4

Calcium

BACKGROUND INFORMATION

Overview

Calcium accounts for 1 to 2 percent of adult human body weight. Over 99 percent of total body calcium is found in teeth and bones. The remainder is present in blood, extracellular fluid, muscle, and other tissues, where it plays a role in mediating vascular contraction and vasodilation, muscle contraction, nerve transmission, and glandular secretion.

In bone, calcium exists primarily in the form of hydroxyapatite (Ca 10 (PO4)6 (OH)2), and bone mineral is almost 40 percent of the weight of bone. Bone is a dynamic tissue that is constantly undergoing osteoclastic bone resorption and osteoblastic bone formation. Bone formation exceeds resorption in growing children, is balanced with resorption in healthy adults, and lags behind resorption after menopause and with aging in men and women. Each year, a portion of the skeleton is remodeled (reabsorbed and replaced by new bone). The rate of cortical (or compact) bone remodeling can be as high as 50 percent per year in young children and is about 5 percent per year in adults (Parfitt, 1988). Trabecular (or cancellous) bone remodeling is about five-fold higher than cortical remodeling in adults. The skeleton has an obvious structural role and it also serves as a reservoir for calcium.



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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride 4 Calcium BACKGROUND INFORMATION Overview Calcium accounts for 1 to 2 percent of adult human body weight. Over 99 percent of total body calcium is found in teeth and bones. The remainder is present in blood, extracellular fluid, muscle, and other tissues, where it plays a role in mediating vascular contraction and vasodilation, muscle contraction, nerve transmission, and glandular secretion. In bone, calcium exists primarily in the form of hydroxyapatite (Ca 10 (PO4)6 (OH)2), and bone mineral is almost 40 percent of the weight of bone. Bone is a dynamic tissue that is constantly undergoing osteoclastic bone resorption and osteoblastic bone formation. Bone formation exceeds resorption in growing children, is balanced with resorption in healthy adults, and lags behind resorption after menopause and with aging in men and women. Each year, a portion of the skeleton is remodeled (reabsorbed and replaced by new bone). The rate of cortical (or compact) bone remodeling can be as high as 50 percent per year in young children and is about 5 percent per year in adults (Parfitt, 1988). Trabecular (or cancellous) bone remodeling is about five-fold higher than cortical remodeling in adults. The skeleton has an obvious structural role and it also serves as a reservoir for calcium.

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride Physiology of Absorption, Metabolism, and Excretion Calcium is absorbed by active transport and passive diffusion across the intestinal mucosa. Active transport of calcium into enterocytes and out on the serosal side is dependent on the action of 1,25-dihydroxyvitamin D (1,25(OH)2D), the active form of vitamin D, and its intestinal receptors. This mechanism accounts for most of the absorption of calcium at low and moderate intake levels. Passive diffusion involves the movement of calcium between mucosal cells and is dependent on the luminal:serosal calcium concentration gradient. Passive diffusion becomes more important at high calcium intakes (Ireland and Fordtran, 1973). It has long been recognized that fractional calcium absorption varies inversely with dietary calcium intake (Ireland and Fordtran, 1973; Malm, 1958; Spencer et al., 1969). For example, when calcium intake was acutely lowered from 2,000 to 300 mg (50 to 7.5 mmol)/day, healthy women increased their fractional whole body retention of ingested calcium, an index of calcium absorption, from 27 percent to about 37 percent (Dawson-Hughes et al., 1993). This adaptation required 1 to 2 weeks and was accompanied by a decline in serum calcium and a rise in serum parathyroid hormone (PTH) and 1,25(OH)2D concentrations. In general, the adaptive rise in the fraction of calcium absorbed as intake is lowered is not sufficient to offset the loss in absorbed calcium that occurs with a decrease in calcium intake, however modest that decrease. This is clear from the demonstrations that absorbed calcium and calcium intake, throughout a wide intake range, are positively related (Gallagher et al., 1980; Heaney et al., 1975). Fractional calcium absorption varies through the lifespan. It is highest (about 60 percent) in infancy (Abrams et al., 1997a; Fomon and Nelson, 1993) and rises again in early puberty. Abrams and Stuff (1994) found fractional absorption in Caucasian girls consuming a mean of about 925 mg (23.1 mmol)/day of calcium to average 28 percent in prepubertal children, 34 percent in early puberty (the age of the growth spurt), and 25 percent 2 years later. Fractional absorption remains at about this value (25 percent) in young adults, with the exception that it increases during the last two trimesters of pregnancy (Heaney et al., 1989). With aging, fractional absorption gradually declines. In postmenopausal women, fractional absorption declined by an average of 0.21 percent/year (Heaney et al., 1989). Bullamore and colleagues (1970) reported that men lose absorption efficiency with aging at about the same rate as women. Renal calcium excretion is a function of the filtered load and the

