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¶

of nonunions requires a systematic approach to identifying

Summary: A substantial proportion of fractures can present with and addressing these issues, in addition to addressing the
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nonunion, and the management of nonunion continues to present mechanical environment.

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
MANAGING INFECTION IN THE SETTING
treatment of more than one of these factors. This article reviews OF NONUNION
common factors that may contribute to nonunion including infection, Infection is an important consideration in the workup
impaired biology, and metabolic disorders. In addition, new and and treatment of a patient with nonunion. When assessing for
evolving strategies for diagnosing the cause and effectively treating infection, consideration should be given to risk factors of
nonunion including the diagnosis of infection, metabolic workup, infection, including patient factors such as conditions of
bone grafting, cell-based therapies, and biological adjuvants are immune compromise, malnutrition, or smoking status and
reviewed and discussed. injury factors such as open fractures, delayed wound healing,
or previous external fixation. Infection should be strongly
Key Words: nonunion, fracture healing, infection, stem cells, bone considered as a potential contributing factor to nonunion in
graft, metabolic causes of nonunion the presence of any of these risk factors.1 In addition, any
(J Orthop Trauma 2018;32:S52–S57) 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
INTRODUCTION nonunion who were considered at risk of infection based on
Most operatively and nonoperatively managed fractures the risk factors described above.2 They reported on a cohort
heal, but a considerable number fail to unite. This subset of of 93 patients who underwent a standardized preoperative and
fractures with nonunion continue to present a treatment intraoperative workup for infection, including standardized
challenge for orthopaedic surgeons. Causes that contribute blood work [white blood cell (WBC) count, erythrocyte sed-
to the formation of nonunion include biological, mechanical, imentation rate], and C-reactive protein, nuclear studies (a
patient, and injury factors, and frequently the cause of combined WBC/sulfur colloid scan), and intraoperative Gram
nonunion may be multifactorial. Successful management staining, and WBC count per high powered field. The authors
can often require that multiple factors are addressed concur- reported that the use of simple blood tests (WBC count,
rently. Common difficulties encountered in the treatment of erythrocyte sedimentation rate, and C-reactive protein) pro-
nonunions include managing infection, addressing impaired vided the best predictors of infection, particularly when the
biology, and assessing patients for metabolic disorders, which results of those 3 tests were used in combination. Their rec-
compromise their healing capacity. Successful management ommendation was that these simple blood tests alone be used
for the preoperative assessment of infection.
Accepted for publication December 11, 2017. Intraoperative cultures are the gold standard for the
From the *Division of Orthopaedic Surgery, St. Michael’s Hospital, University diagnosis of infection and should be obtained from any
of Toronto, Toronto, ON, Canada; †Department of Orthopaedic Surgery, patient undergoing revision surgery for nonunion. Olszewski
UC Davis School of Medicine, Sacramento, CA; ‡Department of Ortho- et al reported a multicenter series of a large cohort of patients
paedic Surgery, Stanford University School of Medicine, Palo Alto, CA;
§Texas Orthopedic Hospital/Fondren Orthopedic Group and Department of undergoing revision surgery for nonunion who had a negative
Orthopaedic Surgery, University of Texas Health Science Center at Hous- workup for infection (no clinical signs of infection and
ton, Houston, TX; kDepartment of Orthopaedics, Boston University Med- negative blood work) but were considered at risk because
ical Center, Boston, MA; and ¶Department of Orthopaedic Surgery, New of the presence of risk factors.1 Four-hundred and fifty-three
York University School of Medicine, New York, NY. at-risk patients had intraoperative cultures sent at the time of
M. Lee is a consultant for DePuy Synthes and receives research support from
DePuy Synthes. P. Tornetta has intellectual property rights from Smith & revision surgery and 91 patients (20%) had a “surprise” pos-
Nephew and publications with Wolters Kluwer. The remaining authors itive culture. The majority (.90%) were treated with culture-
report no conflict of interest. specific antibiotics, whereas a small percentage (9%) of re-
Reprints: Aaron Nauth, MD, MSc, FRCSC, Division of Orthopaedic Surgery, sults were regarded as contaminants. Most cultures grew
St. Michael’s Hospital, University of Toronto, 55 queen street East, Suite
800, Toronto, ON, Canada M5C 1R6 (e-mail: [email protected]).
