SUPPLEMENT ARTICLE
Principles of Nonunion Management: State of the Art
Aaron Nauth, MD, MSc, FRCSC,* Mark Lee, MD,† Michael J. Gardner, MD,‡ Mark R. Brinker, MD,§
Stephen J. Warner, MD,§ Paul Tornetta III, MD,k and Philipp Leucht, MD¶
Summary: A substantial proportion of fractures can present with
Downloaded from https://journals.lww.com/jorthotrauma by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3tIQ5gQCIeyxrcaswHnWSuhxit1bkeoWqUpqTNMTJpKnQhAFRzFyS7Q== on 10/29/2018
nonunion, and the management of nonunion continues to present
a challenge for orthopaedic surgeons. A variety of biological,
mechanical, patient, and injury factors can contribute to the
occurrence of nonunion, and often the cause of nonunion may be
multifactorial. Successful management often requires assessment and
treatment of more than one of these factors. This article reviews
common factors that may contribute to nonunion including infection,
impaired biology, and metabolic disorders. In addition, new and
evolving strategies for diagnosing the cause and effectively treating
nonunion including the diagnosis of infection, metabolic workup,
bone grafting, cell-based therapies, and biological adjuvants are
reviewed and discussed.
Key Words: nonunion, fracture healing, infection, stem cells, bone
graft, metabolic causes of nonunion
(J Orthop Trauma 2018;32:S52–S57)
INTRODUCTION
Most operatively and nonoperatively managed fractures
heal, but a considerable number fail to unite. This subset of
fractures with nonunion continue to present a treatment
challenge for orthopaedic surgeons. Causes that contribute
to the formation of nonunion include biological, mechanical,
patient, and injury factors, and frequently the cause of
nonunion may be multifactorial. Successful management
can often require that multiple factors are addressed concur-
rently. Common difficulties encountered in the treatment of
nonunions include managing infection, addressing impaired
biology, and assessing patients for metabolic disorders, which
compromise their healing capacity. Successful management
Accepted for publication December 11, 2017.
From the *Division of Orthopaedic Surgery, St. Michael’s Hospital, University
of Toronto, Toronto, ON, Canada; †Department of Orthopaedic Surgery,
UC Davis School of Medicine, Sacramento, CA; ‡Department of Ortho-
paedic Surgery, Stanford University School of Medicine, Palo Alto, CA;
§Texas Orthopedic Hospital/Fondren Orthopedic Group and Department of
Orthopaedic Surgery, University of Texas Health Science Center at Hous-
ton, Houston, TX; kDepartment of Orthopaedics, Boston University Med-
ical Center, Boston, MA; and ¶Department of Orthopaedic Surgery, New
York University School of Medicine, New York, NY.
M. Lee is a consultant for DePuy Synthes and receives research support from
DePuy Synthes. P. Tornetta has intellectual property rights from Smith &
Nephew and publications with Wolters Kluwer. The remaining authors
report no conflict of interest.
Reprints: Aaron Nauth, MD, MSc, FRCSC, Division of Orthopaedic Surgery,
St. Michael’s Hospital, University of Toronto, 55 queen street East, Suite
800, Toronto, ON, Canada M5C 1R6 (e-mail: nautha@smh.ca).
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/BOT.0000000000001122
S52 | www.jorthotrauma.com J Orthop Trauma  Volume 32, Number 3 Supplement, March 2018
Copyright Ó 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
of nonunions requires a systematic approach to identifying
and addressing these issues, in addition to addressing the
mechanical environment.
MANAGING INFECTION IN THE SETTING
OF NONUNION
Infection is an important consideration in the workup
and treatment of a patient with nonunion. When assessing for
infection, consideration should be given to risk factors of
infection, including patient factors such as conditions of
immune compromise, malnutrition, or smoking status and
injury factors such as open fractures, delayed wound healing,
or previous external fixation. Infection should be strongly
considered as a potential contributing factor to nonunion in
the presence of any of these risk factors.1 In addition, any
patient presenting with a fracture nonunion after surgical
treatment should be considered and worked up for infection.