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride efficiency of reabsorption; the latter is regulated primarily by the PTH level. With aging, the urinary loss of calcium decreases (Davis et al., 1970), possibly because of an age-related decrease in intestinal calcium absorption efficiency and an associated reduction in filtered calcium load. Endogenous fecal calcium excretion does not change appreciably with aging (Heaney and Recker, 1994). Racial differences in calcium metabolism have been noted in children and adults. In children and adolescents aged 9 to 18 years, Bell and colleagues (1993) found that African Americans had similar calcium absorption efficiency but lower urinary calcium excretion than Caucasians. Abrams and colleagues (1996a) found absorption efficiency to be similar in prepubertal African American and Caucasian girls or boys but greater in African American girls after menarche. In their study, urinary calcium excretion was lower in African American girls before menarche but similar in postmenarcheal African American and Caucasian girls. These metabolic differences may contribute to the widely observed higher bone mass in African American children (Bell et al., 1991; Gilsanz et al., 1991) and adults (Cohn et al., 1977; Liel et al., 1988; Luckey et al., 1989), and to lower fracture rates in African American adults in the United States (Farmer et al., 1984; Kellie and Brody, 1990). However, their implications for the calcium intake requirement are not clear, and observed differences do not warrant race-specific recommendations at this time. Factors Affecting the Calcium Requirement Bioavailability When evaluating the food sources of calcium, the calcium content is generally of greater importance than bioavailability. Calcium absorption efficiency is fairly similar from most foods, including milk and milk products and grains (major food sources of calcium in North American diets). It should be noted that calcium may be poorly absorbed from foods rich in oxalic acid (spinach, sweet potatoes, rhubarb, and beans) or phytic acid (unleavened bread, raw beans, seeds, nuts and grains, and soy isolates). Soybeans contain large amounts of phytic acid, yet calcium absorption is relatively high from this food (Heaney et al., 1991). In comparison to calcium absorption from milk, calcium absorption from dried beans is about half and from spinach is about one tenth. Because diets used in metabolic studies and in the general population contain calcium from a variety of sources, and because the specific foods used in

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride most of the published studies were not described, adjusting for varying bioavailability was not considered in setting the calcium intake requirements. Bioavailability of calcium when measured from nonfood sources, or supplements, depends on the presence or absence of a meal and the size of the dose. Supplement solubility is not very important (Heaney et al., 1990a), but tablet disintegration (for example, breaking apart) is essential (Whiting and Pluhator, 1992). In studies that measured calcium absorption under similar test conditions, a 250 mg (6.2 mmol) elemental calcium load given with a standardized breakfast meal resulted in average fractional absorption rates of calcium from calcium citrate malate, calcium carbonate, and tricalcium phosphate of 35, 27, and 25 percent, respectively (Heaney et al., 1989, 1990a; Miller et al., 1988; Smith et al., 1987). Under the same conditions, absorption of calcium from milk was similar at 29 percent. Individuals with achlorhydria absorb calcium from calcium carbonate poorly unless the supplement is taken with a meal (Recker, 1985). The efficiency of absorption of calcium from supplements is greatest when calcium is taken in doses of 500 mg (12.5 mmol) or less (Heaney et al., 1975, 1988). Physical Activity The concept that weight-bearing physical activity or mechanical loading determines the strength, shape, and mass of bone is generally accepted (Frost, 1987). The mechanisms by which exercise influences bone mass and structure are currently under investigation (Frost, 1997). Although exercise and calcium intake both influence bone mass, it is unclear whether calcium intake influences the degree of benefit derived from exercise. Under the extreme condition of immobilization, rapid bone loss occurs despite consumption of 1,000 mg (25 mmol)/day of calcium (LeBlanc et al., 1995). In a 3-year calcium intervention study in children aged 6 to 14 years, both calcium and exercise influenced the rate of bone mineralization, but their effects appeared to be independent (Slemenda et al., 1994). Specker (1996) reviewed published prospective exercise studies in which calcium intake data were provided. Sixteen studies were identified, 15 conducted in women and 1 in men. High daily calcium intakes (over 1,000 mg [25 mmol]) enhanced the bone mineral density (BMD) benefits from exercise at the lumbar spine, but enhancement at the radius was less pronounced. Additional prospective studies are needed to test and compare individual and combined effects of calcium and exercise.

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride Currently, there is insufficient evidence to justify different calcium intake recommendations for people with different levels of physical activity. Nutrient-Nutrient Interactions Sodium. Sodium and calcium excretion are linked in the proximal renal tubule. High sodium chloride intake results in increased absorbed sodium, increased urinary sodium, and an increased obligatory loss of urinary calcium (Kurtz et al., 1987). Quantitatively, 500 mg of sodium as sodium chloride has been shown to draw about 10 mg (0.25 mmol) of calcium into the urine in postmenopausal women (Nordin and Polley, 1987). This linkage holds at moderate and high calcium intakes, but some dissociation occurs at low calcium intakes (Dawson-Hughes et al., 1996), probably because low calcium intakes induce higher PTH levels, and PTH promotes the reabsorption of filtered calcium in the distal renal tubule. In children and adolescents, urinary sodium is an important determinant of urinary calcium excretion (Matkovic et al., 1995; O'Brien et al., 1996). An association between salt intake (or sodium excretion) and skeletal development has not been demonstrated in children or adolescents, but one longitudinal study in postmenopausal women identified a correlation between high urinary sodium excretion and increased bone loss from the hip (Devine et al., 1995). Thus, although indirect evidence indicates that dietary sodium chloride has a negative effect on the skeleton, the effect of a change in sodium intake on bone loss and fracture rates has not been reported. Although there is some concern related to the effects of the high salt content of American diets (from processed foods, etc.), available evidence does not warrant different calcium intake requirements for individuals according to their salt consumption. Protein. Protein increases urinary calcium excretion, but its effect on calcium retention is controversial. In balance studies involving use of formula diets in which the phosphorus content was stable, 1 g of dietary protein from both animal and vegetable sources increased urinary calcium excretion by about 1 to 1.5 mg (Linkswiler et al., 1981; Margen et al., 1974). Walker and Linkswiler (1972) found that urinary calcium increased by about 0.5 mg for each gram of dietary protein, as protein intake increased above 47 g/day. In a recent study, a high protein intake (2.71 ± 0.75 g/kg/day) had no measurable effect on urinary pyridinium cross-links of collagen, an index of bone resorption (Delmas, 1992), in young adults consum-