coagulase-negative staphylococci. Overall, the results demon-
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. strated that those patients who had a “surprise” positive cul-
DOI: 10.1097/BOT.0000000000001122 ture had lower union rates (73% vs. 96%), a higher chance of

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J Orthop Trauma  Volume 32, Number 3 Supplement, March 2018 Principles of Nonunion Management

recurrent infection (12% vs. 4%), and required more second- length of stay have also been cited as a possible limitation
ary surgeries than those who had a negative culture. However, of autograft.11
successful treatment was achieved in 92% of those patients The 2 most common options for autograft harvest
with a “surprise” positive culture who received antibiotic include iliac crest bone graft (ICBG) and the Reamer-
treatment, with 21% of those requiring additional surgery to Irrigator-Aspirator (RIA). Both options provide large quanti-
achieve union or eradicate infection. ties of bone graft. RIA can harvest up to 60 ccs of graft
When the diagnosis of infection is confirmed before material, whereas the ICBG can provide approximately 30
treatment in the setting of nonunion, a staged treatment ccs. Bone graft harvested with both methods contains skeletal
approach is recommended. The initial stage should consist of progenitor cells, osteoblasts, monocytes, and bone lining
debridement, removal of any loose or chronically infected cells, and progenitor cells within the harvested graft material
hardware, revision fixation/stabilization of the nonunion, and have been shown to be capable of tripotent differentiation
the treatment of infection with culture-specific local and (able to form bone, cartilage, and fat).12 A commonly cited
systemic antibiotics. Local antibiotic treatment can be potential disadvantage of RIA graft harvest is the relatively
achieved by a variety of methods including antibiotic nails,3 low number of bone-forming cells present within the graft
antibiotic cement beads,4 bioresorbable antibiotic pellets,4 or material because these cells are flushed away through the
antibiotic cement spacers. Antibiotic cement spacers can not collection filter due to the high flow rate of the irrigation
only help to eradicate infection but can also promote the fluid.13 A randomized controlled trial comparing the 2 harvest
formation of an osteogenic induced membrane (Masquelet options revealed that the RIA system was overall more cost-
technique).5 There are also a number of options for revision effective than posterior ICBG because of the longer operating
fixation including both temporary (external fixation and anti- room time associated with the graft harvest from the posterior
biotic nails) and definitive (intramedullary nails and plates) superior iliac spine.14 There was no difference in the union
forms of fixation. Soft tissue coverage may also be required in rate between RIA (82%) and ICBG (86%) and no difference
the form of flap or rotational coverage at this stage as well. in the complication rate, although graft harvest site pain was
The second stage generally proceeds after a period of sys- reported to be lower with the RIA.
temic antibiotic therapy and when both clinical and serolog- Although autograft does provide the necessary biologic
ical signs of infection are absent. This reconstructive stage to elements, recent trends have indicated a shift toward other
address the nonunion may consist of definitive fixation, bone forms of bone healing augmentation, often less painful, less
grafting, other biologic treatment, or bone transport, depend- time-consuming, and less invasive alternatives. The question
ing on the specific characteristics of the nonunion.6,7 arises whether it is time for a new gold standard for the
treatment of nonunions.
Although the young skeleton is rich in skeletal pro-
BONE GRAFTING: WHAT IS THE IDEAL TYPE? genitor cells, this abundance of bone-forming cells decreases
The mainstay of surgical treatment for nonunions with with age, and recent research has shown that the frequency of
impaired biology (atrophic nonunion) is autologous bone bone progenitor cells in the middle aged and elderly is
grafting. Three attributes are essential for successful graft- significantly reduced.15 Bone marrow aspirate concentrate
ing: osteogenesis, osteoinduction, and osteoconduction. (BMAC), obtained by bone marrow aspiration and centrifu-
Osteogenesis is defined as a cell’s ability to differentiate into gation, is currently used to increase the nucleated cell fraction
a bone matrix producing osteoblasts. Osteoinduction is the of bone marrow aspirate and by doing so increases the num-
ability of a growth factor to induce osteogenic differentiation ber of bone progenitor cells within a certain volume. There-
of skeletal progenitor cells or induce osteoid deposition by fore, BMAC may represent a superior option to ICBG or RIA
osteoblasts. Osteoconduction describes the ability of a mate- because of the increased number of osteogenic cells, which
rial to provide a scaffold for the attachment and subsequent directly contribute to the bone-forming potential of the graft,
bone matrix deposition of bone-forming cells. All 3 ele- particularly in the middle-aged and elderly patients. Both
