Mineral salts are responsible for structural functions involving the skeleton and soft tissues and for regulatory functions including neuromuscular transmission, blood clotting, oxygen transport, and enzymatic activity. Calcium, phosphorus, and magnesium are required in relatively large amounts and are designated as macrominerals. These are discussed in this chapter. Minerals needed in smaller amounts are called trace elements; these are discussed in Chapter 14.
Calcium is the most abundant mineral in the human body, making up 1.5 to 2% of the total body weight. Approximately 1,200 g of calcium are present in the body of an adult human; more than 99% of that amount is found in bones. All living animals possess powerful mechanisms both to conserve calcium and to maintain constant cellular and extracellular concentrations (Arnaud, 1978, 1988; Exton, 1986). These functions are so vital to survival that during severe dietary deficiency or abnormal losses of calcium from the body, they can demineralize bone to prevent even minor degrees of hypocalcemia (i.e., low plasma calcium). Thus, bone acts as a vital physiological tissue providing a readily available source of calcium for maintenance of normal plasma calcium levels, 50% of which is ionized and physiologically active (Arnaud, 1988).
People need more calcium in their diets when they are forming bone, when intestinal absorption of calcium is impaired, and when there are inordinate losses of calcium to the environment (e.g., through increased renal excretion or lactation). If there is insufficient dietary calcium during bone formation, linear growth will be impeded and peak bone mass may not be achieved. If it is insufficient when intestinal absorption is impaired or when there are inordinate losses, the serum concentration of calcium ion (Ca2+) can be maintained at normal levels only at the expense of bone calcium (Arnaud, 1988).
Phosphorus, along with calcium, is essential for calcification of bones (85% of body phosphorus is located in the skeleton). The remainder of body phosphorus is needed in soft tissues as a cofactor in myriad enzyme systems essential in the metabolism of carbohydrates, lipids, and proteins. In the form of high-energy phosphate compounds, phosphorus contributes to the metabolic potential. The phosphate ion also plays an important role in acid/base balance.
Of total body magnesium, 60 to 65% is found in bone and 27% is located in muscles (Shils, 1988). Magnesium is second only to potassium as the most predominant cation within cells and is essential both for the functions of many enzyme systems and for neuromuscular transmission.
Historical trends in the amounts of various minerals present in the food supply have been reported by the U.S. Department of Agriculture
(USDA) since 1909 (see Table 3-3). These data do not represent actual consumption, however, since they fail to document how much food was wasted. Per-capita calcium availability in the food supply increased 23% from 750 mg/day during 1909-1913 to 920 mg/day in 1985 (see Table 3-3). The change resulted primarily from an increased supply of dairy products during this period. The per-capita availability of phosphorus in the food supply has remained fairly steady at 1,500 mg/day since 1909-1913, and that of magnesium has declined from 380 mg/day during 1909-1913 to 320 mg/day in 1985 (see Table 3-3). The decline resulted primarily from the decreased use of grains and flour and increased practice of low-extraction milling.
Information on current intakes of calcium, phosphorus, and magnesium has been collected in national surveys, including the 1977-1978 Nationwide Food Consumption Survey (USDA, 1984), the second National Health and Nutrition Examination Survey (Carroll et al., 1983), the Continuing Survey of Food Intakes of Individuals (USDA, 1986, 1987), and the Total Diet Study (Pennington et al., 1986) (see Chapter 3). In USDA surveys, calcium intakes have been reported in terms of the 1980 Recommended Dietary Allowance (RDA), which is highest (1,200 mg) at ages 11 to 18 years and is only 800 mg for ages 1 to 10 and 18 and above (NRC, 1980). Mean intakes below the RDA do not necessarily mean that individuals in the group are malnourished. Nutrient requirements differ from individual to individual, and the RDAs are set at high enough levels to cover the requirements of practically all healthy people in the population. Furthermore, these nationwide surveys do not reflect the usual or habitual intakes of individuals. It is inappropriate, therefore, to conclude that failure to meet the RDA indicates that an individual has an inadequate calcium intake, although the risk that some people will have inadequate intakes increases as the mean intake falls further below the RDA. Percentages of the RDA are reported here only to indicate relative intakes on the days surveyed.
Mean intakes of calcium are lower for females than for males and lower for blacks than for whites. USDA surveys indicate that females ages 9 to 19 had somewhat higher intakes in 1965 than during 1977-1978, but that older women (51 to 75 years of age) had higher intakes during 1977-1978 than in 1965 (Figure 13-1) (USDA, 1984). Mean intakes for women 19 to 50 years old were higher in 1985 than in the previous surveys (USDA, 1987).
The 1985 survey indicated that 22% of women ages 19 to 50 consumed the RDA or more, 24% consumed between 70 and 99%, 26% consumed between 50 and 69%, and 29% consumed less than 50% of the RDA. The mean intake for black women
was 55% of the RDA compared with 77% for white women. Calcium intakes were lower among men and women in the older age group (35 to 50 years old) and among those living in poverty. Among children 1 to 5 years of age, 45% consumed 100% or more of the calcium RDA, while 39% consumed 70 to 99%. The 1977-1978 survey based on a 1-day intake indicated that males ages 9 to 18 maintained an average calcium intake at 90% of the RDA or above, whereas females in the same age range had progressively lower calcium intakes. Females ages 9 to 11 years, 12 to 14 years, and 15 to 18 years consumed 89, 72, and 64% of the calcium RDA, respectively. In 1985, men and women ages 19 to 50 reported mean calcium intakes of 360 and 397 mg/1,000 kcal, or 115 and 74% of the RDA, respectively. This reflects the lower caloric intake of women.
Major food sources of calcium include milk and milk products. Although leafy greens such as turnip, collard, and mustard greens are good sources, they are not consumed in large amounts by the U.S. population as a whole. The Joint Nutrition Monitoring Evaluation Committee (JNMEC) concluded that calcium deserves public health monitoring priority because of the low dietary intakes by women and the possible association of low intakes with osteoporosis in elderly women (DHHS/ USDA, 1986).
Mean daily intakes of phosphorus for men and women 19 to 50 years of age were 1,536 mg and 966 mg, respectively, in 1985, compared with an RDA of 800 mg for this age group. Children ages 1 to 5 years consumed a mean of 992 mg/day (USDA, 1986, 1987). Major food sources of phosphorus in the U.S. diet include milk and milk products, meats, poultry, fish, and grain products. Some forms of dietary phosphorussuch as phytic acid, which is found in cereals and seedsare not well absorbed. However, dietary deficiency of phosphorus is unlikely because of its wide distribution in foods. JNMEC judged that phosphorus intake by the U.S. population is generally adequate, requiring less monitoring than certain other nutrients (DHHS/USDA, 1986).
