International Orthopaedics

https://doi.org/10.1007/s00264-017-3734-5

REVIEW ARTICLE

Diaphyseal long bone nonunions — types, aetiology, economics,

and treatment recommendations
Markus Rupp 1 & Christoph Biehl 1 & Matthäus Budak 1 & Ulrich Thormann 1 & Christian Heiss 1 & Volker Alt 1

Received: 8 May 2017 / Accepted: 12 December 2017

# SICOT aisbl 2017

Abstract
The intention of the current article is to review the epidemiology with related socioeconomic costs, pathophysiology, and
treatment options for diaphyseal long bone delayed unions and nonunions. Diaphyseal nonunions in the tibia and in the femur
are estimated to occur 4.6–8% after modern intramedullary nailing of closed fractures with an even much higher risk in open
fractures. There is a high socioeconomic burden for long bone nonunions mainly driven by indirect costs, such as productivity
losses due to long treatment duration. The classic classification of Weber and Cech of the 1970s is based on the underlying
biological aspect of the nonunion differentiating between Bvital^ (hypertrophic) and Bavital^ (hypo−/atrophic) nonunions, and
can still be considered to represent the basis for basic evaluation of nonunions. The Bdiamond concept^ units biomechanical and
biological aspects and provides the pre-requisites for successful bone healing in nonunions. For humeral diaphyseal shaft
nonunions, excellent results for augmentation plating were reported. In atrophic humeral shaft nonunions, compression plating
with stimulation of bone healing by bone grafting or BMPs seem to be the best option. For femoral and tibial diaphyseal shaft
fractures, 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 and
femur, biomechanical stability should be addressed by augmentation plating or exchange nailing. Hypotrophic or atrophic
nonunions require additional biological stimulation of bone healing for augmentation plating.

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

Introduction Epidemiology and socioeconomic cost

Historically, the definition of delayed union and nonunion is
related to healing time. If a fracture does not heal within a
usually adequate period of time, it is first considered as de-
layed union. Despite the slow and delayed fracture healing
process, union of the fracture is still possible without surgical
intervention. For nonunions, bone healing without surgical
intervention cannot be expected [1]. According to the United
States Food and Drug Administration (FDA), a nonunion is
established after a minimum of nine months after trauma with
no visible progressive signs of healing for three months [2].
* Volker Alt
volker.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
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]. A
recent study from Scotland found 4895 nonunion cases treated
as inpatients between 2005 and 2010, averaging 979 per year,
with an overall incidence of 18.94 per 100,000 population per
annum [6].
Nonunion rates vary significantly due to different anatomic
regions, soft-tissue injury, and fracture fixation principles used
for surgical treatment. Regarding humeral shaft fractures,
which account for 0.5 to 3% of all fractures, nonunion rates
are 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% in
modern antegrade nailing of femoral shaft fractures [9, 10].
For tibial shaft fractures, an overall nonunion rate of 4.6% was
reported after intramedullary nailing for closed and open tibial
shaft fractures [11]. Vallier et al. described a nonunion rate