Stucken et al reported on a large series of patients with
nonunion who were considered at risk of infection based on
the risk factors described above.2 They reported on a cohort
of 93 patients who underwent a standardized preoperative and
intraoperative workup for infection, including standardized
blood work [white blood cell (WBC) count, erythrocyte sed-
imentation rate], and C-reactive protein, nuclear studies (a
combined WBC/sulfur colloid scan), and intraoperative Gram
staining, and WBC count per high powered field. The authors
reported that the use of simple blood tests (WBC count,
erythrocyte sedimentation rate, and C-reactive protein) pro-
vided the best predictors of infection, particularly when the
results of those 3 tests were used in combination. Their rec-
ommendation was that these simple blood tests alone be used
for the preoperative assessment of infection.
Intraoperative cultures are the gold standard for the
diagnosis of infection and should be obtained from any
patient undergoing revision surgery for nonunion. Olszewski
et al reported a multicenter series of a large cohort of patients
undergoing revision surgery for nonunion who had a negative
workup for infection (no clinical signs of infection and
negative blood work) but were considered at risk because
of the presence of risk factors.1 Four-hundred and fifty-three
at-risk patients had intraoperative cultures sent at the time of
revision surgery and 91 patients (20%) had a “surprise” pos-
itive culture. The majority (.90%) were treated with culture-
specific antibiotics, whereas a small percentage (9%) of re-
sults were regarded as contaminants. Most cultures grew
coagulase-negative staphylococci. Overall, the results demon-
strated that those patients who had a “surprise” positive cul-
ture had lower union rates (73% vs. 96%), a higher chance of
J Orthop Trauma  Volume 32, Number 3 Supplement, March 2018
recurrent infection (12% vs. 4%), and required more second-
ary surgeries than those who had a negative culture. However,
successful treatment was achieved in 92% of those patients
with a “surprise” positive culture who received antibiotic
treatment, with 21% of those requiring additional surgery to
achieve union or eradicate infection.
When the diagnosis of infection is confirmed before
treatment in the setting of nonunion, a staged treatment
approach is recommended. The initial stage should consist of
debridement, removal of any loose or chronically infected
hardware, revision fixation/stabilization of the nonunion, and
the treatment of infection with culture-specific local and
systemic antibiotics. Local antibiotic treatment can be
achieved by a variety of methods including antibiotic nails,3
antibiotic cement beads,4 bioresorbable antibiotic pellets,4 or
antibiotic cement spacers. Antibiotic cement spacers can not
only help to eradicate infection but can also promote the
formation of an osteogenic induced membrane (Masquelet
technique).5 There are also a number of options for revision
fixation including both temporary (external fixation and anti-
biotic nails) and definitive (intramedullary nails and plates)
forms of fixation. Soft tissue coverage may also be required in
the form of flap or rotational coverage at this stage as well.
The second stage generally proceeds after a period of sys-
temic antibiotic therapy and when both clinical and serolog-
ical signs of infection are absent. This reconstructive stage to
address the nonunion may consist of definitive fixation, bone
grafting, other biologic treatment, or bone transport, depend-
ing on the specific characteristics of the nonunion.6,7
BONE GRAFTING: WHAT IS THE IDEAL TYPE?
The mainstay of surgical treatment for nonunions with
impaired biology (atrophic nonunion) is autologous bone
grafting. Three attributes are essential for successful graft-
ing: osteogenesis, osteoinduction, and osteoconduction.