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride ing 1,600 mg (40 mmol)/day of calcium, possibly because of the variability in this measure (Shapses et al., 1995). While dietary protein intake increases urinary calcium excretion, it should be recognized that inadequate protein intakes (34 g/day) have been associated with poor general health and poor recovery from osteoporotic hip fractures (Delmi et al., 1990). Similarly, serum albumin values have been shown to be inversely related to hip fracture risk (Huang et al., 1996). Available evidence does not warrant adjusting calcium intake recommendations based on dietary protein intake. Other Food Components Caffeine. Caffeine has a modest negative impact on calcium retention (Barger-Lux et al., 1990) and has been associated with increased hip fracture risk in women (Kiel et al., 1990). The association of caffeine consumption with accelerated bone loss has been limited to postmenopausal women with low calcium intakes (Harris and Dawson-Hughes, 1994). Specifically, associations with bone loss from the spine and total body were identified in women who consumed less than about 800 mg (20 mmol)/day of calcium and the amount of caffeine present in two or more cups of brewed coffee. Consistent with this is the observation that the negative effect of caffeine on BMD can be offset by the addition of dietary calcium (Barrett-Connor et al., 1994). Caffeine induces a short-term increase in renal calcium excretion (Massey and Wise, 1984) and may modestly decrease calcium absorption (Barger-Lux and Heaney, 1995); its effect on dermal calcium loss has not been evaluated. In summary, the skeletal effects of caffeine are modest at calcium intakes of 800 mg (20 mmol)/day and above. Available evidence does not warrant different calcium intake recommendations for people with different caffeine intakes. Special Populations Amenorrheic Women. Conditions that produce lower levels of circulating estrogen alter calcium homeostasis. Young women with amenorrhea resulting from anorexia nervosa have reduced net calcium absorption, higher urinary calcium excretion, and a lower rate of bone formation when compared with healthy eumenorrheic women (Abrams et al., 1993). Exercise-induced amenorrhea also results in reduced calcium retention and lower bone mass (Drinkwater et al., 1990; Marcus et al., 1985).

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride Menopausal Women. Decreased estrogen production at menopause is associated with accelerated bone loss, particularly from the lumbar spine, for about 5 years (Gallagher et al., 1987). During this period, women lose an average of about 3 percent of their skeletal mass per year. Lower levels of estrogen are accompanied by decreased calcium absorption efficiency (Gallagher et al., 1980; Heaney et al., 1989) and increased rates of bone turnover. These observations may be interpreted several ways. First, lowered estrogen levels primarily affect the skeleton, leading to increased bone resorption, an increase in circulating ionized calcium, a decrease in 1,25 (OH)2D, and reduced stimulus for active intestinal transport of calcium (Gallagher et al., 1980). A second interpretation is that estrogen deficiency primarily reduces the efficiency of dietary calcium utilization and that this reduced efficiency produces a bone loss related to calcium substrate deficiency (Gallagher et al., 1980). A third interpretation is that estrogen has primary effects on both bone and the intestine. The impact on what the dietary calcium intake should be to meet requirements in the above scenarios differs. Increasing calcium intake would provide little skeletal benefit if the primary effect of estrogen withdrawal is at the skeleton. That is, increasing calcium intake would increase absorbed calcium but not the deposition of calcium in bone. The excess absorbed calcium would be excreted in the urine. In contrast, increasing calcium intake should correct the problem (for example, prevent bone loss) if estrogen deficiency primarily reduces calcium absorption efficiency. Examination of the skeletal response to calcium supplementation in premenopausal and early postmenopausal women provides some insight. In a longitudinal calcium supplement trial in women aged 46 to 55 years, Elders et al. (1994) found that 2,000 mg (50 mmol)/day of supplemental calcium significantly reduced bone loss from the lumbar spine in premenopausal women but not in the early postmenopausal women. The effect of calcium supplementation on metacarpal cortical thickness was not significantly related to the menopausal status of the women in this study. In a different study of women with low usual calcium intakes, supplementation with 500 mg (12.5 mmol)/day of calcium had no significant impact on bone loss from the spine or other sites in early postmenopausal women, but it significantly reduced bone loss in women more than 5 years beyond menopause (Dawson-Hughes et al., 1990). From these and other studies (Aloia et al., 1994; Prince et al., 1991; Riis et al., 1987) (see Table 4-1), it is apparent that increasing calcium intake will not prevent the rapid trabecular bone loss that occurs in the first 5 years after menopause. Calcium responsiveness of cortical bone

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride TABLE 4-1 Randomized Controlled Calcium Intervention Trials in Postmenopausal Women   Calcium Intake (mg/day) Relative Change in BMD or BMC in Calcium Group Compared with Placebo   Site N Diet Supplementa Year 1 Year 2 or More, Annualized Statistically Significant Change in BMD or BMC in Calcium Group Compared with Placebo Spine Early postmenopausal Aloia et al., 1994b 70 500 1,700 Pj S or N no Dawson-Hughes et al., 1990 67 <400 500 Sh or N i S no Elders et al., 1991d 248 1,150 1,000 and 2,000 P S or N yes Riis et al., 1987 25 ~1,000c 2,000 P S or N no Late Menopausal Dawson-Hughes et al., 1990 169 <400 500 (CCM) P S or N yes       500 (CC) P S or N no     400– 500 (CCM) P S or N no     650 500 (CC) S or N S or N no Prince et al., 1995 126 800 1,000 P S or N no Reid et al., 1995 78 750 1,000 P S or N yes Radius (Proximal) Early postmenopausal Aloia et al., 1994b 70 500 1,700 S or N P no Dawson-Hughes et al., 1990 67 <400 500 P P no Prince et al., 1991e 80 800 1,000 P P no Riis et al., 1987 25 ~1,000 2,000 P P yes Late postmenopausal Dawson-Hugheset al., 1990 169 <400 500 (CCM) P P yes       500 (CC) P S or N yes     400–650 500 (CCM) P P no       500 (CC) P P no Recker et al., 1996: Prevalent vertebral fracture group 94 ~450 1,200 (CC) — — yes Non-prevalent vertebral fracture group 99 ~450 1,200 (CC) — — no

