Abstract
Introduction: Bone circulation plays an important role in bone
physiology, but has been relatively poorly studied, because most techniques of
circulatory research are difficult to apply to bone. This article summarizes
briefly some of the important aspects of the physiology of bone blood flow
most relevant to orthopaedics.
Methods: The gold standard for experimental measurement of bone
blood flow is the radioactive microsphere technique, though advances are being
made in other techniques, such as positron emission tomography, laser and
ultra-sound Doppler velocimetry, and near infrared spectroscopy, that may
provide useful clinical measurement in the future.
Results: Multiple vascular pathways contribute to an adaptive
response to traumatic disruption of bone circulation. The microcirculation is
not merely a passive conduit for blood flow, but plays an active role in
controlling bone processes such as osteochondral ossification.
Discussion: The pathophysiology of bone circulation has been
associated with osteonecrosis, but more and more evidence is pointing to the
importance of bone circulation in fracture repair and osteoporosis, both of
which are potentially very exciting areas for future studies.
It is sometimes difficult to appreciate the vitality of bone. The nature of
bone itself makes it exceptionally difficult to investigate the circulation,
and techniques that are applicable to many tissues are frequently difficult or
impossible to apply to bone. Early microscopists, such as Janssen, van
Leeuwenhoek, Havers, and Albinus, helped to demonstrate the basic anatomy of
bone and its circulation in the 16th and 17th centuries.
However, it is only during the last couple of decades that research into the
physiology of bone circulation has developed. It is now understood that the
circulation in bone is not merely a passive conduit for the supply of
nutrients to bone. Knowledge of the physiology of bone circulation is
important for an understanding of bone mineralization, fracture repair, and
osteoporosis.
Despite the wide range of bone shapes (resulting from adaptation to the
mechanical function required of each bone) and the differing proportions of
cortical bone, trabecular bone, and marrow, the characteristics of the
organization of the vasculature within all bones are similar. As has been
pointed out by Brookes and
Revell1, "The
pattern of vascularization [in the appendicular skeleton] comprising a
principal nutrient artery in a central position, many small nutrients in the
periphery, a capillary net in compact bone substance, and profuse sinusoids in
the contained marrow, does not depart significantly from the vascular
organization of a typical long bone." It is the aim of this review to
outline the general principles of the vascular organization of bone. For
detailed descriptions of individual bones, readers are referred to recent
books by Brookes and
Revell1 (1998) and
Crock (1996)2.
As is the case in other tissues, the vascular system in bone can be divided
into afferent vessels, efferent vessels, and a microvascular network. The
components of these three units in bone are:
Afferent VesselsEpiphyseal arteriesMetaphyseal arteriesNutrient arteryPeriosteal arteriesMicrovascular NetworkMedullary sinusoidsCortical capillariesPeriosteal capillariesEfferent VesselsCollecting sinusesEpiphyseal veinsMetaphyseal veinsNutrient veinsPeriosteal veins
Afferent Vessels
Epiphyseal arteriesMetaphyseal arteriesNutrient arteryPeriosteal arteries
Epiphyseal arteries
Metaphyseal arteries
Nutrient artery
Periosteal arteries
Microvascular Network
Medullary sinusoidsCortical capillariesPeriosteal capillaries
Medullary sinusoids
Cortical capillaries
Periosteal capillaries
Efferent Vessels
Collecting sinusesEpiphyseal veinsMetaphyseal veinsNutrient veinsPeriosteal veins
Collecting sinuses
Epiphyseal veins
Metaphyseal veins
Nutrient veins
Periosteal veins
None of the components of these units can be assumed to be independent.
There are considerable anastomoses between the various systems, and there is
still disagreement about the relative contribution of each of these sources to
the overall nutrition of different parts of the bone.
The typical organization of circulation in the diaphysis of a long bone is
illustrated in Figure 1. For
the cortex, the main supply is the nutrient artery. The nutrient artery
traverses the cortex at a very acute angle and does not branch within the
cortex. In the medullary cavity, the nutrient artery divides into ascending
and descending medullary arteries. Vessels radiate from these medullary
arteries to the cortex. In normal bone, there is centrifugal flow through
cortical bone. Exchange vessels within the haversian canals are parallel to
the axis of the bone. These vessels drain to venules on the periosteal surface
of the bone. This organization appears to be functionally important, allowing
for a relatively high intramedullary pressure, which may contribute to
movement of interstitial fluid in bone.
