Continuing Education Activity

The four major factors that influence bone healing are biomechanics, osteogenic cells, scaffolds, and growth factors. In some circumstances, this process does not go as expected, and healing does not occur without additional intervention. A diagnosis of nonunion can typically be made when there is no evidence of progression of the healing process for 3 months or no healing after 9 months from the time of injury. This activity reviews the risk factors, evaluation, and management of tibial nonunion and highlights the role of interprofessional team members in collaborating to provide well-coordinated care and enhance outcomes for affected patients.

Objectives:

• Identify the etiology of tibial nonunion.

• Review risk factors for tibial nonunion.

• Identify management strategies for tibial nonunion.

• Explain modalities to improve care coordination among interprofessional team members in order to improve outcomes for patients affected by tibial nonunion.

Introduction

The process of fracture healing requires a precise balance of biology and stabilization during the healing process. There are four pillars for adequate bone healing: mechanics, osteogenic cells, scaffolds, and growth factors. In some circumstances, this process does not go as expected, and healing does not occur without additional intervention. Definitions vary among different studies, but overall, a diagnosis can be made when there is no evidence of progression of the healing process for 3 months or no healing after 9 months of the injury.[1][2][3][4] This condition will not only have a detrimental effect on the patient’s quality of life, comparable to advanced hip arthrosis and worse than congestive heart failure; but it also has a high impact on the total care costs, double the cost of fractures that heal adequately. Despite the different options available, the treatment of tibial nonunions still is challenging for the surgeon.[1],[2],[3],[5][6]

Etiology

The "diamond concept” was introduced by Giannoudis et al., aiming to describe what is needed to achieve adequate fracture healing.[8][7] This concept highlights the importance of three biological factors: osteogenic cells, osteoconductive scaffolds, and growth factors, and a fourth factor known as mechanical stabilization. If one or more of these factors are altered, adequate fracture healing will be threatened.

Epidemiology

Approximately 6 million fractures are reported per year in the United States. Of these, between 1.9% to 15% result in nonunion. This rate will vary depending on the fractured bone and the characteristics of the fracture (i.e., open vs. closed). In tibial fractures, the rate of non-union is close to 1.1% if treated nonoperatively and nearly 5% if treated operatively.[8][9] The likelihood of nonunion drastically increases in cases of open fractures.[7]

Pathophysiology

As mentioned, an adequate interplay between host biology, reduction technique, and surgical stabilization is the key to achieve fracture healing. The development of a nonunion is multifactorial. Factors that contribute to the development of a nonunion include the following, listed here with known risk factors[8][10][11]:

Fracture and Injury-Related Factors

• High-energy fractures with significant comminution
• Type of fracture (closed/open)
• Location and pattern (highly comminuted or butterfly fragments)
• The extent of soft tissue injury
  • Extensive soft tissue and periosteal stripping increase the risk of nonunion. The inner cambium layer of the periosteum contains osteoprogenitor cells that can contribute to fracture healing. 
  • Reamed intramedullary nails cause injury to the endosteal blood supply. The periosteal blood supply has been shown to increase following reaming.
• Bone loss and fracture gaps (greater than 3 mm) 
• Lack of cortical continuity
• Infection

Biology and Patient-Related Factors (Local and Systemic)

• Smoking (The most significant risk factor) 
• Nutritional status
• Diabetes
• Inadequate blood supply 
• Vitamin D deficiency
• Renal insufficiency
• Medications (steroids, NSAIDs, opiates, etc.)

Surgical-Related Factors

• Inadequate stabilization

• Biological factors are dependent on the patient host and surgical technique.

• Host factors that can affect the biology at the fracture site include the presence of underlying comorbidities (e.g. diabetes), medication (e.g. steroids, non-steroidal anti-inflammatory drugs).

• Nonunions can also be caused by local infection.

History and Physical

The evaluation of patients with a suspected or established nonunion should begin with a thorough review of the medical history so risk factors can be identified. Collect information about the type of fracture, fixation method, and previous treatments. When interviewing patients, they might manifest the persistence of pain at the fracture site and/or functional limitations. One indication that a nonunion is not present is the patient will not have pain with ambulation or when using the extremity. The physical exam should be done in a standard fashion, with an evaluation of the neurovascular status and range of motion. Special attention should be drawn to any signs of infection (skin or soft tissue changes) and mobility at the fracture site, which might indicate the absence of adequate callus formation.[12]

Evaluation

It is challenging to clinically diagnose septic versus aseptic nonunion [13]. As the management varies significantly based on the presence or absence of sepsis, so ruling it out is of prime concern whilst evaluating a case of non-union. In general, patients with a suspected nonunion should be initially evaluated as per the following:

Imaging: plain radiographs, including AP, lateral, oblique, and weight-bearing films. It is important to look for signs (e.g., gaps or callus formation) or absence of healing, bone quality, signs of infection, associated deformities or length discrepancies, as well as the characteristics of the two fragments (i.e., contact, stability, and bone loss). Once this has been done, the nonunion can be adequately categorized as atrophic, hypertrophic, or oligotrophic. If possible, a comparison with original and postoperative follow-up films should be done to create a timeline and a better understanding of the nonunion process [12]. In cases where the fracture site cannot be adequately visualized as a consequence of the hardware or the bone quality, a CT scan is advised. This study will allow better identification of the fracture site and assessment of any rotational deformity. Finally, bone scans can be used to assess bone metabolism.[12] Radiologic studies should be complemented with

Laboratory analysis:

• Basic workup such as complete blood count, C-reactive protein (CRP), and erythrocyte sedimentation rate can be helpful in ruling out an infection, although the borderline elevation in inflammatory markers is often nonspecific [14]. CRP is an acute-phase reactant, which is the most accurate predictor of infection when nonunion is suspected and a helpful prognostic marker when the infection is treated. It significantly rises within 6 hours after the onset of infection or in the setting of tissue damage, then peaks at 48-72 hours and returns to normal levels 5-21 days after infection is treated.
• Evaluation for any associated metabolic diseases and full endocrine profile (i.e., Vitamin D, calcium levels) can guide towards the etiology of the nonunion [12].

The definitive diagnosis of septic nonunion requires isolation of microorganisms from an open tissue biopsy [15]. Swabs are not reliable as they are often [16]contaminated with resident flora [17].

Depending on its cause, nonunion classifications are as follows:

• Septic (infected) or aseptic: Septic tibial non-union can be a spot diagnosis with evidence of discharging sinus, bone exposure, or implant loosening.
• Pseudarthrosis
• Hypertrophic - characterized by inadequate immobilization, but adequate blood supply persists 
• Atrophic - characterized by inadequate immobilization and inadequate blood supply in the early stages of fracture healing 
• Oligotrophic - characterized by inadequate reduction with the persistence of fracture diastasis; no callus can form

Treatment / Management

Treatment of nonunions should aim to achieve healing of the fracture while preserving functionality. The following are available options for the treatment of non-unions[12]:

Nonoperative Treatment

Conservative treatment/weight-bearing: In some circumstances and special patient characteristics (e.g., elderly patients not eligible for operative treatments), nonunions can be treated with weight-bearing and watchful waiting. Weight-bearing can be coupled with operative methods such as dynamization or bone excision.

Electrical stimulator/electromagnetic fields: Growth factors are stimulated in response to the electric and electromagnetic fields.[12][18]

Ultrasound (low-intensity pulsed ultrasound [LIPUS]): Low sine waves will promote bone healing by increasing the osteoblastic response [19]. 

Injection of bone marrow aspirate percutaneously [12]

Extracorporeal shock wave therapy: This was reported to be as equally effective as an operative intervention for cases of stable hypertrophic nonunion [12].

Operative Treatments

Septic versus aseptic non-union is the key variable when planning a surgical strategy to manage a case of tibial non-union, hence intraoperative culture should always be performed to diagnose a subclinical infection. Other variables to consider for management are patient's characteristics, the site of non-union, radiologic findings, presence, or absence of angular or rotational deformities [20]. A staged approach is a gold standard when managing septic tibial nonunions [21][22]. Whilst a single procedure can suffice in managing aseptic tibial non-union [12][23]. 

Single-stage approach: This involves surgical debridement of all non-viable tissues and bone ends, multiple cultures to be taken from the nonunion site or canal reaming followed by revision open reduction and internal fixation or exchange nailing. Antibiotic administration is tailored to culture results and sensitivities [24][25]. When open treatment is essential, autologous bone grafting has been recommended as an adjunct [16]. 

Staged approach: usually indicated for septic tibial nonunion. This involves steps to control infection followed by definitive surgery.

• Debridement: This involves excising all infected tissues e.g sinus tracts, scars, granulation tissue, and devitalized soft tissue. Also, involves removing all loose implants and Opening the medullary canal using both flexible and rigid reamers. Multiple cultures should be taken at this stage and antibiotics tailored based on the sensitivity results.
• Management of bone defects: In tibial nonunion, bone defects are commonly encountered in the anterior and medial aspects with consequent varus and recurvatum deformities. This can be managed by minimal resection followed by telescoping bone. Alternatively, oblique bone ends can be constructed which is amenable to perpendicular compression. Both options achieve stability [26].
• Local antibiotic elution: This can be achieved using antibiotic-impregnated cement as spacers that deliver a significant concentration of antibiotics locally. In the meantime, it blocks any dead spaces [27].
• Definitive Surgery: Aims at the reconstruction of bony defects, managing limb length discrepancy, and achieving bony stability with the consequent union. 

