IV.D.4. - Osteoporosis
is the fifth most abundant element in the biosphere, after oxygen,
silicon, aluminum, and iron. It is present in high concentration
in seawater and in all fresh waters that support an abundant biota.
Fortuitously, the calcium ion has just the right radius to fit
neatly within the folds of various peptide chains. Calcium thereby
stabilizes and activates a large number of structural and catalytic
proteins essential for life. In this capacity calcium serves as
a ubiquitous second messenger within cells, mediating such diverse
processes as mitosis, muscle contraction, glandular secretion,
blood coagulation, and interneuronal signal transmission. Controlling
these activities requires careful regulation of the concentration
of calcium in critical fluid compartments. This regulation is
accomplished in two basic ways.
a cellular level, calcium is ordinarily sequestered within intracellular
storage compartments. It is released into the cell sap when needed
to trigger various cellular activities, and then quickly pumped
back into its storage reservoirs when the activity needs to be
terminated. This control mode is exemplified by the accumulation
and release of calcium by the sarcoplasmic reticulum of striated
muscle. The second type of control, utilized by many tissues in
higher organisms, is the tight regulation of the calcium level
in the blood and extracellular fluids that bathe all the tissues.
Individual cells, needing a pulse of calcium, simply open membrane
channels and let calcium pour in from the bathing fluid; they
then pump it back out when the particular activity needs to cease.
the Regulation of Calcium Levels
mode of control requires both a reserve supply of calcium and
a place to put an excess of calcium: In the first mode, the source
and sink are within the cell; and in the second, they are outside
the cell but still within the organism. The extracellular calcium
reserve (and sink) in the higher vertebrates has, over the course
of evolution, become the organ system we call bone. Along the
way, building on the hardness of calcium deposits, bone acquired
the mechanical and structural functions that have become its most
fossil record shows that bone evolved independently many times
over the course of vertebrate evolution, usually in a marine environment
where bone probably functioned primarily as a sink for calcium
(since the fluid in contact with the gill surfaces represented
an essentially inexhaustible source). The hardness of bone served
many useful, but secondary purposes, ranging from dermal armor,
to teeth, to internal stiffening. As mechanisms of controlling
concentration of minerals in the internal environment evolved
to higher levels of refinement and an internal sink became less
necessary, the internal skeleton dropped out of many fish genera,
which retained only the structural portions that were vital
teeth and dermal armor.
in amphibians and terrestrial vertebrates, living outside of a
buoyant medium, the internal stiffening could not be dropped.
It provided structural support and mechanical strength, and it
permitted movement against gravity. Also, deprived of constant
contact with a bathing medium high in calcium, the organism now
became more dependent upon internal reserves of calcium to ensure
maintenance of constant calcium concentrations in the extracellular
this need for a calcium reserve in terrestrial vertebrates is
virtually self-evident, it is useful to note that the sink function,
sequestering of excess calcium, remains important on dry land
as well. (If calcium were constantly in short supply, of course,
then a reserve sufficient to serve a structural function could
never be accumulated in the first place.) Typically, in the life
of a terrestrial vertebrate, the reserve function of the skeleton
is called upon only intermittently. At other times the skeleton
stores excesses of calcium made available from the environment.
This process, as already noted, is constantly needed in a marine
habitat but occurs mainly on feeding for most terrestrial vertebrates.
vertebrates came out onto dry land, two sometimes competing objectives
had to be managed: maintaining the extracellular fluid calcium
level and maintaining the size of the skeletal reserve. Whereas
the former could be managed in a marine environment by adjusting
fluxes of ions across the gill membranes, on dry land it had to
be done by adjusting the net flow of calcium into and out of bone.
In this process bone mass itself actually changes as the skeleton
functions to support the body fluid calcium levels, and skeletal
structural strength necessarily changes in parallel. The size
of the reserve, which is the basis for bone strength, is ultimately
limited by forces acting outside the skeleton, that is, by adjusting
inflow from ingested foods and outflow through the kidney, as
well as by a mechanical feedback system within the skeleton (see
following discussion). It must be noted, however, that the extraskeletal
portion of that regulatory system works adequately only when ingested
food contains sufficient calcium.
Abundance in the Diets of Terrestrial Vertebrates
is so abundant in even the terrestrial environment that most wild
foods contain relatively large quantities of it. In fact, much
of the calcium content of several leafy plants, notably the halophytes
(for example, spinach), represents a plant tissue analogue of
the bony sink of marine vertebrates. In other words, the plant
creates calcium deposits as a means of keeping calcium levels
from rising too high in plant tissue fluids. However, that sequestered
calcium remains a part of the plant and hence becomes available
to the animal eating it.
the time they eat sufficient food to meet total energy needs,
most mammals have inevitably ingested a great deal of calcium.
This calcium load is generally so great that higher vertebrates
have evolved mechanisms to prevent being swamped by an excess
of calcium. One of these has been the development of a relative
absorptive barrier at the intestine, and the second has been the
ability to damp out any elevations in extracellular fluid calcium
by promptly transferring an excess of absorbed calcium into bone.
there are some delicate trade-offs involved here, particularly
in terrestrial vertebrates, where the structural significance
of the skeleton is crucial (even if a secondary function, from
an evolutionary standpoint). The absorptive barrier can only be
partial, or it would not be possible to accumulate adequate skeletal
mass to serve a structural function, nor to repay temporary withdrawals
from the reserve. Urinary excretion might take care of an absorbed
surplus, and in fact certainly does so in most vertebrates, but
calcium is relatively insoluble, and renal capacity for handling
large excesses of calcium is limited by the propensity of the
kidney tissue to calcify. Thus, organisms evolved mechanisms for
temporarily putting excess calcium into the skeleton during the
absorptive phase after feeding and then withdrawing it from the
skeleton, as needed, during periods of fasting or starvation.
need for a reserve during fasting is not because calcium is consumed
in the various metabolic processes that it activates (as would
be the case, for example, with ascorbic acid or the B vitamins)
but because calcium is lost every day through skin and excreta.