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride Femoral neck Early postmenopausal Aloia et al., 1994b 70 500 1,700 P P yes Dawson-Hughes et al., 1990 67 <400 500 P S no Late menopausal Chevalley et al., 1994 93 600 800 Pf   no Dawson-Hughes et al., 1990 169 <400 500 (CCM) P P yes       500 (CC) P P no     400– 650 500 (CCM) P S or N no       500 (CC) P S or N no Prince et al., 1995g 126 800 1,000 P P no Reid et al., 1995 78 750 1,000 P S or N yes Total Body Early postmenopausal Aloia et al., 1994b 70 500 1,700 P P yes Late postmenopausal Reid et al., 1995 78 750 1,000 P P yes a Calcium sources: Dawson-Hughes: citrate malate (CCM), carbonate (CC); Aloia, Ettinger, and Riis: CC; Prince: lactate-gluconate (1991, 1995), milk powder (1995); Elders and Reid: (lactate-gluconate + CC) or citrate; Chevalley: CC or osseino-mineral complex. b All women treated with 400 IU (10 µg) vitamin D per day. c Estimate based on national norm rather than on intake of study subjects. d Randomized open trial. e All women participated in exercise program. f An 18-month study in 82 women and 11 men. g Supplement tablets and milk powder significantly reduced bone loss at the trochanter. h S = Similar change in BMD or BMC when compared with placebo. i N = Negative, but not necessarily significant, change in BMC or BMD when compared with placebo. j P = Positive, but not necessarily significant, change in BMC or BMD when compared with placebo. SOURCE: Adapted, with permission, from Dawson-Hughes B. ©1996. Calcium. In: Marcus R, Feldman D, Kelsey J, eds. Osteoporosis. San Diego: Academic Press, Inc. Pp. 1103 and 1105.

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride appears to be less dependent on menopausal status. In summary, from available evidence, the calcium intake requirement for women does not appear to change acutely with menopause. appears to be less dependent on menopausal status. In summary, from available evidence, the calcium intake requirement for women does not appear to change acutely with menopause. Lactose Intolerance. About 25 percent of adults in the United States have lactose intolerance and develop symptoms of diarrhea and bloating after ingestion of a large dose of lactose, such as the amount present in a quart of milk (about 46 g) (Coffin et al., 1994). Primary lactase deficiency begins in childhood and may become clinically apparent in adolescence. In adults, the prevalence of lactose intolerance, as estimated by a positive breath-hydrogen test, is highest in Asians (about 85 percent), intermediate in African Americans (about 50 percent), and lowest in Caucasians (about 10 percent) (Johnson et al., 1993a; Nose et al., 1979; Rao et al., 1994). Lactose-intolerant individuals often avoid milk products entirely although avoidance may not be necessary. Studies have revealed that many lactose-intolerant people can tolerate smaller doses of lactose, for example, the amount present in an 8 oz glass of milk (about 11 g) (Johnson et al., 1993b; Suarez et al., 1995). In addition, lactose-free dairy products are available. Although lactose-intolerant individuals absorb calcium normally from milk (Horowitz et al., 1987; Tremaine et al., 1986), they are at risk for calcium deficiency because of avoidance of milk and other calcium-rich milk products. Although lactose intolerance may influence intake, there is no evidence to suggest that it influences the calcium requirement. Vegetarian Diets. Consumption of vegetarian diets may influence the calcium requirement because of their relatively high contents of oxalate and phytate, compounds that reduce calcium bioavailablity. In contrast to diets containing animal protein, however, vegetarian diets produce metabolizable anions (for example, acetate, bicarbonate) that lower urinary calcium excretion (Berkelhammer et al., 1988; Sebastian et al., 1994). On balance, lacto-ovovegetarians and omnivores appear to have fairly similar dietary calcium intakes (Marsh et al., 1980; Pedersen et al., 1991; Reed et al., 1994) and, on the same intakes, to have similar amounts of urinary calcium excretion (Lloyd et al., 1991; Tesar et al., 1992). BMD has been examined and compared in several cross-sectional studies of lactoovovegetarians and omnivores. Among premenopausal women, spinal BMD did not differ significantly in the two groups (Lloyd et al., 1991). Postmenopausal lacto-ovovegetarians are reported to have higher cortical bone mass than omnivores, as indicated by higher midradius density (Marsh et al., 1980; Tylavsky and Anderson,