Mean intakes of magnesium in 1985 were 193 mg/day for children 1 to 5 years of age (115% of 1980 RDA) (USDA, 1987). For adults ages 19 to 50, mean intakes were 207 mg/day for women (67% of the 1980 RDA) (USDA, 1987) and 329 mg/day for men (94% of the 1980 RDA) (USDA, 1986). Major food sources of magnesium include grain products, vegetables, dairy products, meat, poultry, and fish. JNMEC found no association of magnesium intake with any chronic disease (DHHS/USDA, 1986). However, since significant portions of the population have magnesium intakes below recommended levels, they recommend further investigation of the role of magnesium nutritional status in disease and health.
Evidence Associating Minerals with Chronic Diseases
Osteoporosis is a disease characterized by an absolute decrease in bone mass that results in an increased susceptibility to fracture, especially of the wrist, spine, and hip. It is common in postmenopausal women and in the elderly of both sexes and constitutes an important public health problem (Kelsey, 1984, 1987) (see Chapters 5 and 23).
Relative Importance of Bone Cell Activities and Mineral Balance as Determinants of Bone Mass
Bone is a metabolically active tissue that is turning over constantly. This process is regulated by cellular activities that resorb (osteoclastic) and form (osteoblastic) bone. In normal adult bone, resorption is precisely balanced by formation. Furthermore, these activities are coupled so that when one increases or decreases, the other shifts in degree and direction so that little or no net change in the amount of bone ensues. The driving forces for changing net bone mass are intrinsic to the cellular processes that govern bone resorption and formation. Thus, functional uncoupling of these cellular processes is required to either increase or decrease bone mass. Calcium balance generally reflects the degree to which coupling of bone formation and resorption is in balance. Negative calcium balances indicate that bone resorption exceeds formation; positive balances indicate the opposite.
In contrast to cellular processes in bone, calcium, phosphorus, and magnesium play a more passive role in any mass changes that occur in bone. They must be present at physiological concentrations in extracellular fluids for bone mineralization (formation) to occur normally. Dietary minerals contribute to this physiological state by helping to replace minerals that have been lost by obligatory processes (in urine, feces, and sweat).
Peak Bone Mass As A Factor In Modifying Osteoporosis Risk
The level of bone mass achieved at skeletal maturity (peak or maximal bone mass) is a major factor modifying the risk for osteoporosis. The more bone mass available before age-related bone loss occurs, the less likely it will decrease to a level at which fracture will occur (Heaney, 1986; Marcus, 1982; Parfitt, 1983). Normally, longitudinal bone growth is completed sometime during the second decade of life. It is axiomatic that positive calcium balance is needed for this to occur normally, and it is easy to calculate that the required average daily body retention of calcium during this 20-year period is approximately 110 mg/day for females and 140 mg/day for males. During the adolescent growth spurt, the required calcium retention is two to three times higher than these average values (Garn, 1970; Nordin et al., 1979). To achieve such retention, the RDA for calcium has been set at 1,200 mg/day for people 10 to 18 years of age (NRC, 1980). If obligatory calcium losses in urine, feces, and sweat are not greater than average, the calcium RDAs are adequate provided that 50% of the calcium ingested is absorbed. A lower percentage of absorption or calcium intakes less than 1,200 mg/day without compensatory increases in the absorption rate would not provide adequate quantities of calcium to achieve peak bone growth. It is not known if teenagers have such levels of calcium absorption nor is it known whether absorption rates in teenagers can increase in response to reduced calcium intakes.
Opinion is mixed as to the age at which peak bone mass is achieved. The only data concerning this issue were collected in cross-sectional studies. These studies suggest that the metacarpal cortical area (Garn, 1970), phalangeal density (Albanese et al., 1975), combined cortical thickness (Matkovic et al., 1979), and bone mineral content of the spine (Krolner and Pors Nielsen, 1982) do not reach maximum levels until sometime during the middle of the third or the early part of the fourth decade of life. Such data suggest that peak bone mass may not be achieved until 5 to 10 years after longitudinal bone growth has ceased. During this period, cortical porosity, which increases during the adolescent growth spurt, is probably filled in and bone cortices become thicker. The quantity of bone mass that can be added is unclear; it has been variously estimated to range from 5 to 10% (Parfitt, 1983). The optimum calcium retention needed to achieve this apparent increment in bone mass is not yet known but probably ranges from 40 to 60 mg/day (Garn, 1970; Nordin et al., 1979; Parfitt, 1983). This association of bone mass with calcium intake is suggested by the results of a Yugoslavian study in which there was a 5 to 10% higher metacarpal bone mass in the inhabitants of a "high-calcium" district starting at age 30 years and extending at least to age 75 years when the investigation terminated (Matkovic et al., 1979).
It is a logical extension of the above that the quantity of dietary calcium required to achieve peak bone mass would be greater than that required to replace obligatory losses through urine, feces, and sweat (approximately 200 to 300 mg/ day). Thus, the period during which positive calcium balance needs to be maintained to achieve peak bone mass should probably be extended beyond the period of longitudinal bone growth to perhaps ages 25 to 30 years (Heaney, 1986; Marcus, 1982; Parfitt, 1983).
Bone Loss As A Factor Modifying Osteoporosis Risk
Another major factor modifying osteoporosis risk is the rate at which bone is lost as life progresses. After peak bone mass is achieved, bone mass appears to be maintained without much change until 40 to 45 years of age. Subsequently, bone is lost at a rate of 0.2 to 0.5% per year in men and women until the eighth or ninth decade of life. In women, bone loss accelerates to 2 to 5% per year immediately before and for approximately 10 years after menopause (Heaney, 1986) and then returns to its former rate0.2 to 0.5% per year.
Decreased Calcium Absorption As A Factor In Osteoporosis Risk
Intestinal calcium absorption and the ability to adapt to low-calcium diets are impaired in many postmenopausal women (Heaney, 1985, 1986; Heaney et al., 1977) and elderly people of both sexes (Alevizaki et al., 1973; Avioli et al., 1965; Bullamore et al., 1970; Gallagher et al., 1979; Ireland and Fordtran, 1973; Nordin et al., 1976). The pathogenesis of these abnormalities is controversial, but evidence suggests that they may be due either to a functional decrease in the ability of the kidney to produce the major biologically active metabolite of vitamin D1,25-dihydroxy vitamin D [1,25(OH)2D3] (Gallagher et al., 1979; Riggs et al., 1981)or to absolute decreases in renal 1,25(OH)2D3 production due to renal diseases such as that occurring in old age (Tsai et al., 1984) (discussed in Chapter 11). The findings that levels of serum immunoreactive parathyroid hormone (Gallagher et al., 1980; Insogna et al., 1981; Marcus et al., 1984;
Orwoll and Meier, 1986) and bioactive parathyroid hormone (Forero et al., 1987) increase with age imply that these defects in calcium absorption result in sufficient degrees of hypocalcemia to induce chronic hyperparathyroidism (secondary hyperparathyroidism). It is well established that hyperparathyroidism increases the bone remodeling rate and that a high rate of remodeling leads to accelerated bone loss whenever intrinsic imbalance favors the process of resorption over formation (Parfitt, 1980; Sakhaee et al., 1984).
