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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
      • 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
 
 

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Questions (14)

(OBQ06.262) Which of the following is a mechanism by which low-intensity pulsed ultrasound is reported to stimulate fracture healing? Review Topic

QID: 273
1

decreasing intracellular calcium concentration

5%

(28/585)

2

decreasing temperature

1%

(5/585)

3

produces nanomotion at the fracture site

91%

(530/585)

4

decreases proteoglycan synthesis

2%

(9/585)

5

inhibits integrins

1%

(7/585)

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PREFERRED RESPONSE 3
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(OBQ08.44) Which of the following statements regarding COX-2 is FALSE? Review Topic

QID: 430
1

It causes mesenchymal stem cells to differentiate into osteoblasts

28%

(802/2866)

2

COX-2 knockout mice heal fractures more quickly than control mice

58%

(1650/2866)

3

COX-2 is an enzyme which converts arachidonic acid to prostaglandin endoperoxide H2

4%

(111/2866)

4

Most NSAIDS non-specifically inhibit both COX-1 and COX-2 enzymes

6%

(182/2866)

5

The expression of COX-2 is upregulated in several human cancers

4%

(105/2866)

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(OBQ05.64) Which of the following is most often implicated as an etiology for a hypertrophic nonunion? Review Topic

QID: 950
1

Malreduction with open plating

1%

(9/610)

2

Smoking

2%

(11/610)

3

Inadequate mechanical stability

94%

(572/610)

4

Open injury with significant soft tissue stripping

0%

(3/610)

5

Infection

2%

(11/610)

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PREFERRED RESPONSE 3

(OBQ06.27) The nonunion as seen in Figure A will most likely unite by what intervention? Review Topic

QID: 138
FIGURES:
1

Increased mechanical stability

94%

(1701/1814)

2

Decreased mechanical stability

2%

(31/1814)

3

Increased biology at the fracture site

2%

(40/1814)

4

Decreased biology at the fracture site

0%

(6/1814)

5

Antibiotics and resection of pseudoarthrosis

1%

(16/1814)

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PREFERRED RESPONSE 1

(OBQ10.41) In rat models looking at the effect of malnutrition on fracture healing, amino acid supplementation in a nutritionally deprived rat increases all of the following EXCEPT Review Topic

QID: 3129
1

Serum albumin

3%

(78/2389)

2

Body mass

14%

(323/2389)

3

Quadriceps total protein content

8%

(197/2389)

4

Fracture callus mineralization

39%

(923/2389)

5

Insulin-like growth factor 1 (IGF-1) mRNA expression

35%

(840/2389)

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PREFERRED RESPONSE 5

(OBQ09.84) What is the mechanism of action of capacitive coupling (CC) stimulation when used as an adjunctive therapy for bone healing? Review Topic

QID: 2897
1

Reduces oxygen concentration and increases local tissue pH

8%

(154/1948)

2

Stimulates transmembrane calcium translocation via voltage-gated calcium channels

65%

(1271/1948)

3

Upregulates TNF alpha

1%

(27/1948)

4

Transmits mechanical energy to stimulate bone formation

23%

(455/1948)

5

Upregulates osteoclast activity

1%

(27/1948)

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PREFERRED RESPONSE 2

(OBQ04.109) Type X collagen expression by hypertrophic chondrocytes is characteristic of which of the following aspects of fracture healing? Review Topic

QID: 1214
1

Inflammation

1%

(6/473)

2

Granulation tissue formation

11%

(50/473)

3

Cartilage callus formation and calcification

79%

(376/473)

4

Bone deposition

1%

(7/473)

5

Bone remodeling

5%

(25/473)

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(OBQ10.273) Level 1 evidence has shown Low-intensity Pulsed Ultrasound Stimulation (LIPUS) decreased the time to fracture union in all of the the following injuries EXCEPT? Review Topic

QID: 3361
1

Radius shaft fracture

8%

(174/2049)

2

Distal radius fracture

11%

(224/2049)

3

Tibia shaft fracture treated with casting

9%

(179/2049)

4

Tibia shaft fracture treated with reamed intramedullary nailing

55%

(1119/2049)

5

Scaphoid fracture

17%

(349/2049)

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PREFERRED RESPONSE 4

(OBQ05.1) What type of fracture healing occurs in a femoral shaft fracture treated with an intramedullary nail? Review Topic

QID: 38
1

Primary fracture healing

5%

(80/1754)

2

Secondary fracture healing

91%

(1601/1754)

3

Extramembranous ossification

2%

(35/1754)

4

Haversian remodelling

1%

(11/1754)

5

"Cutting cone" remodelling

1%

(13/1754)

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PREFERRED RESPONSE 2
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