Further, during childbearing, calcium is transferred from the
mother to the progeny, both in utero and through lactation. Hence,
there is an obligatory calcium need throughout life, first to
accumulate skeletal mass during growth and then to offset daily
losses at all ages.
and Bone Mass
has no capacity simply to soak up or release calcium ions on need.
Rather, these functions are served by forming and destroying actual
packets of bony tissue. Collectively these processes of formation
and resorption are termed "bone remodeling." Remodel
ing occurs throughout life and serves several essential functions.
the adult skeleton, the first step in remodeling is almost always
bone resorption; the old material has to be cleared away before
new bone can be deposited. In reabsorbing bone, osteoclasts attach
to a bony surface and secrete acid to dissolve the mineral and
proteolytic enzymes to digest the matrix. They thereby physically
remove a volume of bone. The calcium content of that volume is
released into the bloodstream and becomes available both to support
the level of calcium in the extracellular fluids of the body against
the various drains to which it may be subject and to meet the
calcium demands of bony sites elsewhere in the body that happen
currently to be in their mineralization phase.
is formed by osteoblasts, which first deposit a protein matrix
on an excavated surface and then act on it to create crystal nuclei
of calcium phosphate. Thereafter, these nuclei grow by accretion,
without further cell work, spontaneously adding calcium and phosphate
ions drawn out of the blood that flows past the mineralizing site.
Once deposited at any given site, calcium is permanently trapped
and can be removed only by the process of bone resorption at that
fluxes into and out of bone, in the mature adult, are typically
in the range of 300 to 500 milligrams of calcium (mg Ca) per day,
or about two to four times as large as the aggregate of the external
calcium fluxes (absorption and excretion).
balance between bone formation and resorption is adjusted so as
to keep the calcium concentration of the extracellular fluid constant.
The process is mediated mainly through the action of what are
termed "calciotrophic hormones" principally parathyroid
hormone, calcitonin, and calcitriol with parathyroid hormone
being the most important in mature adults, and calcitonin and
calcitriol notably more important in infancy.
hormone secretion is evoked by a fall in extracellular fluid calcium
level, and calcitonin secretion by a rise. Parathyroid hormone
acts to raise falling calcium levels by activating bone remodeling,
by reducing renal calcium losses, and by increasing renal synthesis
of calcitriol, the active hormonal form of vitamin D (which enhances
intestinal absorption efficiency). Activation of remodeling helps
raise a falling calcium level because resorption precedes formation,
and thus in its early phases, remodeling provides a temporary
surplus of calcium. Calcitonin, in contrast, lowers elevated calcium
levels by temporarily suppressing bone resorption, thus stopping
the release of calcium from bone.
activity of maintaining the constancy of extracellular fluid calcium
concentration is termed "calcium homeostasis." The bodys
ability to adjust bone remodeling balance is an important physiological
defense of the calcium levels in the extracellular fluids of the
body, providing needed calcium when the level would otherwise
drop and soaking up surplus calcium when it would otherwise rise.
the calcium abundance in the diets of virtually all mammals, the
reserve function in subhuman species operates mainly during periods
of excessive skeletal demand or transient environmental scarcity.
Such episodic withdrawal from the reserves is illustrated most
clearly in what happens during antler formation in several species
of deer each spring. Antlers consist of bone; their growth is
usually so rapid that absorbed food calcium cannot keep up with
demand, particularly given the relatively poor nutritional quality
of early spring food sources. Accordingly, parathyroid hormone
secretion increases sharply when antler formation begins, and
a burst of bone remodeling is initiated throughout the skeleton.
Because the initial phase of remodeling is resorptive, a temporary
surplus of calcium is made available for antler mineralization.
Later, antler growth slows or stops, and the remodeling loci throughout
the skeleton enter their own phase of bone formation (which proceeds
at a somewhat slower pace than for the antlers). Those sites then
get the calcium they need from a diet that now contains calcium-rich
summer grasses and foliage.
over the year, environmental calcium is usually quite sufficient
to permit deer to build and to discard all that accumulated antler
calcium annually, and then to start the process all over again.
Remodeling is adjusted in this case to help with a temporary calcium
long as the microscopic scaffolding of bone from which calcium
is borrowed remains intact, as in the deer, there is always the
potential for restoration of most or all of the bone lost through
remodeling imbalances. But this is only true if adequate exogenous
calcium becomes available in time. This borrowing mechanism creates
a structural problem for the skeleton when absorbed dietary calcium
remains chronically below the demand created by daily losses.
Since, under those circumstances, the calcium borrowed from bone
cannot be repaid, the remodeling imbalance continues and bone
mass continues to be eroded. If this process reaches the point
where structural elements are lost (for example, trabecular plates
are perforated or trabecular spicules disconnected), much of the
loss becomes effectively irreversible, and the deficiency can
no longer be corrected, at least by restoring the missing nutrient.
Control of Skeletal Mass
the ability of the skeleton to release calcium for homeostatic
purposes (by tearing down its own bony substance) is effectively
limitless, the ability to store excess calcium is much more limited.