Thus, it appears that the ability of the intestine to support calcium homeostasis progressively declines with age and that elderly people are increasingly forced to rely on their own bones rather than on the external environment as a source of calcium for maintaining normal extracellular free calcium (Arnaud et al., 1981). The degree to which this occurs depends on the severity of the described defects in calcium absorption, the level and bioavailability of dietary calcium, and whether specific therapeutic means are taken to correct defects in calcium absorption. The quantitative contribution, if any, of this homeostatic mechanism to the decrease in bone mass and the increase in incidence of fractures in the elderly is not known and is the subject of intensive investigation.
Problems In Estimating Bone Mass And Calcium Intake
In most epidemiologic studies of the relationship of dietary calcium to bone mass, investigators have used radiograms (measurements of cortical bone width, area, or calculated volume from x-ray images of metacarpal bones). Such measurements are easy to obtain in the field. Moreover, their precision is similar to the more elegant single- or dual-photon absorptiometry and quantitative computed tomography techniques (Cohn, 1981; Mazess, 1983); however, they are less sensitive and specific. In addition, these cortical bone measurements do not accurately reflect bone mass in the trabecular or spongy bone compartment where rapid turnover occurs. Thus, population-based data obtained with cortical width or area measurements may not detect subtle changes that other, more sensitive and specific techniques might easily detect. Such changes that are detected reflect, at best, those that have occurred in cortical bone and not in trabecular bone. Trabecular bone makes up at least 50% of the bone in the spine (Nottestad et al., 1987) and is affected to the greatest extent early in menopause (Riggs and Melton, 1986).
The methods used to assess dietary calcium intake in these studies have varied from "the best available estimates" (Nordin, 1966) to 7-day replicate dietary records and 47-category interviews (Garn, 1970), to chemical analyses of foodstuffs (Matkovic et al., 1979). Most authors have been aware of the inherent inaccuracies of dietary recall data, and because of the even greater inaccuracies of estimates of calcium intake over a lifetime, most have relied on estimates of current calcium intake. Thus, even the most careful approaches to providing accurate calcium intake data can be faulted, and their interpretation must be approached with caution, especially in relation to estimates of bone mass based on a measurement technique with inherent flaws.
Calcium Intake And Bone Mass
Published reports have shown either no relationship or only a modestly positive relationship between dietary calcium and cortical bone mass. Garn et al. (1969) found the same rate of loss of metacarpal cortical mass in more than 5,800 subjects from seven countries, despite wide variations in calcium intake between groups. In fact, low calcium intakes by some ethnic groups were associated with bone mass values higher than in groups with high calcium intakes over a lifetime. On the other hand, in a 10-state nutrition survey, Garn et al. (1981) found a statistically significant increase in metacarpal cortical area in people in the highest, as compared to the lowest, percentile of calcium intake. In a similar analysis, using data from the first Health and Nutrition Examination Survey (HANES I), investigators observed a significant positive correlation between calcium intake and metacarpal cortical width for all 2,250 subjects (Carroll et al., 1983; DHEW, 1979). When the 960 white women in the study were excluded, the significance of the correlation disappeared.
Matkovic et al. (1979) investigated metacarpal bone mass and the incidence of hip fracture in two regions of Yugoslavia whose inhabitants ingested greatly different quantities of calcium (500 mg/day compared to 1,100 mg/day largely through dairy products). The inhabitants of the high-calcium district ingested more calories, fats, and protein and less carbohydrates than the low-calcium district. However, the regions were similar in their agrarian economy, and except for a significantly longer lower limb length in the high-calcium district, ages, weights, and other anthropomorphic indices were identical. The inhabitants of the high-calcium district had a 50% lower incidence of
hip fractures and a significant increase in metacarpal cortical bone volume as compared with the inhabitants of the low-calcium district. Because the differences in bone mass as a function of age were constant, it is more likely that high lifelong calcium intakes in this population increased peak cortical bone mass than that it prevented bone loss. In contrast to the decreased incidence in hip fractures observed in the high-calcium district, the incidence of fractures of the distal forearm (the distal 3 cm of the radius or ulna) was the same in the two regions. This is of interest because the fracture sites at the hip generally are composed mainly of cortical bone, whereas those at the wrist are mainly of trabecular bone. The results of a correlation study reported by Anderson and Tylavsky (1984) are highly relevant in this regard. Those investigators related current and lifelong calcium intake to bone mineral content (measured by single-photon absorptiometry) at the distal radius (mixture of cortical and trabecular bone) and at the midshaft of the radius (largely cortical bone) in residents of four North Carolina communities. They found a positive correlation of bone mineral content with calcium intake at the midshaft site but no correlation at the distal site.
Several clinical studies have been conducted to examine the relationship between calcium intake and bone mass. Using radiograms, Smith and Frame (1965), Smith and Rizek (1966), and Garn (1970) found no association between current calcium intake and current bone mass. Similarly, Lavel-Jeanet et al. (1984) and Pacifici et al. (1985) observed no correlation of calcium intake with vertebral density as measured by quantitative computed tomography. Most recently, Riggs et al. (1987) found no relationship between the calcium intakes (range, 260 to 2,003 mg/day; mean, 922 mg/day) of 106 normal women ages 23 to 84 years and the rates of change in bone mineral density at the midradius (determined by single-photon absorptiometry) and the lumbar spine (determined by dual-photon absorptiometry) over a mean period of 4.1 years.
In contrast to the negative observations made by Lavel-Jeanet et al. (1984) and by Pacifici et al. (1985) with quantitative computed tomography of the spine, Kanders et al. (1984), using dual-photon absorptiometry, found that the BMC of L2 through L4 vertebrae in young women with a high calcium intake was higher than that in women with a low intake. In a longitudinal study of 76 healthy postmenopausal women, Dawson-Hughes et al. (1987) found, using dual-photon absorptiometry, that women with calcium intakes less than 405 mg/day lost spinal bone density at a significantly greater rate than those with an intake of greater than 777 mg/day (p <.026).
Calcium Intake and Osteoporosis
Nordin (1966) reported the results of an intercountry comparison of calcium intake and osteoporotic fractures. Despite inconsistency in the methods used to report calcium intakes in the 12 countries surveyed, it was possible to demonstrate an inverse rank-order relationship between frequency of osteoporotic vertebral fracture as determined by spine x-ray and calcium intakes. Japanese women, whose calcium intake averaged 400 mg/day, had the highest frequency of fracture, whereas women in Finland had the highest intake (1,300 mg/day) and the lowest fracture frequency. This relationship did not hold for some countries. For example, in The Gambia and Jamaica, calcium intakes were low but osteoporotic fractures were rare. As reported by Matkovic et al. (1979), the hip fracture incidence in the Yugoslav district with a high calcium intake was 50% lower than in the low calcium district. But no difference was detected in the incidence of fractures around the wrist.