Osteogenesis is defined as a cell’s ability to differentiate into
a bone matrix producing osteoblasts. Osteoinduction is the
ability of a growth factor to induce osteogenic differentiation
of skeletal progenitor cells or induce osteoid deposition by
osteoblasts. Osteoconduction describes the ability of a mate-
rial to provide a scaffold for the attachment and subsequent
bone matrix deposition of bone-forming cells. All 3 ele-
ments are essential for successful healing in the setting of
atrophic nonunion.8
Autograft has been the gold standard for atrophic
nonunion treatment for decades.9 Bone graft, harvested from
any location within the skeleton, possesses all 3 of the above-
mentioned qualities. In addition, its risk profile with regard to
disease transmission and surgical complications is favorable
when compared with allograft and recombinant growth factor
use. Last, acquisition of autograft is cost-effective, particu-
larly when compared with other off-the-shelf products. How-
ever, there are several disadvantages that exist with autograft
use. The most commonly cited complication is harvest site
pain, although recent studies have reported that with precise
surgical technique, the use of local anesthesia and appropriate
postoperative analgesia, these sequelae can be minimized.10
Costs associated with increased operating room time and
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Principles of Nonunion Management
length of stay have also been cited as a possible limitation
of autograft.11
The 2 most common options for autograft harvest
include iliac crest bone graft (ICBG) and the Reamer-
Irrigator-Aspirator (RIA). Both options provide large quanti-
ties of bone graft. RIA can harvest up to 60 ccs of graft
material, whereas the ICBG can provide approximately 30
ccs. Bone graft harvested with both methods contains skeletal
progenitor cells, osteoblasts, monocytes, and bone lining
cells, and progenitor cells within the harvested graft material
have been shown to be capable of tripotent differentiation
(able to form bone, cartilage, and fat).12 A commonly cited
potential disadvantage of RIA graft harvest is the relatively
low number of bone-forming cells present within the graft
material because these cells are flushed away through the
collection filter due to the high flow rate of the irrigation
fluid.13 A randomized controlled trial comparing the 2 harvest
options revealed that the RIA system was overall more cost-
effective than posterior ICBG because of the longer operating
room time associated with the graft harvest from the posterior
superior iliac spine.14 There was no difference in the union
rate between RIA (82%) and ICBG (86%) and no difference
in the complication rate, although graft harvest site pain was
reported to be lower with the RIA.
Although autograft does provide the necessary biologic
elements, recent trends have indicated a shift toward other
forms of bone healing augmentation, often less painful, less
time-consuming, and less invasive alternatives. The question
arises whether it is time for a new gold standard for the
treatment of nonunions.
Although the young skeleton is rich in skeletal pro-
genitor cells, this abundance of bone-forming cells decreases
with age, and recent research has shown that the frequency of
bone progenitor cells in the middle aged and elderly is
significantly reduced.15 Bone marrow aspirate concentrate
(BMAC), obtained by bone marrow aspiration and centrifu-
gation, is currently used to increase the nucleated cell fraction
of bone marrow aspirate and by doing so increases the num-
ber of bone progenitor cells within a certain volume. There-
fore, BMAC may represent a superior option to ICBG or RIA
because of the increased number of osteogenic cells, which
directly contribute to the bone-forming potential of the graft,
particularly in the middle-aged and elderly patients. Both
autograft and exogenous sources of osteoinductive proteins
[such as bone morphogenetic proteins (BMPs) and platelet-
derived growth factor] supply pro-osteogenic cues to the site
of desired bone healing.16 However, both do so in supraphy-
siological doses and without adhering to any physiologic
timeline for release. By contrast, BMAC provides a concen-
trated population of cells, which release physiologic doses of
osteogenic growth factors, in a timed, coordinated manner,
which is responsive to the microenvironment. Therefore,
BMAC may represent the best-suited substitute for osteoin-
ductive agents. Finally, decades of research has provided
a plethora of commercially available osteoconductive scaffold
options with varying pore sizes, resorption rates, and mechan-
ical/handling properties, and the osteoconductive properties
of autograft are easily replaced with unlimited, off-the-shelf
supply. Therefore, BMAC in combination with commercially
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Nauth et al J Orthop Trauma  Volume 32, Number 3 Supplement, March 2018
available, osteoconductive scaffolds may provide the optimal
combination of osteogenic cells, osteoinductive proteins, and
limitless graft volume, without the invasive techniques
required to harvest autograft and thus may represent the
approach of the future.