This is because, as has already been noted, calcium can be stored
only by forming new bone in excess of the amount resorbed. But
there has to be some ceiling here. Otherwise, in a typically calcium-rich
environment, higher vertebrates, storing continuing surpluses
of calcium, would become all bone.
much bone an organism possesses when calcium intake is not the
limiting factor depends mainly upon the degree of mechanical strain
each bone experiences. Throughout the terrestrial vertebrates
each bone adjusts its density (through balancing resorption and
formation) so that it experiences in the range of 1,000 to 1,500
microstrain in ordinary use. (Strain is the bending any structure
undergoes when it is loaded; 1,000 microstrain is a dimensional
deformation of 0.1 percent.) So far as is now known, no surplus
of nutrients will lead to more bone accumulation than what is
required to produce and maintain that degree of stiffness. Thus,
homeostatically, bone mass is adjusted to support body fluid calcium
levels; and structurally, bone mass is regulated to produce an
optimal stiffness (not too massive, not too flimsy).
control system regulating this structural aspect of bone mass
is not fully understood, but it is known to be site-specific and
to be intrinsic to bone (rather than extrinsic as with calcium
homeostasis). What this system amounts to is that local bone formation
exceeds local bone resorption when bone deforms excessively, making
it stiffer, and the opposite occurs when local bone deformation
is minimal. Thus, like muscle, bone hypertrophies with use and
atrophies with disuse.
the intraosseous stiffness-optimizing system and the extraosseous
calcium homeostatic system alter bone mass by regulating the balance
between bone formation and bone resorption, that is, they both
use the remodeling apparatus to alter bone density. In certain
circumstances they reciprocally influence one another. For example,
when the homeostatic system acts to reduce density, it thereby
leads to increased strain on routine loading of the skeletal region
involved. This, in turn, creates a signal to restore lost bone
as soon as environmental calcium becomes available once again.
departure from optimal mass levels is always downward borrowing
and then paying back. There is only limited capacity to store
calcium above current structural needs for bone. Although the
homeostatic surplus is literally vast, relative to metabolic functions
of calcium, there is virtually no bodily ability to build a structural
surplus, at least relative to current levels of mechanical usage.
Instead, the structural reserve of the skeleton lies in the fact
that normal bone can withstand greater deformation than the 1,000
to 1,500 microstrain of everyday use. The limit is closer to 7,000
microstrain, but its actual value depends upon how rapidly and
how often a load is experienced. This margin of safety is what
protects us from fracture when we experience low-level falls and
is a disorder of bone characterized by excessive fragility due
either to a decrease in bone mass or to microarchitectural deterioration
of bone tissue (or both). It is a structural weakness in an organ
system that, as has already been noted, serves as a source and
a sink for calcium in its primary evolutionary function.
bony fragility that constitutes osteoporosis is expressed in a
propensity to develop fractures on minor injury. This fragility
may involve virtually any bone in the skeleton. Stereotypical
fracture syndromes involve such regions as the spine, the upper
end of the femur (hip fracture), and various extremity sites,
for example, wrist and shoulder. But ribs, pelvis, hands, and
feet are also common fracture sites in patients with osteoporosis.
is not a unitary disorder and does not have a single pathogenesis.
Basic engineering considerations make it clear that the strength
and stiffness of bone, as is true for any structure, derive from
four main sources: the intrinsic physical properties of its component
material; the mass density of that material; the spatial arrangement
of the material; and the loading history of a given member (which
expresses itself in an accumulation of ultramicroscopic defects
called "fatigue damage"). When any structure fails under
load, it is because of relative weakness due to insufficiency
of one or more of these strength determinants.
most of the osteoporotic fracture syndromes there is, currently,
no recognized abnormality of the bony material itself. The bony
substance in the skeleton of patients with osteoporosis is qualitatively
much like the bony substance in normal individuals. Instead, the
principal bases for weakness in osteoporotic bone are to be found
in (1) a decreased amount of bony material, or mass density (to
which the term "osteoporosis" literally refers); (2)
accumulated fatigue damage in that bone which is present; or (3)
architectural defects in the latticework of trabecular (or cancellous)
bone. These latticework defects, in turn, are of two types, microfractures
of trabecular elements, which have previously occurred under loading
but have not yet fully healed (and which thereby render the latticework
weak), and preferential severance (and loss) of the horizontal
bracing trabecular elements that give the lattice much of its
of several of the more important contributing factors are illustrated
in Figure IV.D.4.1. Where nutrition, and specifically calcium,
come into this complex interplay of fragility factors is predominantly
through their effect on bone mass density, that is, through the
size of the calcium reserve. Thus, although important, calcium
intake is only one of several interacting factors that can lead
to osteoporosis. Some individuals will develop fragility fractures
because bone mass is reduced, but others will develop them because
of failure to repair fatigue damage or because of defective trabecular
architecture. Even in regard to decreased bone mass, calcium shares
the stage with other important factors such as gonadal hormone
deficiency, physical inactivity, and a variety of lifestyle factors
such as alcohol abuse and smoking. These factors also reduce bone
mass, but their action on bone is largely independent of nutrition.
(High blood alcohol levels poison bone cells, just as they do
cells of other tissues. Hence, it is not surprising that bone
tissue fails variously in habitual alcohol abusers. The mechanism
of the effects of tobacco is unknown. Smoking women have earlier
menopause and lower postmenopausal estrogen levels than nonsmokers,
but this is probably only part of the explanation.)
the multifactorial character of osteoporosis causation was fully
understood, there had been confusion about the importance of calcium,
mainly because published studies did not always show a protective
effect of an adequate calcium intake. Figure IV.D.4.1 forcefully
emphasizes why a universal protective effect is an unrealistic
expectation. All that an adequate calcium intake can do is to
help the organism build the largest possible skeleton during growth
and to protect the skeleton against one-sided calcium withdrawals
during maturity. But a high calcium intake will not counteract,
for example, effects of alcohol abuse or physical inactivity.
available evidence suggests that if a fully adequate calcium intake
could be assured for every member of the population, as much as
50 percent of the osteoporosis burden of the developed nations
would be alleviated. Even so, there would still be 50 percent
that persists. These cases would have bases other than nutritional
A Disorder of a Nutrient Reserve
osteoporosis, when caused by inadequate calcium intake (either
during growth or during the adult years), can be said to represent
a nutritional disorder, it is important to recognize that the
primary metabolic function of calcium is never even remotely compromised.