Most clinical studies show lower calcium intakes by osteoporotic patients than by age-matched controls (Hurxthal and Vose, 1969; Lutwak and Whedon, 1963; Nordin, 1961; Riggs et al., 1967; Vinther-Paulsen, 1953). Dietary calcium was lower than 800 mg/day in patients and controls in all these investigations. In another study, intakes were greater than 800 mg/day in patients and controls, and no differences in calcium intake between the two groups were observed (Nordin et al., 1979). The results of that study support the view of Heaney (1986) that low dietary calcium may play a permissive rather than a causative role in the development of osteoporosis and that this role can be demonstrated best when dietary calcium is below a "saturation" level.
Effect Of Calcium Supplementation On Bone Mass
The long-term effects of calcium supplementation on bone mass are not yet established. The results of short-term investigations (2 years or less) are mixed. In general, they show a slowing of bone loss measured at sites composed mostly of cortical bone but not at sites composed of trabecular bone. All studies in which estrogen treatment was used as a companion protocol have shown that calcium supplementation is inferior to estrogen in slowing
cortical bone loss and that estrogen prevents trabecular bone loss completely. Some of these studies were randomized (Lamke et al., 1978; Recker and Heaney, 1985; Recker et al., 1977; Riis et al., 1987; Smith et al., 1981), but only two were blinded (Riis et al., 1987; Smith et al., 1981). In the study by Smith et al. (1981), 40% of the subjects were lost to follow-up.
The results of Recker et al. (1977) reflect those of the others. These investigators showed that after 2 years, a 1.04-g supplement of calcium given as the carbonate salt to 22 women between 55 and 65 years of age resulted in a 0.22% decrease in metacarpal cortical bone area as compared with a 1.18% decrease in 20 placebo-treated age-matched women (p <.05). By contrast, there was no difference in bone mineral content of the distal radius (mixture of trabecular and cortical bone). The reduction of metacarpal cortical bone loss with calcium supplementation was less than the reduction resulting from estrogen treatment of 18 age-matched women, which completely prevented bone loss at the distal radius (Recker et al., 1977).
In a similar but nonrandomized study, Horsman et al. (1977) administered 800 mg of elemental calcium as the gluconate salt to 24 postmenopausal women over a 2-year period and found a significant decrease in bone loss from the ulna (cortical bone) compared to 18 placebo-treated control subjects. However, calcium treatment caused little if any diminution of the bone loss observed at the distal radius or in metacarpal cortices. Similarly, Nilas et al. (1984) found no change in bone mineral content at the distal radius when three groups of women with calcium intakes varying from below 550 mg/day to more than 1,150 mg/day were given a 500-mg elemental calcium supplement daily. In contrast, a randomized and blinded investigation in postmenopausal women by the same group (Riis et al., 1987) showed that daily administration of 2,000 mg of elemental calcium as the carbonate salt for 2 years slowed bone loss at the proximal forearm and slowed calcium loss from the total skeleton, whereas the loss of bone from sites composed predominantly of trabecular bone was no different from that of placebo-treated control subjects. As in previous studies, bone mineral content remained constant at all measurement sites in subjects receiving estrogen.
In a nonrandomized study, Ettinger et al. (1987) observed that calcium supplementation up to 1,500 mg/day as the carbonate salt had no effect on bone mineral content in the spine as assessed by quantitative computed tomography, distal radius, or metacarpal cortical bone mass in 44 postmenopausal women as compared with 25 age-matched women who elected not to receive treatment. By contrast, in 15 women who elected to take low-dose conjugated estrogen (0.3 mg/day) combined with 1,500 mg of calcium per day, there was complete protection against bone loss. This latter observation is of considerable theoretical and practical interest, because this same group of investigators previously demonstrated that conjugated estrogen at the same low dose, given without calcium, failed to prevent vertebral bone loss (Cann et al., 1980). Thus, it is possible that dietary calcium plays a sex hormone-dependent permissive role in the maintenance of bone mass.
Riggs et al. (1976) showed that the increased bone resorption surfaces observed in biopsies of the iliac crest bone from osteoporotic patients are partially restored by combined calcium and vitamin D supplementation. This effect was associated with a decrease in serum immunoreactive parathyroid hormone (iPTH) within the normal rangean event the authors justifiably speculated was responsible for the decrease in resorption surfaces. The results of several other investigations, not involving bone histomorphometry, are consistent with this apparent antiresorption effect of calcium supplementation. Recker et al. (1977) showed that bone resorption, as assessed by kinetic analysis of plasma 45Ca decay curves, was decreased by supplementation of postmenopausal women with calcium carbonate. Horowitz et al. (1984) reported that oral calcium suppresses hydroxyproline excretion, a well-established index of bone resorption, in osteoporotic postmenopausal women.
Effect of Calcium Supplementation on Fracture
The evidence relating calcium supplementation to fracture prevalence is scanty. The only study of substance comes from the Mayo Clinic, where Riggs et al. (1982) conducted a nonrandomized but prospective assessment of the effect of various treatments of postmenopausal females with generalized osteopenia on the occurrence of future vertebral fractures. In that study, eight subjects received calcium carbonate (1,500 to 2,500 mg/ day) and 19 received calcium plus vitamin D (50,000 IU once or twice a week). Both groups had 50% fewer vertebral fractures than did 27 placebo-treated and 18 untreated patients.
Safety of Calcium Supplementation
Calcium supplementation is safe in the absence of condi-
tions that cause hypercalcemia or nephrolithiasis (Heath and Callaway, 1985). Thus, in normal individuals, calcium intakes ranging from 1,000 to 2,500 mg/day do not result in hypercalcemia (FDA, 1979) and extremely high intakes (>2,500 mg/day) are required to produce hypercalciuria (>300 mg within 24 hours) (Knapp, 1947). Elemental calcium intakes in excess of 3 to 4 g/day should be avoided because they will cause hypercalcemia in most subjects (Ivanovich et al., 1967). Constipation can be a limiting side effect of calcium supplementation in many people and is particularly bothersome in the elderly. Calcium carbonate is currently the favored and cheapest form of supplemental calcium. Other anionic forms (e.g., calcium gluconate, calcium lactate) are equally effective but are generally more expensive.
There is no completely satisfactory animal model of age-related or postmenopausal osteoporosis. Nevertheless, the animal studies on dietary calcium and bone mass conducted thus far have produced results consistent with those from human studies. However, almost all reports concern young growing or aged animals and thus differ from investigations in humans (Leichsenring et al., 1951; Malm, 1953; Zemel and Linkswiler, 1981), which in general focus on young or middle-aged adults.
