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Updated: Sep 12 2023

Fracture Healing

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  • Introduction
    • Fracture healing involves a complex and sequential set of events to restore injured bone to pre-fracture condition
      • stem cells are crucial to the fracture repair process
        • periosteum and endosteum are the two major sources
    • Fracture stability dictates the type of healing that will occur
      • mechanical stability governs the mechanical strain
      • when the strain is below 2%, primary bone healing will occur
      • when the strain is between 2% and 10%, secondary bone healing will occur
    • Modes of bone healing
      • primary bone healing (strain is < 2%)
        • intramembranous healing
          • occurs via Haversian remodeling
        • occurs with absolute stability constructs
      • secondary bone healing (strain is between 2%-10%)
        • involves responses in the periosteum and external soft tissues.
          • endochondral healing
            • occurs with non-rigid fixation, as fracture braces, external fixation, bridge plating, intramedullary nailing, etc.
      • bone healing may occur as a combination of the above two process depending on the stability throughout the construct
      • Type of Fracture Healing with Treatment Technique
      • Cast treatment
      • Secondary: endochondral ossification
      • External fixation
      • Secondary: endochondral ossification
      • IM nailing 
      • Secondary: endochondral ossification
      • Compression plate
      • Primary: Haversian remodeling
  • Secondary Bone Healing
      • Stages of Fracture Healing
      • Inflammation
      • Hematoma forms and provides a source of hematopoietic cells capable of secreting growth factors.
      • Macrophages, neutrophils, and platelets release several cytokines
      •     this includes PDGF, TNF-Alpha, TGF-Beta, IL-1,6, 10,12
      •     they may be detected as early as 24 hours post-injury
      •     lack of TNF-Alpha (ie. HIV) results in delay of both endochondral/ intramembranous ossification
      • BMPs, fibroblasts and mesenchymal cells migrate to fracture site and granulation tissue forms around fracture ends
      •     During fracture healing granulation tissue tolerates the greatest strain before failure
      • Osteoblasts and fibroblasts proliferate
      •     Inhibition of COX-2 (ie NSAIDs) causes repression of runx-2/osterix, which are critical for differentiation of osteoblastic cells
      • Repair
      • Primary callus forms within two weeks. If the bone ends are not touching, then bridging soft callus forms.
      •     The mechanical environment drives differentiation of either osteoblastic (stable enviroment) or chondryocytic (unstable environment) lineages of cells
      • Endochondral ossification converts soft callus to hard callus (woven bone).
      • Medullary callus also supplements the bridging soft callus
      •     Cytokines drive chondocytic differentiation.
      •     Cartilage production provides provisional stabilization
      • Type II collagen (cartilage) is produced early in fracture healing and then followed by type I collagen (bone) expression
      • Amount of callus is inversely proportional to extent of immobilization
      •     Primary cortical healing occurs with rigid immobilization (ie. compression plating)
      •     Endochondral healing with periosteal bridging occurs with closed treatment
      • Begins in middle of repair phase and continues long after clinical union
      •     Chondrocytes undergo terminal differentiation
      •             Complex interplay of signaling pathways including, indian hedgehog (Ihh), parathyroid hormone-related peptide (PTHrP), FGF and BMP
      •             These molecules are also involved in terminal differentiation of the appendicular skeleton
      •     Type X collagen types is expressed by hypertrophic chondrocytes as the extraarticular matrix undergoes calcification
      •     Proteases degrade the extracellular matrix
      •     Cartilaginous calcification takes place at the junction between the maturing chondrocytes and newly forming bone
      •             Multiple factors are expressed as bone is formed including TGF-Betas, IGFs, osteocalcin, collagen I, V and XI
      •     Subsequently, chondrocytes become apoptotic and VEGF production leads to new vessel invasion
      •     Newly formed bone (woven bone) is remodeling via organized osteoblastic/osteoclastic activity
      • Shaped through
      •     Wolff's law: bone remodels in response to mechanical stress
      •     Piezoelectric charges: bone remodels is response to electric charges: compression side is electronegative and stimulates osteoblast formation, tension side is electropostive and simulates osteoclasts
  • Variables that Influence Fracture Healing