Thus, those forms of osteoporosis that result from inadequate
calcium intake can be said to be disorders of a nutritional reserve,
and not nutritional deficiency in the usual sense (as might occur
with vitamin C and scurvy, or with vitamin D and rickets). Fat
may be the only analogue of this unique nutritional situation,
serving not only as an energy reserve but as insulation for warm-blooded
organisms living in a cold environment.
difference between these two types of nutritional deficiency is
illustrated schematically in Figure IV.D.4.2, which contrasts
the effects produced by depletion of the body content of a nutrient
such as vitamin C with the effects of calcium depletion. In the
former case, where the reserves are only that, and serve no other
function, health is maintained until the entire reserve is depleted.
Then, as the active metabolic pool declines, dysfunction develops.
With calcium, by contrast, any depletion of the reserve produces
a corresponding decrease in skeletal strength. The skeleton would
be rendered totally useless as a structure long before the metabolic
pool of calcium would be compromised.
of the problems this arrangement creates for the nutritional scientist
is that a deficiency of calcium sufficient to compromise the structural
dimension of the reserves will have no impact upon the basic metabolic
function of calcium. Thus, a calcium deficiency sufficient to
produce osteoporosis will not be reflected in appreciable decreases
in calcium concentration in the circulating fluids, nor in the
critical cell compartments where calcium functions as a second
messenger, nor even in the ready availability of calcium ions
for that crucial function. For this reason there are no blood
or urine tests that, alone or in combination, are diagnostic either
for this phase of calcium deficiency or for osteoporosis.
requirement for a specific nutrient has traditionally been defined
as the intake necessary to prevent the expression of the disease
or disability associated with deficiency of that nutrient. In
recent years there has been a tendency to broaden that definition
to read: the intake required to promote optimal health. In the
case of calcium, neither approach is particularly apt, as the
foregoing discussion has emphasized, inasmuch as health in this
instance is not a matter of the basic metabolic function of calcium
but of the size of the calcium reserve. Hence a calcium requirement
relative to bone health needs to be defined as the intake necessary
(1) for building the largest bone mass possible within the genetic
program of the individual, and (2) for maintaining that reserve
against unbalanced withdrawals after growth has ceased. Any unrepaired
decrease in the size of the reserve, other things being equal,
reduces bone strength.
for a Calcium Requirement
providing during times of need is precisely what a reserve is
for, this process cannot properly be considered harmful in itself.
A problem develops only when the process is one-sided, with reserves
drawn down but not replenished. In this connection, it will be
useful to review here both certain quantitative aspects of how
the body maintains constant calcium levels in its blood and extracellular
fluids, and how and why an unbalanced situation develops.
mentioned previously, foods available to high primates and huntergatherer
humans in their natural states are rich in calcium. In fact, nutrient
densities of such foods average in the range of 70 to 100 mg Ca/100
kilocalories (kcal). When calculated for an energy intake sufficient
to sustain a huntergatherer of typical body size, this density
range translates to a daily calcium intake of 2,000 to 3,000 mg,
substantially in excess of what most modern humans get, and four
to six times what an adult female in the United States typically
after the advent of cultivated cereal grains at the agricultural
revolution did humans shift from a diet with a high calcium density
to one with a low calcium density.
absorption. As already noted, calcium absorption is inefficient,
averaging in the range of 30 percent of ingested intake in healthy
adults at intakes in the range of the current Recommended Dietary
Allowance (RDA) (800 mg for adults). Absorption efficiency varies
inversely as roughly the square root of ingested intake, which
means that although efficiency rises as intake falls, the evoked
rise in absorption fraction will not be sufficient to offset the
actual drop in intake.
digestive secretions themselves contain calcium (typically in
the range of 150 mg/day in a healthy adult). Because this calcium
is secreted along the length of the gut, it is reabsorbed at only
about 85 percent the efficiency of ingested calcium (which is
itself absorbed inefficiently). This secreted calcium constitutes
a cost of digestion, and most of it will be lost in the feces.
two-directional traffic means that net absorption will always
be less than gross absorption. For example, at an intake of 600
mg/day and an absorption efficiency of 30 percent, net absorption
will be only about 63 mg, or barely 10 percent of intake. In fact,
at low intakes, net absorption will commonly be negative, that
is, there will be more calcium going out in the feces than is
coming in by way of the mouth. This does not represent intestinal
pathology but is an inevitable consequence of the combination
of low absorption efficiency and calcium secretion with the digestive
quantitative character of this relationship is depicted schematically
in Figure IV.D.4.3, which shows various iso-absorption contours
relating intake and absorption efficiency to various values for
net absorption (from 0 to 500 mg Ca/day). For example, to achieve
a net absorption of 200 mg/day (close to the figure required to
offset extraintestinal losses in healthy adults), intake must
be 1,030 mg at an absorption efficiency of 30 percent, and 1,605
mg at an absorptive efficiency of 20 percent.
fact of low, and even negative, net absorption might be construed
to indicate that the organism does not need much calcium after
all, but that would be a misreading of the evidence. With the
naturally high calcium intake of the huntergatherer diet,
the customary exposure of the gut is to a calcium-rich ingestate,
and even with low absorption efficiency, net absorption would
always be positive. But in fact, the low absorptive performance
of the gut in mammals is an evolutionary adaptation to this environmental
surfeit. Unfortunately, a low absorption fraction is maladaptive
for modern diets. Our bodies have adapted to a high-calcium diet,
and the time span from the agricultural revolution to the present
has been much too short to have allowed evolution toward greater
nutrient factors interfere with calcium absorption and thereby
raise the calcium requirement. Certain kinds of fiber bind calcium
and thereby reduce its absorption. Wheat bran does this, for example.
However, this is not true for all fiber: The fiber of green leafy
vegetables does not interfere at all with absorption. Overall,
the effect of fiber in our diets is relatively small, and even
widely ranging fiber intakes would not be expected to exert very
large effects on calcium absorption. A second factor reducing
calcium absorption is caffeine, a substance widely considered
among the lay and the scientific communities to be a risk factor
for osteoporosis. It turns out, however, that the caffeine effect
is also small and, except for very high daily coffee intakes,
would not pose much of a problem. For example, the negative effect
on calcium absorption of a single brewed cup of coffee is such
that calcium balance deteriorates by about 3 mg. This quantity
is so small that its impact can be easily offset by as little
as an ounce of milk.
and dermal losses. Urinary and dermal calcium losses are also
important determinants of nutrient requirement. Dermal losses
occur through sweat and also through shed epithelial structures
(dry skin, nails, and hair all of which contain calcium).