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride 1988). However, in a 5-year study, postmenopausal lacto-ovovegetarians and omnivores with similar calcium intakes lost radius BMD at similar rates (Reed et al., 1994). Bone data on strict vegetarians (vegans) are not available, but there is evidence in this group to indicate lower intakes of calcium (among other nutrients) in premenopausal women (Janelle and Barr, 1995), and lower body weight in children (Sanders and Purves, 1981). In conclusion, available data do not support the need for a different calcium intake recommendation for vegetarians. Intake of Calcium The USDA 1994 Continuing Survey of Food Intakes by Individuals (CSFII), showed that mean daily calcium intake, based on an adjusted 24-hour recall which allows for varying degrees of departure from normality and recognizes the measurement error associated with one-day dietary intakes (Nusser et al., 1996), was about 25 percent higher in males than in females aged 9 years and older in the United States (925 vs. 657 mg [23.1 vs. 16.4 mmol]) (Cleveland et al., 1996) (see Appendix D for data tables). The fifth percentiles of intake from the 1994 CSFII for males and females aged 9 and over were 431 and 316 mg (10.8 and 7.9 mmol)/day. The corresponding median intake was 865 and 625 mg (21.6 and 15.6 mmol)/day and the ninety-fifth percentile intakes were 1,620 and 1,109 mg (40.5 and 27.7 mmol)/day. In males, daily intake peaked in the age range of 14 through 18 years (at 1,094 mg [27.4 mmol]) whereas it was highest in females aged 9 through 13 years (at 889 mg [22.2 mmol]). After age 50, median daily calcium intake remained almost constant for males aged 71 and above (708 to 702 mg [17.7 to 17.6 mmol]) and declined for women (571 to 517 mg [14.3 to 12.9 mmol]). Data from the first phase of the Third National Health and Nutrition Examination Survey (NHANES III) are similar (Alaimo et al., 1994). Unfortunately, national survey data from Canada are not currently available. Food Sources of Calcium According to data for 1994, 73 percent of calcium in the U.S. food supply is from milk products, 9 percent is from fruits and vegetables, 5 percent is from grain products, and the remaining 12 percent is from all other sources (CNPP, 1996). Grains are not particularly rich in calcium, but because they may be consumed in large quantities, they can account for a substantial proportion of

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride thiasis (Robertson, 1985). A number of dietary factors seem to play a role in determining the incidence of this disease. In addition to being associated with increased calcium intakes, nephrolithiasis appears to be associated with higher intakes of oxalate, protein, and vegetable fiber (Massey et al., 1993). Goldfarb (1994) argued that dietary calcium plays a minor role in nephrolithiasis because only 6 percent of the overall calcium load appears in the urine of normal individuals. Also, the efficiency of calcium absorption is substantially lower when calcium supplements are consumed (Sakhaee et al., 1994). The issue is made more complex by the association between high sodium intakes and hypercalciuria, since sodium and calcium compete for reabsorption at the same sites in the renal tubules (Goldfarb, 1994). Other minerals, such as phosphorus and magnesium, also are risk factors in stone formation (Pak, 1988). These findings suggest that excess calcium intake may play only a contributing role in the development of nephrolithiasis. Two recent companion prospective epidemiologic studies in men (Curhan et al., 1993) and women (Curhan et al., 1997) with no history of kidney stones found that intakes of dietary calcium greater than 1,050 mg (26.3 mmol)/day in men and greater than 1,098 mg (27.5 mmol)/day in women were associated with a reduced risk of symptomatic kidney stones. This association for dietary calcium was attenuated when the intake of magnesium and phosphorus were included in the model for women (Curhan et al., 1997). This apparent protective effect of dietary calcium is attributed to the binding by calcium in the intestinal lumen of oxalate, which is a critical component of most kidney stones. In contrast, Curhan et al. (1997) found that after adjustment for age, intake of supplemental calcium was associated with an increased risk for kidney stones. After adjustment for potential confounders, the relative risk among women who took supplemental calcium, compared with women who did not, was 1.2. Calcium supplements may be taken without food, which limits opportunity for the beneficial effect of binding oxalate in the intestine. A similar effect of supplemental calcium was observed in men (Curhan et al., 1993) but failed to reach statistical significance. Neither study controlled for the time that calcium supplements were taken (for example, with or without meals); thus, it is possible that the observed significance of the results in women may be due to different uses of calcium supplements by men and women. Clearly, more carefully controlled studies are needed to determine the strength of the causal association between calcium

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride intake vis-à-vis the intake of other nutrients and kidney stones in healthy individuals. The association between calcium intake and urinary calcium excretion is weaker in children than in adults. However, as observed in adults, increased levels of dietary sodium are significantly associated with increased urinary calcium excretion in children (Matkovic et al., 1995; O'Brien et al., 1996). Hypercalcemia and Renal Insufficiency (Milk-Alkali Syndrome) The syndrome of hypercalcemia and, consequently, renal insufficiency with or without metabolic alkalosis is associated with severe clinical and metabolic derangements affecting virtually every organ system (Orwoll, 1982). Renal failure may be reversible but may also be progressive if the syndrome is unrelieved. Progressive renal failure may result in the deposition of calcium in soft tissues including the kidney (for example, nephrocalcinosis) with a potentially fatal outcome (Junor and Catto, 1976). This syndrome was first termed milk-alkali syndrome (MAS) in the context of the high milk and absorbable antacid intake which derived from the “Sippy diet” regimen for the treatment of peptic ulcer disease. MAS needs to be distinguished from primary hyperparathyroidism, in which primary abnormality of the parathyroid gland results in hypercalcemia, metabolic derangement, and impaired renal calcium resorption. As the treatment of peptic ulcers has changed (for example, systemically absorbed antacids and large quantities of milk are now rarely prescribed), the incidence of this syndrome has decreased (Whiting and Wood, 1997). A review of the literature revealed 26 reported cases of MAS linked to high calcium intake from supplements and food since 1980 without other causes of underlying renal disease (Table 4-10). These reports described what appears to be the same syndrome at supplemental calcium intakes of 1.5 to 16.5 g (37.5 to 412.5 mmol)/day for 2 days to 30 years. Estimates of the occurrence of MAS in the North American population may be low since mild cases are often overlooked and the disorder may be confused with a number of other syndromes presenting with hypercalcemia. No reported cases of MAS in children were found in the literature. This was not unexpected since children have very high rates of bone turnover and calcium utilization relative to adults (Abrams et al., 1992). A single case of severe constipation directly linked to daily calcium supplementation of 1,000 mg (25 mmol) or more has been reported in an 8-year-old boy, but this may represent an idio-

