ARTICLE IN PRESS Current Orthopaedics (2007) 21, 258–261
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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:
[email protected] (V. Perumal),
[email protected] (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
ARTICLE IN PRESS 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
ARTICLE IN PRESS 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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