For the most part dermal losses are unregulated and thus constitute
an irreducible daily drain that must be offset from the diet or,
failing that, from the bony reserves.
calcium in humans is determined predominantly by body size and
by intake of protein and sodium and only to a lesser degree by
calcium intake itself. Protein intake increases urinary calcium
loss largely through the catabolism of sulfur-containing amino
acids and the excretion of the consequent sulfate load (an endogenous
equivalent, as it were, of the acid rain problem produced by burning
sulfur-containing fossil fuels). High sodium intake also tends
to wash calcium out through the kidneys. High sodium intake is
another major dietary change that has occurred for the most part
only very recently. Hunter-gatherers and high primates typically
have sodium intakes nearly two orders of magnitude (something
on the order of 100 times) lower than modern-day humans. In Switzerland,
where careful records of salt imports have been kept, per capita
salt consumption has increased by a factor of 10 since 1850 alone.
calcium rises with body weight from infancy to adolescence. Infants
can reduce urinary calcium losses to near zero when calcium intake
drops. Children have an intermediate ability to conserve calcium
at the kidney, and adolescents, strikingly, maintain high urinary
calcium values irrespective of their calcium intake. This makes
them, at a time when calcium requirements for bone growth are
at their absolute maximum, particularly vulnerable to environmental
scarcity. A partial explanation for the change with age may lie
in the fact that infants and small children have relatively low
salt intakes, and instead of burning ingested protein as fuel,
they build at least some of it into new tissue. Thus neither of
the factors driving the higher urine calcium values of older persons
are prominent early in life.
combination of unrecovered digestive juice calcium, minimal urinary
calcium loss, and dermal loss, which occur under conditions of
calcium restriction, constitutes what is called "obligatory
loss." In normal adults consuming typical Western diets,
this loss amounts to something in the range of 150 to 250 mg/day,
probably more often on the higher side of the range than on the
lower. Whenever the absorbed intake is insufficient to compensate
for this obligatory loss, bone remodeling will be adjusted so
that resorption exceeds formation and thus bone mass will decrease.
In other words, the organism calls upon its calcium reserves.
Recommended Dietary Allowance (RDA) is a population-level estimate
of the daily intake that would be sufficient to meet the actual
requirement for a given nutrient for virtually every member of
the population. RDAs are deliberately set above the average requirement
so as to assure meeting the needs of those with above-average
RDAs for calcium in the United States are 800 mg/day for children
up to age 11, 1,200 mg/day from ages 12 to 24, and 800 mg/day
thereafter. (During pregnancy and lactation, the RDA rises to
1,200 mg/ day.) There is growing evidence that these requirements
are low, and what follows will summarize the best current information
about what the true requirement may be. In this connection it
is worth recall ing once again that wild plant foods are rich
in calcium. As a result, the human calcium intake for foragers
was almost certainly substantially above not only current intakes
but even the RDAs. While there has been a bias in the scientific
community in favor of current dietary practices, there should
be no surprise when evidence indicates that intakes closer to
(though still on the low side of) what our foraging forebears
apparently got, may in fact better meet our needs.
intake. One aspect of the relationship of calcium to bone
health, relevant to a consideration of requirement, is the fact
that calcium is a threshold nutrient. This means that calcium
intake will limit the amount of bone a growing organism can acquire,
at least up to some threshold value, and that above that intake
further increases will no longer have any effect on bone mass
accumulation. This concept is illustrated in Figure IV.D.4.4,
which shows, first in Panel A, what the idealized relationship
between intake and bone mass accumulation during growth would
look like, and then, in Panel B, what experiments studying the
effect of calcium intake on bone accumulation during growth have
actually found in laboratory animals.
far as bone is concerned, the optimal intake during growth would
be an intake at or above the threshold, and the RDA would be a
value sufficiently above the average threshold value to
allow for the fact that different individuals will have differing
values at which the threshold occurs. This interindividual variation
reflects differences in absorption efficiency and in ability to
restrict urinary loss.
is important to recognize, in this regard, that calcium intakes
below the threshold value will not necessarily limit growth in
stature. It takes very serious depletion for that effect to occur,
and even then it is hard to be certain that a low intake of calcium
is the responsible factor, since intake of other essential nutrients
is commonly reduced under such circumstances, as well.
happens during growth under conditions of suboptimal calcium intake
is, instead, simply that the skeleton achieves its genetically
programmed external size and shape but is internally flimsier,
meaning the bone cortices are thinner and more porous, and the
trabeculae thinner and more widely spaced. Less mass is spread
over a growing volume and the structure is thus intrinsically
it is relatively easy to do threshold experiments in laboratory
animals (as in Figure IV.D.4.4), it is much harder to do (or to
justify) such experiments in growing children. Instead of the
threshold approach, much of the judgment in regard to calcium
requirement and RDAs during growth has been based upon actual
food practices in populations that seem to be developing "normally."
There is an obvious circularity in that reasoning, because if
current bone mass values are normative, then current intakes are
manifestly sufficient to support "normal" bone development.
Thus current intakes conform with the requirement, the average
child is getting what he or she needs, and all is right in this
best of all possible worlds.
osteoporosis has now reached epidemic proportions in the developed
nations, and failure to develop the peak bone mass genetically
programmed has to be considered a partial explanation. Thus current
intakes, although "normal" in the sense of being usual,
are not necessarily optimal.
the threshold intake. A traditional approach to the determination
of nutrient requirements has been to perform what is technically
referred to as a metabolic balance study a study in which
human subjects live in a laboratory environment and in which intake
and output of the nutrient under study are carefully measured.