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride syncratic reaction of calcium ions exerted locally in the intestine or colon (Frithz et al., 1991). Calcium/Mineral Interactions Calcium interacts with iron, zinc, magnesium, and phosphorus (Clarkson et al., 1967; Hallberg et al., 1992; Schiller et al., 1989; Spencer et al., 1965). Calcium-mineral interactions are more difficult to quantify than nephrolithiasis and MAS, since in many cases the interaction of calcium with several other nutrients results in changes in the absorption and utilization of each. Thus, it is virtually impossible to determine a dietary level at which calcium intake alone disturbs the absorption or metabolism of other minerals. Nevertheless, calcium clearly inhibits iron absorption in a dose-dependent and dose-saturable fashion (Hallberg et al., 1992). However, the available human data fail to show cases of iron deficiency or even reduced iron stores as a result of calcium intake (Snedeker et al., 1982; Sokoll and Dawson-Hughes, 1992). Similarly, except for a single report of negative zinc balance in the presence of calcium supplementation (Wood and Zheng, 1990), the effects of calcium on zinc absorption have not been shown to be associated with zinc depletion or undernutrition. Neither have interactions of high levels of calcium with magnesium or phosphorus shown evidence of depletion of the affected nutrient (Shils, 1994). Thus, in the absence of clinically or functionally significant depletion of the affected nutrient, calcium interaction with other minerals represents a potential risk rather than an adverse effect, in the sense that nephrolithiasis or hypercalcemia are adverse effects. Still, the potential for increased risk of mineral depletion in vulnerable populations such as those on very low mineral intakes or the elderly needs to be incorporated into the uncertainty factor in deriving a UL for calcium. Furthermore, because of their potential to increase the risk of mineral depletion in vulnerable populations, calcium-mineral interactions should be the subject of additional studies. Dose-Response Assessment Adults: Ages 19 through 70 Years Data Selection. Based on the discussion of adverse effects of excess calcium intake above, the most appropriate data available for identifying a critical endpoint and a no-observed-adverse-effect level (NOAEL) (or lowest-observed-adverse-effect level [LOAEL]) con-

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride cern risk of MAS or nephrolithiasis. There are few well-controlled, chronic studies of calcium that show a dose-response relationship. While there are inadequate data on nephrolithiasis to establish a dose-response relationship and to identify a NOAEL (or LOAEL), there are adequate data on MAS that can be used. Identification of a NOAEL (or LOAEL) and Critical Endpoint. Using MAS as the clinically defined critical endpoint, a LOAEL in the range of 4 to 5 grams (100 to 125 mmol)/day can be identified for adults (Table 4-10). A review of these reports revealed calcium intakes from supplements (and in some cases from dietary sources as well) in the range of 1.5 to 16.5 g (37.5 to 412.5 mmol)/day. A median intake of 4.8 g (120 mmol)/day resulted in documented cases. Since many of these reports included dietary calcium intake as well as intake from supplements, an intake in the range of 5 g (125 mmol)/day represents a LOAEL for total calcium intake (for example, from both supplements and food). A solid figure for a NOAEL is not available, but researchers have observed that daily calcium intakes of 1,500 to 2,400 mg (37.5 to 60 mmol) (including supplements), used to treat or prevent osteoporosis, did not result in hypercalcemic syndromes (Kochersberger et al., 1991; McCarron and Morris, 1985; Riggs et al., 1996; Saunders et al., 1988; Smith et al., 1989; Thys-Jacobs et al., 1989). Consideration of hypercalciuria may have additional relevance to the derivation of a UL for adults. Hypercalciuria is observed in approximately 50 percent of patients with calcium oxalate/apatite nephrolithiasis and is an important risk factor for nephrolithiasis (Lemann et al., 1991; Whiting and Wood, 1997). Therefore, it is plausible that high calcium intakes associated with hypercalciuria could produce nephrolithiasis. Burtis et al. (1994) reported a significant positive association between both dietary calcium and sodium intake and hypercalciuria in 282 renal stone patients and derived a regression equation to predict the separate effects of dietary calcium and urinary sodium on urinary calcium excretion. Setting urinary sodium excretion at 150 mmol/day and defining hypercalciuria for men as greater than 300 mg (7.5 mmol) of calcium/day excreted (Burtis et al., 1994), the calcium intake that would be associated with hypercalciuria was 1,685 mg (42.1 mmol)/day. For women, for whom hypercalcemia was defined as greater than 250 mg (6.2 mmol)/day excreted, it would be 866 mg (21.6 mmol)/day. The results of these calculations from the Burtis et al. (1994) equation suggest that calcium intakes lower than AI levels derived earlier in this chapter for females could result in hypercalciuria in susceptible individuals.