Nordin (1960) reviewed the extensive literature describing the many species in which bone mass decreases as a result of calcium deficiency. in all these studies, it is clear that the bone disease produced by calcium deficiency resembles osteoporosis in humans. Low-calcium diets cause a loss of trabecular bone in adult cats (Bauer et al., 1929) and a generalized thinning of bone in dogs Gaffe et al., 1932). After feeding adult cats a low-calcium diet for 5 months, Jowsey and Gershon-Cohen (1964) found that the animals had decreased skeletal weight, decreased density of bone as determined radiographically, and microradiographic evidence of increased bone resorption. These changes were partially reversed by feeding the animals a diet containing increased calcium. Many investigators have demonstrated that low-calcium diets lead to increased bone resorption typical of hyperparathyroidism and a generalized decrease in bone mass in rats and mice (Bell et al., 1941; de Winter and Steendijk, 1975; Gershon-Cohen et al., 1962; Harrison and Fraser, 1960; Ornoy et al., 1974; Rasmussen, 1977; Salomon, 1972; Salomon and Volpin, 1970; Shah et al., 1967; Sissons et al., 1985).
Of interest in relation to the possible influence of calcium deficiency on fracture is the study by Ferretti et al. (1985), who showed that femora from rats maintained on a low-calcium diet for 5 months had reduced inertial parameters and load resistance in comparison to femora from chronically thyroparathyroidectomized (thyroxinetreated) animals or animals fed a high-calcium diet. Griffiths et al. (1975) showed that rhesus monkeys on a low-calcium diet for several years developed radiological and histological changes in their skeletons that were consistent with hyperparathyroidism and osteoporosis.
The lack and diminished levels of estrogen are risk factors for osteoporosis. Estrogen replacement therapy reduces the loss of bone mass associated with oophorectomy and markedly reduces risk of hip and vertebral fracture (see Chapter 23). It is not clear whether the addition of calcium supplements to hormone-replacement therapy results in added benefit.
Although data from animal studies suggest that high levels of dietary phosphorus increase bone loss, detailed studies in humans show little to no effect of high phosphorus intake on calcium balance (see section on Phosphorus, below).
Studies over the past half century indicate that high intakes of purified isolated protein increase the renal excretion of calcium (see Chapter 8). However, epidemiologic studies have shown no adverse effect of high dietary protein on either rate of hip fracture (Matkovic et al., 1979) or metacarpal cortical bone mass (Garn et al., 1981). As discussed in Chapters 8 and 23, the calciuric effect of protein is considerably reduced when increased protein intake is accompanied by high phosphorus intakea common occurrence, since most foods in the United States with a high protein content also contain high levels of phosphorus.
Dietary fiber has been reported to chelate calcium and other minerals in the gastrointestinal tract (Dobbs and Baird, 1977; Ismail-Beigi et al., 1977; McCance and Widdowson, 1942). This observation led to concern that high-fiber diets may increase risk of bone loss and osteoporotic fracture. However, there is little evidence that high-fiber diets alone induce calcium deficiency in
people who otherwise consume a balanced diet (see Chapters 10 and 23).
Although some drugs (e.g., thiazide diuretics) increase renal tubular reabsorption of calcium, they do not appear to influence calcium balance or changes in bone mass (Sakhaee et al., 1985). Phosphate-binding antacids such as the nonprescription aluminum hydroxide gels, if taken chronically even at low doses, can cause phosphate depletion and an accompanying increase in bone resorption and urinary calcium excretion (Maierhofer et al., 1984; Spencer and Lender, 1979; Spencer et al., 1982). It is not clear, however, whether the phosphate-binding type of antacid is related to age-related bone loss, particularly in calcium-deficient people.
Contraction of smooth muscle depends on the interaction among the contractile proteinsactin and myosinand is the end result of a cascade of reactions initiated by a rise in cytosolic free calcium concentrations (Johansson and Somlyo, 1980). This observation led to the hypothesis that dietary calcium influences blood pressure and possibly risk for hypertension.
Within the past decade, considerable new evidence from human studies has suggested a role for dietary calcium in blood pressure regulation. However, views and theories are still in conflict, in part because of the wide range in study findings. For example, in an analysis of data from HANES I, McCarron et al. (1984) concluded that reduced calcium intake was the best predictor of increased blood pressure among all variables analyzed. Similar conclusions were reached in studies conducted in California (Ackley et al., 1983), Puerto Rico (Garcia-Palmieri et al., 1984), and the Netherlands (Kok et al., 1986).
Other investigators have reached different conclusions. For example, Feinleib et al. (1984) reanalyzed the HANES I data studied by McCarron et al. (1984), controlling for age and weight of subjects, and found no significant association between calcium intake and blood pressure. Harlan et al. (1984) found systolic blood pressure and calcium intake to be negatively correlated in women but positively correlated in men. Gruchaw et al. (1985) concluded that dietary calcium was not a significant predictor of blood pressure. In a large prospective study of omnivorous Japanese men in Hawaii, Reed et al. (1985) found inverse associations between intakes of calcium, potassium, protein, and milk (determined from 24-hour dietary recalls) and both systolic and diastolic blood pressure levels, although it was not possible to determine whether any of these dietary components had an independent effect on blood pressure.
The inconsistency among epidemiologic findings may be, in part, a result of the high degree of collinearity among other dietary factors associated with blood pressure (e.g., potassium and protein) and the limitations in the methods of assessing calcium intake in noninstitutionalized populations (Kaplan and Meese, 1986; Lau and Eby, 1985).
Acute elevations of serum calcium by intravenous infusions of calcium sharply raises blood pressure (Weidmann et al., 1972). Chronic hypercalcemia due to primary hyperparathyroidism is frequently accompanied by hypertension (Rosenthal and Roy, 1972), which is often reversible after the hyperparathyroidism is cured by removing abnormal parathyroid tissue (Blum et al., 1977). Serum calcium within the normal range has also been shown to correlate with high blood pressure (Bianchetti et al., 1983; Kesteloot, 1984a).
Hypertensive patients have been shown to have mild hypercalciuria (Morris et al., 1983; Strazzullo et al., 1986) and lower levels of serum ionized and ultrafiltrable calcium than normotensive patients, even in the absence of differences in total serum calcium (Folsom et al., 1986). Postnov and Orlov (1985) reported that the cells of hypertensive patients bind calcium less avidly than normotensives, and Erne et al. (1984) found increased calcium levels in platelets from hypertensive patients. Resnick et al. (1986) reported alterations in the serum concentrations of the calcium-regulating hormones (i.e., parathyroid hormone, calcitonin, and calcitriol) in hypertensive patients that are associated with differences in the renin-aldosterone system. Although all these reported changes indicate that calcium metabolism is probably perturbed in primary hypertension, it is not clear whether they are the cause or the result of the hypertension, and taken together, they do not support any single coherent theory of disordered blood pressure regulation.