The balance between intake and output is computed, and for nutrients
that are not altered by their metabolism, such as minerals like
calcium, that balance is a surrogate for body retention or loss,
that is, skeleton building or destruction.
of the problems with the metabolic balance technique is that although
theoretically ideal, the result that it produces is inherently
imprecise. That problem can be minimized by doing a large number
of such studies, because the uncertainty range about the average
estimate of balance declines as the square root of the number
of studies. But balance studies are so difficult and expensive
to perform that few investigators can accumulate a large enough
experience to give the required precision at the several levels
of intake that must be studied in order to determine the requirement.
Matkovic of Ohio State University has attempted to solve this
problem by assembling all of the published balance studies performed
on growing humans, spanning a 70-year period from 1922 to 1991.
After excluding those that did not meet certain a priori criteria,
he was able to assemble over 500 published studies, a number large
enough to give some reasonable certainty to the estimates and
also to ascertain whether the threshold behavior observed in animals
(Figure IV.D.4.4) is also found in growing humans.
and I, working together on this project, found that the threshold
behavior did, in fact, apply to growing humans, one example of
which is shown in Figure IV.D.4.5. This work also allowed us to
estimate the average threshold intake at various stages during
growth. These threshold values are presented in Table IV.D.4.1,
by age group from infancy through age 30. Equivalently, these
values are average requirements for the population of growing
humans. As already noted, the corresponding values for RDAs would
be higher still. It can be seen that all of the threshold values
in Table IV.D.4.1 are above the current RDAs in the United States.
Nevertheless, intakes at or above these threshold values would
have been common in human hunter-gatherers living in equilibrium
with their environment, and hence, although such intakes would
be atypical by modern standards, they can hardly be considered
evidence. This means of estimating requirements during growth
is probably the best available approach to the problem, and although
it produces values above the current RDAs, it is important to
recognize that its estimates are not, in fact, at variance with
other recent data, which tend to show that, other things being
equal, more calcium intake during growth leads to more bone mass
accumulation. Thus, very recently C. C. Johnston, Jr., and his
colleagues from Indiana University reported results of a double-blind,
placebo-controlled study in identi cal twin children. Calcium
supplementation given to one member of a twin pair produced more
bone mass accumulation than in the unsupplemented twin. A striking
feature of that study was the fact that the unsupplemented members
of each twin pair averaged an intake that was already above the
official RDA for calcium for the age concerned. This behavior
suggests that the official RDA value is below the threshold (see
R. R. Recker and his colleagues from Creighton University have
recently reported results from a longitudinal study of bone mass
accumulation in women aged 20 to 30. They showed both that bone
mass continues to accumulate at a rate of about 1 percent per
year to age 30, and that calcium intake (specifically the calcium-to-protein
ratio of the diet) was the single most important determinant of
how much bone was added during that decade.
age 30 until menopause in women, and from age 30 until the beginning
of senescence in men, the requirement for calcium can be defined
as the intake necessary to offset obligatory losses, or, put another
way, the intake needed simply to keep the body in equilibrium,
neither gaining nor losing calcium. Current estimates indicate
that the mean requirement is in the range of 800 to 1,200 mg/day
for typical Western diets for both men and women. It would probably
be substantially less in individuals who have low protein or low
sodium intakes (or both). This is because, as already noted, both
high protein and high sodium intakes increase urinary calcium
loss and hence decrease the ability of the body to conserve calcium
when calcium intake is reduced.
this observation is not to suggest that calcium is somehow a "good"
nutrient and that protein and sodium are somehow "bad."
Rather, it simply emphasizes that requirements are not abstract
absolute values but are reflections both of metabolic activity
of the organism and of other constituents in the diet.
one can judge from the food habits of contemporary hunter-gatherers,
they would not have had much experience with sodium; however,
high-protein diets would have been common. Meat is a very efficient
food source, rich in many essential nutrients, and some studies
have suggested that for human foragers, protein intake might have
accounted for as much as 35 percent of total calories a
higher intake than even that achieved by typical citizens of developed
nations. But the diet of hunter-gatherers, as has already been
noted, was also very high in calcium, and so a high protein intake
would not have created an effective calcium deficiency as it does
when calcium intake is as low as is commonly found in U.S. diets.
during Postmenopause and Senescence
the declining years, the calcium requirement can no longer be
defined as the intake required to offset obligatory losses. This
is because bone loss occurs now for intrinsic reasons as well
as for homeostatic ones. Even the richest of diets cannot totally
prevent this kind of bone loss.
bone loss. The first example is the bone loss that occurs
in women during the early postmenopause (from cessation of menses
to 510 years later). To the extent that there has been any
controversy or apparent disagreement about the importance of an
adequate calcium intake in adults, that controversy has centered
around what occurs during this brief period in a womans
life. This is a time when typical women lose something approaching
15 percent of the bone mass they possessed immediately before
cessation of ovarian function. Virtually without exception, studies
of calcium intake or calcium supplementation during this time
have shown that calcium has little or no effect on this bone loss.
is now general agreement that bone loss at this time is due almost
exclusively to loss of gonadal hormones. (The same type of loss
follows castration in males.) While many of the details of the
mechanism remain uncertain, it can be said that this loss reflects
a downward adjustment of bone mass to a new steady state, just
as occurs with immobilization. During that approach to a new postmenopausal
equilibrium value, nonhormonal forces, such as calcium or exercise,
are without effect simply because the change in bone mass
is due specifically to the diminution of gonadal hormones and
not to low calcium intake or inadequate exercise. In fact, during
the few years after menopause, so much calcium may be made available
from bone that there may be no external calcium requirement at
all. However, when the new steady state is approached and bone
loss slows, all the old interactions reappear.
conceptual framework was not available to investigators until
recently, which may explain why so many previously published studies
of the effect of calcium chose to address the early postmenopausal
period. Those years are, of course, the time when bone loss is
the most rapid and the value of successful intervention is most
evident, so it is not surprising that it has been extensively
studied. But loss at that life stage is caused by estrogen lack
and is best prevented by estrogen replacement.
