Robert P Heaney. Cambridge World History of Food. Editor: Kenneth F Kiple & Kriemhild Conee Ornelas. Volume 1. Cambridge, UK: Cambridge University Press, 2000.
Calcium and Life
Calcium 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.
At 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.
Bone and the Regulation of Calcium Levels
Each 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 prominent features.
The 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.
But 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 fluids.
While 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.
Once 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.
Calcium Abundance in the Diets of Terrestrial Vertebrates
Calcium 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.
By 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.
But 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 stand-point).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.
The 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.
Bone Remodeling and Bone Mass
Bone 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.” Remodeling occurs throughout life and serves several essential functions.
In 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.
Bone 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 site.
Remodeling 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).
The 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.
Parathyroid 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.
The activity of maintaining the constancy of extra-cellular fluid calcium concentration is termed “calcium homeostasis.” The body’ s 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.
Given 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.
Averaged 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 “cash-flow” problem.
So 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.
Intrinsic Control of Skeletal Mass
While 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.
How 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).
The 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.
Both 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.
This 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 homeo-static 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 bumps.
Definition and Expression
Osteoporosis 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.
The 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.
Bases for Bony Fragility
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 ultra-microscopic 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.
In 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 stiffness.
Interactions 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.)
Until 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.
Nevertheless, 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 inadequacy.
Osteoporosis: A Disorder of a Nutrient Reserve
Although 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.
The 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.
One 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.
A 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.
The Bases for a Calcium Requirement
Because 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.
As mentioned previously, foods available to high primates and hunter–gatherer 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 hunter–gatherer 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 ingests.
Only 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.
Intestinal 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.
Furthermore, 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.
This 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 juices.
The 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.
The 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 hunter–gatherer 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 absorptive efficiency.
Some 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.
Renal 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.
Urine 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.
Urine 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.
The 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 Allowances
A 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 needs.
The 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 recalling 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.
Requirements during Growth
Threshold 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.
As 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.
It 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.
What 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 weaker.
While 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.
However, 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.
Estimating 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.
One 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.
Velimir 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.
He and I, working together on this project, found that the threshold behavior did, in fact, apply to growing humans. 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 unnaturally high.
Corroborating 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 identical 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.
Similarly, 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.
Requirement during Maturity
From 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.
Incidentally, 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.
If 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.
Requirements during Postmenopause and Senescence
During 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.
Menopausal bone loss. The first example is the bone loss that occurs in women during the early post-menopause (from cessation of menses to 5–10 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 woman’ s 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.
There 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.
This 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.
Senescence. 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 intake.
However, 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.
This 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.
The 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.
The 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.
Calcium Intake and Bone Remodeling
We 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.
Effecting this repair depends first upon the body’ s 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.
How 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.
Although 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 calcium deprivation.
In 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.
Thus, 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.
That, 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.
Recovery after Illness, Injury, and Disability
One 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.
What 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.
Periodic episodes of this sort over a person’ s 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.
Calcium in the Treatment of Osteoporosis
Although 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.
One 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.
Because 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.
Although 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 one.
American 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 effect.
Calcium 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 in an important way to their osteoporotic fracture burdens.