Herta Spencer. Cambridge World History of Food. Editor: Kenneth F Kiple & Kriemhild Conee Ornelas. Volume 1, Cambridge University Press, 2000.
This chapter deals with the history of calcium and its metabolism in adult humans. It should be read in conjunction with Chapter IV.D.4 on osteoporosis, which contains a further discussion of calcium requirements and the effects of a deficiency in adults, and with Chapter IV.A.4 on vitamin D, which deals with the history of rickets, a disease caused in part by a deficiency of calcium resulting from reduced intake or poor absorption.
Bone is the main depository of calcium. Fully 99 percent of the body’s calcium is in the skeleton, with the rest in extracellular fluid and soft tissues. As early as the sixteenth century, it was recognized by a Dutch physician that the skeleton is not an inactive but a dynamic tissue under hormonal influence and capable of remodeling throughout life (Lutwak, Singer, and Urist 1974). Two specific types of bone cells acted upon in these processes are the osteoblasts (involved in bone formation) and the osteoclasts (involved in bone resorption).
Another important discovery in the history of calcium was made by Sidney Ringer more than 100 years ago. He demonstrated that the contractility of cardiac muscle was stimulated and maintained by the addition of calcium to the perfusion fluid (Ringer 1883). It has also been shown that this important effect of calcium is not limited to cardiac muscle but has a generalized, activating effect in practically all differentiated cells (Opie 1980; Rubin 1982; Campbell 1986). However, in addition to calcium, the presence of specific concentrations of sodium and potassium are needed to achieve this effect (Mines 1911; Lowenstein and Rose 1978).
The state of calcium in the body investigated many decades ago has been subsequently summarized (“The Classic” 1970). The amount of calcium in the body is greater than that of any other positively charged mineral (1,160 grams [g]). Its place of storage is the skeleton, although the small amounts present in the compartments of the extracellular fluid and those of the soft tissues are of great physiological importance because the calcium stored in bone maintains equilibrium with other calcium pools in the body (Rubin 1982).
The interaction and balance of vitamin D, calcitonin, and parathyroid hormone (PTH) are the pillars of normal calcium metabolism, and they play an important role in maintaining a highly controlled calcium homeostasis and normal serum calcium level. This process is based on the direct or indirect action of these substances on the skeleton. Vitamin D is produced by ultraviolet radiation of sunlight on the skin, which yields the vitamin D precursor ergosterol (Hess and Weinstock 1924).The hormones calcitonin and PTH are created, respectively, by the C cells of the thyroid gland and by the parathyroid glands. A deficiency as well as an excessive production and secretion of these three substances can lead to the development of specific disease states.
Vitamin D, discovered at the beginning of the third decade of the twentieth century, is the substance that acts to prevent rickets. Many of the original reports of the discovery of vitamin D have been republished (Robertson 1969; Pramanik, Gupta, and Agarwal 1971) and are cited here for those who wish to consult them. In addition, the early discovery of the physiological importance of calcium (Ringer 1883) has been redescribed (Fye 1984; Ebashi 1987). The chemical structure of vitamin D was identified by a German chemist, Adolf Windaus, in 1931, and the subsequent commercial production of vitamin D practically eliminated the occurrence of rickets—the vitamin D deficiency disease of children—although treatment with cod-liver oil (rich in vitamin D) also played an important role in the eradication of this disease.
Even though our basic knowledge of vitamin D was obtained between 1919 and 1924, it was not until the 1960s that the vitamin D metabolites were discovered (Lund and DeLuca 1966; Ponchon and DeLuca 1969; Olson, Jr., and DeLuca 1973; DeLuca 1979, 1980, 1988). H. F. DeLuca postulated that vitamin D must be hydroxylated first in the liver and subsequently by 1-alpha-hydroxylation in the kidney to produce the vitamin D hormone 1-alpha-25-dihydroxyvitamin D3,1,25(OH)2D3. This is the important vitamin D metabolite that actively affects the absorption of calcium from the intestine. Further studies regarding the mechanism of calcium absorption from the intestine are credited to R. H. Wasserman, who discovered the vitamin D–dependent “calcium binding protein” (CaBP) in the duodenum (Kallfelz, Taylor, and Wasserman 1967; Wasserman, Corradina, and Taylor 1968; Wasserman and Taylor 1968).
Rickets, caused by vitamin D deficiency, was produced experimentally in the 1920s, and much was learned about this illness, which occurs in infancy and childhood at ages of rapid growth (Sherman and Pappenheimer 1921; Steenbock and Black 1924; Pettifor et al. 1978; Pettifor and Ross 1983). Rickets was common in the early part of the twentieth century, and more than 100 years ago it was recognized that a lack of sunlight was responsible, particularly in northern latitudes, where deprivation is most likely to occur. It was also noted that sunlight is curative (Palm 1890; Huldschinsky 1919; Mellanby 1921).
