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from enhanced angiogenesis by mechanical stimulation [17], which
enhanced the transportation of some mesenchymal stem cells
carrying ER-
α
to the site [29]. Hence, estrogen deficiency-induced
osteoporotic fractured bone is effective to respond to mechanical
stimulation, where mechanical loading can increase the expression of
ER-
α
at fracture callus for mechanical signal transduction and hence
fracture enhancement.
The effect of aging on osteoporotic fracture healing (type II)
Our current understanding of the effects of aging on fracture repair
comes fromwork in animal models. Although the sequence of fracture
healing has been aptly described, less is known about the age-related
changes to each step. Previous animal studies have described
dysregulation of key processes, such as mesenchymal cell differenti-
ation, inflammatory cell activity, and local revascularization [30
–
35].
While these findings are derived from rodent models, the same
interconnected components are required for robust bone regeneration
in human patients. Therefore, to answer the question of how aging
affects the success of fracture repair, one must examine changes in cell
behavior, vascular response, and extracellular matrix activity.
Unsurprisingly, bone synthesis depends on cell differentiation and
growth. Mesenchymal stem cells are specifically responsible for bone
regeneration. Derived from a variety of local and systemic sources,
notably the periosteum and endosteum, these progenitor cells may
differentiate into osteoblasts, chondroblasts, and stromal cells [36].
Previous murine studies have demonstrated age-related delays in
chondrocyte and osteoblast differentiation in non-stabilized fractures
[31]. During the early phases of repair, juvenile mice are able to initiate
more robust periosteal reactions and more rapid cell proliferation than
middle-aged and elderly mice, generating greater numbers of ColII-
expressing chondrocytes and osteocalcin-expressing osteoblasts.
During later phases of repair, juvenile fracture calluses contain more
trabecular bone formation and display swifter bone remodeling.
Although middle-aged and elderly animals eventually healed, their
protracted responses suggest overall deficits in aged mesenchymal
stem cell activities. Interestingly, bone marrow transplantation
experiments have shown that rejuvenation of inflammatory cell
lineages independent of skeletogenic cell lineages enhances fracture
repair in aged animals [35]. When aged animals received juvenile bone
marrow, more robust callus formation and more rapid callus
remodeling were observed, indicating that independent functionality
of both mesenchymal stem cells and inflammatory cells is necessary
for successful healing. So, while the interactions among different cell
populations during bone regeneration have been explored [4,37,38],
the age-related breakdown of these relationships remains unidentified
and warrants further research.
Given the burst of cellular activity following fracture, reestablish-
ment of the local vascular supply is paramount to successful bone
regeneration. Since surrounding blood vessels are concurrently
damaged during skeletal injuries, a harsh ischemic microenvironment
develops at the fracture site [32]. To further complicate healing in aged
models, angiogenesis and vasculogenesis are impaired due to
substantially suppressed expression of anabolic factors such as
Hypoxia Inducible Factor-1-alpha (HIF-1
α
) and Vascular Endothelial
Growth Factor (VEGF) [39]. Moreover, matrix metalloproteinase (MMP)
activity diminishes with age, which leads to poor degradation of
cartilaginous matrixes and prevents adequate vascular invasion during
endochondral ossification [40
–
44]. The combination of decreased
oxygen tension, hindered revascularization, and minimal nutrient
exchange results in cell death as well as delayed osteoblast and
chondroblast cell activity [45
–
47]. Previous animal studies suggest
manipulation of the VEGF pathway to restore angiogenesis in impaired
healing models, such as induced ischemic fractures [48
–
51]. While
these treatments undoubtedly rescue otherwise delayed bone regen-
eration, a recent human study suggests VEGF deficiency may not be
responsible for the avascularity seen in aged fracture calluses. The
report describes similar expression of VEGF and Platelet-Derived
Growth Factor (PDGF) in middle-aged and elderly patients at a given
time point, indicating dysfunction outside of angiogenesis may be
responsible for poor unions in aged populations [52]. The seemingly
different conclusions that exist within current research provoke
thought and indicate that more investigations must be conducted to
properly assess fracture repair in elderly populations.
In addition to coordinated cellular and vascular proliferation,
fracture repair depends on the establishment of an interim extracel-
lular matrix template. The matrix at the site of injury provides a stable
scaffold for cellular migration and growth factor adhesion. During the
initial phase of fracture repair, a fibrin-rich matrix coalesces with
platelets to form a hematoma that sequesters pro-inflammatory
cytokines and other potent bioactive factors required for cell
proliferation, cell differentiation, and osteoinduction [44,53
–
56].
Without the hematoma and its constituents, the cascade of healing
responses fails to occur and terminates in either delayed- or non-union
[57,58]. Age-related changes in matrix composition, disturbances of
cell-matrix interactions, and alterations in growth factor concentration
increase the likelihood of deviations from the normal wound healing
sequence [59
–
63]. In animal models of fracture healing, increased age
and related disease states are associated with loss of extracellular
matrix regulation. For example, collagenous and fibrotic tissues
established during early wound repair persist and prevent normal
replacement by bone and cartilage tissues, resulting in delayed healing
[31,44,64,65]. While the interactions between the extracellular matrix
and surrounding tissues have been sufficiently characterized, the exact
mechanisms underlying such sub-optimal cellular behavior in aged
matrixes during fracture repair have yet to be discovered [61,66,67].
However, given the current research on the restoration of the
extracellular matrix in other system, such findings may be readily
applied in the context of bone regeneration [68
–
70].
Because of the multifaceted nature of bone regeneration, many
questions surrounding fracture healing remain unanswered, regardless
of age or outcome. So, to understand the process in older populations, a
plethora of work must be undertaken to elucidate age-related changes
in biological responses in addition to altered relationships between
aged cell types. Overcoming these challenges is critical to the
development of novel therapies targeted to fractures attributed to
type II osteoporosis.
Future of osteoporotic fracture research
–
small animal model for
metaphyseal fracture healing
Although the above observations nicely summarize the animal
studies and filled in some of our current knowledge gaps in our
understanding of osteoporotic fractures related to type I and type II
osteoporosis, one phenomenon of osteoporosis is that it is mainly
manifested by the microarchitectural deterioration of trabecular bone
at the distal radius, proximal humerus and proximal femur [71,72].
This is one of the main reasons why osteoporotic fractures most
frequently occur at these anatomical sites and in vertebra bodies
which are also associated with a remarkable amount of trabecular
bone [72
–
74]. There is also published data on differences in bone
healing between the metaphyseal and diaphyseal region of long bones
with less periosteal callus formation in the metaphysis than in the
diaphysis [75].
Despite the high number of articles on the pathophysiology and
microarchitectural bone alterations in osteoporosis, there is only
limited data in fracture healing in non-osteoporotic vs. osteoporotic
bone. A lot of knowledge on non-osteoporotic fracture healing has
been generated from small animal studies in rats and mice. These
experiments have frequently used the fracture model of Bonnarens
and Einhorn with a midshaft fracture of the femur or tibia with
internal fixation by intramedullary roding [76]. Several studies on
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–
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