B.

Fatigue Damage and Mechanical Competence

After a certain number of load cycles, tiny cracks appear that are
detectable at first at the ultramicroscopic level, but were probably preceded by
damage at the submicroscopic and molecular levels. if cyclical loading continues,
the cracks extend and accumulate into microscopic and the microscopic damage
and eventually into overt structural failure. biological materials such as bone also
undergo fatigue damage but differ from man-made materials in their capacity for
self-repair. the occurence of fatigue damage has been demonstrated
unequivocally in cortical bone.and there is compelling evidence that
expermentally induced fatigue damage in cortical bone induces repair by
remodeling, so that the damaged bone is removed and replaced by new
undamaged bone. it is reasonable to assume that the same applies to load-
bearing cancellous bone,which also develops fatigue damage with repetitive
cyclical loading. microfractures in cancellous bone heal by callus formation
rather than by remodeling, and although often called fatigue fracture,most of
them can be explained, not by fatigue, but by buckling.

Evidently, a mayor function of remodeling is provide a means for replacing

load-bearing home that has undergone fatigue microdamage,indeed,it is quile
possible that all BMU origination events in the peripheral skeleton are triggered
by microdamage,and that this mechanism has evolved a light skeleton.it seems
unlikely that such consisten symmetry could be the expression of fatigue
damage repair,but it might be an expression of fatigue damage prevention.

Because of bilateral symmetry in local bone geometry and mass, there will
be bilateral symmetry in the local strains engendered by mechanical loading.

The contrast between the prevention of fatigue and other forms of

damage by keeping bone age below some criticalvalue and the repair of such
damage by removal of the bone involved is unulogous to the contrast between
anticipatory and reactive homeostatis,except that the busis of the anticipation is
genetic rather than physiologic. More speciffically, it exemplifies the distinction
between targeted and post targeted remodeling, a distinction that establishes an
order of priority jfor differnt remodeling project.

((((((HALAMAN 77)))))

The mechanism of targeted remodeling in load-bearing bone is now much

clearer.the only cell that is in the rigthy location to detect microscopic damage is
the osteocyte. This cell can be actived by mechanically induced strain to
increase the synthesis of various proteins and prostaglandins, nitrous oxide, and
no doubt other signaling molecules, effects that probably mediate the addition of
bone to the nearest bone surface during growth, but microdamage repair
requires the origination of a new BMU as previously described.in the adult rat
ulna ,there is a close relationship ,both spatial and temporal,between
experimentally induced fatigue damage,osteocytes undergoing DNA
fragmentation during apoptosis, and resorption spaces containing osteoclast,but
estocytes death is preceded by increased expression of bax, a pro-apoptotic
gene. Osteocytes more than 1 to 2 mm from the damaged bone show incresed
expression of Bcl2,an anti-apoptotic gene.osteocytes exert a genereal
suppressant effects on bone remodeling, but BMU origination requires a positives
signal,either from dying osteocytes or from surrounding Bcl2 expressing
osteocytes, which serves also as a beacon or homing signal for the advancing
BMU . wheather the signal is biochemical,electrical,hydraulic,or neural is
unknown.many other factors can influence one or more steps in this complex
process,but their role is premissive, not regulato,whereas the bone removed in
response to unloading is replaced,whereas the bone removed in response to
unloading is replaced incompletely or not at all.ry.in unloaded bone
also,osteocyte apoptosis serves as a beacone fore osteoclastic removal of bone
perceived as no longer needed,but the bone removed for damage repair is
completely replaced.

C. Metabolic Functions of Remodeling

The foregoing argument has established three interconnected facts. First,the

primary function of metaphyseal cancellous bone in the extremities is
mechanical load bearing. Second, the reason why load-bearing bone
competence. Third, the rate of turnover of load bearing bone adjacent to fatty
marrow,wheather cortical or cancellous,is low. Clearly, a low rate of turnover,of
the order of 2-5 % per year, is sufficient to maintain the mechanical competence
of bone, regardless of is location in the skeleton or its geometric
features.consequently, the rate of turnover of axial cancellous bone adjacent to
hematopoitec marrow is much higher than is necessary to maintain mechanical
competence.Remodeling rate were higher in the past because of changes in
nutrition and physical activity ,but even the lower rates in pre-agricultural human
were much higher than needed for maintenance.unless this mechanically surplus
or spare remodeling is simply a form of occupational therapy for cells with
nothing better to do,it must serve an entirely different purpose. This conclusion
will not surprise the many endocrinologists who have always believed tha the
main purpose of bone remodeling was to support calcium homeostasis,but the
restriction of this function mainly to cancellous bone adjacent to red marrow has
not previously been emphasized. The relative importance of the mechanical and
methabolic aspects or remodeling, debated inclonclusively for many years, is
evidently different in differnt regions of the skleton,although both are essential
to the organism as a whole.

