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J.Orthopaedics 2007;4(1)e7
Introduction:
The rate of fracture healing is accelerated
and abundant callus develops in patients who have a head injury
and fractures. There are several clinical phenomena that present
with an enhancement of bone formation. Clinical presentation of
up regulated bone formation, like heterotopic ossification is
either acquired, which occur with incidents such as brain
injury, spinal cord injury, blunt trauma, burns, infection,
neurologic disease and post surgical complications, or
inherited, such as fibrodysplasia ossificans progressiva and
progressive osseous heteroplasia. There is a well-established
relationship between brain injury and heterotopic ossification.
Patients with brain injury are known to have an increased
tendency to form ectopic bone and are given corticosteroids,
nonsteroidal anti-inflammatory drugs, disphosphonates, and
radiotherapy as a preventative measure. There is a reported
10--86% incidence of heterotopic ossification associated with
brain injury. Early clinical reports were inconclusive or
demonstrated no evidence of accelerated union or increased
formation of callus. Histologic analysis of the callus revealed
findings characteristic of mature woven bone at the periphery.
There is evidence to suggest that fractures
heal more rapidly in patients with a head injury as a result of
systemic factors released from the site of this injury.
The mechanism underlying this is unclear. Patients sustaining
severe head injury and fractures of long bones or large joints
often show enhanced osteogenesis, with hypertrophic callus
formation and/or heterotopic ossification. Nervous tissue
produces a great number of neuropeptides and neurotransmitters,
which are known to affect osteoblasts metabolism, possibly
through receptors on osteoblastic cell lines. These mediators
would also likely play a critical role in the internal
homeostatic switch relating to bone formation.
Several studies have addressed the issue of
released mediators, in addition to BMP, in brain-injured
patients in relation to increased bone growth. Trauma to the CNS
may increase the release of, or decrease uptake of, bone
formation mediators that can enter the systemic circulation.
Alternatively, other chemicals may be released from the brain,
which act to stimulate local production of BMP or other
mediators. Investigators hypothesized that the BMPs and their
receptors are involved in neuronal plasticity that occurs after
traumatic brain injury (TBI). Both scenarios would result in
altered bone formation.
Review:
Perkins and Skirving1
compared two groups of patients with and without head injury, in
whom fractures of the femoral shaft had been fixed by inter
medullary nailing. They concluded that the callus was
significantly greater in the group with head injury and the mean
time to radiological union was reduced.
Spencer2 compared fractures
of the long bones at different sites in surviving adults with
severe head injury with those in an age and gender matched
control group without head injury. They concluded that the
greatest healing response was found in the patients with the
most head injury and this directly correlated with an
accelerated time of union of the fracture.
Renfree KJ et al 3 inferred
the release of circulating osteogenic factor from the site of
head injury is a possible explanation for the connection between
CNS injury and the formation of new bone at a distant location.
Studies in vitro showing that both the proliferation of
osteoblast and the production of alkaline phosphatase are
stimulated by serum from patients with head injury have provided
evidence for this hypothesis. Other possible factors affecting
the repair of fractures after head injury include altered
neuronal activity and drug intervention.
Beeton, C A
et al4 concluded that they had measured the
circulating level of insulin-like growth factor-1 (IGF-1) and
IGF binding protein-3 (IGFBP-3) in serum because of their known
involvement in the stimulation of the activity of osteoblasts
and the healing of fractures. The serum level of IGF-1 was
significantly lower in patients with both head injury and
fracture, and fracture only compared with that in healthy
volunteers.Their findings showed, however, that the level of
IGF-1 and IGFBP-3 varied from week to week in both the patients
and healthy control subjects. These results indicate that the
levels of circulating IGF-1 and IGFBP-3 are unlikely to be
responsible for the altered healing of fractures seen in
conjunction with head injury.
Spencer RF5 stated using a
simple method of quantifying fracture healing, 53 patients who
had limb fractures and also severe head injuries were studied;
they were compared with 30 patients who had limb fractures but
no head injury. Those with head injuries had a greater healing
response and united more rapidly. Radiological and histological
analysis revealed that the terms "myositis ossificans" and "heterotopic
bone" might be more appropriate than "fracture callus" to
describe the healing response in these patients.
Beeton, C A
et al 6 inferred that IL-6 may be involved in
altered healing of a fracture after head injury.They measured
the circulating level of interleukin-6 (IL-6) and its soluble
receptor (sIL-6R) and soluble glycoprotein 130 (sgp130) in serum
from patients who had sustained a head injury with and without
fracture and compared these with levels found in control
subjects.Within 12 hours of injury the serum level of IL-6 was
significantly higher in patients with head injury and fracture
compared with the control group. Levels of IL-6 were also
significantly higher in patients with head injury and fracture
compared with fracture only. While there was no significant
difference in circulating levels of sIL-6R in the initial
samples they were increased one week after surgery in patients
with head injury and fracture and with head injury only. In
addition, reduced levels of sgp130 in patients with head injury
with and without fracture indicated a possible reduction of the
inhibitory effect of this protein on the activity of IL-6.
Uwe Scherbel et al 7 inferred a possible link between brain injury and bone
formation is through the bone morphogenic proteins (BMPs). Their
study was to test this phenomenon at the histologic and
molecular level by using a well-established head injury model in
rats. The lateral fluid percussion model is the most widely used
and characterized method of inducing brain injury in rats. Rats
were subjected to severe experimental lateral fluid percussion
(FP) injury (3.0--3.6 atm) as described by McIntosh et al. [18].
They utilized a reliable tibia fracture model described by
Bourque et al. [2] and Otto et al. [23] for rats. One group
(n=5) of rats traumatic brain injury (TBI), another group (n=5)
of rats was exposed to TBI and an experimental fracture, the
third group was only exposed to experimental fracture (n=5) and
sham animals (n=5) were subjected to anesthesia without injury.