BIOLOGIC THERAPIES FOR NONUNION
Many biological and mechanical factors have been
implicated in the etiology of fracture nonunion, and fre-
quently more than 1 factor is present. When abundant callus
formation is present, such as in a hypertrophic nonunion,
typically improved mechanical stabilization with internal
fixation and possibly compression is effective to achieve
healing. However, in the setting of atrophic nonunion, where
minimal callus formation is present, appropriate treatment
includes augmentation of the biologic potential at the non-
union site. Traditionally, autologous ICBG has been the gold
standard for this purpose. However, concerns over donor site
morbidity have led surgeons to seek alternative sources of
osteogenesis. More recently, intramedullary femoral reaming
and debris aspiration (RIA bone graft) has provided a prom-
ising source of osteogenic material, however this still requires
a separate surgical procedure and has its own unique
complication profile.17,18 In addition, both iliac crest autograft
and RIA graft have limited supply. Investigators continue the
search for an effective biologic material to augment nonunion
healing that avoids the complications associated with harvest
and is not limited in its quantity. Several options are currently
available including demineralized bone matrix (DBM),
BMPs, and systemic parathyroid hormone (PTH) therapy.
In 1965, Marshall Urist identified a substance in
demineralized bone that led to osteoinduction in extraskeletal
sites (heterotopic bone formation).19 Acid extraction of allo-
genic bone leaves a residual of type I collagen, other non-
collagenous proteins, and multiple growth factors. This
growth factor profile was subsequently identified as the trans-
forming growth factor b superfamily. Among these, BMPs
comprised at least 15 of the proteins responsible for osteo-
genesis. The extraction process was streamlined and commer-
cialized, and DBM was approved by the FDA. Since that
time, several methodologically weak studies have suggested
clinical efficacy of DBM for nonunion treatment.20,21 At pres-
ent, the variability in growth factor concentration between
products and between lots of a single product,22 as well as
lack of Level I evidence regarding clinical efficacy, has lim-
ited its widespread use for nonunion treatment.
Among the transforming growth factor b proteins, sev-
eral BMPs were identified to be potently osteoinductive.
BMP-2 and BMP-7 were commercialized. BMP-7 was
FDA approved for recalcitrant nonunions based on the piv-
otal study by Friedlaender et al.23 In this study, 124 tibial
nonunions were treated with reamed intramedullary nailing
and randomized to autograft or BMP-7. Equivalent union
and complication rates were reported in the 2 treatment
groups, and the authors concluded that BMP-7 was a safe
and effective alternative to autograft in this setting. Since
that time, reports of complications in spine surgery, ques-
tions about appropriate dose, the formation of antibodies,
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and the high cost of this compound have decreased initial
enthusiasm.
Subcutaneous intermittent injection of PTH is potently
osteogenic, and has recently been commercialized as teripara-
tide (Forteo, Eli Lilly). This agent is FDA approved and very
effective in osteoporosis treatment. Animal studies have been
conclusive in showing its strong efficacy in stimulating bone
formation in fracture healing and fusions.24 Several human
studies have been conducted in acute fractures,25,26 and
although early evidence is promising, clear indications are
lacking. This systemic therapy for achieving nonunion heal-
ing is currently limited to case reports but may be a useful
adjunct in the future.
The search for the ideal biologic stimulant in nonunion
treatment persists. Autografts, both from the iliac crest and
the femoral canal, provide reliable substrates but are limited
by complications and quantity. Novel approaches and materi-
als continue to be developed and tested. Before selecting an
autograft alternative, the surgeon should become familiar with
the advantages and disadvantages of that product and should
critically analyze the evidence supporting its use.
CELL-BASED THERAPIES FOR
NONUNION MANAGEMENT
Few recent developments in orthopaedic basic science
garner more interest than cell-based therapies for bone
regeneration. However, compared with the other critical
components of bone formation, surgeons have had the most
limited access to a bone-forming cell population. A myriad of
alternatives are currently available to surgeons at the point of
care, although high-quality clinical data remain elusive. Three
of the most actively studied technologies/techniques are
viable allograft products, lipoaspirate cell harvest, and
endosteal bone harvest via reaming aspiration.