Measurement of blood flow to the skeleton is technically difficult, and
although several techniques have been used in experimental models, there is no
widely used technique for the measurement of bone blood flow in the clinical
situation. The problems of measuring blood flow that are particular to bone
are: (a) there are 206 separate bones in the skeleton; (b) as discussed above,
each bone has multiple arterial inputs and venous outflows; and (c) each bone
is heterogeneous, comprising varying proportions of cortical bone, cancellous
bone, and marrow (both hematopoietic and fatty).
Because of this heterogeneity of the tissue, it is also important to
specify precisely the region of bone that is being measured, and this problem
accounts for some of the discrepancies in values of bone blood flow published
in the literature. From a practical orthopaedic perspective, techniques to
measure regional blood flow are normally more informative than those that
measure total skeletal blood flow.
While several techniques have been used in experimental research on bone
blood flow, the "gold standard" is the radioactive microsphere
technique. This technique is invasive, as it requires sampling of tissue, and
is therefore inappropriate for use as a clinical measurement. Radioactively
labeled particles, about 15 µm in diameter, are injected into the
ventricle, and then are trapped in the microcirculation. The distribution of
microspheres in tissues is proportional to the fraction of cardiac output
perfusing the tissues, and sampling blood from a peripheral artery at a fixed
rate, together with measurement of radioactivity in the tissue, permits
quantitative measurement of blood flow. Typical values of blood flow are shown
in Table I.
Other techniques that can provide a more general indication of perfusion
and that have possible clinical application include: positron emission
tomography, laser and ultrasound Doppler velocimetry, radionuclide scanning,
near infrared spectroscopy, and intraoperative measurement of oxygen
tension.
Capillaries in general can be divided into three types: continuous,
fenestrated, and sinusoidal. Electron microscopy studies have shown that
capillaries in cortical bone are typical continuous capillaries. Studies of
capillary permeability in bone have used the outflow dilution technique. It
has been shown that transcapillary transport is diffusion limited rather than
flow limited. Capillaries in hematogenous marrow are described as
sinusoids.
Several years ago, it was suggested that there was a discrete bone fluid
space, which was separated from the perivascular fluid space in the haversian
canals3. Experiments
aimed directly at measuring mineral influx and efflux have shown that fluxes
in both directions are predominantly passive but that there is a small active
component in the efflux from
bone4. The exact
mechanism of active control is uncertain. It was originally suggested that
there was a membrane delineating the bone fluid space, which then defined a
potassium-rich bone fluid
space3. However,
such a discrete potassium-rich space has not been found. It is possible that
the cells are controlling the solubility, or that osteocyte processes may
actively control fluid permeability in bone. It is not only control of mineral
fluxes that is important in extravascular fluid transport. Hypoxia and small
reductions in pH increase osteoclast activity in cell and tissue
cultures5,6.
These findings could explain bone loss associated with many pathological
conditions involving local hypoxia or acidosis, and the bone vasculature may
therefore have a very important role in controlling these parameters.
Typically, an osteon within cortical bone is approximately 200 µm in
diameter. This means that osteocytes within the bone matrix can be as much as
100 µm in distance from a capillary. Cortical bone has a very extensive
network of channels, allowing communication between plasma and bone matrix.
Canaliculi, approximately one-tenth of a micrometer in diameter, radiate from
the haversian canals and form a complex network connecting osteocytes with the
haversian canal and other osteocytes. Radiating from the canaliculi are
submicroscopic interfibrillar spaces of bone matrix. The extent of these
networks is so great that it has been estimated that the surface area of the
canalicular system is approximately 250 mm2/mm3, (i.e.,
each cubic millimeter [mm3] of bone contains 250 mm2 of
canalicular surface) and the interfibrillar spaces represent an exchange area
of the order of 35,000 mm2/mm3. The vascular system,
canalicular network, and bone cells comprise the fluid space of bone. There
are precise measurements of the fluid composition of bone. In fact, in mature
cortical bone, the fluid space amounts to about 0.287 mL/mL of bone by volume
of the cortex. The distribution of bone fluid between vascular, cellular, and
interstitial (extravascular and extracellular) spaces is as follows: vascular
space comprises 6.3% of the total fluid space; cellular space, 25.1%; and
interstitial space, 68.6%. These values are for mature cortical bone; fluid
spaces are larger in immature bone.