after intramedullary nailing of 7.1% and 4.2% after plating of
distal tibia shaft fractures with all nonunions occurring after
open 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 cases
and nonunion rates of 0–6.4% for Gustilo-Anderson type I
and II, and of 42.1–69.2% for Gustilo-Anderson type IIIB
open tibial fractures [14].
For the analysis of the socioeconomic burden of non-
unions, direct costs of the treatment and indirect cost, such
as 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$ 11,686
for those with union of tibial shaft fractures within 24 months
after fracture [15]. Khunda et al. calculated £ 26,000/patient
for the direct costs of the treatment of complex tibial nonunion
with the Taylor spatial frame in the United Kingdom [16].
Another study from the United Kingdom estimated direct
treatment costs between £ 7000 and £ 79,000 per case for
the National Health Service (NHS) [6].
However, indirect costs are the key driver for overall costs
in fracture and nonunion patients. Hak et al. record indirect
costs to be 67–79% in the Canadian and 82.8–93% in the
European 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 the
materials effused for the consolidation of a fracture can never
be converted into a bony callus, if subjected to frequent mo-
tion and disturbance^ — this determination is still as valid
today as it was when first published in the 5th edition of
Astley Coopers <Treatise on Dislocations and Fractures of
the Joints>, Churchill, London, in 1842 [17]. Biomechanical
reasons, 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 supply
and severe bone and soft tissue damage, are held responsible
for disturbance in fracture healing including infections and
large bone defects. Based on these findings, Weber and
Cech 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 radiological
criteria: hypertrophic nonunions, so called elephant foot non-
unions, are characterized by exuberant callus formation due to
inadequate biomechanical stability; in oligotrophic nonunions
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immobilizing scaffolding due to fracture diastasis is not able
to create consolidation by callus formation. Horse’s hoof non-
unions are characterized by less callus formation and can be
regarded as a milder form of elephant foot nonunions, which
neither produce immovable stability nor allow
interfragmentary mobility. Secondly, non-viable nonunions
are regarded as biologically non-reactive as they show no
biological activity on bone scans. This is mainly attributable
to inadequate vascular supply to the fracture or nonunion site.
In comminuted fractures, nonunions result from absence of
fracture healing between non-viable bone fragments, whereas
the main fragments are viable and not the primary reason for
nonunion development. Third, defect nonunions are charac-
terized by bone loss, mainly caused by the trauma itself or by
infection and subsequent sequester formation. Fourthly, atro-
phic nonunions are the final stage of non-viable nonunions
with 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 most
popular classification system for nonunions. However, scien-
tific evidence does not completely support the clinical and
radiological findings described by Weber and Cech as several
similarities were reported in the histological analysis of atro-
phic and hypertrophic nonunions. Fibrous, cartilaginous and
connective tissue were found in varying degree [18], whereas
atrophic nonunions were histologically characterized as acel-
lular and oligocellular compared to more cellular hypertrophic
nonunions [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 nonunion
stromal cells for mesenchymal stem cell (MSC) related
markers 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, Reed
et al. could show that the vessel density reaches the same level
as that of healing bone but at a later time-point [21]. Hofmann
reported 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 from
hypertrophic nonunion compared to bone tissue samples of
healthy individuals [22]. Being capable of degrading extracel-
lular matrix proteins, matrix metalloproteinases (MMPs) play
an important role in extracellular matrix remodeling in various
tissues of the organism. In enchondral fracture repair, a pivotal
role of MMPs for osteoclast independent cartilage callus deg-
radation is described [23]. In line with impaired enchondral
bone healing due to delaying cartilage callus removal by
MMP inhibition, Fajardo et al. showed an up regulation of
MMP-7 and MMP-12 as well as binding and degrading of
bone morphogenetic protein (BMP)-2 by both MMPs
in vitro [23, 24]. Levels of Dickkopf-1 protein, an antagonist
of the Wnt signaling pathway and consequent suppressor of
International Orthopaedics (SICOT)

Fig. 1 a Biological reactive,

viable nonunions. a) Elefant foot
nonunion. b) Horse hoof
nonunion. c) Oligotrophic
nonunion. All three types are
characterized by well
vascularized fragment ends. b
Biological non-reactive, non-
viable nonunions. a) Torsion
wedge nonunion with partial ne-
crosis of the torsion wedge. b)
Comminuted fracture nonunion,
necrotic intermediate fragment. c)
Defect nonunion. d) atrophic non-
reactive nonunion

fracture repair, were higher in atrophic nonunion stromal cells
compared to bone marrow stromal cells [18]. Furthermore, a
genetic predisposition for nonunion development was eluci-
dated by identifying polymorphisms in blood and bone callus
samples of nonunion patients [25, 26].
Risk factors
Fracture personalities and patient variables are important risk
factors for nonunion development. Claes et al. could show the
impact of the fracture gap size for healing time and nonunion
development in a sheep model with a critical fracture gap size
of 2 mm in the tibia as well as in patients with tibia shaft
fractures treated with external fixation. Fracture gaps larger
than 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 union
and nonunion in tibia shaft fractures after unreamed
intramedullary nailing for fracture gaps larger than 3 mm as
well (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 higher
risk for nonunion in fractures with gaps larger than 3 mm in a
retrospective analysis of tibia shaft fractures after
intramedullary nailing (Hazard ratio 2.69, CI 95%, 1.68–
4.31). [30]. The significance of fracture gaps <1 cm compared
to fractures without gap in the context of Bnegative outcomes^
in tibia shaft fractures after intramedullary nailing was recent-
ly documented in the prospective SPRINT trial with an anal-
ysis of 1226 tibia shaft fractures (OR 2.40, CI 95% (1.47–
3.94)) [31].