Symptoms of rickets include impaired calcification and excess formation of cartilage in areas of bone growth.The adult form of the disease is called osteomalacia, in which newly formed osteoid does not calcify. This occurs in persons who voluntarily or for other reasons are homebound and therefore not exposed to sunlight.
Several early investigators stated that both rickets and osteomalacia can also be caused by a nutritional deficiency of calcium (McCollum et al. 1921; Theiler 1976; McCollum et al. 1995). Although such a situation would be uncommon, it is possible that the theory was proposed because healing of rickets occurred when a low, insufficient calcium intake of barely more than 100 milligrams (mg)/day was raised to 1,200 mg/day with the simultaneous use of vitamin D. More recent investigators believed it unlikely that vitamin D deficiency alone could produce rickets or osteomalacia but that these diseases occur when there is coexistent calcium deficiency (Pettifor et al. 1981).
The hormone calcitonin was discovered in 1962 by Harold Copp, who reported that it originates in the parathyroid glands (Copp et al. 1962; Copp 1967, 1969). Calcitonin decreases the calcium level in blood, and this effect was ascribed to decreased bone resorption.The first report of the use of calcitonin in humans came shortly after its discovery (Foster et al. 1966), and further studies revealed that this hormone actually originates in the C cells of the thyroid gland—which, for a while, gave rise to the use of the name “thyrocalcitonin” (Hirsch and Munson 1969). It has been shown experimentally that calcitonin affects not only bone resorption but also bone formation (Baylink, Morey, and Rich 1969).
Because of the ability of calcitonin to cause a decrease in bone resorption, it has been utilized in the treatment of patients with Paget’s disease—a deforming and frequently disabling bone disease diagnosed in England more than a century ago (Paget 1877; Bijvoet, Van der Sluys Veer, and Jansen 1968; Shai, Baker, and Wallach 1971; Woodhouse Bordier, et al. 1971). Two available types of calcitonin, primarily salmon calcitonin but also porcine calcitonin, have been joined by human calcitonin. All three types have been (and still are) used in investigative studies of their comparative effectiveness in treating Paget’s disease.
Parathyroid hormone (PTH), discovered in the early 1920s (Collip 1925), consists of four small pea-sized structures, two of which are located on the upper pole and two at the lower pole of each thyroid lobe. When parathyroid glands, which produce PTH, are functioning normally, the level of secretion depends on the serum calcium level, which in turn depends, in part, on the fraction of the dietary calcium that is absorbed from the intestine and the amount of calcium released from the skeleton by bone resorption. The dietary contribution of calcium to the serum calcium level influences the extent of bone resorption that is induced by PTH to maintain the well-controlled homeostasis of the normal serum calcium level.
The most common clinical aberration of calcium metabolism in hyperparathyroidism is a high level of serum calcium, a low level of serum phosphorus, and frequently, but not invariably, elevated levels of the serum enzyme alkaline phosphatase. There may also be evidence of bone loss on roentgenograms (which can mimic osteopenia) and, more rarely, cystic bone lesions. Kidney stone formation and peptic ulcer of the stomach may also result.
When there is hyperfunction of any of the four parathyroid glands, and excess PTH is secreted, a pathological condition develops that is called primary hyperparathyroidism. This endocrine disorder that affects bone metabolism (primarily the metabolism of calcium and phosphorus) was discovered in the early 1920s in Vienna and discussed in print two years later (Mandl 1926). In 1925, the condition was observed in the United States (Hannon et al. 1930), and shortly after, the first series of patients with hyperparathyroidism in the United States was described (Albright, Aub, and Bauer 1934). A classic study of the parathyroid glands followed in the late 1940s (Albright and Reifenstein 1948).
The symptoms and the treatment of hyperparathyroidism have been extensively discussed in older medical textbooks, which state, as did the classic article by F. Albright, J. C. Aub, and W. Bauer in 1934, that the cause of primary hyperparathyroidism is the enlargement of one or more of the parathyroid glands to form a benign tumor (an adenoma) or a multiple adenomata. However, we now know that the adenoma of a single parathyroid gland or multiple adenomata of the parathyroid glands are the result of hyperfunction of the parathyroid glands—the increased secretion of PTH. The conventional treatment for primary hyperparathyroidism is the surgical removal of the enlarged parathyroid gland or glands.
Reports in the literature also attest to the importance of the role of vitamin D in normal parathyroid function (Mawer et al. 1975).There are also reports of vitamin D deficiency in hyperparathyroidism (Woodhouse, Doyle, and Joplin 1971; Lumb and Stanbury 1974; Mawer et al. 1975; Stanbury 1981), and the use of vitamin D has been recommended for the medical treatment of patients with primary hyperparathyroidism (Woodhouse et al. 1973).