It is interesting to do some simple arithmetic, combining these fluid space
data with the blood flow data presented earlier. Although blood flow to bone
is relatively low in absolute terms, it is very high if expressed in terms of
cellular mass of the tissue. This suggests that blood flow to bone may have
another role, apart from nutrition of bone cells, and that an important aspect
of blood flow is the homeostatic control of plasma calcium concentrations, as
suggested by Reeve et
al.7.
It has been speculated that, because distances between osteocytes and
capillaries are relatively large in microvascular terms, diffusion may not be
sufficient to supply these cells and that a more rapid turnover of
interstitial fluid in bone aids the process of cell nutrition. The fluid
pressures of intramedullary tissue have been measured and have been shown to
be unusually high, indicating a transcortical pressure gradient that parallels
the general direction of blood flow in the cortical diaphysis (endosteum to
periosteum)8.
Experimental evidence suggesting that convective flow may contribute to the
nutrition of osteocytes comes mainly from studies on the rate of labeled
protein molecules (such as albumin, Thorotrast [thorium dioxide], or ferritin)
through
bone9,10.
A problem with this type of experiment is in confirming that there is no
movement of these tracers postmortem during processing of the tissues. Using
mathematical modeling, it was argued that mechanical loading would enhance
perfusion and aid nutrition of
osteocytes11, but
McCarthy and Yang argued that the nutritional requirements of osteocytes were
unknown but presumably relatively low and that mechanical load may not be
required12.
Both local and systematic mechanisms operate to control bone blood flow. As
in most tissues, neural, humoral, and metabolic parameters all contribute to
the regulation of vascular resistance in bone. Bone and periosteum are
innervated by both sympathetic and sensory nerves. Several different staining
techniques have been used to study the distribution of nerve fibers in bone.
Most nerves are perivascular, and the periosteum, metaphysis, and epiphysis
are more densely innervated than cortical bone. As well as noradrenergic
sympathetic fibers, peptidergic nerves containing substance P, calcitonin
gene-related peptide (CGRP), vasoactive intestinal peptide, and neuropeptide Y
have also been
described13.
Innervation is denser near the epiphyseal plate, bone marrow, and periosteum.
Many substance P and CGRP immunoreactive fibers have been observed in
association with blood vessels in both periosteum and cortical bone. It has
been shown that CGRP is a potent vasodilator. During fracture repair,
periosteal CGRP-containing nerve fibers are very actively proliferating
elements, and it has been suggested that vascular control and stimulation of
angiogenesis is a major function of CGRP during the fracture-healing
process14.
The most precise physiological measurements of vascular reactivity of bone
have been performed in experimental preparations that perfuse the nutrient
supply of a long bone and in which perfusion pressure is continuously
monitored to investigate changes in vascular
resistance15. It
has been shown that, in general, the vasculature in bone responds to most
vasoconstrictor and vasodilator substances; however, a comparison of the
vasoreactive responses in bone compared with those in other tissues showed
that bone is relatively hypersensitive to vasoconstrictors and relatively
hyposensitive to
vasodilators16.
More recently, increasing interest has been directed toward the role of the
endothelium in controlling vascular tone. Vasodilation to nitric oxide has
been demonstrated in bone preparations. The response to nitric oxide is
modified by exposure to ischemia and reperfusion. Damage to the endothelium
could be an important factor in the failure of vascularized bone
grafts17. It has
also been demonstrated that nitric oxide is released from osteoblasts in
response to fluid shear, and is also released after mechanical stimulation of
bone for just fifteen minutes. Endothelin is a potent vasoconstrictor released
from vascular endothelial cells. Hypoxia has been shown to stimulate
endothelin release, as have thrombin, angiotensin II, transforming growth
factor-beta, and
endotoxin18.
It has often been shown that angiogenesis precedes osteo-genesis in many
practical situations, and this empirical observation has led to the suggestion
that the blood vessels play an active role in the process of osteogenesis and
not just a passive role of providing substrates for the process of
osteogenesis19.
