Fracture Healing - Basic Science

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
  - the periosteum and endosteum are the two major sources
Fracture stability dictates the type of healing that will occur
- the 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.
    - enchondral 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: enchondral ossification
External fixation	Secondary: enchondral ossification
IM nailing	Secondary: enchondral ossification
Compression plate	Primary: Haversian remodeling

Secondary Bone Healing

Stages of Fracture Healing
Inflammation	Hematoma forms and provides source of hemopoieitic 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 enchondral/intramembranous ossification 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 Enchondral 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) enchondral healing with periosteal bridging occurs with closed treatment
Remodeling	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 BMPs, 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 piezoelectic 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 enchondral 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