The nutritional importance of calcium for normal growth and maintenance has been recognized since studies were carried out with experimental animals several decades ago. Those studies that focused on the human calcium requirement, for example, were conducted as early as the 1920s (Sherman 1920), and the importance of calcium in the human metabolism (and its use in therapy) was recognized in the early 1930s (Cantarow 1933). Subsequently, it was shown that a nutritionally high calcium intake resulted in an increased growth rate of children (Stearns, Jeans, and Vandecar 1936; Jeans and Stearns 1938).Textbooks on the importance of calcium began to appear by the late 1930s (Shohl 1939), and the effect of dietary factors on the intestinal absorption of calcium was examined in the early 1940s in a study demonstrating that the presence of dietary protein is necessary for the intestinal absorption of calcium (McCance, Widdowson, and Lehmann 1942).
Early in the 1950s, the interaction in humans of dietary calcium with phosphorus was investigated (Leichsenring et al. 1951), and at about the same time, two studies of the human calcium requirement were carried out in prisons, one in Peru (Hegsted, Moscoso, and Collazos 1952) and one in Scandinavia (Malm 1958). Both of these investigations reported a very low calcium requirement of about 250 mg/day. However, shortly thereafter, it was made clear that a calcium intake of 1,000 mg is necessary to achieve calcium balance (Whedon 1959).
The calcium requirement for skeletal maintenance was investigated at the beginning of the 1970s (Garn 1970), and this study was followed by a determination of the calcium requirement both for middle-aged women (Heaney, Recker, and Saville 1977) and for elderly people (Heaney et al. 1982). In 1984, a strictly controlled metabolic study revealed that 800 mg/day of calcium is insufficient for middle-aged men and that an intake of 1,200 mg is desirable (Spencer, Kramer, Lesniak, et al. 1984). This recommendation was subsequently adopted at a National Institutes of Health Consensus Conference (1995).
As hinted at by the prison studies already mentioned, some investigators believed that humans can adapt to a long-term low calcium intake. Experimentally, however, this was not found to be the case at a calcium intake of 200 mg/day in adults (Spencer and Kramer 1985). It is important to note that bioavailability of calcium for absorption is greatly reduced by substances such as fiber (in large amounts) and phytate in food (Harrison and Mellanby 1934; Mellanby 1949; Ismail-Beigi et al. 1977; Cummings 1978). The negative effect of phytate on calcium has been extensively investigated (Reinhold et al. 1973), but it has also been shown that calcium bioavailability depends on the availability of trace minerals such as copper, iron, and manganese (Strause et al. 1994), and that deficiencies of these trace elements decrease the calcium concentration in bone. The trace element zinc, for example, affects intestinal absorption of calcium in humans (Spencer et al. 1987; Spencer, Norris, and Osis 1992).
The impact of other substances—such as lactose—on the absorption of calcium was reported as early as 1940 (Mills et al. 1940), and 20 years later, a follow-up report was published (Greenwald, Samachson, and Spencer 1963). An extensive review of human calcium requirements was published in the early 1970s (Irwin and Kienholz 1973), and other such surveys have subsequently appeared (Bronner and Peterlik 1995; Bronner and Stein 1995).The suggested recommended dietary allowance (RDA) of calcium in the United States is determined by the Food and Nutrition Board of the National Academy of Science.
Osteoporosis is the most common systemic bone disorder in the United States, affecting an estimated 20 million women and perhaps 10 million men. The incidence of osteoporosis is highest for women in the decade after menopause. It occurs much later in men—between the seventh and eighth decades of life. The high incidence of osteoporosis is a major public health problem because of serious complications that may require extensive and costly medical care. The bone loss in women at middle age and older is the result of hormonal deficiency (the loss of estrogen), aging, and other factors that appear to play an important role in causing—or intensifying—the loss of calcium from the skeleton. It has become more and more evident that sufficient calcium intake over the years can play a major role in preventing osteoporosis in later life (Matkovic et al. 1979; Sandler et al. 1985).
The disease develops insidiously over many years, is often asymptomatic, and is frequently discovered accidentally during radiological examination for unrelated medical conditions (Spencer and Kramer 1987). Unfortunately, this means that treatment of osteoporosis is frequently delayed until it is quite advanced, and it may not be detected until complications such as skeletal fractures arise. In the past, physicians assumed that there was no effective treatment available for this disorder. However, in recent years, effective therapeutic modalities have become available for the treatment and even for the prevention of the disease. Among the newer treatment modalities are the biphosphonates (Fogelman et al. 1986; Francis 1995).
When the diagnosis of bone loss is established roentgenographically, osteoporosis is usually advanced, because 30 percent of bone mineral must be lost before the loss will show up on conventional skeletal X rays. The vertebral bodies show poor mineralization and become biconcave; adjacent vertebrae have a “fish-mouth” appearance; and there may be wedging of the involved vertebrae. These changes in bone structure are usually associated with loss of body height, kyphosis, deformity of the chest, and the presence of a “dowager’s hump.” Routine X rays of the skeleton are not reliable indicators of bone density because of differences in techniques and in subjective interpretations of X-ray findings.