The Bclassical^ technical question in intramedullary nailing
of long bone shaft fractures has been for decades: to ream or
not to ream? Reamed nailing is supposed to provide better
biomechanical stability due to the use of thicker nails, whereas
benefits of unreamed nailing are seen in the conservation of
the endosteal blood supply. Despite several meta-analyses,
this question has not been finally answered. The above men-
tioned SPRINT trial showed that reamed compared with
unreamed nailing had a statistically decreased risk for negative
outcomes in closed fractures [11]. However, this relationship
was no longer significant when autodynamization and
dynamization 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 comorbidities
are 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 and
rheumatism (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 in
patients 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, and
opioids (1.84; 1.73–1.95) [32].
Treatment options
As mentioned above, there are both mechanical and biological
underlying factors for the development of nonunions. Based
on these observations, Giannoudis et al. introduced the so-
called Bdiamond concept^ for successful bone healing empha-
sizing the impact of the mechanical environment, osteogenic
cells, scaffolds, and growth factors [33].
These four different aspects are discussed in the following
paragraphs with nail dynamization being a special property for
intramedullary 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 of
intramedullary nails was reported in fracture and delayed
union animal models [35, 36], dynamization of intramedullary
nails 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
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an enhancement of the micromovement at the fracture site
resulting 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 regaining
sufficient stability of the fracture gap against possible loss of
reduction several weeks after initial nailing.
Unstable atrophic nonunions were outlined as risk factors
for dynamization, whereas unstable hypertrophic nonunions
are regarded as suitable for nail dynamization [42]. Open frac-
tures correlate with failure of dynamization and the callus
diameter seems to be a predictive parameter for the
dynamization procedure. A high callus to diaphysis ratio, as
can 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 exchange
nailing treatment were estimated [43].
If dynamization is taken into consideration, perfect
timing for this intervention has not been determined, yet.
Dynamization too early, after one week of rigid fracture
fixation, shows impaired bone formation, while late
dynamization, after three or four weeks, improves fracture
healing in an external fixator animal model [44, 45].
Vaughn et al. could not show any evidence between time
of dynamization and success rates of dynamization in fem-
oral and tibial shaft fractures [43]. Regarding the technical
procedure, there seems to be some evidence that bone union
rates are significantly higher in patients with delayed union
when dynamization was carried out by preserving a screw
in a dynamic locking hole (93.3%) compared to those with
all screws removed at one end of the nail (58.3%) [46].
Furthermore, the group treated with all screws removed
for dynamization showed a higher bone union rate for early
dynamization after ten to 24 weeks (83%) compared to
patients treated with late dynamization after 24 weeks
(33%) (Fig. 2). Interestingly, no difference between earlier
dynamization and dynamization after 24 weeks was ob-
served in the patients with a preserved screw in the dynamic
locking hole. The working group of Litrenta showed no
difference in time of failed or successful dynamization in
intramedullary nailing of aseptic tibial nonunion. They re-
ported a union rate of 83% for dynamization and showed
that a gap defined as a minimum of 5 mm distraction in an
area of no cortical contact was a statistically negative factor
for dynamization [47].
As the humerus is a non-weight bearing bone, dynamization
of nails in humeral diaphyseal shaft fractures is not a sound
option. Experimental studies could show a relatively positive
relation between compression and bone healing. For distrac-