ments are essential for successful healing in the setting of autograft and exogenous sources of osteoinductive proteins
atrophic nonunion.8 [such as bone morphogenetic proteins (BMPs) and platelet-
Autograft has been the gold standard for atrophic derived growth factor] supply pro-osteogenic cues to the site
nonunion treatment for decades.9 Bone graft, harvested from of desired bone healing.16 However, both do so in supraphy-
any location within the skeleton, possesses all 3 of the above- siological doses and without adhering to any physiologic
mentioned qualities. In addition, its risk profile with regard to timeline for release. By contrast, BMAC provides a concen-
disease transmission and surgical complications is favorable trated population of cells, which release physiologic doses of
when compared with allograft and recombinant growth factor osteogenic growth factors, in a timed, coordinated manner,
use. Last, acquisition of autograft is cost-effective, particu- which is responsive to the microenvironment. Therefore,
larly when compared with other off-the-shelf products. How- BMAC may represent the best-suited substitute for osteoin-
ever, there are several disadvantages that exist with autograft ductive agents. Finally, decades of research has provided
use. The most commonly cited complication is harvest site a plethora of commercially available osteoconductive scaffold
pain, although recent studies have reported that with precise options with varying pore sizes, resorption rates, and mechan-
surgical technique, the use of local anesthesia and appropriate ical/handling properties, and the osteoconductive properties
postoperative analgesia, these sequelae can be minimized.10 of autograft are easily replaced with unlimited, off-the-shelf
Costs associated with increased operating room time and 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 and the high cost of this compound have decreased initial
combination of osteogenic cells, osteoinductive proteins, and enthusiasm.
limitless graft volume, without the invasive techniques Subcutaneous intermittent injection of PTH is potently
required to harvest autograft and thus may represent the osteogenic, and has recently been commercialized as teripara-
approach of the future. 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
BIOLOGIC THERAPIES FOR NONUNION formation in fracture healing and fusions.24 Several human
Many biological and mechanical factors have been studies have been conducted in acute fractures,25,26 and
implicated in the etiology of fracture nonunion, and fre- although early evidence is promising, clear indications are
quently more than 1 factor is present. When abundant callus lacking. This systemic therapy for achieving nonunion heal-
formation is present, such as in a hypertrophic nonunion, ing is currently limited to case reports but may be a useful
typically improved mechanical stabilization with internal adjunct in the future.
fixation and possibly compression is effective to achieve The search for the ideal biologic stimulant in nonunion
healing. However, in the setting of atrophic nonunion, where treatment persists. Autografts, both from the iliac crest and
minimal callus formation is present, appropriate treatment the femoral canal, provide reliable substrates but are limited
includes augmentation of the biologic potential at the non- by complications and quantity. Novel approaches and materi-
union site. Traditionally, autologous ICBG has been the gold als continue to be developed and tested. Before selecting an
standard for this purpose. However, concerns over donor site autograft alternative, the surgeon should become familiar with
morbidity have led surgeons to seek alternative sources of the advantages and disadvantages of that product and should
osteogenesis. More recently, intramedullary femoral reaming critically analyze the evidence supporting its use.
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 CELL-BASED THERAPIES FOR
complication profile.17,18 In addition, both iliac crest autograft NONUNION MANAGEMENT
and RIA graft have limited supply. Investigators continue the Few recent developments in orthopaedic basic science
search for an effective biologic material to augment nonunion garner more interest than cell-based therapies for bone
healing that avoids the complications associated with harvest regeneration. However, compared with the other critical
and is not limited in its quantity. Several options are currently components of bone formation, surgeons have had the most
available including demineralized bone matrix (DBM), limited access to a bone-forming cell population. A myriad of
BMPs, and systemic parathyroid hormone (PTH) therapy. alternatives are currently available to surgeons at the point of
In 1965, Marshall Urist identified a substance in care, although high-quality clinical data remain elusive. Three
demineralized bone that led to osteoinduction in extraskeletal of the most actively studied technologies/techniques are
sites (heterotopic bone formation).19 Acid extraction of allo- viable allograft products, lipoaspirate cell harvest, and
genic bone leaves a residual of type I collagen, other non- endosteal bone harvest via reaming aspiration.