Subsequent laboratory studies have given further direct support to this
hypothesis and have also led to the suggestion of a role for the endothelium
in normal skeletal homeostasis. Rat fetal calvarial cells and endothelial
cells that have been isolated from rat liver or bovine aorta have been
inserted into diffusion chambers placed subcutaneously in rats. The amount of
mineralization and alkaline phosphatase activity was significantly higher in
chambers containing both calvarial and endothelial cells compared with
chambers containing either calvarial cells or endothelial cells. Endothelial
cells alone seemed to enhance angiogenesis around the diffusion
chambers20.
Cell-culture experiments have demonstrated that isolated microvessel cells
(both endothelium and pericyte) have a mitogenic effect on osteoblast-enriched
calvarial cells and that this effect is mediated by soluble
factors21. It was
also shown that the microvessel cells produced a prolonged reduction in the
expression of markers of the osteoblast phenotype. A central role for vascular
endothelial growth factor in controlling mineralization during endochondral
bone formation has also been
demonstrated22.
Recent advances in vascular biology show that the endothelium is not a
passive barrier between blood and vascular smooth muscle but is an active
tissue in its own right, releasing vasoconstrictor and vasodilator substances
and secreting immunoregulatory factors, and also serving as a target for
circulating hormones and local regulatory factors. It has been shown that
vascular endothelial cells produce potential modulators of bone activity, such
as fibroblast growth factor, interleukins 1 and 6, colony-stimulating factors,
prostacyclin, endothelin-1, and nitric oxide. Vascular endothelial cells
cloned from fetal bovine bone have been shown to respond to parathyroid
hormone, progesterone, estrogen, insulin-like growth factors, platelet-derived
growth factor, basic fibroblast growth factor, and endothelial cell growth
factor23. It has
therefore been argued that bone vascular endothelial cells should be
considered to be part of the bone-cell communication
network24 and to be
involved in the coupling process between bone formation and
resorption25.
Trauma to a bone will always produce a certain amount of vascular damage.
The degree of damage will depend on the degree of injury to the bone.
Normally, there will be disruption to the nutrient artery, and there will also
be an appreciable amount of vascular damage to the bone if there is a large
degree of associated soft-tissue damage. Fixation of a fracture can also cause
vascular disruption. There are several processes in which it is important to
study the hemodynamic response in fracture repair. These include vascular
damage, critical perfusion, effects of fixation devices, effects of
soft-tissue damage, requirements for muscle flaps, and mechanisms of fracture
repair.
Considering the variety of approaches to fracture fixation that are
available, such as nonoperative treatment, external fixation devices, internal
plates, and intramedullary nailing with or without reaming, it is clear from
the complex vascular anatomy of bone that these will all have different
effects on local blood flow. Intramedullary reaming and use of an
intramedullary nail will clearly compromise the medullary circulation. A
compression plate placed on the periosteal surface, on the other hand, will
impair the periosteal circulation. The relative importance of these two
pathways during fracture-healing will determine the effect of these fixation
devices on the vascular response and the subsequent pattern of repair.
The adaptability of circulation in bone has been clearly demonstrated in an
experimental study of intramedullary
reaming26. Reaming
alone did not result in an overall acute decrease in cortical blood flow,
whereas the blood flow to the periosteum increased by a factor of six.
Osteotomy of the tibia did result in a decrease of flow to the cortex, but
when an osteotomized tibia was reamed, there was no further significant
decrease in bone blood flow. These data demonstrate the importance of the
periosteum to bone blood flow and the functional anastomoses between the
periosteal and nutrient supplies to bone.
The importance of the periosteum was further emphasized in a study with
external fixation devices. It was found that removing the periosteum for a
length of 2 cm on either side of a fracture gap and placing a 4-cm long
silicone rubber sheath over the fracture ends effectively devascularized the
fracture and resulted in
nonunion27.
Compression plates induce a degree of avascularity beneath the plate. In one
study28 in which a
combination of intravital staining of blood circulation and polychrome
fluorescent labeling of bone remodeling was used, the authors concluded that
early bone porosis in the vicinity of the implants was the result of internal
remodeling of cortical bone that was induced by necrosis rather than unloading
due to stress-shielding.