tion, as it occurs rather than compression in the hanging upper
extremities, reports have been inconsistent [48].
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a b
Fig. 2 X-rays series of a delayed union treated with dynamization of the
nail after surgical treatment of an AO type 42 A1 fracture with closed
reduction and internal fixation (CRIF) by locked reamed intramedullary
nailing 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
In summary, being a quickly performed, cost saving minor
surgery, dynamization can be recommended as first line sur-
gical therapy. Comminuted fractures and fracture gaps are risk
factors for secondary loss of reduction after dynamization and
must definitely be considered. Hitherto, the best timing for
dynamization is not clear, but dynamization of delayed union
is more promising than dynamization of established femoral
and 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 an
Binternal 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 entire
intramedullary canal and the use of more locking screws also
contribute to a biomechanical more stable construct [49]. The
latest developments of implants transferred the angle stable
locking concept in plate fixation to nails resulting in angle-
stable locking nails. Studies of the mechanical efficacy of
those systems are inconsistent. Mechanical stiffness seems to
depend more on the number of locking screws rather than on
the angle-stable locking technique [51].
Regarding aseptic nonunion treatment, reamed exchange
nailing in aseptic tibial shafts can achieve high rates (97%) of
nonunion 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. figured
out that patients with fibular osteotomy proceeded to union
2.9 months faster than those without fibular osteotomy, and this
trended toward significance (P = 0.067) [53]. Because the fib-
ula has no statistically significant impact on the stability of
diaphyseal tibial fractures treated with intramedullary nailing,
it seems to be a feasible method to enable earlier union (Fig. 3).
c d
after full weight-bearing of 6 weeks with absence of fracture gap bridging.
Decision for dynamization was made and carried out after 12 weeks. c X-
rays 4 weeks after dynamization with removal of both proximal static
locking bolts, d X-rays after 12 weeks after dynamization with consoli-
dation of the fracture
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 risk
factors such as smoking reduced the success rate to 66% [55].
According to Tsang et al., infection, bone gaps of more than
5 mm, and an atrophic pattern of nonunion were statistically
significant risk factors for failure of exchange nailing in tibia
shaft fracture. Only 11 out of 31 infected nonunions (35.4%)
healed after one exchange nail procedure [56]. In humeral shaft
nonunions, inconsistent results of exchange nailing have been
reported. Lin et al. reported in 22 patients out of 23 (95.6%)
bony union after revision exchange nailing. Nonunions were
addressed with open reduction, additional K-wire fixation, and
either antegrade or retrograde nailing in 19 cases [57]. McKee
et al. compared exchange nailing with open reduction, plate
fixation, 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 achieved
by plate fixation and autologous bone graft application [58]. A
consolidation rate of 46.1% (6/13) after exchange nailing for
humeral shaft nonunions is described by Flinkkilä [59]. A re-
cent review on union rates after surgical treatment of humeral
shaft nonunions showed the highest healing rate of 98% in
patients who underwent plate fixation with autologous bone
grafting (ABG) compared to plate fixation without bone
grafting (95%). In contrast to plate fixation, union rates were
lower in revision surgery with intramedullary nailing: 88% for
intramedullary nailing with ABG (n = 164) and 66% for
intramedullary nailing without ABG (n = 78). External fixation
also yielded a high healing rate of 98%, but was associated with
the highest complication rate [8].
Bone grafts and bone morphogenetic proteins
In the case of atrophic nonviable nonunions, biological issues
such as poor vascular supply are considered to be the main
reason of nonunion development. Besides improvement of the
 International Orthopaedics (SICOT)