Bone loss during senescence in both men and women is a complex
process and has many determinants. This is to some extent true
earlier in life as well, but nonnutritional factors loom larger
during the declining years of life. As a general rule, mechanical
loading on the skeleton decreases with age, in part because older
people do less strenuous work and in part, also, because with
maturity they become more graceful and efficient in what they
do. Thus, some downward adjustment in bone mass simply reflects
a decline in mechanical need. Inevitably that decreases the effective
strength reserve, which is useful to resist the impact of falls.
As already noted, the mechanical adjustment system responds to
current usage, not to potential injury. This type of decline in
skeletal mass is not nutritionally related and, in the practical
order, cannot be appreciably altered by assuring a high calcium
a number of changes also occur in the calcium economy of the aging
person. There is a decline in absorption efficiency at the intestine,
a partial resistance to vitamin D action on the intestine, and
a decrease in the ability to synthesize calcitriol, the active
hormonal form of vitamin D. Additionally, in women who are deprived
of estrogen after menopause, there is deterioration in the ability
to conserve calcium at the kidney. For all of these reasons, older
persons absorb calcium less well from the diet and retain less
of what they do absorb.
means that calcium intake requirement rises in the elderly. Unfortunately,
actual intake tends to go in the wrong direction. With a decline
in physical activity, there is a tendency for food intake itself
to go down, and that almost always reduces the intake of all nutrients,
calcium among them. This combination of increased need and decreased
intake in the elderly sets the stage for intake-related bone loss.
majority of investigations of the relationship of calcium intake
to bone status in the elderly particularly the double-blind,
placebo-controlled trials of B. Dawson-Hughes and her colleagues
at Tufts University and of Petra Elders and her colleagues at
the Free University of Amsterdam show that additional calcium
intake will reduce, to a substantial extent, the degree of bone
loss that is otherwise occurring in ostensibly normal, healthy
individuals. Total intakes shown to be adequate for this purpose
have generally been in the range of 1,000 to 2,000 mg of Ca/day.
As already noted, although such intakes are higher than current
practice, they cannot be considered high when compared with the
typical intakes of our foraging ancestors.
fact that published studies show such a dramatic reduction in
what had otherwise been considered an inevitable, age-related
loss of bone indicates that a substantial fraction of that loss
was not inevitable after all but was diet-related. This conclusion
is even more forcefully emphasized by the findings of three important
European studies. One, performed in France, randomized more than
3,200 elderly women (average age 84) to receive either a placebo
or 1,200 mg calcium plus 800 IU vitamin D. Not only did the supplemented
women stop losing bone, but fractures also declined dramatically
within 18 months of starting treatment. The other studies, one
undertaken in Finland and the other in Switzerland, although differing
somewhat in design from the French study, nevertheless also clearly
showed fracture reduction in elderly individuals given calcium
or vitamin D supplements.
Intake and Bone Remodeling
have already noted that one of the causes of bone fragility is
the accumulation of unrepaired microscopic fatigue damage, something
that occurs inevitably in all structural materials when they are
loaded, but which, given the living character of bone in most
vertebrates, is susceptible of repair. That repair is accomplished
by bone remodeling, which has been visited, so far in this chapter,
mainly as a means of altering bone mass. In fact, bone remodeling
has the dual function of both adjusting mass and replacing damaged
bone. Failure to effect that replacement in a timely fashion permits
fatigue damage to accumulate to the point where serious structural
failure can occur on application of relatively small forces.
this repair depends first upon the bodys ability to sense
the presence of microscopic damage. Available evidence suggests
that the threshold of bone sensitivity to such damage is determined
to a substantial extent by the circulating level of parathyroid
hormone (PTH). But PTH secretion, in turn, is influenced predominantly
by calcium need, and ultimately, therefore, by calcium intake.
Thus, a constant high-calcium diet, particularly with the intake
spread out over the course of the day, leads to low PTH levels,
and therefore to a low sensitivity of the apparatus that detects
fatigue damage. The practical import of these considerations is
not known for certain, but several investigators have expressed
concern about the possible dangers of a constant suppression of
the remodeling process.
could this be a problem if, as already noted, human hunter-gatherers
had calcium intakes substantially higher than we now experience?
Presumably, their PTH levels would have been substantially below
ours. However, there is no fossil evidence that hunter-gatherers
suffered an undue fracture burden. Thus either the PTH levels
in human foragers were not, in fact, constantly low, or the threshold
for detection of fatigue damage is below even the low PTH levels
produced by a chronic high calcium intake. The former seems to
be the more likely explanation.
average calcium intakes would have been high for the hunter-gatherers,
it becomes clear on reflection that under field conditions, food
intake, and thus calcium intake, could not have been a constant
affair. There would have been inevitable periods of fasting and
of environmental scarcity. In fact, the PTH mechanism evolved
precisely to handle such times of calcium need, and its very presence
in mammals may be taken as presumptive evidence of at least periodic
addition to seasonal variation in food availability, females were
subject to the regular predictable calcium drain of pregnancy
and lactation. Another example of periodic need, already cited,
is antler formation in deer. At the beginning of antler formation,
there is a burst of PTH-mediated remodeling throughout the skeleton.
This causes, as it were, a flurry of "spring housecleaning,"
which, if it had not occurred earlier, serves to remodel areas
of fatigue damage that had accumulated in the skeleton over the
preceding year. In this way, antler formation in male deer produces
a drain analogous to that produced by pregnancy and lactation
in female mammals generally.
even superficial reflection serves to make clear that the "natural"
situation would have been one in which PTH is periodically evoked,
and therefore one in which conditions would periodically be right
for resorption and replacement of damaged bone.
however, is not the situation that obtains in civilized, adult,
affluent humans who have few children, who lactate even less often,
and who rarely experience prolonged periods of fasting or deprivation
in other words, typical adults in developed nations. Is
a constant high intake of calcium optimal for these individuals?