    • Internal variables
      • blood supply (most important)
        • initially the blood flow decreases with vascular disruption
        • after few hours to days, the blood flow increases
          • this peaks at 2 weeks and normalizes at 3-5 months
        • un-reamed nails maintain the endosteal blood supply
          • reaming compromises of the inner 50-80% of the cortex
          • looser fitting nails allow more quick reperfusion of the endosteal blood supply versus canal filling nails
      • head injury may increase osteogenic response
      • mechanical factors
        • bony soft tissue attachments
        • mechanical stability/strain
        • location of injury
        • degree of bone loss
        • pattern (segmental or fractures with butterfly fragments)
          • increased risk of nonunion likely secondary to compromise of the blood supply to the intercalary segement
    • External variables
      • Low Intensity Pulsed Ultrasound (LIPUS)
        • exact mechanism for enhancement of fracture healing is not clear
          • alteration of protein expression
          • elevation of vascularity
          • development of mechanical strain gradient
        • accelerates fracture healing and increases mechanical strength of callus (including torque and stiffness)
          • the beneficial ultrasound signal is 30 mW/cm2 pulsed-wave
        • healing rates for delayed unions/nonunions has been reported to be close to 80%
      • bone stimulators
        • four main delivery modes of electrical stimulation
          • direct current
            • decrease osteoclast activity and increase osteoblast activity by reducing oxygen concentration and increasing local tissue pH
          • capacitively coupled electrical fields (alternating current, AC)
            • affect synthesis of cAMP, collagen and calcification of carilage
          • pulsed electromagnetic fields
            • cause calcification of fibrocartilage
          • combined magnetic fields
        • they lead to elevated concentrations of TGF-Beta and BMP
      • COX-2
        • promotes fracture healing by causing mesenchymal stem cells to differentiate into osteoblasts
      • radiation (high dose)
        • long term changes within the remodeling systems
        • cellularity is diminished
    • Patient factors
      • diet
        • nutritional deficiencies
          • vitamin D and calcium
          • as high as 84% of patients with nonunion were found to have metabolic issues
            • greater than 66% of these patients had vitamin D deficiencies
        • in a rat fracture model
          • protein malnourishment decreases fracture callus strength
          • amino acid supplementation increases muscle protein content and fracture callus mineralization
        • gastric bypass patients
          • calcium absorption is affected because of duodenal bypass with Roux-en-Y procedure
            • leads to decreased Ca/Vit D levels, hyperparathyroidism (secondary) & increased Ca resportion from bone
          • treat these patients with Ca/Vit D supplementation
          • gastric banding does not lead to these abnormalities because the duodenum is not bypassed
      • diabetes mellitus
        • affects the repair and remodeling of bone
          • decreased cellularity of the fracture callus
          • delayed endochondral ossification
          • diminished strength of the fracture callus
        • fracture healing takes 1.6 times longer in diabetic patients versus non-diabetic patients
      • nicotine
        • decreases rate of fracture healing
        • inhibits growth of new blood vessels as bone is remodeled
        • increase risk of nonunion (increases risk of pseudoarthrosis in spine fusion by 500%)
        • decreased strength of fracture callus
        • smokers can take ~70% longer to heal open tibial shaft fractures versus non-smokers
      • HIV
        • higher prevalence of fragility fractures with associated delayed healing
        • contributing factors
          • anti-retroviral medication
          • poor intraosseous circulation
          • TNF-Alpha deficiency
          • poor nutritional intake
      • medications affecting healing
        • bisphosphonates are recognized as a cause of osteoporotic fractures with long term usage
          • recent studies demonstrated longer healing times for surgically treated wrist fractures in patients on bisphosphonates
          • long term usage may be associated with atypical subtrochanteric/femoral shaft fractures
        • systemic corticosteroids
          • studies have shown a 6.5% higher rate of intertrochanteric fracture non unions
        • NSAIDs
          • prolonged healing time becaue of COX enzyme inhbition
        • quinolones
          • toxic to chondrocytes and diminishes fracture repair
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