Fig. 3 X-rays series of a

nonunion treated with exchange
nailing 11 months after surgical
treatment of an AO type 42 C2
fracture with CRIF by locked
reamed intramedullary nailing. a
No bony consolidation was
observed 7 months after CRIF. b
Coronal CT sections show the gap
9 months after initial surgery,
nonunion. c Postoperative
controls after exchange nailing of
the tibia with a dynamically-
locked tibial nail and fibula
osteotomy 11 months after initial
surgery. d 6 weeks postoperative
controls after exchange nailing
show beginning bony consolida-
tion. e 3 months after revision
surgery advanced consolidation
was documented. f 6 months after
exchange nailing X-rays show
complete fracture consolidation

mechanical stability, the purpose of the surgical therapy is to
address and to improve the biological environment according
to the Bdiamond concept^ [33].
Autogenous bone grafting provides all required properties for
bone formation: osteogenesis, osteoconduction and
osteoinduction, and is associated with low costs, absence of
disease transmission or rejection of the graft [60, 61]. Classical
harvest sites for cancellous autogenous bone grafting are the
iliac crest, proximal tibia, distal tibia, and the distal radius.
General limitations of autogenous bone grafting are limited
availability and donor site morbidity, such as chronic donor
site 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 described
due to a lower amount of available and biological active cells
in the graft [64]. Vascularized bone graft techniques were
established to overcome these limitations, with free
vascularized fibula bone grafts being the most frequently used
technique [65].
The reamer-irrigator-aspirator (RIA) is an alternative meth-
od for the harvesting of autogenous cancellous bone graft
material from the intramedullary canal of the femur by an
intramedullary 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 rates
in 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 cells
are removed during the production. Therefore, allografts pri-
marily serve as structural scaffold exhibiting osteoconductive
potential [60, 68]. After cases of transmission of blood borne
diseases such as HIV were reported in the 1980s and 1990s,
screening methods as well as new methods of processing and
preparation of bone grafts were established. Between 1990
and 2000 more than 1,000,000 bone allografts were implanted
without a reported evidence of HIV or hepatitis transmission
in the US [69]. The risk of viral transmission associated with
blood is reported for hepatitis B as one in 63,000, for hepatitis
International Orthopaedics (SICOT)
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 is
local infection of the allograft. The main reason for infection
is 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 the
osteoinductive potential of demineralized bone matrix
(DBM) and to discover the underlying BMPs, which belong
to 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 adjunct
to standard care using open fracture reduction and
intramedullary unreamed nail fixation and for single level
lumbar interbody spine fusion as a substitute for autogenous
bone graft in adults. RhBMP-7 (eptotermin alfa, Osigraft®
Olympus Biotech, Hopkinton, MA) was approved by the
FDA in 2002 for the treatment of tibia nonunion of at least
nine months duration, secondary to trauma, in skeletally ma-
ture patients, in cases where previous treatment with autograft
has failed or use of autograft was unfeasible. The trial of
Friedlaender et al. showed comparable clinical success rates
between rhBMP-7 (81%) and autogenous bone graft (85%) as
an adjunct to intramedullary nailing in 124 tibial shaft non-
unions after an observation period of nine months. This trial
had a non-inferiority study design to demonstrate safety and
efficacy and was not intended to show superiority of rhBMP-7
over autogenous bone grafting.
Currently, there is still a lack of sound randomized con-
trolled trials on the effects of BMPs compared to standard of
care treatment in nonunions, mainly attributable to the re-
quired large sample size with several hundreds of patients
and associated high costs for such a clinical study.
However, the general concept of stimulation of bone
healing by BMPs [75] was confirmed in several case reports
and 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 for
rhBMP-7 and rhBMP-2 currently remains the only commer-
cially available BMP.
Cell therapy
The initial phase of bone healing is characterized by the onset
of inflammation. MSCs, endothelial cells and immune cells
migrate toward the fractured bone region. Osteoprogenitor
cells, originating from the periosteum, the bone marrow, and
the surrounding tissue react to the signals sent by the
haematoma and migrate into the fracture area [80]. Hence, it
is not surprising that low levels of progenitor cells at nonunion
sites and in bone marrow of nonunion patients [81] as well as a
systemic mesenchymal and osteogenic cell pool defect were
observed [82]. To improve the cellular environment in a dis-
turbed bone healing process, the application of bone marrow
was proposed due to its osteogenic potential, which was first
observed by Gougeon in the nineteenth century [83]. Later,
Friedenstein et al. showed that new bone was formed by
fibroblast-like bone marrow cells in vitro after necrosis of
hematopoietic cells, which led to the first isolation of MSCs
in this context [84]. Furthermore, it could be shown that those
cells are multipotent and can differentiate to osteocytic,
chondrocytic, and adipocytic lineages [85]. Before isolating
MSCs from bone marrow, several preclinical and clinical stud-
ies had confirmed the efficiency of bone marrow implantation
to 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 large
bone defect [88]. Based on these findings, several clinical
studies were performed using MSCs in a single or combined
manner with osteoconductive or osteoinductive substances.
Homma et al. described the use of percutaneous autologous
bone 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 in
plastic bags containing cell culture medium and anticoagulant
solution. After filtration to separate cellular aggregates, the
aspirate 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 bone marrow stromal cells
after three weeks of tissue culture combined with a carrier of
calcium sulfate in pellet form [90]. Hernigou et al. found a
correlation between the number and concentration of progen-
itor cells applied at the nonunion site and subsequent bone
formation in percutaneous autologous bone grafting [91].
Quarto et al. described a case series of patients with diaphyseal
bone defects treated by ex vivo expanded osteoprogenitor
cells placed on macroporous hydroxyapatite scaffolds [92].
Another approach was conducted by Wittig et al. with the
loading of MSCs on collagen microspheres (CM) and their
incorporation into platelet-rich plasma (PRP) clots. This com-
bination of MSCs was shown to induce new bone formation in
long 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 stability
and compression to the nonunion site to achieve bony consol-
idation. Furthermore, bone resection with or without shorten-
ing with subsequent bone segment transport or lengthening
can be performed. Drawbacks are foremost pin loosening
 International Orthopaedics (SICOT)