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride TABLE 4-10 Case Reports of Milk Alkali Syndrome (single dose/day) a Studies Ca Intake (g/d) b Duration Mitigating Factors Abreo et al., 1993 9.6c >3 mo None reported   3.6c >2 y None reported   10.8d Not stated None reported Brandwein and Sigman, 1994 2.7c 2 y, 8 mo None reported Bullimore and Miloszewski, 1987 6.5d 23 y Alkali in antacid Campbell et al., 1994 5d 3 mo None reported Carroll et al., 1983 4.2d 30 y None reported   2c 5 y None reported   3.8d 2 mo Vitamins A and E   2.8d 10 y NaHCO3, 5 g/d French et al., 1986 8c 2 y None reported   4.2c >2 y Thiazide Gora et al., 1989 4c 2 y Thiazide Hart et al., 1982 10.6d Not stated NaHCO3, 2 g/d Kallmeyer and Funston, 1983 8d 10 y Alkali in antacid Kapsner et al., 1986 10d 10 mo None reported   6.8d 7 mo None reported   4.8c 2 d 10-y history of antacid use Kleinman et al., 1991 16.5d 2 wk 10-y history of antacid use Lin et al., 1996 1.5c 4 wk None reported Muldowney and Mazbar, 1996 1.7c 13 mo (52 wk) None reported Schuman and Jones, 1985 9.8d 20 y None reported   4.8d 6 wk 10-y history of antacid intake Whiting and Wood, 1997 2.4c >1 y None reported Whiting and Wood, 1997 2.3–4.6c >1 y None reported Number of Subjects 26     Mean 5.9 3 y, 8 mo   Median 4.8 13 mo   Range 1.5–>16.5 2 d–23 y   a Case reports of patients with renal failure are not included in this table. b Intake estimates provided by Whiting and Wood (1997). c Calcium intake from supplements only. d Calcium intake from supplements and diet.

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride Although Burtis et al. (1994) identified what could be defined as LOAELs for hypercalciuria, 1,685 mg (42.1 mmol)/day in men and 866 mg (21.6 mmol)/day in women, these values are not considered as appropriate for use as the LOAEL for healthy adults as they were based on patients with renal stones. However, they support for the need for conservative estimates of the Tolerable Upper Intake Level (UL). Uncertainty Assessment. An uncertainty factor (UF) of 2 is recommended to take into account the potential for increased risk of high calcium intake based on the following: (1) 12 percent of the American population is estimated to have renal stones, (2) hypercalciuria has been shown to occur with intakes as low as 1,700 mg (42.5 mmol)/day in male and 870 mg (21.7 mmol)/day in female patients with renal stones (Burtis et al., 1994), and (3) concern for the potential increased risk of mineral depletion in vulnerable populations due to the interference of calcium on mineral bioavailability, especially iron and zinc. TABLE 4-11 Case Reports of Milk Alkali Syndrome (multi- and increasing doses)   Ca Intake (Dose 1) (g/d) Duration (mo) Ca Intake (Dose 2) (g/d) Duration Beall and Scofield, 1995 1 a 13 2.4 a 2 wk   1 13 4.2 2 wk   0.3 a 6 1.8 a 1 mo Carroll et al., 1983 2.5 13 3 13 mo Dorsch, 1986 Not reported 13 2.1 a 6 mo Hakim et al., 1979 1 a 13 2.5 a 3.5 wk Malone and Horn, 1971 Not reported 13 3 a 4.5 wk Newmark and Nugent, 1993 Not reported 13 8.4 a <1 y (“recent”) Schuman and Jones, 1985 Not reported 13 4.6 6 wk Number of Subjects 9   9   Mean 1.2 12 3.6 16.7 Median 1 13 3 4.5 Range 0.3–2.5 6–13 1.8–8.4 2–53 wk a Data do not include intake of calcium from dietary sources.

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride Derivation of the UL. A UL of 2.5 g (62.5 mmol)/day is calculated by dividing a LOAEL of 5 g (125 mmol)/day by the UF of 2. The data summarized in Table 4-11 show that calcium intakes of 0.3 to 2.5 g (7.5 to 62.5 mmol)/day have not been shown to cause MAS and provide supportive evidence for a UL of 2,500 mg (62.5 mmol)/day for adults. The estimated UL for calcium in adults is judged to be conservative. For individuals who are particularly susceptible to high calcium intakes, such as those with hypercalcemia and hyper-absorptive hypercalciuria, this level or below should be protective. UL for Adults 19 through 70 years 2,500 mg (62.5 mmol)/day Infants: Ages 0 through 12 Months The safety of calcium intakes above the levels provided by infant formulas and weaning foods has recently been studied by Dalton et al. (1997). They did not find any effect on iron status from calcium intakes of approximately 1,700 mg (42.5 mmol)/day in infants, which was attained using calcium-fortified infant formula. However, further studies are needed before a UL specific to infants can be established. UL for Infants 0 through 12 months Not possible to establish for supplementary calcium Toddlers, Children, and Adolescents: Ages 1 through 18 years Although the safety of excess calcium intake in children ages 1 through 18 years has not been studied, a UL of 2,500 mg (62.5 mmol)/day is recommended for these life stage groups. Although calcium supplementation in children may appear to pose minimal risk of MAS or hyperabsorptive hypercalciuria, risk of depletion of other minerals associated with high calcium intakes may be greater. With high calcium intake, small children may be especially susceptible to deficiency of iron and zinc (Golden and Golden, 1981; Schlesinger et al., 1992; Simmer et al., 1988). However, no dose-response data exist regarding these interactions in children or the development of adaptation to chronic high calcium intakes. After age 9, rates of calcium absorption and bone formation begin to increase in preparation for pubertal development, but a conservative UL of 2,500 mg (62.5 mmol)/day (from diet and supplements) is recommended for children due to the lack of data. UL for Children 1 through 18 years 2,500 mg (62.5 mmol)/day