Most intervention studies of calcium supplementation demonstrate a mild short-term reduction in blood pressure in certain normotensive and hypertensive subjects (Belizan et al., 1983;
Grobbee and Hofman, 1986; McCarron and Morris, 1985; Resnick et al., 1984a; Singer et al., 1985). In some patients with hypertension and high levels of plasma renin, blood pressure may actually rise in response to calcium supplementation (Resnick et al., 1984b). No clinical trial of adequate size and design to test the hypothesis that increasing dietary calcium reduces hypertension risk has yet been reported.
Most animal studies on the relationship of calcium metabolism and hypertension have compared the spontaneously hypertensive rat (SHR) to its normotensive controlthe Wistar-Kyoto rat (WKR) (Young et al., 1988). The results are confusing and controversial. Most investigators (Bindels et al., 1987; Lau et al., 1984b; McCarron et al., 1981; Stem et al., 1984; Wright and Rankin, 1982) reported that serum concentrations of ionized calcium [Ca2+] are lower in the SHR than in the WKR. Some (Lau et al., 1984b; McCarron et al., 1981), but not all (Bindels et al., 1987; Hsu et al., 1986), agree that urinary calcium excretion is increased in SHRs. Although difficult to measure, serum iPTH has generally been reported to be slightly increased in the serum of SHRs (Bindels et al., 1987; McCarron et al., 1981; Stem et al., 1984), whereas serum 1,25-dihydroxycholecalciferol has been found to be increased (Bindels et al., 1987; Lau et al., 1986), decreased (Kurtz et al., 1986; Lucas et al., 1986; Merke et al., 1987; Schedl et al., 1986; Young et al., 1986), or unchanged (Kawashima, 1986; Schedl et al., 1984, 1986; Stem et al., 1984), depending to some extent upon the age and sex of the SHRs studied. Measurements of intestinal calcium absorption by a variety of techniques have been inconsistent (Bindels et al., 1987; Gafter et al., 1986; Hsu et al., 1986; Lau et al., 1984b, 1986; Lucas et al., 1986; McCarron et al., 1985, 1986; Roullet et al., 1986; Schedl et al., 1984; Stem et al., 1984; Toraason and Wright, 1981). It is thus difficult to ascribe the hypercalciuria in the SHR to intestinal hyperabsorption of calcium. Interestingly, studies that have measured bone calcium content (Izawa et al., 1985; Lucas et al., 1986) show it to be decreased in older (22 to 52 weeks) SHRs. These data do not help determine if the recorded abnormalities in calcium metabolism observed in the SHR are the cause, the result, or merely associated with its hypertension. However, they do suggest a pathogenic sequence for the changes in mineral and bone metabolism in SHRs. Such a sequence would include hypercalciuria due to a renal leak of calcium, leading to a decrease in serum calcium, secondary hyperparathyroidism, and finally, bone demineralization. As discussed above in the section on Clinical Studies, some of these same abnormalities have been observed in hypertensive humans. Thus, whether or not they are ultimately proved to be related etiologically to hypertension, they should be investigated independently in the SHR as a potential animal model of a clinical disorder of mineral and bone metabolism that might coexist with, or be caused by, certain hypertensive states.
Dietary calcium supplementation lowers blood pressure in SHRs (Ayachi, 1979; Kageyama et al., 1986; Lau et al., 1984a; McCarron et al., 1981, 1985). These observations suggest a possible etiologic link between the abnormalities of calcium metabolism and the hypertension found in SHRs; however, they fall well short of the evidence needed to prove a causative relationship.
The relationship of calcium intake to risk of colon cancer has been examined in a number of epidemiologic studies. In one 19-year cohort study of 1,954 people in the United States, the calcium and vitamin D intake of people with colorectal cancer was significantly lower than in those without the disease (Garland et al., 1985). Mean calcium intake was 290 mg/1,000 kcal for colorectal cancer subjects and 328 mg/1,000 kcal for controls.
The results of case-control studies are inconsistent. G.R. Howe (National Cancer Institute of Canada, personal communication, 1989) found no association between dietary calcium and colorectal cancer in a reanalysis of an earlier study by Jain et al. (1980), who examined the role of a number of nutrients in relation to colorectal cancer risk. However, a protective effect of calcium with increasing intake was suggested in a case-control study conducted in Marseilles, France (Macquart-Moulin et al., 1986). The relative risk for the highest quartile of consumption compared to the lowest was 0.7. The association just failed to achieve statistical significance and was not further considered in a multivariate model. In addition, no association between calcium intake and risk of colorectal cancer was found in case-control studies conducted in Belgium (Tuyns et al., 1987a) and in Melbourne, Australia (Kune et al., 1987). In the Melbourne study, however, there was a suggestion
of a protective effect in females when calcium intake was considered as a univariate.
Intercountry comparisons of calcium availability and colorectal cancer mortality rates also do not support a protective role for calcium intake. One comparison of 38 countries (G. McKeown-Eyssen, University of Toronto, and E. Bright-See, Ludwig Institute for Cancer Research, personal communication, 1989) gave a correlation of .51 between estimates of per-capita calcium availability and colorectal cancer mortality that was reduced to -.03 when the investigators controlled for fat intake. Studies of colon cancer incidence in rural Finland, other parts of Scandinavia, and New York that show a protective effect of dietary fiber (IARC, 1977; Jensen et al., 1982; Reddy et al., 1978) could also be explained by differences in calcium intake since the main contributor to dietary fat intake in the low-risk areas was milk products. However, there were no direct measurements of calcium intake in those study areas.
In a pilot study of the effect of calcium supplementation on proliferation of colonic cells in patients considered to be at increased risk for colon cancer, Lipkin and Newmark (1985) found that the daily administration of 1.2 g of elemental calcium as calcium carbonate led to a reduction of colonic crypt labeling with tritiated thymidine, in vitro, that approximated the pattern seen in a low-risk control population.
Tuyns et al. (1987b) found a weak protective effect of dietary calcium against risk of esophageal cancer. However, the finding was not statistically significant and was substantially weaker than the protective effect found for vitamin C.
Dietary calcium has been found to have a significant effect on the colonic epithelium of laboratory animals under several different experimental conditions. Calcium reduces the loss of superficial epithelial cells or the compensatory proliferation of basal crypt cells that occurs in animals exposed to bile and fatty acids or excess dietary fats. This effect has been seen in animals into which bile and fatty acids have been instilled intrarectally (Wargovich et al., 1983), in animals whose colons were perfused with bile acids (Rafter et al., 1986), in animals whose diets were supplemented with cholic acid (Bird et al., 1986), in animals given oral boluses of fat (Bird, 1986), and in animals fed high-fat diets (Caderni et al., 1988). Two studies that did not show an effect of calcium in reducing the number of colonic tumors also showed no cancer-promoting effect of high dietary fat (Bull et al., 1987).