Viable allografts represent an interesting product con-
cept available to surgeons at the point of care as a ready-to-
use, packaged product. A limited number of these products
are available at this time. Conceptually, the development of
these products followed improvements in the cadaver donor
screening process, which improved the safety and comfort
level with the use of fresh allograft material. These products
required the development of proprietary techniques to harvest
viable mesenchymal stem cells from fresh allograft bone
tissue. In these products, the cells are then provided in some
form of carrier/vehicle, such as DBM and/or allograft chips as
a complete, free-standing regenerative matrix. The distin-
guishing feature of this type of complete graft substitute
concept relies on the presence of a viable cell population. One
study of a specific viable allograft product provided a func-
tional and comparative analysis.27 The authors demonstrated
functionally competent mesenchymal cells and cell numbers
similar to a typical BMAC procedure. Clinical reports of the
viable allograft combinations are limited but include studies
of the spine, foot and ankle, and maxillofacial reconstruc-
tions.28,29 All of these studies are level 4 case series, and
high-level evidence regarding the efficacy of viable allografts
is lacking. However, there are no reports of disease transmis-
sion to date, and their early clinical safety profile seems
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J Orthop Trauma  Volume 32, Number 3 Supplement, March 2018
favorable. Further studies are necessary to understand their
efficacy and to clarify indications.
Lipoaspirates are a newer concept for autologous
mesenchymal cell harvest. This technique represents a sim-
ple, yet elegant approach for physical separation of cells
from a manual lipoaspirate and uses a proprietary canister
to isolate the desired cell population. This technique was
developed to obtain microfragmented adipose tissue with
an intact stromal vascular niche and mesenchymal cells
with a high regenerative capacity.30 This technique repre-
sents the newest and most unique approach to cell harvest
for bone regeneration, and clinical experience with its use
has been very limited. A proof-of-concept study demon-
strates one of the proposed techniques for autologous cell
regeneration including ex vivo cell expansion, optimization
of delivery using DBM, followed by second-stage reim-
plantation.31 Of the 3 patients reported in the article, 1
patient healed, 1 developed nonunion, and 1 experienced
a deep infection. Clearly further basic science and clinical
studies are required to better understand the osteogenic
potential of this cell population and evaluate its role in
clinical applications.
Intramedullary bone graft harvest (RIA) is likely the
most studied technique for accessing autogenous cells for
regenerative applications. Several publications have evaluated
intramedullary reaming debris as a source of viable osteo-
blastic progenitor cells.32,33 A large number of cells are found
on the surface of the bony spicules liberated during the
mechanical reaming process. Two further considerations war-
rant a further analysis of the possibility that endosteal reaming
with RIA may represent an optimal approach to liberating
a potent bone progenitor cell population. First, there is a tra-
ditional schema with an osteoblastic cell niche along the end-
osteal surface with osteoblasts and hematopoietic precursors
and a separate vascular niche more centrally along sinusoids
with the mesenchymal cell population. A recent study used
a novel technique to enzymatically separate cells from the
central and endosteal regions.34 A significant number of pro-
genitors were found in both regions. In fact more progenitors
were found along the endosteum, and these cells had a higher
proliferative capacity. This finding suggests that mechanical
reaming of the endosteal zone likely liberates a large number
of mesenchymal progenitor cells.
Further support for this cell harvesting concept comes
from evaluations of the waste water from the reaming
process, with the RIA. One study compared the progenitor
cell numbers in samples of RIA waste fluid from patients
undergoing nonunion treatment with age-matched bone
marrow aspirate samples in trauma patients.35 All of the
RIA samples had cell counts well above the classically ref-
erenced threshold for successful healing from Hernigou et al
of 55,00036; in fact, the average number of cells was over
300,000, representing a very high volume of liberated pro-
genitors. Further studies are underway to improve the ability
to concentrate progenitors liberated from the RIA at the
point of care. Theoretically, surgeons will soon have the
ability to enrich structural and inductive grafts of choice
with a large number of endogenous bone-forming
progenitors.
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Principles of Nonunion Management
METABOLIC WORKUP OF NONUNIONS
Impaired fracture healing occurs in approximately 5%–
10% of all patients, and a subset of these patients will develop
a fracture nonunion, where bony union will not occur without
further intervention. The etiology of a nonunion can be mul-
tifactorial and include characteristics of the fracture, such as
mechanical instability, insufficient vascularity, and poor sur-
face characteristics and suboptimal bony contact.37 In addi-
tion, patient factors including cigarette smoking, alcohol
abuse, malnutrition, and anti-inflammatory medication use
can be detrimental to fracture healing.38–42 However, some
fractures fail to unite despite excellent fixation and a seem-
ingly heathy host with adequate local biology. In this subset
of patients who present with a fracture nonunion, metabolic
and endocrine abnormalities should be suspected as a potential
etiology for their nonunion.