When demineralization of bone is seen on an X ray, this finding does not differentiate between osteoporosis and other demineralizing bone diseases, such as multiple myeloma or hyperparathyroidism. Reliable methods—such as bone density measurements using single and double photon absorptiometry and determining the cortical index—are now available for diagnosing osteoporosis earlier and with more precision than the use of conventional radiographs offers. However, photon absorptiometry (Mazess et al. 1988) is not routinely done because the equipment is not available in all medical centers. Cortical index measurements can be determined by analyzing X rays of the hand and by relating the cortical thickness to the total width of the metacarpal bone.
Another method of determining bone density is radiographic absorptiometry, which utilizes radiographs of the hands and a computer scanner. Newer, sophisticated methods of analyzing bone mass are available in specialized centers. In general, X rays of the thoracic and lumbar spine can indicate the potential existence of postmenopausal osteoporosis. Bone biopsies (needle biopsies) can establish the differential diagnosis of osteoporosis, but this technique is invasive and not acceptable to many patients.
As already noted, a low calcium intake, over prolonged periods of time, results in calcium loss from the skeleton and in a negative calcium balance (Table IV.B.1.1). This condition has an adverse effect on the maintenance of the normal bone structure, and a continued loss of calcium from the skeleton results from bodily efforts to maintain a normal serum calcium level. Moreover, a low calcium intake stimulates the parathyroid glands to excess secretion of PTH, which in turn leads to increased bone resorption in order to maintain the homeostasis of the normal serum calcium level.
Table IV.B.1.1. Calcium balances of males and females during a low calcium intake
The retention of calcium from a high calcium intake, however, is frequently lower for those with osteoporosis than it is for nonosteoporotic subjects or for patients who suffer from other conditions of bone loss, such as hyperparathyroidism or hyperthyroidism. The absorption of calcium from the intestine is decreased in elderly persons, including osteoporotic females.This appears to be caused in part by a relative vitamin D deficiency that occurs with aging (Tsai et al. 1984) but may also result from generalized functional changes of the intestinal mucosa with age, relating to the absorbability of nutrients in general.
Yet even when calcium is administered by the intravenous route (bypassing the intestine), the retention of calcium is low in osteoporotic patients, indicating the inability of the skeleton to accept the added calcium that has entered the circulation directly (Spencer, Hausinger, and Laszlo 1954). Blood levels of the active vitamin D metabolite 1,25(OH)2D3 have been shown to be low in these patients (Tsai et al. 1984). In the differentiation of calcium loss in conditions other than osteoporosis, the determination of urinary hydroxyproline and of free cortisol levels may be helpful.
Although calcium is the major mineral of the bone structure, other minerals—such as phosphorus, magnesium, zinc, and fluoride—are also important because of the interaction of calcium with these elements and their specific functions in the body. Before these interactions are considered, however, the calcium requirement—the amount of calcium needed to maintain a normal calcium status—requires some attention. The data employed in the following discussion were derived from studies carried out under strictly controlled dietary study conditions in the Metabolic Research Unit at the Veterans Administration (VA) Hospital at Hines, Illinois.
The Calcium Requirement
An adequate intake of calcium throughout life has been shown to play an important role in maintaining the normal bone structure and to contribute to the peak bone mass that is achieved at between 25 and 30 years of age (Heaney 1982; Heaney et al. 1982). The bone mass begins to decline after age 35, and this decrease accelerates in females after the menopause. One can safely assume that the adverse and deleterious effects of aging on the bone mass and on the bone structure would be diminished in advancing age if the skeleton could be more robust at the time when the inevitable and accelerated bone loss begins.
In view of these considerations, the questions arise: What should be the daily calcium intake for the elderly? Is the RDA for calcium adequate for this age group (National Research Council 1989)? For calcium, the RDA for young persons up to the age of 24 years is 1,200 mg, but it is reduced to 800 mg/day for all age groups after age 25, including elderly women (National Research Council 1989). It therefore has seemed important to examine whether the 800 mg calcium intake is adequate to maintain a normal calcium balance at middle age (and to prevent excessive calcium and bone loss) and thereby maintain a normal calcium status and a normal skeletal structure in women with advancing age.
Our studies showed that the calcium balance of middle-aged males was only slightly positive, +30 mg/day with an intake of 800 mg calcium (Table IV.B.1.2)—without considering the dermal loss of calcium, which is usually not determined in metabolic balance studies. The latter is stressed because in calcium balance studies, only the urinary and fecal calcium excretions are determined, and the sum of these excretions is related to the calcium intake. A large percentage of these fully ambulatory middle-aged males (34 percent) were in negative calcium balance at the 800 mg/day intake level. Increasing the calcium intake from 800 to 1,200 mg/day resulted in a significant increase of the calcium balance (Spencer, Kramer, Lesniak, et al. 1984). Yet adding another 800 or even 1,100 mg calcium to the 1,200 mg intake did not significantly improve the calcium balance (Table IV.B.1.2). Such a plateau of the calcium balance at the 1,200 mg calcium intake indicates a threshold for the intestinal absorption of calcium at this level (Spencer and Kramer 1987).