collagenous proteins, and multiple growth factors. This Viable allografts represent an interesting product con-
growth factor profile was subsequently identified as the trans- cept available to surgeons at the point of care as a ready-to-
forming growth factor b superfamily. Among these, BMPs use, packaged product. A limited number of these products
comprised at least 15 of the proteins responsible for osteo- are available at this time. Conceptually, the development of
genesis. The extraction process was streamlined and commer- these products followed improvements in the cadaver donor
cialized, and DBM was approved by the FDA. Since that screening process, which improved the safety and comfort
time, several methodologically weak studies have suggested level with the use of fresh allograft material. These products
clinical efficacy of DBM for nonunion treatment.20,21 At pres- required the development of proprietary techniques to harvest
ent, the variability in growth factor concentration between viable mesenchymal stem cells from fresh allograft bone
products and between lots of a single product,22 as well as tissue. In these products, the cells are then provided in some
lack of Level I evidence regarding clinical efficacy, has lim- form of carrier/vehicle, such as DBM and/or allograft chips as
ited its widespread use for nonunion treatment. a complete, free-standing regenerative matrix. The distin-
Among the transforming growth factor b proteins, sev- guishing feature of this type of complete graft substitute
eral BMPs were identified to be potently osteoinductive. concept relies on the presence of a viable cell population. One
BMP-2 and BMP-7 were commercialized. BMP-7 was study of a specific viable allograft product provided a func-
FDA approved for recalcitrant nonunions based on the piv- tional and comparative analysis.27 The authors demonstrated
otal study by Friedlaender et al.23 In this study, 124 tibial functionally competent mesenchymal cells and cell numbers
nonunions were treated with reamed intramedullary nailing similar to a typical BMAC procedure. Clinical reports of the
and randomized to autograft or BMP-7. Equivalent union viable allograft combinations are limited but include studies
and complication rates were reported in the 2 treatment of the spine, foot and ankle, and maxillofacial reconstruc-
groups, and the authors concluded that BMP-7 was a safe tions.28,29 All of these studies are level 4 case series, and
and effective alternative to autograft in this setting. Since high-level evidence regarding the efficacy of viable allografts
that time, reports of complications in spine surgery, ques- is lacking. However, there are no reports of disease transmis-
tions about appropriate dose, the formation of antibodies, sion to date, and their early clinical safety profile seems

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J Orthop Trauma  Volume 32, Number 3 Supplement, March 2018 Principles of Nonunion Management

favorable. Further studies are necessary to understand their METABOLIC WORKUP OF NONUNIONS
efficacy and to clarify indications. Impaired fracture healing occurs in approximately 5%–
Lipoaspirates are a newer concept for autologous 10% of all patients, and a subset of these patients will develop
mesenchymal cell harvest. This technique represents a sim- a fracture nonunion, where bony union will not occur without
ple, yet elegant approach for physical separation of cells further intervention. The etiology of a nonunion can be mul-
from a manual lipoaspirate and uses a proprietary canister tifactorial and include characteristics of the fracture, such as
to isolate the desired cell population. This technique was mechanical instability, insufficient vascularity, and poor sur-
developed to obtain microfragmented adipose tissue with face characteristics and suboptimal bony contact.37 In addi-
an intact stromal vascular niche and mesenchymal cells tion, patient factors including cigarette smoking, alcohol
with a high regenerative capacity.30 This technique repre- abuse, malnutrition, and anti-inflammatory medication use
sents the newest and most unique approach to cell harvest can be detrimental to fracture healing.38–42 However, some
for bone regeneration, and clinical experience with its use fractures fail to unite despite excellent fixation and a seem-
has been very limited. A proof-of-concept study demon- ingly heathy host with adequate local biology. In this subset
strates one of the proposed techniques for autologous cell of patients who present with a fracture nonunion, metabolic
regeneration including ex vivo cell expansion, optimization and endocrine abnormalities should be suspected as a potential
of delivery using DBM, followed by second-stage reim- etiology for their nonunion.
