Nonunion Management

Nonunion is defined as a fracture that will not heal without intervention (typically no radiographic progress for 3 months and greater than 9 months from injury). The Weber-Cech classification distinguishes hypertrophic (elephant foot/horse hoof with abundant callus - mechanical failure requiring stability) from atrophic (no callus, avascular ends - biological failure requiring bone graft and stability). All nonunions must have infection excluded (CRP, ESR, aspirate/biopsy for culture). The Diamond Concept guides treatment: optimise cells (osteogenic cells), scaffolds (bone graft), growth factors (BMP), and mechanical stability. Key: hypertrophic just needs compression plating; atrophic needs resection of avascular ends plus biological augmentation.

Nonunion is defined as a fracture that will not heal without intervention. Often defined as no radiographic progress for 3 consecutive months and at least 9 months from injury.

Weber-Cech Classification

Viable (Vascular) Nonunion:

• Hypertrophic (Elephant foot): Abundant callus, very vascular. Mechanical failure.
• Slightly Hypertrophic (Horse hoof): Less callus but some biological activity.

Non-viable (Avascular) Nonunion:

• Oligotrophic: Minimal callus, bone ends present but inactive.
• Atrophic: No callus, avascular ends. May be comminuted or with bone loss.

Normal Fracture Healing Process

Normal fracture healing proceeds through overlapping phases:

1. Inflammation (Days 1-7): Hematoma formation, inflammatory cells, cytokines (IL-1, IL-6, TNF-α)
2. Soft callus (Weeks 1-4): Chondrogenesis, fibrous callus formation
3. Hard callus (Weeks 4-12): Woven bone replaces cartilage (endochondral ossification)
4. Remodeling (Months to years): Woven bone replaced by lamellar bone, cortical restoration

Why Nonunion Develops

Nonunion occurs when the normal healing cascade is disrupted by mechanical or biological factors:

Mechanical Factors (Hypertrophic Nonunion):

• Excessive motion at fracture site prevents bridging
• Inadequate fixation (undersized nail, loose screws, plate failure)
• Distraction (gap greater than 2mm impairs bridging)
• Biology is intact (abundant callus visible), but instability prevents consolidation

Biological Factors (Atrophic Nonunion):

• Vascular disruption: Severe soft tissue injury (Gustilo IIIB/C), stripping of periosteum during surgery
• Avascular bone: Scaphoid waist, femoral neck (intracapsular), talus body
• Infection: Low-grade biofilm infection suppresses osteoblast function
• Metabolic: Diabetes, smoking (nicotine vasoconstriction), malnutrition, Vitamin D deficiency
• Medications: NSAIDs (inhibit COX-2 needed for bone healing), corticosteroids (impair osteoblast function)

The Diamond Concept

Giannoudis et al (2007) proposed the "Diamond Concept" - healing requires optimization of all four elements:

1. Osteogenic cells (MSCs, osteoprogenitor cells from periosteum, bone marrow, circulation)
2. Osteoconductive scaffold (bone graft matrix, collagen, HA/TCP ceramics)
3. Osteoinductive signals (BMPs, PDGF, TGF-β, VEGF)
4. Mechanical stability (absolute or relative depending on healing mechanism)

Fifth element (added later): Vascularity - adequate blood supply for oxygen, nutrients, cell delivery

Atrophic nonunion fails on biology (elements 1-3, 5). Hypertrophic nonunion fails on mechanics (element 4).

Infection and Nonunion

Biofilm formation:

• Bacteria (especially Staphylococcus epidermidis, Propionibacterium acnes) form biofilm on implants/bone
• Biofilm protects bacteria from antibiotics and immune system
• Bacterial toxins and inflammatory cytokines inhibit osteoblast function
• Result: Infected nonunion - will not heal without infection eradication

Clinical clue: Any nonunion with persistent pain, elevated CRP/ESR, or sinus drainage should be cultured.

