(ii) Factors contributing to non

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Current Orthopaedics (2007) 21, 258–261
Available at www.sciencedirect.com
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MINI-SYMPOSIUM: FRACTURE HEALING
(ii) Factors contributing to non-union of fractures
Venkatachalapathy Perumal, Craig S. Roberts
Department of Orthopaedic Surgery, University of Louisville School of Medicine, 210 East Gray Street,
Suite 1003, Louisville, KY 40202, USA
KEYWORDS
Non-union;
Local factors;
Systemic factors
Summary
Non-union of a fracture can be caused by various factors. This review summarizes current
concepts of systemic conditions (malnutrition, diabetes, nicotine usage, osteoporosis and
non-steroidal anti-inflammatory drugs (NSAIDs) usage) and local factors (infection,
vascularity, biomechanical instability, poor bone contact, iatrogenic factors and magnitude
of injury) that may be of etiological relevance. Key points for assessing non-unions include
checking for malnutrition and peripheral neuropathy, advising smoking cessation, avoiding
NSAIDs, and identifying clinical and radiological signs of delayed healing at the earliest
possible instance. The prevention of non-union is preferable to the treatment of nonunion.
& 2007 Elsevier Ltd. All rights reserved.
Introduction
There is no universal definition of fracture non-union. The
traditionally generally accepted definition is of an interval
of at least 9 months from the time of fracture without
fracture healing, during which multiple therapeutic measures have been tried. Waiting the traditional 9 months to
diagnose a non-union is unrealistic and is associated with
prolonged morbidity, inability to return to work, narcotic
dependence and emotional impairment. Non-union of
fractures is a multifactorial phenomenon. This review
summarises current concepts and understanding of factors
which contribute to the non-union of fractures. We review
systemic conditions (malnutrition, diabetes, nicotine usage,
Corresponding author. Tel.: +1 502 852 6964;
fax: +1 502 852 7227.
E-mail addresses: drvenkat_perumal@yahoo.co.in (V. Perumal),
craig.roberts@louisville.edu (C.S. Roberts).
0268-0890/$ - see front matter & 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.cuor.2007.06.004
osteoporosis and nonsteroidal anti-inflammatory drug
(NSAID) usage) and local factors (infection, vascularity,
biomechanical instability, poor bone contact, iatrogenic
factors and magnitude of injury) (Table 1).
Systemic medical conditions
Malnutrition and vitamin deficiency
Patients with long bone fractures have increased rates of
catabolism and significant urinary protein loss that may lead
to negative nitrogen balance. Protein malnutrition affects
callus composition rather than size early in the process of
fracture healing.1 Histological and mechanical testing shows
that malnutrition negatively affects early callus composition.1 Guarniero et al.2 also showed the beneficial effects of
protein nutritional support on the healing of long bone
fractures. Protein malnutrition affects both membranous
and endochondral bone formation. Protein deficiency has
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Factors contributing to non-union of fractures
Table 1
Etiology of non-union.
Local causes
Systemic causes
Infection
Malnutrition and vitamin
deficiency
Systemic medical
conditions
Smoking
Metabolic bone disorders
Medications
Mechanical instability
Inadequate vascularity
Poor bone contact
Iatrogenic
Magnitude of injury
a negative effect on early proliferation and differentiation
events of those cells required for fracture repair.
Vitamin B6 deficiency causes changes in bone which
causes imbalance in the coupling between osteoblasts and
osteoclasts, as a result of marked diminution of Glucose-6
phosphate deficiency (G6PD) activity in the periosteal region
of the bone formation and in the developing callus, which
significantly delays the maturation of the callus and union.3
This suggests vitamin B6 status may be important in fracture
healing deficiency.
Diabetes
Perlman and Thordarson4 studied 88 patients with ankle
fusions and showed a 28% non-union rate in patients who had
diabetes. Sensory neuropathy was implicated as a possible
cause of non-union. Morgan et al.5 reported a 95% arthrodesis rate and failed to obtain fusion only in those patients
noted preoperatively to have a neuropathy. Frey et al.6 also
concluded that diabetes contributed to non-union of ankle
fusions.
Cigarette smoking and nicotine usage
Although some studies show no clear association between
smoking and bone mass, there is overwhelming evidence of
an increased incidence of osteoporosis and osteoporotic
fractures in patients who smoke cigarettes. There is a 5–10%
bone density deficit in patients who smoked compared with
patients who were non-smokers.
Human studies of the effect of smoking on bone healing
focuses on spinal fusion. Brown et al.7 found a 40%
pseudarthrosis rate in patients who smoked and an 8%
pseudarthrosis rate in those who did not smoke. The
difference was attributed to a mean peripheral oxygen
saturation of 78.5% in the individuals who smoked versus a
mean peripheral oxygen saturation of 92.9% in those who did
not smoke. Schmitz et al.,8 in their study with a follow-up of
146 patients with closed and grade I open tibial fractures,
showed a 69% delay in radiographic union in the group of
individuals who smoked. In a double-blind, prospective
randomized study using a rabbit model, Wing et al.9
demonstrated that chronic nicotine exposure was associated
with decreased spinal fusion rates. Discontinuing smoking
before surgery improved fusion rates. McKee et al.10 showed
a higher rate of non-union in smokers who underwent
Ilizarov limb reconstruction. Chen et al.11 reported that 30%
259
of patients who smoked had delayed union or non-union
after ulnar shortening osteotomy. Nicotine inhibits alkaline
phosphatase and collagen production and stimulates deoxyribonucleic acid synthesis, possibly secondary to increased
cell death and turn over. Cigarette smoking has been shown
to decrease collagen deposition by 30–50%. Feitelson et al.12
showed that 2 weeks of nicotine treatment caused
decreased bone blood flow.