Several metabolic abnormalities have been associated
with impaired fracture healing including vitamin D defi-
ciency, diabetes, hypogonadism, and imbalances of calcium,
growth hormone, and PTH.37,38,43 Of these, disorders affect-
ing vitamin D, calcium, and PTH most directly affect bone
metabolism during fracture healing and have a prevalence of
up to 50% in certain populations.37,44,45
In patients with a nonunion, metabolic bone disease
should be suspected when one or more of the following
criteria are present: (1) a persistent nonunion despite adequate
treatment without obvious technical error, (2) a history of
multiple low-energy fractures with at least 1 progressing to
a nonunion, and (3) a nonunion of a minimally displaced
pubic rami or sacral ala fracture. When these criteria were
used, 84% of patients with a nonunion were newly diagnosed
TABLE 1. Metabolic and Endocrine Related Laboratory Tests
(Serum Tests Unless Otherwise Noted)
Vitamins and Calcium
minerals
Calcium (24 h urine)
Phosphorus (phosphate, PO4)
Alkaline phosphatase
Magnesium
25-hydroxyvitamin D [Vitamin D 25(OH)]
1,25-dihydroxyvitamin D [Vitamin D 1,25(OH)2]
Hormones Intact parathyroid hormone
Thyroid Function Test
Adrenocorticotropic hormone
Cortisol
Cortisol (24 h urine)
Growth hormone
Insulin-like growth factor 1 (IGF-1)
Dehydroepiandrosterone sulfate
Follicle stimulating hormone
Luteinizing hormone
Total estrogen
Estradiol (E2)
Testosterone
Free testosterone
Prolactin
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Nauth et al J Orthop Trauma  Volume 32, Number 3 Supplement, March 2018
with one or more metabolic or endocrine abnormalities,
including vitamin D deficiency, calcium imbalances, central
hypogonadism, thyroid disorders, and PTH disorders.43
Patients identified using these criteria should undergo
metabolic and endocrine evaluation, with blood and urine
laboratory testing for abnormalities in a defined set of
vitamins, minerals, and hormones related to bone healing
(Table 1). In addition to vitamin D metabolites, PTH, cal-
cium, and phosphate, the laboratory testing should also
include stress-related hormones (adrenocorticotropic hormone
and cortisol), anabolic (dehydroepiandrosterone sulfate and
growth hormone) and sex (follicle stimulating hormone,
estrogen, estradiol, and testosterone) hormones, thyroid func-
tion tests, and alkaline phosphatase, a marker of bone turn-
over. A comprehensive endocrine and metabolic profile is
used rather than a few specific metabolic tests so that any
imbalances can be interpreted in the context of a full profile.
Once a patient with a nonunion has been diagnosed
with an endocrine or metabolic disorder, treatment should be
performed using a team-based approach. Medical manage-
ment of all diagnosed endocrine and metabolic disorders
should be performed by an endocrinologist with specializa-
tion or experience in metabolic bone disease. Management of
the nonunion with operative and nonoperative methods
should be performed by an orthopaedic surgeon. In general,
medical treatment should not inhibit surgical intervention.
However, medical management alone may induce nonunion
healing without surgery by providing a biologic stimulus. In
a group of 31 patients with well-established nonunions and
a newly diagnosed metabolic disorder, 8 patients were healed
of their nonunion following medical treatment alone without
operative intervention,43 highlighting the importance of these
metabolic and endocrine abnormalities for the nonunion
etiology.
CONCLUSIONS
The etiology of nonunion is frequently multifactorial,
and often successful treatment requires the assessment and
management of multiple factors. Infection, metabolic disor-
ders, and impaired biology at the fracture site are important
considerations in addition to the mechanical environment. An
understanding of the variety of available options for treating
these and the evidence supporting their use is critical to
success in nonunion management.
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