History

Patient presents months to years after initial fracture with:

Pain:

• Persistent pain at fracture site despite "adequate" healing time
• Pain with weight-bearing or activity (mechanical pain suggests instability)
• Constant pain or night pain (suggests infection or severe instability)

Functional Impairment:

• Unable to return to work or activities of daily living
• Ongoing use of walking aids (crutches, walker)
• Reduced range of motion of adjacent joints

Timeline:

• Typically greater than 9 months from injury
• No radiographic progression over 3 consecutive months (FDA definition)
• History of previous failed treatments (may have had bone grafting, revision fixation already)

Risk Factors to Elicit:

• Smoking (2-3x higher nonunion risk - dose dependent)
• NSAIDs (particularly high-dose, prolonged use post-fracture)
• Diabetes mellitus (especially if poorly controlled, HbA1c greater than 8%)
• Malnutrition (low albumin, low Vitamin D)
• Osteoporosis or metabolic bone disease
• Corticosteroid use (chronic, greater than 7.5mg prednisolone daily)
• Severe soft tissue injury at time of original fracture (Gustilo III open fracture)

Examination

Inspection:

• Muscle atrophy of limb (chronic disuse)
• Scars from previous surgeries
• Sinus tract (pathognomonic for infection if present)
• Swelling, erythema (infection)
• Malalignment (varus/valgus deformity, rotational)

Palpation:

• Tenderness at nonunion site
• Palpable gap or instability (if implants failed)
• Warmth (infection)

Movement:

• Abnormal motion at fracture site (should be stable if healed)
• Pain with stress (axial loading, bending, rotation)
• Adjacent joint stiffness (compensatory, prolonged immobilization)

Neurovascular Exam:

• Check for nerve injury from previous surgery or chronic hardware irritation
• Assess vascular status (chronic injury may have vascular compromise)

Red Flags for Infection

• Draining sinus
• Persistent pain despite apparently stable fixation
• Multiple failed surgeries without union
• Elevated inflammatory markers (CRP, ESR) at presentation
• Previous open fracture (Gustilo II/III)

Imaging

Plain Radiographs:

• Orthogonal views (AP and lateral minimum)
• Look for:
  • Callus formation (hypertrophic vs atrophic vs oligotrophic)
  • Fracture line visibility (persistent gap, sclerosis of bone ends)
  • Hardware position (loose screws - lucency around threads, broken plate/screws, nail backing out)
  • Alignment (varus/valgus, angulation, rotation, shortening)
  • Bone stock (comminution, bone loss, osteopenia)

CT Scan:

• Best for assessing bone healing (more sensitive than X-ray for cortical bridging)
• 3D reconstruction helps surgical planning (visualize deformity, bone stock, implant position)
• Identify sequestrum or bone loss in infected cases

MRI:

• Assess for infection (bone marrow edema, fluid collections, sinus tracts, soft tissue abscess)
• Evaluate vascularity of bone ends (signal characteristics)
• Less useful for bony detail than CT

Nuclear Medicine:

• Bone scan (Tc-99m MDP): High sensitivity but low specificity (increased uptake at nonunion regardless of infection)
• White cell scan (In-111 WBC) or FDG-PET: More specific for infection
• Not routinely needed - reserve for difficult cases where infection suspected but cultures negative

Laboratory Investigations

Exclude Infection (Essential):

• CRP (C-reactive protein): Elevated suggests infection (though may be mildly elevated in chronic nonunion without infection)
• ESR (erythrocyte sedimentation rate): Less specific, but persistently elevated concerning
• WBC count: Usually normal in chronic low-grade infection
• Tissue culture: Gold standard
  • CT-guided biopsy or aspiration of nonunion site
  • Minimum 5 tissue specimens (not swabs!)
  • Prolonged culture (14 days) to catch slow-growing organisms (Propionibacterium, Cutibacterium)

Assess Metabolic/Nutritional Status:

• Vitamin D (25-OH Vitamin D): Target greater than 75 nmol/L for optimal bone healing
• Calcium, phosphate, alkaline phosphatase, PTH: Screen for metabolic bone disease
• Albumin, pre-albumin: Markers of nutritional status (low albumin = poor healing)
• HbA1c: If diabetic, target less than 7% for healing
• Thyroid function (TSH, free T4): Hyperthyroidism impairs healing

Specialized Tests (If Indicated):

• DEXA scan: Assess bone mineral density (osteoporosis)
• Bone turnover markers: CTX (resorption), P1NP (formation) - research use
• Genetic testing: Rare cases (osteogenesis imperfecta, hypophosphatasia)

Exclude Infection

Essential in all nonunions.

• Bloods: CRP, ESR, WCC
• Aspiration/biopsy: Culture (prolonged incubation for low-grade organisms)
• Imaging: MRI may show sequestrum, fluid collections

If infected nonunion: Treatment is different (debridement, antibiotic course, then reconstruction).