Table IV.B.1.2 also shows that urinary calcium was the same whether the calcium intake was 800, 1,200, or 2,000 mg/day. Only when the calcium intake was increased further—to 2,300 mg/day—did urinary calcium increase. This point is emphasized because of the widespread—and unjustified—concern that increasing the calcium intake beyond the 800 mg level may result in kidney stone formation. Such a concern does become important, however, if there is a history of kidney stone formation or even a family history of renal stones, because a certain percentage of kidney stone formers are hyperabsorbers of calcium.
Although these findings came from studies carried out in an all-male VA hospital, there is no reason to assume that they would not also apply to females of similar age (average 54 years) or older. Indeed, in view of the large percentage of the male subjects with negative calcium balances at the 800 mg calcium intake level, and in view of the known calcium loss suffered by middle-aged and older women, it seems clear that the calcium intake of older women should be at least as great as that of considerably younger persons—that is, 1,200 mg/day (National Research Council 1989). Thus, some have recommended that the calcium intake of postmenopausal women should be increased to 1,500 mg/day (Heaney 1982).
Table IV.B.1.2. Studies of the calcium requirement
Note: Calcium intake greater than 250 mg was due to the addition of calcium gluconate tablets to the constant low-calcium diet.
It is also important to consider that although calcium intake may be adequate, there are certain factors that influence the utilization of calcium. The following subsections describe the effects of various minerals, nutrients, and drugs—phosphorus, magnesium, fluoride, zinc, strontium, protein, alcohol, and medications—on the metabolism of calcium.
The mineral phosphorus is present in practically all cells of the body and is closely linked to the metabolism of both calcium and protein. The main storehouse of phosphorus is the skeleton, and the bone crystal hydroxyapatite consists of calcium phosphate. But significant amounts of phosphorus are also contained in the soft tissues. Calcium cannot be retained by itself in bone but is retained together with phosphate. In fact, in calcium balance studies, the retention of calcium improved during high phosphorus intakes (Spencer et al. 1965; Spencer, Kramer, Osis, et al. 1978a).
These observations were made during a high phosphorus intake of 2,000 mg/day, compared with a phosphorus intake of 800 mg/day in the control study. But although the phosphorus intake was increased by a factor of approximately 2.5 (from 800 to 2,000 mg/day) in these investigations, no adverse effect of phosphorus on calcium absorption or calcium balance was observed, regardless of whether the high phosphorus intake was given during a very low calcium intake of 200 mg/day or during a high calcium intake of 2,000 mg/day (Spencer et al. 1965; Spencer, Kramer, Osis, et al. 1978a).
With a high phosphorus intake, fecal calcium was slightly but not significantly increased. Therefore, the intestinal absorption of calcium, determined with tracer doses of 47Ca, was also not decreased (Spencer Kramer, Osis, et al. 1978a). This result is in contrast to the general unjustified belief that a high phosphorus intake decreases humans’ intestinal absorption of calcium. Such an assumption is based primarily on animal studies (Draper, Sie, and Bergan 1972; LaFlamme and Jowsey 1972).
The difference in effect, however, points out the difficulty and unreliability of extrapolating animal data to humans. Very few, if any, strictly controlled dietary studies of the effect of phosphorus on calcium absorption have been carried out in humans, and it is possible that amounts of phosphorus greater than 2,000 mg/day may have adverse effects on calcium absorption. The recently reported beneficial effect of biphosphonates in the treatment of osteoporosis (Watts et al. 1990) may result from the action of phosphate in inhibiting bone resorption by decreasing the activity of the osteoclasts (the bone-reabsorbing cells) (Hodsman 1989). Inorganic phosphate has been reported to have this effect (Yates et al. 1991). The usual dietary phosphorus intake is approximately 1,200 mg/day, most of it from proteins in dairy products and meat.
The main impact of added phosphorus on calcium metabolism is a consistent decrease in urinary calcium, regardless of whether the high phosphorus intake occurs during a low or high calcium intake (Goldsmith et al. 1967; Goldsmith et al. 1969; Spencer, Kramer, Osis, et al. 1978a).The decrease in urinary calcium during a high phosphorus intake is usually believed to reflect decreased calcium absorption. However, as already noted, the intestinal absorption of calcium did not decrease during a high phosphorus intake (Spencer, Kramer, Osis, et al. 1978a). Although there was a slight increase in fecal calcium during the high phosphorus intake in our studies (Spencer et al. 1965; Spencer, Kramer, Osis, et al. 1978a), this increase was not significant.