All living organisms require phosphorus to maintain their structure and function. In biologic fluids, it exists as phosphate ion. A major element in hydroxyapatite, phosphorus is a key inorganic constituent of bone. In cells, it is an important part of many life-sustaining compounds, such as phospholipids, phosphoproteins, and nucleic acids; the hormonal second messengers, cyclic adenosine monophosphate, cyclic guanine monophosphate, and inositol polyphosphates; and 2,3-diphosphoglycerate, which is the regulator of oxygen release by hemoglobin. Phosphorus is also the repository of metabolic energy in the form of the high-energy phosphate bond, an allosteric regulator of many enzymes, and an active participant in many physiological buffer systems. Serum concentrations of phosphate serve as one of the regulators of the rate of renal production of 1,25(OH)2D3.
Hypophosphatemia is a serious complication of many medical disorders (e.g., acute alcoholism, during the withdrawal phase); however, the food supply is so replete with phosphorus that the condition occurs only under the most adverse nutritional conditions. One exception is found in people who chronically ingest phosphate-binding antacids (see the discussion on Interactions in the section on Calcium). The major clinical manifestation of chronic moderate hypophosphatemia is a defective bone mineralization resembling osteomalacia. Severe hypophosphatemia may cause a life-threatening syndrome that includes blood cell, muscular, hepatic, and central and peripheral nervous system dysfunctions.
Excessive Dietary Phosphorus
Spencer et al. (1978) showed that an increase in phosphorus intake from 800 mg/day (the RDA) to 2,000 mg/day in adult males failed to affect calcium balance regardless of the calcium intake, which ranged from 200 to 2,000 mg/day. Similarly, Heaney and Recker (1982) reported that varying phosphorus intake had no effect on overall calcium balance in perimenopausal women. Both groups observed that urinary calcium excretion varied inversely with dietary phosphorus, implying that fecal calcium excretion must have varied directly with dietary phosphorus because there was no
change in calcium balance. It thus appears that changes in phosphorus intake by normal adult humans have important effects on calcium metabolism (i.e., decreased intestinal calcium absorption and decreased renal excretion of calcium) but that these effects probably cancel one another so that calcium balance is not affected.
The mechanism by which increased dietary phosphorus might decrease intestinal absorption of calcium has been investigated by Portale et al. (1986). Those investigators showed that increasing dietary phosphorus from a low intake of <500 mg/day to 3,000 mg/day decreased the production rate of 1,25(OH)2D3 so that its serum concentration fell from a level 80% greater than normal to the low-normal range. This observation strongly suggests that the ability to adapt to decreases or increases in dietary phosphorus depends on the ability of the kidney to respond by increasing or decreasing its production of 1,25(OH)2D3, respectively.
There is, therefore, a question whether or not increases in dietary phosphorus might adversely influence calcium economy in people whose kidneys have a limited capacity to produce 1,25(OH)2D3 or in those who need to be in positive calcium balance, such as pregnant and lactating women. Portale et al. (1984) reported that normal dietary phosphorus levels were sufficient to suppress plasma concentrations of 1,25(OH)2D3 in children with moderate renal insufficiency. No studies of the influence of dietary phosphorus on calcium and bone metabolism have been reported in other populations that may be unduly sensitive to increments in dietary phosphorus above the RDA [e.g., the young who are building bone or some elderly people who have a decreased ability to absorb or conserve calcium (Sakhaee et al., 1984)], who have a decreased ability to absorb or conserve calcium (Sakhaee et al., 1984), even though concern has been expressed (Bell et al., 1977; Lutwak, 1975) that high phosphorus intakes may contribute to age-related bone loss in humans.
There is considerable evidence in animals that diets containing phosphorus in relatively larger quantities than calcium cause hyperparathyroidism and bone loss (Draper and Bell, 1979; Draper et al., 1972; Krishnarao and Draper, 1972; Krook, 1968; Miller, 1969; Saville and Krook, 1969). Almost all these reports concern young (growing) or aged animals and differ from other investigations of the influence of high-phosphate diets on calcium metabolism in young or middle-aged adult humans (Bell et al., 1977; Leichsenring et al., 1951; Malm, 1953; Zemel and Linkswiler, 1981).
Magnesium is the fourth most common positively charged ion in the body and is the second most abundant intracellular cation (next to potassium). It plays important roles in osmotic pressure maintenance, enzyme activation, muscular activity, energy metabolism, stabilization of nerve function, and maintenance of bone structure. The average adult body contains about 25 g of magnesium, approximately 50 to 60% of which is found in bone.
Hypomagnesemia results either from decreased intestinal absorption of magnesium or from increased renal excretion. The disease occurs only rarely as an isolated dietary deficiency. It is more often associated with severe general nutritional deficiency, intestinal malabsorption syndromes, excessive vomiting and diarrhea, genetic defects in the kidney, uncontrolled diabetes, and prolonged diuretic therapy. Severe hypomagnesemia (serum levels <1.0 mg/dl) can produce cardiac arrythmias, coronary spasm, hypocalcemia, low blood potassium, changes in mental status, seizures, anorexia, and weakness (Miller, 1985).
Magnesium is a potent inhibitor of vascular smooth-muscle contraction. It decreases peripheral vascular resistance and is a vasodilator that may play a role in the regulation of blood pressure. There are no data linking magnesium intake to the prevalence of hypertension. In case-control studies, serum magnesium levels have variously been reported as both higher and lower in hypertensive, compared to normotensive, people. Sangal and Beevers (1982) found an inverse association between serum magnesium and blood pressure in 73 Danish men and women whose mean age was 60 years. Similar findings have been reported by Albert et al. (1958) and Petersen et al. (1977). Kesteloot et al. (1984b) observed an inverse relationship between urinary magnesium and diastolic blood pressure levels in a subsample of the Belgian population. Resnick et al. (1984a) reported a close inverse correlation between erythrocyte magnesium concentration and both systolic and diastolic blood pressure.
The few intercountry comparisons of magnesium intake and blood pressure show no association. Thulin et al. (1980) reported that magnesium intake was similar in normotensive and hypertensive Scandinavian women. Likewise, no relationship between magnesium excretion and blood pressure was seen in a Korean population (Kesteloot, 1984a) or in the NHANES II population in the United States (Harlan et al., 1984).
Data from studies in animals show a consistent inverse effect of magnesium intake on blood pressure. An increase in blood pressure and constriction of arteriolar, capillary, and postcapillary blood vessels has been observed in magnesium-deficient rats (Altura et al., 1984). Berthelot and Esposito (1983) noted a more rapid increase in the blood pressure level and heart rate of SHRs fed a magnesium-deficient diet compared with those fed a diet containing a normal amount of magnesium. SHRs fed a magnesium-supplemented diet (1.05%) had a blunted rise in blood pressure and a significantly lower mean blood pressure level as compared with controls after 22 weeks of feeding.
