Bone Structure and Healing: Cortical vs Cancellous, Fracture Healing, Callus, and Influencing Factors

Bone Anatomy: Structural Compartments

Cortical vs Cancellous Bone

• The diaphysis encompasses the bone shaft between the proximal and distal metaphyses and is composed of dense cortical bone surrounding a medullary canal
• The metaphysis is located between the epiphysis and diaphysis, has thinner cortical bone, and surrounds a core of cancellous bone
• The epiphysis comprises the region between the physis (physeal scar) and the articular surface
• The difference in vascularity between cortical diaphysis and cancellous metaphysis directly affects the rate of fracture healing at each site
• The odontoid dens is a clinically relevant example: it has limited cancellous bone and blood supply, making type II odontoid fractures prone to nonunion, particularly in adults over 50 years

Clinical Relevance of Bone Composition: Graft Material

• Autograft (e.g. iliac crest) is a source of both cortical and cancellous bone
• Cancellous autograft provides osteoblasts and scaffolding for rapid incorporation
• Cortical autograft provides structural support but incorporates more slowly
• Allograft provides a bridge for host osteoblasts and promotes fusion but lacks the osteogenic cells of autograft

Fracture Classification

• Fractures are defined as loss of bone integrity and are among the most common pathological conditions affecting bone
• Imaging must include the whole bone involved; views must include AP and an appropriate lateral
• CT scan is often required for complex anatomy and surgical planning

Fracture Healing: Overview of Mechanisms

Primary vs Secondary Bone Healing

• A fracture held in direct anatomic apposition with rigid fixation across a joint would heal by primary bone union without callus
• A traditional cast on the tibia provides only relative stability and leads to healing with callus
• The local mechanical environment must achieve a strain at or below 2% before bone can form; this is achieved either by progressive tissue stiffening through the natural healing response or by the stability conferred by an orthopaedic implant

Zones and Stages of Fracture Healing

Stage 1: Haematoma and Inflammatory Phase

• Immediately post-fracture, blood accumulates at the fracture site forming a haematoma
• The haematoma also contains devitalised soft tissue, dead bone, and necrotic marrow
• The next stage involves liquefaction and degradation of all nonviable products at the fracture site
• This inflammatory reaction is the foundation upon which subsequent healing proceeds

Stage 2: Soft Callus (Procallus) Formation

• Activated osteoprogenitor cells and soft tissue mesenchymal cells proliferate at the fracture site
• Mesenchymal cells may differentiate into chondrocytes that produce fibrocartilage and hyaline cartilage
• This forms the procallus, which provides some anchorage but not structural rigidity for weight bearing
• The procallus bridges the fracture gap and sets the stage for mineralisation

Stage 3: Hard (Bony) Callus Formation

• Within 2 weeks of injury, activated osteoprogenitor cells deposit subperiosteal trabeculae of woven bone oriented perpendicular to the cortical axis
• Woven bone is also deposited within the medullary cavity
• These processes transform the procallus into bony callus
• Endochondral ossification of the cartilaginous components creates a contiguous network of bone and newly deposited trabeculae
• Bony callus reaches maximal girth at the end of the second or third week and helps to stabilise the fracture site

Stage 4: Consolidation and Union

• By approximately 2 to 3 months, the process leads to complete bony union
• The bone is considered strong enough to allow weight bearing and will appear healed on radiographs

Stage 5: Remodelling

• The excessive callus is reabsorbed and the marrow cavity is recanalized
• Remodelling restores the correct transmission of forces and the contours of the bone
• This is analogous to dermal wound remodelling and is an ongoing, prolonged process

Molecular Mediators of Bone Healing

• Fracture healing is mediated by soluble growth factors and cytokines
• The most extensively studied are bone morphogenetic proteins (BMPs), which belong to the TGF-$\beta$ superfamily
• BMPs stimulate the differentiation of mesenchymal cells into chondrocytes and osteoblasts
• Additional relevant mediators include VEGF, which promotes angiogenesis critical to bone repair
• RANK, RANKL, and OPG are key regulators of osteoclast activity and therefore bone remodelling; polymorphisms in these genes influence bone density and healing capacity

