Bone Nonunion

Etiology

There is no other section that is more critical to understand than the etiology of bone nonunion, because this is a major determinant of treatment. If one knows the cause of nonunion, one can give proper treatment. As discussed above, nonunion is a multifactorial pathologic process. Patient, biology, fracture type, surgeon, and clinical factors all merit consideration in treatment. The recommendation is to optimize each of these factors during treatment. The major patient factor in nonunion is the blood supply. When a bone has a decrease in blood supply, it cannot heal. This can occur with poor nutrition and smoking from poor living habits. Biologic causes of poor blood flow and poor bone healing include diabetes, peripheral vascular disease, vitamin D deficiency, renal insufficiency, and medications (steroids, NSAIDs, opiates). Treatment may contribute to inadequate fracture fixation or stabilization. Lastly, fracture patterns contributing to nonunion include bone loss with fracture gaps greater than 3 mm, lack of cortical continuity, highly comminuted, and butterfly fragments. Clinical factors at the time of presentation can severely limit blood supply, including high-energy fractures with soft tissue compromise and open fractures.[3][4][5]

The study by Steen et al showed that the most important risk factors for bone nonunion are smoking and diabetes.[6] These factors are important for predicting patient-specific risk of nonunion, determining the best surgical treatment, and enabling a more aggressive surgical plan to prevent nonunion. The fracture type has also been shown in multiple studies to be a major risk factor in nonunion.[6]

Classification of Nonunion of Bone Into 4 Categories:

1. Hypertrophic nonunion

• Shown by radiographically abundant callus formation
• Importantly, there is no bridging bone, and the ends are not united
• This finding implies there is adequate blood supply and biology (with the formation of callus), but inadequate stability

2. Atrophic nonunion

• Evidenced by radiographically absent callus, which indicates poor biology (from 1 or several of the causes above) and a lack of blood supply (see above).
• Inadequate fixation

3. Oligotrophic

• Is a balance and combination of atrophic and hypertrophic in that there is incomplete callus formation
• Inadequate reduction

4. Septic nonunion

• Reduces blood flow from organisms consuming the nutrients to healthy bones
• Decreases the new bone formation [7]

Epidemiology

In the United States, 100,000 fractures go on to nonunion.[8] The rate of all fracture nonunion is between 1.9% to 10%. Variable rates of nonunion exist across anatomic regions. Femoral shaft nonunions are estimated to be 8% overall with the use of intramedullary nailing.[9] Tibial shaft nonunions occur at a rate of 4.6% after intramedullary nailing. However, several studies have reported tibia nonunion rates of 10% to 12% overall.[10] Also, soft-tissue damage impairs healing. Studies of open fractures with extensive soft-tissue compromise showed nonunion rates of 16%.[9] Sex is a predictor of nonunion, showing male gender increases the risk of nonunion, and this was proposed to be because of gender-specific activity types and injury patterns. However, this needs to be taken with caution because larger studies have not replicated these findings. Brown and colleagues reported comparable nonunion rates between males and females at 12%.[10]

Pathophysiology

Several physiologic processes contribute to the development of a nonunion. One, a dysfunctional blood supply decreases the fracture's ability to heal, which, in turn, decreases osteogenic cell activity. Second, damage to the osteoconductive scaffold reduces new bone formation due to the greater distance required for bone healing. Third, the pathological biological processes listed above not only decrease blood flow but also reduce new bone formation by decreasing the biologic growth factors needed for bone healing. Fourth, poor mechanical stability at the fracture site can impair fracture healing.[11] If any of these processes are altered negatively, the risk of nonunion increases dramatically, and patients should be counseled accordingly. 

History and Physical

Given the multiple factors contributing to nonunion, it is important to evaluate all aspects of the patient's history to optimize these factors. Ask about injury mechanisms (open vs closed), type of surgical treatments (plate and screw versus intramedullary nailing). One must evaluate patients' medical history for risk factors, including nutritional status, diabetes, smoking, vascular disease, vitamin D status, renal sufficiency, and use of NSAIDs or steroids. One must evaluate fracture type on radiographs and/or computed tomography (comminution, segmental, infection). Clinically, one must ask the patient whether they experience pain at the fracture site with weight-bearing or ambulation. The physical exam should evaluate signs of infection, such as draining sinus tracts or purulence at the incision. It should include the neurovascular exam and the status of the soft tissues. Also, the physician should try to move the fracture site, as mobility of the fracture site is a major criterion for nonunion.[12]

