STAGES OF FRACTURE HEALING

Fracture healing involves a complex and sequential set of events to restore injured
bone to pre-fracture condition
o 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
o the mechanical stability governs the mechanical strain
o when the strain is below 2%, primary bone healing will occur
o when the strain is between 2% and 10%, secondary bone healing will occur
Modes of bone healing
o primary bone healing (strain is < 2%)
also known as Haversian remodeling
occurs with absolute stability constructs
o secondary bone healing (strain is between 2%-10%)
involves responses in the periosteum and external soft tissues. There are
two types
enchondral healing
occurs with non-rigid fixation, as fracture braces, external
fixation, bridge plating, intramedullary nailing, etc.
intramembranous healing
occurs with semi-rigid fixation, such as locked plating (in a
non-absolute stability construct)
secondary bone healing can occur as either enchondral or
intramembranous alone, or a combination of the two.

Type of Fracture Healing with Treatment Technique
Cast treatment Secondary: enchondral ossification
External fixation Secondary: enchondral ossification
IM nailing Secondary: enchondral ossification &
intramembranous
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
o this includes PDGF, TNF-Alpha, TGF-Beta, IL-1,6, 10,12
o they may be detected as early as 24 hours post injury
o 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
o during fracture healing granulation tissue tolerates the greatest
strain before failure
Osteoblasts and fibroblasts proliferate
o 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.
o the mechanical enviroment 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
o cytokines drive chondocytic differentiation.
o 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
o primary cortical healing occurs with rigid immobilization (ie.
compression plating)
o enchondral healing with periosteal bridging occurs with closed
treatment
Remodeling Begins in middle of repair phase and continues long after clinical union
o 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
o type X collagen types is expressed by hypertrophic
chondrocytes as the extraarticular matrix undergoes
calcification
o proteases degrade the extracellular matrix
o 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
o subsequently, chondrocytes become apoptotic and VEGF
production leads to new vessel invasion
o newly formed bone (woven bone) is remodeling via organized
osteoblastic/osteoclastic activity
Shaped through
o Wolff's law: bone remodels in response to mechanical stress
o 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
o 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
o head injury may increase osteogenic response
o 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
o 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%
o 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
o COX-2
promotes fracture healing by causing mesenchymal stem cells to
differentiate into osteoblasts
o radiation (high dose)
long term changes within the remodeling systems
cellularity is diminished
Patient factors
o 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
o 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
o 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
o HIV
higher prevalence of fragility fractures with associated delayed healing
contributing factors
anti-retroviral medication
poor intraosseous circulation
TNF-Alpha deficiency
poor nutritional intake
o 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