Wallach and Verch (1986) reported that numerous organs from SHRs, including the heart, lungs, kidneys, and bone, had 6 to 10% reductions in their magnesium content as hypertension became manifest. An inverse relationship between arterial blood pressure and tissue magnesium was also noted, but the authors could not determine whether the reduced tissue magnesium was a cause of or a response to the developing hypertension.
Resnick et al. (1986) reported that the higher the intracellular free magnesium in male Wistar rats, the lower the blood pressure. The authors suggest that there is a uniform and tightly coupled relationship between levels of intracellular free magnesium and blood pressure, regardless of pathological subtypes of hypertension or dietary conditions.
Populations in areas with hard water (i.e., water with high levels of minerals, including magnesium) have lower rates of cardiovascular diseases than those in areas with soft water (Neri and Johansen, 1978; Schroeder, 1960). This phenomenon, as well as the relationship between magnesium nutrition and cardiac rhythmicity in ischemic heart disease, has been reviewed extensively by Seelig (1974). She concluded that the role of magnesium in maintaining the normal rhythmicity of the heart during ischemic insult may explain the decrease in sudden cardiac death rates in areas with hard water as compared with rates in soft-water areas.
Minerals that are required in relatively large amounts are called macrominerals to distinguish them from trace elementsminerals needed in smaller amounts. Calcium, phosphorus, and magnesium are macrominerals. Low intakes of calcium, which occur commonly, have been associated with age-related osteoporosis. A dietary deficiency of phosphorus is unlikely, due to its wide distribution in foods. The mean population intake of magnesium, although slightly below the RDA, probably does not represent a health hazard.
Maximum bone mass is achieved by approximately 25 to 30 years of age. It is maintained until 35 to 45 years of age and then declines. Decreased skeletal mass is the most important risk factor for fracture of bones and is a significant public health problem in the United States. One of the problems in assessing the relationship of calcium intake to bone mass is the inherent inaccuracy of dietary recall. In addition, metabolic balance studies, although conducted extensively to determine nutritional requirements for calcium, also have important limitations that prevent accurate determination of the amount of dietary calcium needed to achieve balance.
It is important to achieve peak bone mass because the more mass that is available before age-related loss begins, the less likely it will decrease to a level at which fracture will occur. More dietary calcium is required to achieve peak bone mass than to replace obligatory losses of this ion in urine, feces, and sweat. Thus, people under 25 years of age probably need to ingest sufficient calcium to maintain a positive balance. This quantity will vary from person to person, depending on individual efficiencies of intestinal calcium absorption, but 1,200 mg/day probably provides a margin of safety for almost all normal people ages 11 to 25 years.
Once maximum bone mass is achieved, it is maintained without much change for 10 to 20 years. Calcium intake need not be greater than 800 mg/day during this period, because bone building has been completed and intestinal absorption of calcium is normal. However, men and women lose bone at a constant rate of 0.2 to 0.5% per year, starting at ages 40 to 45. For approximately 10
years immediately before, during, and after menopause, women lose bone more rapidly than men (2 to 5% per year). This rapid rate of bone loss in menopausal women returns to the slower rate shared by the sexes after this 10-year period.
Intestinal calcium absorption and the ability to adapt to low-calcium diets are impaired in many postmenopausal women and elderly people of both sexes. The pathogenesis of these abnormalities is controversial, but evidence suggests that they may be due either to a decreased ability of the kidney to produce the major biologically active metabolite of vitamin D, 1,25(OH)2D3, such as after menopause, or to absolute decreases in the production of this metabolite due to renal disease, as in old age. The finding that serum levels of immunoreactive and bioactive parathyroid hormone increase with age implies that defects in calcium absorption are functionally important in that they result in sufficient degrees of hypocalcemia to produce chronic secondary hyperparathyroidisma condition generally associated with bone demineralization. It appears, therefore, that the ability of the intestine to support calcium homeostasis progressively declines with age and that elderly people are increasingly forced to rely on their own bones rather than on the external environment as a source of calcium for maintaining normal extracellular fluid calcium. The degree to which this homeostatic response is needed depends on the severity of the described defects in calcium absorption, the level and bioavailability of dietary calcium, and whether specific therapeutic means are taken to correct defects in calcium absorption.
There is no direct evidence that the impaired intestinal calcium absorption observed during menopause and aging can be overcome by increased calcium intake. Moreover, the evidence that calcium supplementation prevents the trabecular bone loss associated with the menopause is, at best, weak. Thus, calcium supplementation should not be substituted for sex hormone replacement, which prevents postmenopausal bone loss in most women and appears to restore intestinal calcium absorption toward normal. Women taking estrogen replacement should continue to ingest 800 mg of calcium (the RDA). Those menopausal and postmenopausal women at risk for osteoporosis who are unable or refuse to take estrogen may require at least 1,200 mg of calcium per day. Such intakes could delay cortical bone loss and prevent chronic secondary hyperparathyroidism.
The association between decreased calcium intake and hypertension is suggestive but inconclusive. The epidemiologic and animal evidence relating calcium to colorectal cancer risk is also inconclusive. High-phosphorus diets may decrease calcium bioavailability, but they also reduce urinary calcium excretion and their influence on bone mass and the risk of osteoporosis is unknown. There are no known adverse effects of magnesium in the amounts currently consumed in the United States, although animal studies show a consistent inverse association between magnesium intake and blood pressure.
Directions for Research
· The age at which peak bone mass is achieved and the influence of calcium supplementation on peak bone mass need to be determined by longitudinal measurements.
· Additional studies should be conducted to determine the dietary requirement for calcium during and immediately before menopause in different groups of women (e.g., whites, blacks, and Asians). If requirements are known to be increased, investigations can then proceed to determine if therapeutic lowering of the requirement by increasing the fraction of calcium absorbed from the diet will influence the rate at which bone is lost in these patients.
· Long-term studies are needed to determine the effect of calcium supplementation on rate of bone loss in the elderly (65 years and older) in whom intestinal absorption of calcium is decreased.
· Dietary phosphorus, protein, and fiber each have potentially deleterious effects on calcium economy. Their individual and joint effects on calcium balance need to be determined in people such as the elderly who have decreased ability to produce 1,25-dihydroxycholecalciferol and in those such as adolescents who have a need to be in positive calcium balance.
· Continued research is needed to develop noninvasive, quantitative, analytical techniques that can accurately predict individuals at risk for osteoporotic fracture.
· Randomized, prospective, long-term studies in humans should be conducted to determine the influences of calcium supplementation on blood pressure.
· The association between magnesium intake and both blood pressure and cardiovascular diseases in humans needs to be clarified.
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