Summary

• History - open, closed, open reduction internal fixation, intramedullary nail, smoker, diabetes, vascular disease, vitamin D, NSAIDs, steroids
• Radiographs - fracture type, comminuted, segmental, infected
• Physical - pain at the fracture site with weight-bearing, sinus tracts, purulence, and movement at the fracture site

Evaluation

The workup of nonunion is complex and requires a thorough approach. Plain radiographs are the initial test of choice. If dealing with tibia fractures, the RUST (radiographic union score for tibia) score can be calculated. This is a nice objective way to understand the radiographic appearance of nonunion. The score ranges from 4 to 16, with 4 meaning no callus on any of the 4 cortices and 16 meaning complete remodeling of all 4 cortices.[7] Score each cortex separately. A score of 1 equals no evident callus. A score of 2 indicates a callus is present. A score of 3 means the callus is bridging. Finally, a score of 4 indicates bridging of the remodeling bone, with no fracture visible. Add the scores for all cortices to get the final number. Also, one can get a computed tomography scan if the union of the bone on the exam is equivocal. CRP, ESR, and WBC should be evaluated to rule out an infectious process, with findings correlated with the physical exam.[12][13]

Treatment / Management

As with the entire nonunion disease process, treatment requires a multifaceted approach. 

Initial Nonoperative Treatment

• Use of a fracture brace for an extended period of time postoperatively or immobilization in a cast.
• Pulsed low-intensity ultrasound or other external bone stimulation.[14]

Operative Treatment

Treatment is tailored based on the classification of the nonunion. It is important to understand that multiple surgical techniques exist and to use them, tailored to the patient's specific needs.[13][14]

• Hypertrophic nonunion: the goal is to improve mechanical stability with internal fixation
  • Compression plates
  • Exchange nailing
  • Augmented plating with open reduction internal fixation
  • Dynamization of the nail (should not be used in the humerus because dynamization cannot work in a non-weight-bearing limb 

• Atrophic nonunion: the goal is to fix the biology and mechanical stability 
  • Internal fixation with biologic stimulation
    • Biologic stimulation with bone graft
    • Bone morphogenetic protein (BMP):
      • Use of BMP-7 is FDA-approved for tibial nonunions
      • BMP-2 is FDA-approved for 1-level degenerative disk disease in spinal fusion
    • Autologous iliac crest bone graft
    • Intramedullary reaming, irrigation, and debris aspiration
    • Demineralized bone matrix
    • Systemic parathyroid hormone therapy, teriparatide 

• Oligotrophic nonunion: Use a combination of both internal fixation and biologic stimulation, depending on the clinical situation 

• Infected nonunion: Must obtain WBC, ESR, CRP, and nuclear bone scan. Intraoperative cultures are the gold standard for guided antibiotic therapy
  • A 2-staged surgical treatment protocol is the gold standard
    • 1st stage - removal of loose or chronically infected hardware, debridement, and revision fixation of nonunion, and treatment of infection with culture-specific local and systemic antibiotics
      • Modalities used for initial fixation in case of infection
        • Antibiotic beads
        • Antibiotic nails
        • Antibiotic cement spacers
        • Masquelet technique
        • External fixation
        • Soft tissue coverage with a flap
    • 2nd stage
      • Begins after a period of antibiotic therapy when both serologic and clinical signs of infection are absent
      • Definitive fixation proceeds with internal fixation and bone grafting, other biological treatments, and bone transport, depending on specific fracture characteristics. 

Differential Diagnosis

Differential diagnosis for bone nonunion includes: 

• A delayed union requires careful evaluation, as this can change the clinical course and treatment. If a delayed union is suspected, less invasive treatments may be tried first, such as external stimulation (ultrasound, pulsed electromechanical field, or capacitive coupling) or nail dynamization, before pursuing major surgery. 
• Infection

Prognosis

Nonoperative treatments of nonunion can be quite effective. Ultrasound union rates can range from 70% to 93%.[14] The usual course of nonoperative treatment with ultrasound is to place ultrasound therapy within 3 months after the last surgical procedure. Union rates are better when the ultrasound is performed less than 6 months before surgery.[15] The surgical treatment of nonunions has high union rates. Nail dynamization with an 83% union rate.[14] Exchange nailing in humeral shaft fractures has shown a 95.6% union rate.[9] Infected nonunion, however, perturbs a poor prognosis, with most studies showing low union rates after surgical treatment.[9]

Complications

Complications of bone nonunion include:

• Nerve injury, eg, the radial nerve in the humeral shaft fractures
• Persistence of nonunion
• Eventual need for amputation
• Infection with further damage to the surrounding anatomy
• BMP-2 can cause osteolysis, heterotopic bone formation, retrograde ejaculation in spine surgery, and wound complications [16][17]