin this context [84]. Furthermore, it could be shown that thosecells are multipotent and can differentiate to osteocytic,chondrocytic, and adipocytic lineages [85]. Before isolatingMSCs from bonemarrow, several preclinical and clinical stud-ies had confirmed the efficiency of bone marrow implantationto induce bony regeneration [86, 87].

Bruder et al. were the first to demonstrate that MSCs iso-lated from human bone marrow can regenerate bone in a largebone defect [88]. Based on these findings, several clinicalstudies were performed using MSCs in a single or combinedmanner with osteoconductive or osteoinductive substances.Homma et al. described the use of percutaneous autologousbone marrow cell grafting as an efficient and safe treatment.Their one step technique includes the aspiration of bone mar-row at the iliac crest and pooling of the harvested cells inplastic bags containing cell culture medium and anticoagulantsolution. After filtration to separate cellular aggregates, theaspirate is percutaneously injected with a trocar at the non-union gap and its respective bone ends under fluoroscopy[89]. Bajada’s group showed union of a recalcitrant tibial non-union with application of expanded bonemarrow stromal cellsafter three weeks of tissue culture combined with a carrier ofcalcium sulfate in pellet form [90]. Hernigou et al. found acorrelation between the number and concentration of progen-itor cells applied at the nonunion site and subsequent boneformation in percutaneous autologous bone grafting [91].Quarto et al. described a case series of patients with diaphysealbone defects treated by ex vivo expanded osteoprogenitorcells placed on macroporous hydroxyapatite scaffolds [92].Another approach was conducted by Wittig et al. with theloading of MSCs on collagen microspheres (CM) and theirincorporation into platelet-rich plasma (PRP) clots. This com-bination ofMSCswas shown to induce new bone formation inlong bone nonunions [93]. In total, promising results in non-union treatment by local cell therapy are reported. However,there is still a lack of evidence on the optimal cell harvesting,processing, and application technique.

External fixation techniques for nonunions

External fixation for nonunion treatment offers high stabilityand compression to the nonunion site to achieve bony consol-idation. Furthermore, bone resection with or without shorten-ing with subsequent bone segment transport or lengtheningcan be performed. Drawbacks are foremost pin loosening

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and pin infections and patient discomfort with long treatmentduration [94]. Furthermore, regenerate related problems suchas poor bone quality, delayed maturation, premature consoli-dation, and docking site problems requiring revision surgeryincluding bone grafting have been described [95].

Both monolateral and ring fixation systems have been usedsuccessfully for the treatment of nonunions. High union ratesof 91.6% were reported by Harshwal et al. in 37 patientssuffering from femoral or tibial nonunions treated with amonolateral external fixator. Of these 37 patients, 32 weretreated by compression osteosynthesis (monofocal), in six ofthem distraction osteogenesis was carried out after initial com-pression of the nonunion site. Five patients were treated by abifocal protocol with corticotomy and bone transport due tobony defects larger than 3 cm in the tibia and 5 cm in thefemur, respectively [96].

After failed exchange nailing in aseptic and oligotrophicfemoral shaft nonunions, consolidation of the nonunion sitecan be achieved using the Ilizarov fixator technique over the

indwelling nail with slow compression rates (0.25–0.5mmperday) [97]. This has also been described in aseptic humeralshaft nonunions for the combination of Ilizarov or monolateralexternal fixators for compression in combination with anintramedullary fixation device [98].

Resection of the nonunion site allows for a radical removalof fibrous and scar tissue but can result in segmental defectslarger than 5 cm that can be restored by corticotomy at theremaining proximal or distal bone segment with daily gradualdistraction of this bone segment through an external fixatorapparatus [99]. Traditionally, Ilizarov ring fixators were usedfor distraction osteogenesis and bone transport but alsomonolateral techniques have gained more and more interestdue to easier pin insertion and uniplanar application [99].Modern circular fixators like the Taylor spatial frame providenot only distraction options but also correction of bone defor-mity in all planes [16].