plantation.31 Of the 3 patients reported in the article, 1 Several metabolic abnormalities have been associated
patient healed, 1 developed nonunion, and 1 experienced with impaired fracture healing including vitamin D defi-
a deep infection. Clearly further basic science and clinical ciency, diabetes, hypogonadism, and imbalances of calcium,
studies are required to better understand the osteogenic growth hormone, and PTH.37,38,43 Of these, disorders affect-
potential of this cell population and evaluate its role in ing vitamin D, calcium, and PTH most directly affect bone
clinical applications. metabolism during fracture healing and have a prevalence of
Intramedullary bone graft harvest (RIA) is likely the up to 50% in certain populations.37,44,45
most studied technique for accessing autogenous cells for In patients with a nonunion, metabolic bone disease
regenerative applications. Several publications have evaluated should be suspected when one or more of the following
intramedullary reaming debris as a source of viable osteo- criteria are present: (1) a persistent nonunion despite adequate
blastic progenitor cells.32,33 A large number of cells are found treatment without obvious technical error, (2) a history of
on the surface of the bony spicules liberated during the multiple low-energy fractures with at least 1 progressing to
mechanical reaming process. Two further considerations war- a nonunion, and (3) a nonunion of a minimally displaced
rant a further analysis of the possibility that endosteal reaming pubic rami or sacral ala fracture. When these criteria were
with RIA may represent an optimal approach to liberating used, 84% of patients with a nonunion were newly diagnosed
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 TABLE 1. Metabolic and Endocrine Related Laboratory Tests
with the mesenchymal cell population. A recent study used (Serum Tests Unless Otherwise Noted)
a novel technique to enzymatically separate cells from the Vitamins and Calcium
central and endosteal regions.34 A significant number of pro- minerals
genitors were found in both regions. In fact more progenitors Calcium (24 h urine)
were found along the endosteum, and these cells had a higher Phosphorus (phosphate, PO4)
proliferative capacity. This finding suggests that mechanical Alkaline phosphatase
reaming of the endosteal zone likely liberates a large number Magnesium
of mesenchymal progenitor cells. 25-hydroxyvitamin D [Vitamin D 25(OH)]
Further support for this cell harvesting concept comes 1,25-dihydroxyvitamin D [Vitamin D 1,25(OH)2]
from evaluations of the waste water from the reaming Hormones Intact parathyroid hormone
process, with the RIA. One study compared the progenitor Thyroid Function Test
cell numbers in samples of RIA waste fluid from patients Adrenocorticotropic hormone
undergoing nonunion treatment with age-matched bone Cortisol
marrow aspirate samples in trauma patients.35 All of the Cortisol (24 h urine)
RIA samples had cell counts well above the classically ref- Growth hormone
erenced threshold for successful healing from Hernigou et al Insulin-like growth factor 1 (IGF-1)
of 55,00036; in fact, the average number of cells was over Dehydroepiandrosterone sulfate
300,000, representing a very high volume of liberated pro- Follicle stimulating hormone
genitors. Further studies are underway to improve the ability Luteinizing hormone
to concentrate progenitors liberated from the RIA at the Total estrogen
point of care. Theoretically, surgeons will soon have the Estradiol (E2)
ability to enrich structural and inductive grafts of choice Testosterone
with a large number of endogenous bone-forming Free testosterone
progenitors. Prolactin

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Copyright Ó 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Nauth et al J Orthop Trauma  Volume 32, Number 3 Supplement, March 2018

with one or more metabolic or endocrine abnormalities, 5. Stafford PR, Norris BL. Reamer-irrigator-aspirator bone graft and bi
including vitamin D deficiency, calcium imbalances, central Masquelet technique for segmental bone defect nonunions: a review of
25 cases. Injury. 2010;41(suppl 2):S72–S77.
hypogonadism, thyroid disorders, and PTH disorders.43 6. Sadek AF, Laklok MA, Fouly EH, et al. Two stage reconstruction versus
Patients identified using these criteria should undergo bone transport in management of resistant infected tibial diaphyseal non-
metabolic and endocrine evaluation, with blood and urine union with a gap. Arch Orthop Trauma Surg. 2016;136:1233–1241.
laboratory testing for abnormalities in a defined set of 7. Nauth A, McKee MD, Einhorn TA, et al. Managing bone defects. J
Orthop Trauma. 2011;25:462–466.