Several factors other than a decrease in calcium absorption can contribute to the decrease in urinary calcium during a high phosphorus intake; these include decreased bone resorption, increased mineralization, and increased bone formation (Pechet et al. 1967; Flanagan and Nichols 1969). As the intestinal absorption of calcium did not decrease during different high phosphorus intakes up to 2,000 mg/day, the dietary Ca:P ratio does not appear to play an important role in the intestinal absorption of calcium. This viewpoint was also expressed in 1962 by the World Health Organization.
The importance of phosphorus in human health and in calcium metabolism is indicated by the deleterious effects of phosphorus depletion, which is most commonly induced by the use of medications such as aluminum-containing antacids. Even relatively small doses of such antacids induce a considerable loss of calcium (Spencer, Kramer, Norris, et al. 1982). In addition, small doses—as well as larger therapeutic doses (Lotz, Zisman, and Bartter 1968)—induce phosphorus depletion by the complexation of phosphate through aluminum in the intestine. This is evidenced by a very significant increase in fecal phosphorus, which may be as great as the entire dietary phosphorus intake (Table IV.B.1.3).
The loss of phosphorus via the intestine may lead to its removal from bone in order to maintain the phosphorus level in tissues, enzymes, and plasma. The removal of phosphorus from bone appears to be associated with simultaneous removal of calcium from the skeleton, resulting in an increase in urinary calcium and a negative calcium balance. Thus, significant bone loss has been observed in patients who have taken commonly used aluminum-containing antacids for prolonged periods of time.
The prolonged use of intravenous fluids in the absence of food intake may also result in phosphorus depletion, which is associated with clinical symptoms of weakness and fatigue. To our knowledge, no data are available on the relationship of this type of induced phosphorus depletion and calcium metabolism.
Magnesium is an essential nutrient of great importance in controlling normal cardiac rhythm and cardiovascular function. A low magnesium status has been associated with cardiac arrhythmia as well as with cerebrovascular spasm (Altura and Altura 1981). The RDA for magnesium is 300 mg for women and 400 mg for men (National Research Council 1989). Bone is an important repository for magnesium.
Table IV.B.1.3. Effect of aluminum-containing antacids on the calcium and phosphorus balance
|Calcium, mg/day||Phosphorus, mg/day|
aAluminum-magnesium hydroxide, 30 ml three times daily.
bEvery hour while awake (15 doses = 450 ml per day).
Magnesium balance studies have shown great variability of the magnesium balance in different individuals, regardless of magnesium intake. During a relatively low magnesium intake of about 220 mg/day, the magnesium balance is usually negative. However, equilibrium or even positive magnesium balances have been observed during a low magnesium intake in our studies on male subjects (Spencer, Lesniak, Kramer, et al.1980).
The intestinal absorption of dietary magnesium is approximately 50 percent of its intake in persons with normal renal function, regardless of calcium intake (Spencer, Schwartz, and Osis 1988). In contrast, patients with chronic renal failure absorb considerably less magnesium, about one-third that of those with normal renal function (Spencer, Lesniak, Gatza, et al. 1980). It appears that magnesium balance depends on both the present and the past magnesium status of the individual. This was demonstrated by increasing the magnesium intake in adequately nourished subjects from a low of 220 to a relatively high 800 mg/day. Such an increase, however, did not improve magnesium balance when compared with intakes of 220 to 300 mg/day. It would appear, therefore, that the diet of these patients prior to the magnesium absorption studies contained an adequate amount of magnesium.
The interaction of magnesium with calcium warrants discussion because magnesium has been reported to have variable effects on the intestinal absorption of calcium. Reports of some animal studies have suggested that magnesium decreases the intestinal absorption of calcium (O’Dell 1960). But other studies have indicated no change in humans (Schwartz et al. 1973), and still others have reported an increase in calcium absorption. Our investigations under controlled dietary conditions have shown that increasing the magnesium intake more than threefold—from 220 to 860 mg/day—had no effect on the intestinal absorption of calcium (Spencer et al. 1994).
Changing the focus to the effect of calcium on magnesium metabolism, we find reports of the intestinal absorption of magnesium being impaired by calcium in animals (Morris and O’Dell 1961). By contrast, however, our studies on humans—employing both magnesium balance studies and tracer studies using radioactive magnesium (Mg28)—have conclusively shown that both intestinal absorption of magnesium and the magnesium balance did not change when the calcium intake was increased from 200 to 800 and even to 2,000 mg/day (Schwartz et al. 1973).
