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Updated: 12/9/2019
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Fracture Healing
 Basic Science
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Amiethab Aiyer

TOPIC QUESTIONS EVIDENCE VIDEOS CASES

Review Topic 17 / 17 16 / 16 1 /1 1 /1

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 (17) 

QUESTIONS

7 of 17  Previous Next 

(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 |  Tested Concept
QID: 3129

1 Serum albumin

2 Body mass

3 Quadriceps total protein content

4 Fracture callus mineralization

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

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 EVIDENCES (32) 

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definition of fracture union , delayed union ,and non union

  Basic Science - Fracture Healing
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 Login to View Community Videos 6/5/2017

Principles of Fracture Fixation
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Emily Tan

 Basic Science - Fracture Healing

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 CASES (1) 

3/3/2014
Femur Fracture Delayed Healing in 37M (C1809)
Surendra Shetty 239 
 Basic Science - Fracture Healing 4 

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