Bone Healing and Failure - Engineered Bone: Tissue Engineering Intelligence Unit - page 53

The general factors that influence fracture healing are related to the systemic status of the
patient and exogenous systemic influences. These include age, nutritional status, anemia, dia-
betes, hormonal deficiency, drugs (specifically corticosteroids and nonsteroidal anti-inflammatory
drugs), smoking and alcohol abuse.
The influence of age on fracture healing is a well recognized phenomenon. The rate of
fracture healing in children is vastly superior to that of adults and may be related to periosteal
cellularity and vascularity 100,101 and a decline in cellular response to growth factors with age. 4
For successful healing, particularly of long bone fractures, adequate nutrition is required
including adequate intake of calcium and phosphorous. This is particularly relevant it the
elderly population. Delays in callus formation occur with calcium and phosphorous deficien-
cies due to defective mineralization of the callus matrix, an extreme example of this is a Looser's
zone in osteomalacia which is unmineralized osteoid. Protein deficiency has also been shown to
affect the mechanical properties of fracture callus. 102
Anemia has a significant effect on fracture healing with a 33% nonunion rate demonstrated
in anemic rats. 103 Deficient mineralization occurs probably secondary to diminished oxygen
tension and results in decreases callus formation and reduced callus strength.
The effects of diabetes mellitus on fracture healing are profound and are related to a multi-
tude of factors related to nutritional, neurogenic, vascular and cellular causes. 100
The most common hormone deficiency to affect fracture healing is estrogen. Post meno-
pausal women have a higher nonunion rate than men. 100,104 The effects of osteoporosis on
fracture healing have been demonstrated in an ovariectomized calcium deficient rat model. A
40% reduction in fracture callus cross-sectional area and a 23% reduction in bone mineral
density in healing femurs were observed. Callus biomechanical parameters were also signifi-
cantly reduced. Histomorphological analysis revealed a delay in fracture callus healing with
poor development of mature bone. 104 However, others have found that although fracture heal-
ing is delayed in oophorectomized rats, it returns to near normal with the introduction of
estrogen replacement, despite the presence of established osteoporosis. 106 This may suggest
that the delay in fracture healing observed is related to the oophorectomy model rather that to
osteoporosis per se.
The effect of systemic corticosteroids on fracture healing may be significant 107 and is pri-
marily related to the fact that they inhibit differentiation of osteoblasts from mesenchymal
cells 108 and may exert effects on callus tissue by altering the expression of local growth fac-
tors. 109
Nonsteroidal anti-inflammatory drugs have been shown to delay fracture healing in both
clinical series 110 and animal models. 111,112 The mechanism of action is thought to be related to
inhibition of prostaglandins resulting in delayed ossification by diminishing regional blood
flow or hindering primitive osteoblasts. More recently, selective COX-2 nonsteroidal
anti-inflammatory drugs have been shown to impair fracture healing. 113
The detrimental effect of smoking on fracture healing is well documented. 114,115 Smoking
inhibits cellular proliferation during wound healing and promotes vasoconstriction. 116,117 Nico-
tine is thought to be the most potent mediator on the healing process via its vasoconstrictive
effects, carbon monoxide may also have a detrimental effect. 117,118 Significant reduction in
callus formation and callus mechanical properties secondary to nicotine exposure have been
demonstrated in animal fracture models. 119 Chronic alcohol consumption has a detrimental
effect on the bone repair process. There is evidence that ethanol inhibits osteoblast function
and that chronic exposure induces systemic bone loss, particularly at high doses. 100 Animal
studies have shown that ethanol exposure inhibits bone repair in nutritionally deprived rats 120
but not in rats with normal caloric intake. 121
Factors that affect the local fracture milieu are equally important and include; prefracture
condition of the limb, degree of energy imparted to the limb, location of the fracture, condi-
tion of the soft tissue, contamination and infection, surgical insult, fixation method, fracture
gap, and degree of post-stabilization interfragmentary motion.