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(Table 1). In addition to vitamin D metabolites, PTH, cal- grafting. J Am Acad Orthop Surg. 2005;13:77–86.
cium, and phosphate, the laboratory testing should also 9. Sen MK, Miclau T. Autologous iliac crest bone graft: should it still be the
include stress-related hormones (adrenocorticotropic hormone gold standard for treating nonunions? Injury. 2007;38(suppl 1):S75–S80.
and cortisol), anabolic (dehydroepiandrosterone sulfate and 10. Loeffler BJ, Kellam JF, Sims SH, et al. Prospective observational study
of donor-site morbidity following anterior iliac crest bone-grafting in
growth hormone) and sex (follicle stimulating hormone, orthopaedic trauma reconstruction patients. J Bone Joint Surg Am.
estrogen, estradiol, and testosterone) hormones, thyroid func- 2012;94:1649–1654.
tion tests, and alkaline phosphatase, a marker of bone turn- 11. Ackerman SJ, Mafilios MS, Polly DW, Jr. Economic evaluation of bone
over. A comprehensive endocrine and metabolic profile is morphogenetic protein versus autogenous iliac crest bone graft in single-
level anterior lumbar fusion: an evidence-based modeling approach.
used rather than a few specific metabolic tests so that any Spine (Phila Pa 1976). 2002;27(16 suppl 1):S94–S99.
imbalances can be interpreted in the context of a full profile. 12. Kuehlfluck P, Moghaddam A, Helbig L, et al. RIA fractions contain
Once a patient with a nonunion has been diagnosed mesenchymal stroma cells with high osteogenic potency. Injury. 2015;
with an endocrine or metabolic disorder, treatment should be 46(suppl 8):S23–S32.
performed using a team-based approach. Medical manage- 13. Sagi HC, Young ML, Gerstenfeld L, et al. Qualitative and quantitative
differences between bone graft obtained from the medullary canal (with
ment of all diagnosed endocrine and metabolic disorders a Reamer/Irrigator/Aspirator) and the iliac crest of the same patient. J
should be performed by an endocrinologist with specializa- Bone Joint Surg Am. 2012;94:2128–2135.
tion or experience in metabolic bone disease. Management of 14. Dawson J, Kiner D, Gardner W II, et al. The reamer-irrigator-
the nonunion with operative and nonoperative methods aspirator as a device for harvesting bone graft compared with iliac
crest bone graft: union rates and complications. J Orthop Trauma.
should be performed by an orthopaedic surgeon. In general, 2014;28:584–590.
medical treatment should not inhibit surgical intervention. 15. Zhou S, Greenberger JS, Epperly MW, et al. Age-related intrinsic
However, medical management alone may induce nonunion changes in human bone-marrow-derived mesenchymal stem cells and
healing without surgery by providing a biologic stimulus. In their differentiation to osteoblasts. Aging Cell. 2008;7:335–343.
a group of 31 patients with well-established nonunions and 16. Nauth A, Giannoudis PV, Einhorn TA, et al. Growth factors: beyond
bone morphogenetic proteins. J Orthop Trauma. 2010;24:543–546.
a newly diagnosed metabolic disorder, 8 patients were healed 17. Calori GM, Colombo M, Mazza EL, et al. Incidence of donor site mor-
of their nonunion following medical treatment alone without bidity following harvesting from iliac crest or RIA graft. Injury. 2014;45
operative intervention,43 highlighting the importance of these (suppl 6):S116–S120.
metabolic and endocrine abnormalities for the nonunion 18. Lowe JA, Della Rocca GJ, Murtha Y, et al. Complications associated
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19. Urist MR. Bone: formation by autoinduction. Science. 1965;150:
893–899.
CONCLUSIONS 20. Pieske O, Wittmann A, Zaspel J, et al. Autologous bone graft versus
demineralized bone matrix in internal fixation of ununited long bones. J
The etiology of nonunion is frequently multifactorial, Trauma Manag Outcomes. 2009;3:11.
and often successful treatment requires the assessment and 21. Wilkins RM, Kelly CM. The effect of allomatrix injectable putty on the
management of multiple factors. Infection, metabolic disor- outcome of long bone applications. Orthopedics. 2003;26(suppl 5):
ders, and impaired biology at the fracture site are important s567–s570.
22. Bae HW, Zhao L, Kanim LE, et al. Intervariability and intravariability of
considerations in addition to the mechanical environment. An bone morphogenetic proteins in commercially available demineralized
understanding of the variety of available options for treating bone matrix products. Spine (Phila Pa 1976). 2006;31:1299–1306; dis-
these and the evidence supporting their use is critical to cussion 1307–1298.
success in nonunion management. 23. Friedlaender GE, Perry CR, Cole JD, et al. Osteogenic protein-1 (bone
morphogenetic protein-7) in the treatment of tibial nonunions. J Bone
Joint Surg Am. 2001;83-A(suppl 1):S151–S158.
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J Orthop Trauma  Volume 32, Number 3 Supplement, March 2018 Principles of Nonunion Management

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