Address Modifiable Factors

• Smoking cessation (roughly doubles nonunion risk; cease at least 4 weeks pre-op)
• Optimize nutrition (protein, vitamins)
• Control diabetes (HbA1c)
• Avoid NSAIDs (may impair healing)

Differential Diagnosis of the Painful, Non-progressing Fracture

The pattern on imaging and inflammatory markers points to the diagnosis and dictates very different treatment.

Nonunion management carries several genuinely unresolved debates that examiners use to separate safe from outstanding candidates.

• Definition and timing. The "9 months plus 3 months without progression" FDA wording is a regulatory construct, not a biological truth. Many surgeons now diagnose nonunion functionally when union is not expected to occur without intervention regardless of an arbitrary calendar threshold, and tools such as the RUST/RUSH radiographic scores are increasingly used to quantify progression.
• Reamed versus unreamed exchange nailing. Reaming delivers local autograft and a larger, stiffer nail, but the thermal and vascular cost in a compromised diaphysis is debated; the benefit is clearest in hypertrophic patterns and least convincing in atrophic biology.
• rhBMP-2: efficacy versus harm and cost. Despite the BESTT data, routine use in long-bone nonunion is off-label, expensive and associated with heterotopic ossification and inflammatory swelling. Enthusiasm has cooled, and many units reserve it for salvage or graft-volume problems rather than first-line use.
• Masquelet versus distraction osteogenesis (bone transport). For segmental loss there is no high-quality head-to-head trial. Masquelet offers a shorter, more predictable timeline; bone transport avoids large graft harvest and corrects length/deformity but carries prolonged frame time and a high pin-site burden. Choice remains surgeon- and patient-specific.
• Biophysical adjuncts. Low-intensity pulsed ultrasound (LIPUS) and pulsed electromagnetic fields are widely marketed, but large pragmatic trials (e.g. the TRUST trial of LIPUS in tibial fractures) showed no clinically important benefit, so they are not a substitute for addressing stability and biology.
• When to stop limb salvage. The threshold for converting to amputation after repeated failed reconstructions is value-laden; modern prosthetics and shared decision-making mean amputation is a legitimate, sometimes superior, functional choice rather than a failure.

Global Epidemiology

• Tibial shaft fractures carry the highest long-bone nonunion rate; pooled prevalence is approximately 7% (Tian et al, 2020), rising sharply with open, high-energy and Gustilo IIIB/IIIC injuries.
• Smoking roughly doubles nonunion risk worldwide (OR ~2.5); diabetes, NSAID use, BMI over 40, age over 60 and infection are consistent global risk factors.
• In limited-resource settings, delayed presentation, open injuries from road traffic trauma, and constrained access to implants and microsurgery shift the burden toward established and infected nonunion.

Guidelines & Society Positions, Side by Side

Where guidance genuinely converges: exclude infection in every nonunion, correct the dominant deficit (mechanics vs biology), optimise modifiable host factors, and refer complex segmental or infected cases to units with limb-reconstruction and orthoplastic capability.

Registry & Outcome Evidence

• Arthroplasty-style national registries (NJR, AJRR, AOANJRR, Swedish/Norwegian) do not track diaphyseal nonunion directly, but trauma and fracture-outcome datasets consistently identify open tibial fractures, infection and smoking as the dominant drivers of revision for nonunion.
• Reported union rates: reamed exchange nailing ~90% in selected aseptic tibial nonunion; induced membrane technique ~84-90% across long bones and tibia-specific series.

Practice Variation by Resource Setting

• High-resource: routine deep-tissue culture with prolonged incubation, RIA autograft, antibiotic-loaded cement spacers, rhBMP-2 as off-label salvage, microvascular free fibula, and circular frames available.
• Limited-resource: reliance on iliac crest autograft, conventional external fixation and bone transport over costly biologics; emphasis on infection control, soft-tissue coverage and modifiable-factor optimisation. Antibiotic cement spacers (gentamicin/vancomycin-loaded PMMA) remain a low-cost, widely applicable standard for staged infected-nonunion care.
• Antibiotic principles (global): empiric cover then de-escalation guided by deep-tissue culture and sensitivities, typically around 6 weeks of targeted therapy before definitive reconstruction in infected nonunion, in conjunction with infectious-diseases input.