Muscle specimens from around the hip as well as the entire area
of the fractured tibia were taken and processed. Rt-PCR showed
an up regulation of BMP 2 and 4 (2/4) in muscle around the hip
of all brain-injured animals and also in the soft tissue around
the tibia. BMP 2/4 was up regulated in the fractured tibia and
the surrounding soft tissue in all animals with a fractured
tibia. BMP 2/4 was not up regulated in muscle tissue around the
hip in these animals (fractured tibia group).
Their study revealed differences at the
tissue level in animals with head injury with or without tibia
fracture when compared to their controls. There was differential
expression of several genes including BMP 2/4 that was activated
by head injury, perhaps by a circulating factor or direct
nerve-signaling pathway. This might be a possible mechanism by
which head injury induces ectopic ossification.
The brain injured animals showed an up
regulation of BMP 2/4 in muscle specimen around the hip. Their
studies correspondent to the results of TBI may lead to an up
regulation of bone growth via BMP or similar chemical mediators,
directly or indirectly, released from the brain. In support of
this, Groot et al. (1994) recently demonstrated the
differentiation of fetal mouse chondrocytes into functional
osteoid producing osteoblasts when co-cultured with brain
tissue.
Bidner-SM et al 8 studied the possibility that increased circulating growth
factors or circulating factors that stimulate local release of
growth factors mediate the increased osteogenesis. Samples of
serum were obtained from thirty-two subjects: patients who had a
head injury alone, those who had a head injury and fractures of
the lower extremities, those who had only fractures, and control
subjects who had neither a head injury nor a fracture. Severe
head injury was defined as that producing coma of at least three
days' duration. Growth-factor activity was determined by
assessing the effect of serum on the incorporation of thymidine
and on cell counts in primary cultures of osteoblastic cells
from the calvaria of fetal rats. Samples of serum from the two
groups of patients who had a head injury had higher mitogenic
activity and produced a greater increase in the number of cells
than did the samples from the other two groups. The mean levels
of activity were not statistically different between the first
two groups or between the patients who had fractures only and
the control subjects. Dilution studies showed that increased
mitogenic activity in the serum from the patients who had a head
injury was dose-dependent. In three patients in whom it was
studied, the mitogenic activity peaked approximately
thirty-seven days after the head injury was sustained.
Khare GN et al9 proposed a
new hypothesis to explain excessive callus formation seen after
injury to brain or spinal cord. Nervous tissue is very active
metabolically and when damaged or inflamed it extracts, utilizes
and inactivates most of the corticosteroids and other
anti-inflammatory substances present in the blood. Therefore now
very little active corticosteroids are left to exhibit the
inhibitory effect on callus formation. This leads to faster
fracture healing with excessive callus formation in head or
spinal cord injured patients.
C.A. Beeton and N. Rushton10 concluded that there is evidence that
fractures heal more rapidly in patients with co-existing head
injury and that this may be due a factor or factors released
into the blood from the head injury site acting to promote
fracture repair. We aim to identify the factor/s involved by
comparing the effect of serum from patients with head injury
with that of control subjects on the proliferative and
osteogenic responses of human osteoblasts and periosteal cells.
We will then remove known cytokines using inhibitory antibodies
and ultrafiltration to assess their involvement in any
differential response observed. If we are unable to identify the
factor/s we will carry out size fractionation prior to further
purification and characterisation.
Nakase and Yaoita11, 12 both
found mRNA of BMP 2/4 up regulated at the fracture site 48 hours
post injury after rats and mice had been exposed to an
experimental femur fracture.
Conclusion:
The increased rate of fracture healing and
abundant callus formation in patients who have a head injury and
fractures is well known all over the world. In spite of numerous
efforts aimed at clarifying the way in which severe head injury
can influence osteogenesis at a distant site, this phenomenon is
still not understood. There is a well-established clinical
relationship between brain injury and heterotopic ossification.
Though various studies stating certain factors as a reasonable
cause to the phenomenon of the increased rate of fracture
healing and abundant callus formation in patients who have a
head injury and fractures. It may be either due to humoral or
neural mechanism. There are many studies stating certain factors
are not being responsible for this phenomenon. Both accelerated
fracture healing and excess formation of callus are associated
with increased osteoblastic activity and, almost certainly with
proliferation of increased number of osteoblast, whether by
stimulation of so called determined osteoblastic progenitor cell
or by induction of non-committed mesenchymal cell.
BMP 2/4 is up regulated in all brain-injured
animals in the bone and soft tissue (muscle). During
development, members of the BMP family of proteins have been
shown to induce mesenchymal migration, proliferation and
differentiation, leading to cartilage and bone formation.
Histopathological studies of pre-osseous lesions in
fibrodysplasia ossificans progressiva patients reveal a pattern
of lymphocytic infiltration and muscle-cell degeneration
followed by the appearance of highly vascular,
fibroproliferative tissue and then endochondral ossification
with mature lamellar bone and marrow elements. These same
patients were found to overexpress BMP-4 in their lymphocytes.
Identification of the stimulator molecule/s
may lead to improvements in the treatment of patients with poor
rates of fracture healing and bone formation. And it will be
possible to synthesize stimulator molecule by genetic
engineering technique once the real factor being discovered. It
remains unclear if the response of traumatic brain injury is
mediated by a circulating factor or direct nerve-signaling
pathway. Further studies have to be conducted to characterize
the interaction of TBI and bone formation; the results of such
studies will aid understanding of the functional roles of growth
factors as part of a systemic response to TBI in various
morphogenic processes during bone formation. It is clear that
the search for a circulating factor responsible for the altered
healing of fractures after head injury continues.
References:
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