The most important nonmechanical function of bone remodeling concerns the

regulation of calcium homeostasis. Bone is involved in both determining the
stady-state target value for plasma-free calcium and correcting deviations from
the target value. Both of these processes depend on a relatively high rate of
bone remodeling. But in quite different ways.bone mineral also functions as a
reservoir for sodium and as a buffer for hydrogen ion regulation. Bone
remodeling may also provide biochemical support for hematopoieseis as well as
the mechanical support provided by the bone itself.both the number and the
proliferative activity of stem cell are greatest adjacent to the endosteal surfaces,
where they are segregated in microenviromental niches, and for this reason
bone lining cells may need timely replacement.

(((((Halaman 78))))))

Steady-state levels of plasma free calcium can be high normal, or low, regardless
of the directional changes in osteoclastic bone resorption or in calcium
balance .plasma-free calcium is regulated by the joint effects of parathyroid
hormone (PTH) on the renal tubular reabsorption of calcium and the blood-bone
equilibrium. This equilibrium is achieved when the onward and outward fluxes of
calcium at quiescent bone surfaces are equal, and the calcium level at which this
occurs is determined by some effects of PTH on bone lining cells,for this
mechanism to be effective,several condition must be met. First, there must be a
high blood flow, which is ensured by the proximity of hematopoietic marrow,
second, the bone at the surface must retain enough water to permit rapid
diffusion of minerals, which is ensured by a high rate of remodeling. One signal
to surface remodeling is loss of osteocytes, a mechanism that serves to maintain
osteocyte density, probably in the interest of mineral exchange.

A final aspect of the relationship between remodeling and calcium homeostasis

is that the remodeling apparatus can supply a temporary but sustained demand
for calcium lasting for many month by a temporary increase in BMU progression
and activation frequency and a corresponding increase in the remodeling
dependent reversible mineral deficit. Bone loss of location is generalized,
accompanied by high bone turnover and completely revers. During the
adolescent growth spurt, some of the calcium needed for endochondral
ossification and subperiosteal apposition is provided by a further increase in the
already high cortical porosity that subsides after cessation of longitudinal
growth.

((((HAAAAAALLLLLL 79))

IV. IMPLICATIONS FOR UNDERSTANDING OSTEOPOROSIS

“osteoporosis”is a convenient term with which to cover the health implications of

two related phenomena. First, bone mass in inviduals falls with age, second
partly as a result, the incidence of fractures in the population rises with age.
Regrettably, for a variety of nonmedical and nonselentific reasons, it has become
fashionable to define “osteoporosis” as a disease that is either present or absent,
but in this next the term is used only in the former sense.

A.Pathogenesis of fractures

The relationship of bone remodeling to bone loss and to bone fragility will be
consideredseparately, since bone loss is not the only cause of increased bone
fragility.
1.Mechanisms of Bone loss

The most remarkable feature ofvage-related bone loss is its universality. There
are useful analogies between osteoporosis and hypertension, but there are also
differences. Bone loss not only affects almost all persons but almost every bone,
and it is of interest to compare the observed rutes of loss at different skeletal
sites with those predicted from remodeling theory.

For a few years after menopouse, the crate of loss is substantially faster for
vertebral cancellous bone than for either cancellous bone than for either
cancellous bone at other sites or corticalbione, but the wider the age ranger over
which data are collected, the more similar the rates become, for example, 25
years after menopouse the average annount of bone that has been lost in
healthy women is about 35% of the initialvalue, in both the vertebral bodies and
the distal forearm.

All bone loss occurs from one of the one of the internal surfaces of bone, and the
rate of loss from any surfaces location depends on the average bone deficit at
the end of each cycles of remodeling and the frequency with which cycles occur
on that surface.thus, for the same focal imbalance, the rate of bone loss from a
surface is proportional ti the rate or remodeling on that surface.remodeling
theory predicts that for the same focal imbalance, the average rate of loss will be
about five times higher from cancellous bone adjacent to red marrow than from
cancallous bone adjacent to yellowmarrow, because of their difference in
tumover,but sustaineddifference of even half this magnitude have never been
demonstrated.the inescapable conclusion is that the degree of focal remodeling
imbalance in,for example,the calcaneum,is much greater than in the ilium,the
only site where such imbalance has so far been measured.

(((((((((halaman 80 ))))))

This is a remarkable and unexpected coclusion.when bone loss is both

generalized and sustained,as in normal aging, it appears that resoprtion depth at
different sites increases to the extent necessary to bring about roughly the same
rates of fractional bone loss and,as it were,”compensates” for differences in
bone turnover contingent on differences in marrow composition and for
differences in local bone structure and geometry.