Alteration of the stiffness of a fixation device by a factor of two
resulted in a small change in interfragmentary displacement as a result of
feedback control of ground reaction force; however, there was still a fourfold
increase in blood flow at the osteotomy site two weeks after the
osteotomy29. These
data suggest that the effect of micromotion on fracture repair may be a
consequence of stimulation of the vascular response. Corbett et al.
investigated the role of angiogenesis in fracture repair and showed that
nitric oxide-dependent vascular reactivity had a well-defined response during
fracture repair30.
Revascularization of fractures is dependent on vascular endothelial growth
factor, although it was shown in a model of a compound tibial fracture that
muscle flaps were more effective than fasciocutaneous
flaps31.
Osteonecrosis is a common disorder of bone circulation and is particularly
common in the femoral head. Osteonecrosis of bone implies death of bone,
following a circulatory
disturbance32.
Following ischemia, changes occur in hematopoietic marrow, fatty marrow,
vascular structures, and finally bone; indeed, bone cells appear to be the
most resistant to ischemia, and the bone matrix is not affected by enzymes
released by necrotic cells. Some fractures, such as subcapital fractures of
the femoral neck and fractures of the scaphoid, are associated with an
appreciable risk of osteonecrosis; in these cases, the cause of osteonecrosis
is clear. In most other cases, the cause is more complex, with a combination
of general risk factors interacting with local vascular organization, thus
leading to local ischemia. Recognized risk factors include corticosteroid use,
alcohol abuse, smoking, occupational factors, systemic lupus erythematosus,
sickle cell disease, and coagulopathies. Recently, attempts have been made to
produce a synthesis of these risk factors in which they all lead to a final
common pathway leading to osteonecrosis. All of these factors do lead to
intravascular coagulation; however, coagulation may not be the cause of
osteonecrosis but may instead represent an intermediary event initiated by an
underlying etiological factor. The list of underlying factors is growing and
includes familial thrombophilia, hyperlipidemia and embolic lipid,
hypersensitivity reactions, hypofibrinolysis, infection, proteolytic enzymes,
and tissue factor release. Recently, endothelium-dependent nitric oxide
synthase has been implicated in
osteonecrosis33.
Atherosclerosis has been shown to be associated with
osteoporosis34.
There are several reports indicating an association between osteoporosis and
changes in bone hemodynamics. Anatomical studies have shown an increasing
incidence of occlusion of intramedullary vessels, and this is associated with
increasing reliance on the periosteal circulation for perfusion of cortical
bone35. These
occluded vessels are seen in bone at a much earlier age than are comparable
changes seen in other organs. Studies of perfusion of the femoral head have
also shown decreasing blood flow with increasing age and have shown decreased
perfusion in femoral heads of osteoporotic patients compared with controls.
When comparing femoral heads from patients undergoing total hip replacement,
it was found that vessels from patients with femoral neck fractures showed
appreciably greater changes than vessels from patients with
osteoarthritis36.
Although the incidence of both osteoporosis and atherosclerosis increases
with age, there is good evidence to indicate a more direct association. Serum
angiotensin-converting enzyme (ACE) activity is markedly higher in women who
have
osteoporosis37, and
low ACE activity associated with a polymorphism of the ACE gene confers an
improved bone mineral density response in postmenopausal women treated with
hormone-replacement
therapy38. Finally,
forearm endothelial function is impaired in postmenopausal women with low bone
mineral
density37.
In environments in which the distribution of cardiovascular pressures is
changed, bone-density changes correlate with pressure changes, and there is an
apparent increase in bone density in regions with positive changes in
cardiovascular
pressures39. The
response of bone to load depends on local interstitial fluid
pressure40. It has
also been shown that hypertension is associated with higher bone mineral
density measurements for both women and
men41. The
observations on the relationship between osteoporosis and atherosclerosis have
led to the emergence of dual-purpose therapies with use of drugs such as
statins42.
In conclusion, bone circulation plays an important role in bone physiology.
The circulation is not merely a passive conduit for blood flow but plays an
active role in controlling processes in bone. Traditionally, the
pathophysiology of bone circulation has been associated with osteonecrosis,
but more and more evidence is pointing to the importance of bone circulation
in fracture repair and in osteoporosis as well. This is a fruitful area for
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