The following are details of operative treatment options and adjuncts reported in the literature:

 Nail dynamization and nail exchange: Nail Dynamization and exchange have two similar indications; comminuted fractures and absence of cortical contact after IM Nail [9].

• Nail dynamization - A relatively low-cost treatment done when axial stability has been achieved and maintained. The dynamization is achieved by removing interlocking bolts distant to the fracture site facilitating compression and loading across the fracture site [12][9][28].
• Nail exchange - Removal of the prior intramedullary nail, reaming until osseous tissue is present in the reaming flutes, and use of a nail with a larger diameter. With this, the reaming process will biologically activate the fracture site, and better axial and mechanical stability can be achieved[28][9]. Reaming has been reported to be a source of multipotent stem cells and growth factors that expedite the healing process [29]. Sharp reamers should be used to reduce the generated heat which could have a deleterious effect on the vitality of the tissues and consequent healing. 

Fibular Osteotomy (Partial fibulectomy): This procedure can be done on its own or most commonly combined with other procedures. This is mainly indicated where the tibial non-union is causing significant malalignment [30]. Two important requisites have to be fulfilled, a stable nonunion and the fibulectomy has to be done in another site different [12]. 

Open Reduction and Internal Fixation with plate and screws: This is an effective procedure in managing non-union especially when intramedullary nailing is contraindicated or not technically possible. Outcomes are equivalent to other methods in terms of successful healing and incidence of complications [31].

Locking compression plates: It is indicated for managing nonunion of the metaphyseal diaphyseal junction fractures, where the outcomes of exchange nailing would be doubtful. The procedure is performed along with bone grafting and without the removal of the underlying nail by gaining unicortical purchase fixation with locking head screws. It has been shown to have predictable good results [32][33][32].

External fixation: Considered in complex nonunions (e.g., when internal fixation is not possible or not recommended due to infection, substantial deformity, and/or bone loss [12][34][12].

Bone grafting: Traditionally, iliac crest bone graft has been used when poor vascular supply is present. This treatment option aims to provide an adequate environment for bone formation (biological factors of the diamond concept).

Cell therapy: The use of mesenchymal cells within the fracture gap creates a healing environment [35][36].

Amputation: Considered when adequate functional outcomes cannot be achieved.

Differential Diagnosis

Delayed unions are fractures with a slow progression to healing and require some type of intervention.

Prognosis

Prognosis of tibial fractures can be evaluated using the RUST (Radiographic Union Score for Tibial fractures) score, in which all the bone cortices are evaluated, looking for the presence/absence of fracture line and bone callus. The Nonunion Risk Determination (NURD) score considered are the RUST scores, open/closed fracture, compartment syndrome, fracture classification (IIIB tibia), concomitant chronic disease, smoking status, infection, female sex, and American Society of Anesthesiologists (ASA) score. This model allows the clinician to identify those patients at risk of nonunion within 3 months of injury [36]. 

The reported average healing time for cases of aseptic tibial nonunion treated with reaming and exchange nailing was from 5 to 9 months [24][37] and the union rates reported to be between 72% and 100% [38].[24]

Consultations

This condition has myriad presentations, and each patient and their expectations are different, so the surgeon must act accordingly. Consult plastic surgery in those cases in which the soft tissue is compromised or a flap is expected and infectious diseases in cases of an infected nonunion. Consult with physical and occupational therapy should be considered, aiming to achieve independence and early range of motion.

Pearls and Other Issues

Keep in mind the "diamond concept." Minimizing the risk of nonunion is based on patient factors and surgeon-related factors (mechanical). The following can help a practitioner avoid additional risk factors to the patient:

1. Achieving adequate stability during the fixation 
2. Minimizing intraoperative trauma (preserve biology) 
3. Not over-distracting the injury
4. Considering biologic enhancement in cases in which it is considered necessary

Enhancing Healthcare Team Outcomes

Non-union of the tibia may occur for many reasons. Thus, these patients are best managed by an interprofessional team that includes an orthopedic surgeon, physical therapist, infectious disease expert, vascular surgeon, plastic surgeon and wound care nurses. [Level V]

This condition has a myriad of presentations, and each patient and their expectations are different, so the surgeon must act accordingly. Consult plastic surgery in those cases in which the soft tissue is compromised or a flap is expected and infectious diseases in cases of an infected nonunion. Consult with physical and occupational therapy should be considered, aiming to achieve independence and early range of motion.