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride Older Adults: Ages > 70 Years Several physiologic differences in older adults need to be considered in setting the UL for people over age 70. Because this population is more likely to have achlorhydria (Recker, 1985), absorption of calcium, except when associated with meals, is likely to be somewhat impaired, which would protect these individuals from the adverse effects of high calcium intakes. Furthermore, there is a decline in calcium absorption associated with age that results from changes in function of the intestine (Ebeling et al., 1994). However, the elderly population is also more likely to have marginal zinc status, which theoretically would make them more susceptible to the negative interactions of calcium and zinc (Wood and Zheng, 1990). This matter deserves more study. These effects serve to increase the UF on the one hand and decrease it on the other, with the final result being to use the same UL for older adults as for younger adults. UL for Older Adults > 70 years 2,500 mg (62.5 mmol)/day Pregnancy and Lactation The available data were judged to be inadequate for deriving a UL for pregnant and lactating women that is different from the UL for the nonpregnant and nonlactating female. UL for Pregnancy 14 through 50 years 2,500 mg (62.5 mmol)/day UL for Lactation 14 through 50 years 2,500 mg (62.5 mmol)/day Special Considerations Not surprisingly, the ubiquitous nature of calcium results in a population of individuals with a wide range of sensitivities to its toxic effects. Subpopulations known to be particularly susceptible to the toxic effects of calcium include individuals with renal failure, those using thiazide diuretics (Whiting and Wood, 1997), and those with low intakes of minerals that interact with calcium (for example, iron, magnesium, zinc). For the majority of the general population, intakes of calcium from food substantially above the UL are probably safe.

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride Exposure Assessment The highest median intake of calcium for any age group found in the 1994 CSFII data, adjusted for day-to-day variation (Nusser et al., 1996), was for boys 14 through 18 years of age with a median intake of 1,094 mg (27.4 mmol)/day and a ninety-fifth percentile intake of 2,039 mg (51 mmol)/day (see Appendix D). Calcium supplements were used by less than 8 percent of young children, 14 percent of men, and 25 percent of women in the United States (Moss et al., 1989). Daily dosages from supplements at the ninety-fifth percentile were relatively small for children (160 mg [4 mmol]), larger for men (624 mg [15.6 mmol]), and largest for women (904 mg [22.6 mmol]) according to Moss et al. (1989). Risk Characterization Although the ninety-fifth percentile of daily intake did not exceed the UL for any age group (2,101 mg [52.5 mmol] in males 14 through 18 years old) in the 1994 CSFII, persons with a very high caloric intake, especially if intakes of dairy products are also high, may exceed the UL of 2,500 mg (62.5 mmol)/day. Even if the ninety-fifth percentile of intake from foods and the most recently available estimate of the ninety-fifth percentile of supplement use (Moss et al., 1989) are added together for teenage boys (1,920 + 928 mg/day) or for teenage girls (1,236 + 1,200 mg/day), total intakes are just at or slightly above the UL. Although users of dietary supplements (of any kind) tend to also have higher intakes of calcium from food than nonusers (Slesinski et al., 1996), it is unlikely that the same person would fall at the upper end of both ranges. Furthermore, the prevalence of usual intakes (from foods plus supplements) above the UL is well below 5 percent, even for age groups with relatively high intakes. Nevertheless, an informal survey of food products in supermarkets in the Washington, D.C. metropolitan area between 1994 and 1996 showed that the number of calcium-fortified products doubled in the 2-year period (Park Y., February, 1997, personal communication). Therefore, it is important to maintain surveillance of the calcium-fortified products in the marketplace and monitor their impact on calcium intake.

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride RESEARCH RECOMMENDATIONS Balance studies can be used to determine the amount of calcium needed in the diet to support desirable calcium retention. Such studies need to be expanded in the following ways: To the extent possible, balance studies should be augmented with stable or radioactive tracers of calcium to estimate aspects of calcium homeostasis with changes in defined intakes (i.e., fractional absorption, bone calcium balance, and bone turnover rates); Adaptations to changes in the amount of dietary calcium should be followed within the same populations for short-term (2 months) to long-term (1 to 2 years) studies. Different experimental approaches will be needed to define the temporal response to changes in dietary calcium. Short-term studies may be conducted in a metabolic unit whereas the longer-term studies will need to be carried out in confined populations (i.e., convalescent home patients) fed prescribed diets; human study cohorts followed carefully for years with frequent, thorough estimates of dietary intakes; or metabolic studies of individuals fed their usual diets who typically consume a wide range of calcium intakes. All studies should include a comprehensive evaluation of biochemical measures of bone mineral content or metabolism. Bone mineral content and density should be evaluated in long-term studies. Good surrogate markers of osteopenia could be used in epidemiological studies. Assessment of the effect of ethnicity and osteoporosis phenotype on the relationship between dietary calcium, desirable calcium retention, bone metabolism, and bone mineral content. Evaluation of the independent impact of diet, lifestyle (especially physical activity), and hormonal changes on the utilization of dietary calcium for bone deposition and growth in children and adolescents. These studies need to be done in populations for which the usual calcium intakes range from low to above adequate. Epidemiological studies of the interrelationships between calcium intake and fracture risk, osteoporosis, prostate cancer, and hypertension must be pursued to determine if calcium intake is an independent determinant of any of these health outcomes. Control of other factors potentially associated as other risk factors for these health problems is essential (for example, fat intake in relation to cancer and cardiovascular disease; weight bearing activity; and dietary components such as salt, protein and caffeine in relation to osteoporosis). Such epidemiological studies need to be conducted in middle-aged as well as older adult men and women.

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride More carefully controlled studies are needed to determine the strength of the causal association between calcium intake vis-à-vis the intake of other nutrients and kidney stones in healthy individuals. Because of their potential to increase the risk of mineral depletion in vulnerable populations, calcium-mineral interactions should be the subject of additional studies.