As phosphorus and calcium are closely linked, the effect of phosphorus on the metabolism of magnesium might warrant brief mention. Whereas phosphorus, like calcium, decreased the absorption of magnesium in animals (O’Dell 1960), increased amounts of phosphorus—up to 2,000 mg/day—had little effect on the magnesium balance of humans (Spencer, Lesniak, Kramer, et al. 1980), regardless of whether these studies were carried out during a low or high calcium intake. However, a high magnesium intake led to increased fecal phosphorus excretion and to a less positive or even negative phosphorus balance, probably because of the formation of magnesium-phosphate complexes in the intestine. But despite this effect, the calcium balance was not affected (Spencer et al. 1994). Further studies of the effect of magnesium on phosphorus metabolism in humans are needed. Such studies should seek to determine at which level a high magnesium intake has adverse effects on phosphorus metabolism and, potentially therefore, on calcium metabolism.
Fluoride enters the human food chain because of the fluoride content of water and soil. The skeleton is its major repository in the body. Not only is fluoride beneficial in preventing dental caries in children, but there is evidence that it is also important in maintaining the normal bone structure (Zipkin, Posner, and Eanes 1962). Consequently, fluoride affects the metabolism of calcium. Surveys in the United States and in Finland have demonstrated that the prevalence of osteoporosis is lower in places where the water is naturally high in fluoride content than in areas where this condition does not obtain (Bernstein, Sadowsky, and Hegsted 1966).
Because the main storehouse of fluoride is the skeleton, where it is incorporated in the bone crystal hydroxyapatite (leading to its increased strength) (Zipkin et al. 1962), fluoride has been used for the treatment of osteoporosis since the early 1960s (Rich, Ensinck, and Ivanovich 1964; Spencer et al. 1970). As fluoride may interact with various minerals, such as calcium, phosphorus, and magnesium, we investigated the human metabolism of fluoride during the intake of these inorganic elements. During a fluoride intake as high as 45 mg/day (taken as sodium fluoride), the single effect on calcium metabolism was a decrease in urinary calcium, whereas no change occurred in fecal calcium, the intestinal absorption of calcium, and endogenous fecal calcium (the amount of the absorbed calcium excreted into the intestine) (Spencer et al. 1970). There was also little change in the calcium balance, which depended on the decrease in urinary calcium during the high fluoride intake. Increasing phosphorus intake by a factor of 2.5, from 800 to 2,000 mg/day, had no effect on the fluoride balance, regardless of calcium intake (Spencer et al. 1975). Also, increasing magnesium intake approximately threefold during a high fluoride intake had no effect on the fluoride balance (Spencer, Kramer, Wiatrowski, et al. 1978). Several biochemical and therapeutic aspects of the fluoride metabolism in humans have been summarized (Spencer, Osis, and Lender 1981).
The importance of the trace element zinc in human health and nutrition has been emphasized in recent decades. The RDA of zinc is 15 mg/day for men and 12 mg/day for women (National Research Council 1989). Zinc and calcium appear to have the same binding sites in the intestine, and, therefore, the absorption and utilization of one may be inhibited by the other. Animal studies have shown that calcium inhibits the intestinal absorption of zinc (Hoekstra et al. 1956; Luecke et al. 1957), but our studies on humans demonstrated that calcium had no effect on the absorption of zinc (Spencer, Kramer, Norris, et al. 1984). Similarly, phosphorus—used in amounts of up to 2,000 mg/day, alone or combined with the same amount of calcium—did not affect the zinc balance nor the net absorption of zinc (Spencer, Kramer, Norris, et al. 1984). These findings contrasted with those obtained in animal studies, with the different results apparently arising from differences in body weights and differences in the amounts of calcium and phosphorus relative to body weight.
Another question was whether zinc affects the intestinal absorption of calcium. Our calcium absorption studies (using 47Ca as the tracer) have conclusively shown that large doses of zinc (140 mg/day of zinc sulfate) significantly decreased the intestinal absorption of calcium when zinc supplements were given during a low calcium intake of 230 mg/day—but not during a calcium intake of 800 mg/day (Spencer et al. 1987). Further investigations have delineated the dose of zinc and the level of calcium intake at which the decrease of calcium absorption would not occur. Decreasing zinc intake from 140 mg to 100 mg during a low calcium intake of 230 mg/day, and decreasing calcium intake from 800 mg to 500 mg during the high zinc intake of 140 mg/day, in both cases had no adverse effect on the intestinal absorption of calcium (Spencer et al. 1992).
Zinc supplements are freely available “over the counter” and are used in unknown dosages by the public with equally unknown intakes of calcium. This practice is of concern for elderly women who may already have a low calcium status and yet may use large doses of zinc during a low calcium intake. Such a combination would decrease the intestinal absorption of calcium and thereby contribute to further deterioration of the state of calcium metabolism in these individuals.
Little attention is being paid to strontium, which, like calcium, is primarily deposited in bone. Our studies have shown that the average dietary intake of strontium is low, at 1.5 to 2.5 mg/day (Warren and Spencer 1972, 1976). In 1950, it was suggested that strontium used in conjunction with calcium would be effective in therapy for osteoporosis and that the retention of both calcium and strontium would be additive (Shorr and Carter 1950). About 30 years later, other investigators again demonstrated the beneficial effect of strontium as a therapeutic agent for osteoporosis (Marie et al. 1985). Moreover, our investigations indicated that large amounts of elemental strontium, such as daily doses of 600 to 900 mg (taken as strontium lactate), were well retained and well tolerated. However, it was found that after discontinuation of strontium supplements, a very high percentage of the retained strontium was excreted in three to four weeks (Warren and Spencer 1976).