In general, a daily distraction rate of 1 mm is recommendedand provides sufficient osteogenic potential [100] but needs to

Fig. 4 Series of a femoral shaft nonunion after an AO type 32 B3 fracturefinally treated with augmentation plating. a Nonunion 7 months afterexchange nailing, autologous bone grafting, and rhBMP-2 application.

b Postoperative controls after augmentation plating with a locking plate. cX-rays 6 weeks after augmentation plating. d Consolidation 3 monthsafter augmentation plating

Table 1 Treatment recommendations for delayed unions and humeral, femoral, and tibial diaphyseal nonunions without segmental bone defects

Delayed union Hypertrophic nonunion Hypotrophic and atrophic nonunion

Humeral shaft Augmentation plating after failednailing [109]

Compression plating with bone grafting [110]augmentation plating after nailing [109]

Femoral shaft Nail dynamization [111] or earlyaugmentation plating [104, 106]

Augmentation plating with or withoutbone grafting [104, 106] §

Augmentation plating with biological stimulation bybone grafting or biologics [104, 106, 112, 113] §

Tibial shaft Nail dynamization [47]or early exchange nailing [52]

Reamed exchange nailing [52, 56] oraugmentation plating [107, 108]

Reamed exchange nailing or augmentation platingwith biological stimulation by bone grafting or biologics

[52, 114]

§ Because of lower success rates for exchange nailing of femoral shaft fractures compared to augmentation plating, exchange nailing is regarded assecond line therapy

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be adapted to patients’ individual factors. Fixators should beleft about 1.9 months for every 1 cm of bone defect to reachadequate and stable bony consolidation [101]. To reduce theduration of external fixation, the adjunct use of internal fixa-tion devices has been described [102, 103].

Augmentation plating

The improvement of biomechanical stability in diaphyseallong bone nonunions has directed attention to additional platefixation use after failed intramedullary nailing. Mainly rota-tional instability seems to be an important factor in the devel-opment of nonunions, which can be addressed by augmenta-tion plating [104, 105]. Ueng et al. reported a case series on 17diaphyseal femoral nonunions with augmentation plating plusadditional bone grafting from the iliac crest without removalof the nail after failed intramedullary nailing. In all 17 patients,nonunions healed at a mean follow-up of seven months afteraugmentative plate fixation without complications [104]. Asshown in Fig. 4, femoral shaft nonunions can be addressedeffectively by augmentation plating. In this complex case,healing of the nonunion was reached by augmentation platingimprovingmechanical instability, which was the result of a toosmall nail diameter and a remaining fracture gap after initialimprovement worthy reduction of an AO type 32 B3 fracture.Meanwhile several studies confirmed the excellent result ofaugmentation plating for femoral, tibial, and humeral shaftfractures. In femur shaft nonunions, high success rates of100% of augmentation plating with or without autologousbone grafting were reported [106, 107]. For tibial shaft non-unions, augmentation plating also shows a good result be-tween 84.6% [107] and 96.4% [108]. For humeral shaft non-unions augmentation plating seems to be an excellent thera-peutic approach, too. Gessmann et al. reported a 97% successrate of anterior augmentation plating after antegrade or retro-grade intramedullary nailing [109].

Conclusions and treatment recommendations

Surgical treatment of aseptic nonunions should still be per-formed according to the Weber-Cech classification. It remainschallenging for the patient and the surgeon, and is associatedwith significant costs for the health care system.

For humeral diaphyseal shaft nonunions, excellent resultsfor augmentation plating were reported. In atrophic humeralshaft nonunions, compression plating with stimulation of bonehealing by bone grafting or BMPs seems to be the best option(Table 1).

For femoral and tibial diaphyseal shaft fractures,dynamization of the nail is an atraumatic, effective, and cheapsurgical possibility to achieve bony consolidation, particularlyin delayed nonunions before 24 weeks after initial surgery. In

established hypertrophic nonunions, biomechanical stabilityshould be addressed by augmentation plating or exchangenailing. Hypotrophic or atrophic nonunions additionally requirebiological stimulation of bone healing for augmentation plating.

For segmental bone defects, external fixation techniquesremain the treatment of choice. Patient comfort and successrates can be positively influenced by the additional use ofinternal fixation devices.

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Diaphyseal long bone nonunions — types, aetiology, economics, and treatment recommendationsAbstractIntroductionEpidemiology and socioeconomic costAetiology, classification and risk factorsAetiology and risk factorsRisk factors

Treatment optionsNail dynamizationExchange nailingBone grafts and bone morphogenetic proteinsCell therapyExternal fixation techniques for nonunionsAugmentation plating

Conclusions and treatment recommendationsReferences

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