The primary function of the mechanostat is it to ensure that during growth each
bone acquires the strength it need to support the species-specific pattern and
intensity of physical activity customary during adult life.after growth has
ceased ,the mechanostat is much less effective in adapting the bones to an
icrease in mechanical demand, but is highly effective in adapting them to
decrease,accounting for the rapidity,severity, and usual irreversibility of bone
loss consequent on disuse.

2. Mechanism of bone fragility

Bone mass is inversely related to fracture risk,both current and future, but there
are also qualitative abnormalities in bone that contribute to its fragility,the best
known and most well estabilished of these nonmass factor relates to cancellous
bone architecture.when callcellous bone is lost as a result of estrogen deficiency,
whole struktural elements are removed,leaving those that reamian moer widely
separated and less well conected.

(((((((((halamana 81)))))))))))))))))))))))))

This qualitative abnormality is due to delayed apoptosis,and consequent

prolonged life span of osteoclas, not to excessively rapid resorption by individual
osteoclasts,however a more fundamental problem may be loss of BMU
directional control. Although these various changes could be due to resettimg of
the mechanostat set point, the occurrence of severe vertebral osteopenia in elite
athletes with exercise-associated amenorrhea indicated that the effects of
estrogen deficiency are not prevented by increased physical activity.

The second qualitative factor in bone fragility is accumulation of fatigue

microdamage.frost proposed that normally there is such a wide margin of safety
that the adverse effect of bone loss on bone fragillity is mediated, not by a
reduction in instantaneous breaking strength,but by fatigue damage
accumulation due to increased strain in the bone that the margin of safety is not
a great as frost claimed.

Osteocyte death,which can occur spontaneously when bone age exceeds about
20 years,leads to perilacunar hypermineralization,which would make the bone
more brittle and more susceptible to fatigue damage.osteocyte death would also
impair detection of fatigue damage since the process of death is part of the
signaling pathway, and osteocytes can die only once.the repair of microdamage
by a new BMU could be delayed by an age-related decline in any of the
intervening steps previously outlined,or by loss of the directional control needed
for the new BMU to find its target, another likely consequnce of osteocyte death.

Microcracks occur in central cancel lous bone, but they have not been shown to
be more common than expected in patients with vertebral fracture.in the
vertebral body,the perforations and loss of structural elements previously
mentioned occur preferentially in horizontal rather than in vertical trabeculae.the
comprenssive strengh of a vertical trabecula will decline in proportion to the
square of the unsupported length, so that a 50 % reduction in the number of
horizontal trabeculae will lead to a 4-fold increase in the susceptibility to
buckling.based on estimates of in vivo stresses during normal activity, and on
the production of microcracks by experimental comprresion,vertebral
micrifracture can be explained by instantaneous overload as a results of the
architectural change previously mentioned without the need to invoke a fatigue-
based mechanism.nevertheless, a role for defective micridamage repair has not
been ruledout.

(((((((halaman 82)))))))))))
Hip fracture share with vertebral fractures the inverse relationship of risk to bone
mass,but differ from vertebral fracture with respects to the qualitative
contribution to bone fragility.loss of cancellous bone connectivity due to estrogen
deficeiency is less important,whareas fatigue damage accumulation is more
important,although small island of hematopoietic tissue can persist in the upper
femur much longer than at more distal sites, particularly in the femoral head, the
illium.

True bone mineral density increases with age in the femoral shaft cortex but not
in the spine.fatigue microdamage occurs in the cortical bone of both the femoral
neck and the femoral shaft,an in the latter,cracks density increases exponentialli
with age,more so in women than in men.cancellous microfractures in the femoral
head increasese in number with age and with reduction in mineral density and
are significantly more frequent in hip fracture patients than in control, despite a
statement by the authors to contary,because of the lower bone turnover and
differencec in architecture, there is greather reason to invoke a fatigue-based
mechanism than in the spine.all these data indicate that increased bone ag and
its adverse effects on bone fragility are likely to be of major importance in the
pathogenesis of hip fracture.

The factor that influence true bone density and these factors may be altered to
produce change in either direction in patients with vertebral fracture merits more
attention than they have received.

During the treatment of osteoporosis with so-called antiresoptive

drugs,improvement in spinal bone mineral density accounts for only a small part
of the observed reduction in vertebral fracture retes,and the reson for this
discrepancy has received much attention. High bone turnover,assessed by
biochemical indices,contributes indepedently to the beneficial effect of
estrogentherapy and could account for the discrepancy just mentioned.

Each episode of bone remodeling that occurs on a thin unsupported vertical

trabecula, as found in most women more than 5 years post menopouse,