Stability and the Mechanical Environment of Healing

• The healing sequence in a mechanically unstable skeleton progresses: inflammatory reaction $\rightarrow$ fibrous tissue $\rightarrow$ cartilage formation $\rightarrow$ immature (woven) bone $\rightarrow$ mature remodelled bone
• A number of biologic stimulatory molecules and specific mechanical features drive the normal healing response
• There is progressive stiffening of the fracture environment until local strain falls to ≤2%, at which point bone formation can occur
• This threshold may be reached by:
  • The natural tissue stiffening sequence (secondary healing)
  • An orthopaedic implant creating an appropriate local strain environment in conjunction with fracture anatomy and intrinsic fracture stability (primary healing)

Dead Bone and Scaffold: Pathological Relevance

• Dead bone is characterised microscopically by empty lacunae surrounded by necrotic adipocytes
• Released fatty acids from necrotic adipocytes bind calcium and form insoluble calcium soaps
• Remaining trabeculae act as scaffolding for deposition of new bone
• Osteoclasts resorb necrotic trabeculae
• In subchondral bone infarcts, the slow pace of substitution results in collapse of necrotic bone, fracture, and sloughing of articular cartilage
• Articular cartilage over necrotic subchondral bone remains viable due to nutrients within synovial fluid

Complications of Fracture Healing

Nonunion

• Diagnosed before 6 months and commonly suggested by:
  • Persistence of pain on loading
  • Failure of progression of bone healing on radiograph
• Clinically relevant example: the scaphoid bone has significant risk of nonunion even when nondisplaced, due to its tenuous blood supply
  • Any patient with tenderness at the anatomic snuffbox should be placed in a thumb spica splint and re-evaluated within 2 weeks, even with normal initial X-rays
• Fibrous nonunion can occur in spinal fusion when arthrodesis fails; long-term stability requires ingrowth of new bone by the patient's osteoblasts across the unstable defect

Malunion

• Assessed with regard to the specific functional problem produced
• May require corrective surgery for limb alignment, joint function, or longevity

Infection

• Infection after fracture creates a situation similar to osteomyelitis
• Infection and failure of bone healing commonly occur together
• These complications are minimised by good primary fracture care but can still occur and often require specialist management

Factors Affecting Fracture Healing

Patient-Specific Factors

Mechanical and Fracture-Specific Factors

• Fracture pattern: comminuted or displaced fractures are harder to reduce and stabilise, impairing healing
• Stability of fixation: more stable fixation (rigid internal fixation) reduces strain and promotes primary healing; less stable (cast) permits micromotion and secondary healing with callus
• Fracture site anatomy: metaphyseal fractures heal faster than diaphyseal fractures due to vascularity
• Soft tissue envelope: compound fractures with communication to the skin surface increase infection risk and impair healing

Hormonal and Systemic Factors

• PTH: excessive PTH (primary or secondary hyperparathyroidism) leads to unrestrained osteoclast activity, bone resorption, cyst formation, and pathological fractures, impairing the healing environment
• Oestrogen: oestrogen receptor gene polymorphisms affect bone density; oestrogen deficiency (as in post-menopausal women) reduces bone mass and healing potential
• Bisphosphonates: used for osteoporosis but associated with altered bone turnover; chronic use is relevant to bone healing and atypical fracture risk

Growth Factors and Biologics

• BMPs (TGF-$\beta$ superfamily): stimulate mesenchymal cell differentiation into chondrocytes and osteoblasts; most extensively studied promoters of bone healing
• VEGF: promotes angiogenesis; therapeutic restoration of VEGF in animal models significantly improves repair outcomes
• Stem cell-based therapies: endothelial progenitor cells and bone marrow-derived multipotent stem cells have shown promising outcomes in non-healing contexts both in animal studies and early clinical trials

Key Clinical Pearls

• Callus is the hallmark of secondary (indirect) bone healing and is promoted by relative stability (e.g. cast); its absence under rigid fixation is expected and does not indicate failure
• The mechanical environment is the fundamental driver of which healing pathway is followed: strain >2% prevents bone formation; progressive tissue stiffening or implant stability reduces strain to the threshold needed
• Maximal callus girth is reached at the end of weeks 2 to 3 post-injury
• Complete bony union and radiographic healing typically occur by 2 to 3 months, followed by the prolonged remodelling phase
• Sites with limited cancellous bone and blood supply (scaphoid, odontoid dens) are at high risk of nonunion and require early immobilisation and close follow-up
• Infection and nonunion frequently co-exist after fracture and mimic the pathophysiology of chronic osteomyelitis