One cannot say with any assurance one way or the other. Possibly
a periodic calcium "vacation" might be salutary. Possibly
the once common Christian practice of fasting during Lent and
four times a year at the Ember Days, and the still prevalent practice
among observant Muslims of fasting during Ramadan, may evoke effects
that are as salutary for the body as for the soul.
after Illness, Injury, and Disability
common, if not quite universal, feature of even an affluent, protected,
developed-world life is the fact of injury, illness, and disability,
events that, however temporary and repairable, nevertheless enter
the lives of most humans. Generally, these events are periods
of reduced nutrient intake, sometimes of enhanced excretory loss
of critical nutrients, and often periods of reduced mobility and
physical activity as well. Reduced physical activity always leads
to a reduction in bone mass, even in well individuals; such disuse
loss is aggravated in the presence of illness.
happens during recovery from such episodes? Usually, as far as
a sense of well-being, health, and vigor are concerned, we return
to our former status. But if our regular calcium intake is just
sufficient to maintain equilibrium, that is, to offset daily losses,
then, ipso facto, that intake will not be sufficient to permit
replacement of the bone lost during the preceding illness or disability.
We have no consciousness of our bone mass, so we are unaware that
this part of our bodies has not fully recovered.
episodes of this sort over a persons adult life, and particularly
during the declining years, can contribute significantly to age-related
bone loss. Such loss, however, is not necessarily irreversible
until, as already noted, it proceeds to the point where some of
the bony scaffolding is lost. (Then there is no chance of rebuilding
what was once there.) It would seem important, therefore, to ensure,
during recovery from periodic episodes of illness or disability,
that our calcium intake is augmented, for the simple and obvious
reason that the intake must be sufficient, at that time, not only
to offset obligatory losses but also to replace bone mass lost
during the preceding weeks.
in the Treatment of Osteoporosis
calcium is a necessary component of most treatment regimens for
established osteoporosis, it is rarely sufficient by itself. Calcium
is necessary because it is not possible to restore lost
bone without providing adequate quantities of the building blocks
of bone. That means a high calcium intake. But calcium alone is
rarely sufficient because a high calcium intake suppresses bone
remodeling. Although this suppression helps to stabilize bone
mass and slow bone loss, at the same time it impedes substantial
gain in bone mass. Bone gain requires additional stimulation by
osteogenic factors or medications (such as growth hormone or sodium
fluoride). Then, with that kind of bone-building stimulus, an
adequate calcium intake helps to assure that the weakened bone
can be rebuilt without having to shift calcium from other skeletal
regions robbing Peter to pay Paul, as it were.
might wonder why a high calcium intake is compatible with bone
gain during growth yet does not act the same way in older persons
with established osteoporosis. The answer is simply that during
growth, the body produces large quantities of tissue-building
factors such as growth hormone. These factors are nearly absent
in older persons with osteoporosis. Furthermore, the violent mechanical
loading of the skeleton typical of childhood and adolescence creates
a powerful local stimulus to strengthen the skeleton. By contrast,
a partially disabled, hurting, elderly person with one or more
osteoporotic fractures generally decreases his or her physical
activity a situation that leads to bone loss irrespective
of calcium intake.
of lowered calcium absorptive efficiency both with age and with
decreased physical activity, generally large quantities of calcium
are required as part of an osteoporosis treatment regimen. The
exact quantities are uncertain, but they probably fall in the
range of 1,500 to 2,500 mg/day. This is more than most persons
with restricted activity can get from readily available foods,
and some resort will usually have to be made to calcium-fortified
foods or to calcium supplement tablets.
bony fragility is not confined to Caucasians, it is much more
common among whites than among blacks or Asians, and among Caucasians
it is more common among those of northern European ancestry. Partly
for these reasons, most of the research relating calcium to osteoporosis
has been done in Caucasians. Despite a generally lower calcium
intake than their white counterparts, blacks in the United States
have heavier bone mass at all ages, from infancy onward. Moreover
blacks, both in Africa and in the United States, have lower fracture
rates than whites, even after correcting for differences in bone
mass. Asians have bone mass values at least as low as Caucasians
and seem to lose bone with age much as do whites, but available
data suggest that fragility fractures, particularly hip fractures,
are less common among them. These ethnic differences in fracture
rate probably reflect the fact, noted earlier, that fragility
has many bases, and that it takes more than just bone loss to
result in a fracture. For example, the angled upper segment of
the femur is shorter in Asians than in Caucasians. Engineering
analysis has shown that long upper segments are structurally weaker
than short ones. This difference, based ultimately in genetics,
has a mechanical, structural basis, rather than a nutritional
blacks have been studied somewhat more intensively than other
non-Caucasian groups, and thus more is known about their calcium
economy. Norman Bell and his colleagues at the Medical University
of South Carolina have shown that at least a part of the explanation
for their greater bone mass is a generally higher resistance of
their bones to serve as a calcium reservoir. Thus, in maintaining
extracellular fluid calcium levels, blacks require a higher level
of PTH to release calcium from bone than do whites. As noted earlier,
PTH also enhances both intestinal absorption and renal conservation
of calcium. Thus the higher PTH levels of blacks result in better
utilization of dietary calcium, with a consequent skeletal-sparing
is a nutrient, not a drug. The only disorder it can be expected
to prevent or alleviate is calcium deficiency. The skeleton serves
both as structural support for our bodies and as a reserve of
calcium needed to maintain the constancy of body fluid calcium
levels. Calcium deficiency, as it affects us, is a reduction in
the size of the reserve and thus in its structural strength. An
adequate intake will ensure that calcium deficiency will neither
cause skeletal weakness in its own right nor aggravate the weakness
produced by other causal factors. But calcium will not prevent
or reverse the bone loss and fragility due to other factors. The
evidence indicates that calcium deficiency is prevalent in the
adult populations of Europe and North America and that it contributes
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