Fig. 4 Series of a femoral shaft nonunion after an AO type 32 B3 fracture b Postoperative controls after augmentation plating with a locking plate. c
finally treated with augmentation plating. a Nonunion 7 months after X-rays 6 weeks after augmentation plating. d Consolidation 3 months
exchange nailing, autologous bone grafting, and rhBMP-2 application. after augmentation plating

and pin infections and patient discomfort with long treatment
duration [94]. Furthermore, regenerate related problems such
as poor bone quality, delayed maturation, premature consoli-
dation, and docking site problems requiring revision surgery
including bone grafting have been described [95].
Both monolateral and ring fixation systems have been used
successfully for the treatment of nonunions. High union rates
of 91.6% were reported by Harshwal et al. in 37 patients
suffering from femoral or tibial nonunions treated with a
monolateral external fixator. Of these 37 patients, 32 were
treated by compression osteosynthesis (monofocal), in six of
them distraction osteogenesis was carried out after initial com-
pression of the nonunion site. Five patients were treated by a
bifocal protocol with corticotomy and bone transport due to
bony defects larger than 3 cm in the tibia and 5 cm in the
femur, respectively [96].
After failed exchange nailing in aseptic and oligotrophic
femoral shaft nonunions, consolidation of the nonunion site
can be achieved using the Ilizarov fixator technique over the
indwelling nail with slow compression rates (0.25–0.5 mm per
day) [97]. This has also been described in aseptic humeral
shaft nonunions for the combination of Ilizarov or monolateral
external fixators for compression in combination with an
intramedullary fixation device [98].
Resection of the nonunion site allows for a radical removal
of fibrous and scar tissue but can result in segmental defects
larger than 5 cm that can be restored by corticotomy at the
remaining proximal or distal bone segment with daily gradual
distraction of this bone segment through an external fixator
apparatus [99]. Traditionally, Ilizarov ring fixators were used
for distraction osteogenesis and bone transport but also
monolateral techniques have gained more and more interest
due to easier pin insertion and uniplanar application [99].
Modern circular fixators like the Taylor spatial frame provide
not only distraction options but also correction of bone defor-
mity in all planes [16].
In general, a daily distraction rate of 1 mm is recommended
and provides sufficient osteogenic potential [100] but needs to

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 failed Compression plating with bone grafting [110]
nailing [109] augmentation plating after nailing [109]
Femoral shaft Nail dynamization [111] or early Augmentation plating with or without Augmentation plating with biological stimulation by
augmentation plating [104, 106] bone grafting [104, 106] § bone grafting or biologics [104, 106, 112, 113] §
Tibial shaft Nail dynamization [47] Reamed exchange nailing [52, 56] or Reamed exchange nailing or augmentation plating
or early exchange nailing [52] augmentation plating [107, 108] with 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 as
second line therapy
International Orthopaedics (SICOT)
be adapted to patients’ individual factors. Fixators should be
left about 1.9 months for every 1 cm of bone defect to reach
adequate and stable bony consolidation [101]. To reduce the
duration of external fixation, the adjunct use of internal fixa-
tion devices has been described [102, 103].
Augmentation plating
The improvement of biomechanical stability in diaphyseal
long bone nonunions has directed attention to additional plate
fixation 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 17
diaphyseal femoral nonunions with augmentation plating plus
additional bone grafting from the iliac crest without removal
of the nail after failed intramedullary nailing. In all 17 patients,
nonunions healed at a mean follow-up of seven months after
augmentative plate fixation without complications [104]. As
shown in Fig. 4, femoral shaft nonunions can be addressed
effectively by augmentation plating. In this complex case,
healing of the nonunion was reached by augmentation plating
improving mechanical instability, which was the result of a too
small nail diameter and a remaining fracture gap after initial
improvement worthy reduction of an AO type 32 B3 fracture.
Meanwhile several studies confirmed the excellent result of
augmentation plating for femoral, tibial, and humeral shaft
fractures. In femur shaft nonunions, high success rates of
100% of augmentation plating with or without autologous
bone 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% success
rate 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 remains
challenging for the patient and the surgeon, and is associated
with significant costs for the health care system.
For humeral diaphyseal shaft nonunions, excellent results
for augmentation plating were reported. In atrophic humeral
shaft nonunions, compression plating with stimulation of bone
healing 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 cheap
surgical possibility to achieve bony consolidation, particularly
in delayed nonunions before 24 weeks after initial surgery. In
established hypertrophic nonunions, biomechanical stability
should be addressed by augmentation plating or exchange
nailing. Hypotrophic or atrophic nonunions additionally require
biological stimulation of bone healing for augmentation plating.
For segmental bone defects, external fixation techniques
remain the treatment of choice. Patient comfort and success
rates can be positively influenced by the additional use of
internal fixation devices.
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