Osteoporosis
The relationship between fracture healing and osteoporosis
is complex, and the available clinical evidence is inconclusive. Animal research on oophorectomized rats has shown
significant reductions in bone mass and delay in fracture
healing. Available evidence suggests that altered bone
metabolism in osteoporosis seems to delay callus maturation
and decelerate fracture healing.13
Nonsteroidal anti-inflammatory drugs
NSAIDs inhibit osteogenic activity and fracture healing.
Glassman et al.,14 in a retrospective review of 228 patients
who underwent instrumented spinal fusion, reported an
odds ratio with a five-fold increased chance of non-union
with NSAIDs. The pathogenesis of NSAID-inhibiting osteogenesis is not clearly understood. Animal studies show reversibility of NSAID effects when prostaglandin E2 levels are
gradually restored after short-term treatment.15 Late
exposure to NSAIDs, 61–90 days after a humeral shaft
fracture, was associated with non-union.16 There is a
correlation between the use of NSAIDs and non-union,
especially when NSAIDs are used for more than 4 weeks.17
In this series, 70% of patients with non-union had taken
NSAIDs. Although all NSAIDs inhibit fracture healing,
cyclooxygenase-2 (Cox-2 inhibitors) have been shown to
inhibit fracture healing more than the less specific NSAIDs.15
Current evidence suggests that avoidance of NSAIDs in the
post-operative and post-injury period may prevent nonunions.
Local factors
Infection
Although bone infection does not cause non-union per se, it
can contribute to fracture non-union through bone death
because of pus, the creation of gaps by osteolytic infectious
granulation tissue, and motion from loosening of prosthetic
implants. The inflammatory response to bacteria at the site
of the fracture disrupts callus, increases gaps between
fragments, and increases motion between fragments, which
cause fracture union to fail. Infection causes decreased
bone quality, which can cause fixation devices to loosen,
thereby causing non-union.
Inadequate vascularity
The extent of vascular damage is directly correlated with
failure of skeletal repair. However, the exact mechanisms
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260
underlying ischemia-related effects on bone healing are not
well understood. Lu et al.,18 in an animal study, found that
ischemia at the fracture site decreased the amount of bone
formation. Reed et al.19 demonstrated that the number of
blood vessels in atrophic non-unions was significantly fewer
than in a normal healing group, and concluded that early
diminished vascularity may prevent fractures from uniting.
Insufficient vascularity is one of the potential causes of nonunion, and in particular diminished vascularity in the
interfragmentary gap in the first 3 weeks after fracture
may prevent fracture union. Loss of blood supply occurs in
open fractures as a result of the loss of the soft tissue
envelope and damage to nutrient vessels. Karladani et al.20
showed that the risk of developing non-union was higher in
patients with open fractures than those with closed
fractures. The rate of non-union in type III open tibial
fractures was 20–30%.
Biomechanical instability
The stability of fracture fixation and the resulting mechanical conditions existing at the fracture site influence
fracture repair. The size of the fracture callus is a function
of both the magnitude and frequency of interfragmentary
motion. Differentiation of mesenchymal cells towards either
an osteoblast or chondrogenic cell line is dependent on
fracture stability. Epari et al.21 showed that less rigid
fixation increased the time required for the healing of
fractures. Lienau et al.22 also showed initial mechanical
stability to the fracture led to increased vascularity and
tissue differentiation, early callus formation and faster
fracture union.
V. Perumal, C.S. Roberts
fractures. Fracture distraction more than 3 mm during
stabilization of tibial fractures increases four-fold the odds
of developing a non-union.24
Magnitude of injury (high versus low energy)
The magnitude of energy causing a fracture is a good
predictor of fracture healing.20 In a review of 104 tibial shaft
fractures, the positive predictive value of high-energy
trauma (grade III open fractures) for non-union was 26%,
and it was concluded that fractures caused by high-energy
trauma are more likely to develop non-union. Displacement
of the fracture fragments noted radiographically is also a
good indicator of the degree of soft tissue injury. Displacement of the fracture fragments by more than the diameter
of the bone, in distraction or translation, will be associated
with excessive periosteal stripping, diminished vascularity
and thus non-union risk.
Practice points
Check for malnutrition when treating fractures
Check for peripheral neuropathy due to diabetes
Advise smoking cessation
Avoid NSAIDs following fractures
Identify clinical and radiological signs of delayed
healing of fractures
Inform patients of the risk factors of fracture nonunion
Non-union of fractures cannot be prevented in all
cases
Poor bone contact
Bone-to-bone contact is an important requirement for
fracture healing. Poor bone-to-bone contact compromises
the mechanical stability and creates a defect that the
fracture repair process must bridge. Small defects produce
high strain at the fracture site.23 Although osteoblasts do
not tolerate high-strain environment, such environments
can be good for chondroblasts and fibroblasts. Larger
defects have low strain and do not promote osteoblastic
activity. The amount of strain over the fracture site to
produce osteoblastic activity remains unknown. The maximal bridging of a cortical defect through direct osteonal
healing is about 1 mm in animal studies. Poor bone-to-bone
contact at the fracture site may result from various factors
including soft tissue interposition, malposition or malalignment of fracture fragments, bone loss, and distraction of the
fracture fragments. As the defect increases in size, the
chances of fracture union decrease.
Iatrogenic factors
Excessive stripping of the periosteum and damage to the
bone and soft tissue blood supply during implant or fixation
device insertion can decrease vascularity at the fracture site
and contribute to non-union. Intramedullary nailing in
distraction of the fracture site increases the gap between
the fracture fragments and contributes to non-union of
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