Fracture healing
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Fracture healing is a complex biological process involving 4 main stages: hematoma formation, soft callus formation, hard callus (bony callus) formation, and remodeling. It occurs through two mechanisms - primary (direct) healing with rigid fixation, and secondary (indirect) healing with callus formation.
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"fracture healing"[MeSH Terms] AND "bone regeneration"[MeSH Terms]
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Fracture Healing
Fracture healing stages with cell types at each phase (Campbell's Operative Orthopaedics, 15th Ed. 2026)
Overview
Fracture healing is a complex biological process requiring the recruitment of appropriate cells (fibroblasts, macrophages, chondroblasts, osteoblasts, osteoclasts) and expression of genes controlling matrix production, growth factors, and transcription factors - at the right time and in the right anatomic location. It initiates a sequence of inflammation, repair, and remodeling that can restore injured bone to its original state within months if each stage proceeds undisturbed. - Campbell's Operative Orthopaedics, 15th Ed.
Two Mechanisms of Healing
Bone can heal by two distinct pathways, and the clinician can influence which pathway occurs through treatment decisions. - Bailey & Love's, 28th Ed.
1. Direct (Primary) Bone Healing
- Occurs under absolute stability with cortical apposition and no movement/gap between fragments
- No callus formation
- Osteoclastic cutting cones cut directly across the fracture line; following osteoblasts lay down lamellar bone across the fracture
- Analogous to normal skeletal remodeling/homeostasis
- Achieved by: compression plating, lag screws
2. Indirect (Secondary) Bone Healing
- The most common form of bone healing
- Involves callus formation - a transition from one tissue type to another
- Requires some movement (strain) at the fracture site - "a little movement is good, too much movement is bad"
- Perren's strain theory: the tissue that differentiates depends on the amount of strain at the fracture site:
- Strain < 100% → fibrous tissue
- Strain < 10% → soft callus
- Strain < 2% → hard callus and progressive mineralization
Stages of Indirect Fracture Healing
| Stage | Timeframe | Key Events | Cell Types |
|---|---|---|---|
| 1. Hematoma Formation | Day 0-3 | Rupture of blood vessels; hematopoietic cells & clots form the initial framework; inflammatory cells invade, initiating lysosomal degradation of necrotic tissue | Monocytes, PMNs, T cells, macrophages, B cells |
| 2. Soft Callus (Granulation Tissue) | Day 3-10 | Pluripotential mesenchymal stem cells invade and differentiate into fibroblasts, chondroblasts, and osteoblasts; angiogenesis occurs; soft cartilaginous callus forms | Stem cells, chondrocytes, osteoblasts |
| 3. Hard Callus (Bony Callus) | Day 10-21 | Cartilaginous callus undergoes endochondral ossification → replaced by woven bone; hypertrophic chondrocytes and osteoblasts are active | Hypertrophic chondrocytes, osteoblasts, hematopoietic cells |
| 4. Remodeling | Day 21+ (months to years) | Woven bone replaced by lamellar bone; medullary canal restored; bone returns to near-normal morphology and mechanical strength; increased bone scan activity long after clinical union | Osteocytes, osteoclasts, osteoblasts |
Four types of new bone formation during repair: osteochondral ossification, intramembranous ossification, appositional new bone formation, and osteonal migration (creeping substitution). - Campbell's
Growth Factors in Fracture Healing
(From Miller's Review of Orthopaedics, 9th Ed.)
| Growth Factor | Key Actions | Notes |
|---|---|---|
| BMP (Bone Morphogenetic Protein) | Osteoinductive; induces metaplasia of mesenchymal cells into osteoblasts | Target = undifferentiated perivascular mesenchymal cells; signals via serine-threonine kinase receptors; intracellular SMADs serve as mediators |
| TGF-β | Induces mesenchymal cells to produce type II collagen & proteoglycans; induces osteoblasts to synthesize collagen | Found in fracture hematomas; regulates cartilage and bone formation in callus; coating implants with TGF-β enhances bone ingrowth |
| IGF-2 | Stimulates type I collagen, cellular proliferation, cartilage matrix synthesis, and bone formation | Signals through tyrosine kinase receptors |
| PDGF (Platelet-Derived Growth Factor) | Chemotactic - attracts inflammatory cells to the fracture site | Released from platelets; signals through tyrosine kinase receptors |
Collagen Types at Each Biochemical Step
| Step | Collagen Type |
|---|---|
| Mesenchymal | I, II, III, V |
| Chondroid | II, IX |
| Chondroid-osteoid | I, II, X |
| Osteogenic | I |
Endocrine Effects on Fracture Healing
| Hormone | Effect | Mechanism |
|---|---|---|
| Cortisone | Negative (-) | Decreased callus proliferation |
| Thyroid hormone, PTH | Positive (+) | Bone remodeling |
| Growth hormone | Positive (+) | Increased callus volume |
| Calcitonin | Possibly positive (+?) | Unknown |
Factors Affecting Fracture Healing
Systemic Factors
- Age, activity level, nutritional status, hormonal factors
- Diseases: diabetes, peripheral vascular disease, malignancy, immunodeficiency
- Vitamin deficiencies (especially D and C)
- Smoking - the most notable inhibitor: delays healing, increases nonunion risk, decreases callus strength, increases pseudarthrosis risk after spinal fusion by up to 500%
Local Factors
- Blood supply and periosteal integrity
- Severity of soft-tissue injury (especially open fractures)
- Neurovascular disruption
- Bone loss, comminution
- Infection
Treatment Factors
- Degree of surgical trauma
- Type of fixation (rigid vs. flexible)
- Fracture distraction/overdistraction
- Load-induced deformation
Drug Effects
- NSAIDs: inhibit COX-2, which is required for normal endochondral ossification - have adverse effects on healing
- Quinolone antibiotics: toxic to chondrocytes, inhibit fracture healing
- Bisphosphonates: theoretically delay healing (suppress bone resorption), but clinical evidence does NOT support harm when started early post-fracture
Terminology of Bone Healing Outcomes
- Union: Fracture has healed sufficiently to withstand physiological loads with minimal pain; radiologically, bone trabeculae cross the fracture site
- Delayed union: Union that takes longer than expected for a particular fracture location
- Malunion: Union occurs but with a residual deformity
- Nonunion: Failure of the fracture to heal
Radioisotope studies show increased activity at fracture sites long after clinical and radiographic union - confirming remodeling continues for years. - Campbell's Operative Orthopaedics
Sources: Campbell's Operative Orthopaedics 15th Ed. 2026 | Bailey & Love's Short Practice of Surgery 28th Ed. | Miller's Review of Orthopaedics 9th Ed. | Rockwood & Green's Fractures in Adults 10th Ed. 2025
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