It may be speculated that this loss of strontium might not have occurred if calcium intake had been high. Some of our preliminary studies show that the intake of added strontium increases the intestinal absorption of calcium, which could be a significant finding. Further examinations of the effect of strontium on the absorption of calcium are needed because very few substances are known to increase the intestinal absorption of calcium.
Although proteins are not the same sort of nutrients as minerals, the relationship between proteins and the metabolism of calcium is important because proteins play a major role in the formation of the bone matrix and, conversely, have also been reported to bring about an increase in urinary calcium. However, such findings of calcium loss are primarily based on studies using purified proteins (Walker and Linkswiler 1972; Schuette, Zemel, and Linkswiler 1980). Calcium loss does not occur when complex proteins—which are part of the human diet—are used (Spencer, Kramer, Wiatrowski, et al. 1978; Spencer et al. 1983; Spencer, Kramer, and Osis 1988). The widespread belief that “proteins” generally are a cause of calcium loss frequently stems from reports and statements that do not specify or identify the type of protein used. But in considering the calciuric effect of protein in causing calcium loss, it is important to define the source and type of protein: Are the proteins isolated protein fractions, such as specific amino acids, or are they part of complexes of other nutrients, as is usually the case in the human diet?
Our studies, carried out under strictly controlled dietary conditions, have conclusively shown that a high protein intake (using red meat as its source, in large amounts of up to 550 g of meat per day) did not increase urinary calcium excretion (Spencer, Kramer, Osis, et al. 1978b; Spencer et al. 1983). Such a diet was given daily for as long as four months, and an example of the effect of this type of dietary protein on urinary calcium is shown in Table IV.B.1.4.
Moreover, during this high protein intake, there was no change in fecal calcium, nor in calcium balance, nor in the intestinal absorption of calcium, as determined in 47Ca absorption studies. As already discussed, phosphorus decreases urinary calcium excretion. Dietary protein sources such as meat, milk, and cheese have a high phosphate content, which may explain why urinary calcium does not increase during the intake of these complex proteins. Therefore, the high phosphorus content of complex proteins may prevent and/or counteract any increase in urinary calcium—even with the consumption of red meat, an acid-ash food that would be expected to increase the urinary excretion of calcium (Wachman and Bernstein 1968).
Table IV.B.1.4. Effect of a high-protein diet on calcium metabolism
Note: High protein given as red meat; high protein = 2 g/kg body weight compared with 1 gm/kg in the control study.
Effects of Excessive Alcohol Consumption
Alcohol cannot be classified as a nutrient. However, chronic alcoholism can lead to bone loss (Feitelberg et al. 1987; Laitinen and Valimaki 1991) and to the development of osteoporosis. The etiology of osteoporosis in this case is multifactorial, but a major cause may well be the poor diet—especially low intakes of calcium, proteins, and vitamin D—associated with prolonged excessive alcohol consumption. Studies have suggested abnormalities in vitamin D metabolism (Gascon-Barre 1985) as well as in the adrenal function (Mendelson, Ogata, and Mello 1971), both of which affect the metabolism of calcium.
Changes in the pancreatic function in chronic alcoholism also lead to a loss of calcium—in this case because of the complexation of calcium with fat in the abdominal cavity—and there may be other factors not yet identified. Table IV.B.1.5 shows the prevalence of osteoporosis in our patients with chronic alcoholism (Spencer et al. 1986). Thirty-one percent were less than 45 years old, and 50 percent of these relatively young patients suffering from chronic alcoholism and osteoporosis were less than 40 years old (Spencer et al. 1986).
Table IV.B.1.5. Patients with chronic alcoholism and osteoporosis
aAll male patients.
Fifty percent of these patients were less than 40 years old
Table IV.B.1.6. Effect of corticosteroids on the calcium balance
a Aristocort, 20 mg/day for 24 days.
b Aristocort, 40 mg/day for 60 days.
Effect of Medications
Several medications affect the metabolism of calcium, primarily by increasing urinary calcium and thereby causing calcium loss. The effect of glucocorticoids in causing bone loss and osteoporosis, regardless of gender and age, is well known (Lukert and Adams 1976). Table IV.B.1.6 shows two examples of negative calcium balances during treatment with corticosteroids. These medications increase not only urinary but also fecal calcium, resulting in markedly negative calcium balances. This result occurs during both a low calcium intake of approximately 240 mg/day and an approximate tenfold increase of this amount. The data suggested that the loss of calcium induced by glucocorticoids was dose-dependent.