Nutritional Bioavailability of Calcium - American Chemical Society

2 Assaying Calcium Bioavailability in Foods Applicability of the Rat as a Model A R T H U R W. M A H O N E Y and DELOY G. HENDRICKS

Downloaded by CORNELL UNIV on January 18, 2018 | http://pubs.acs.org Publication Date: April 2, 1985 | doi: 10.1021/bk-1985-0275.ch002

Department of Nutrition and Food Sciences, Utah State University, Logan, U T 84322

All middle aged adults lose bone which becomes debilitating when sufficient mineral is lost and fractures occur whether as chronic compression fractures of the vertebrae or as acute fractures of the femoral neck. Evidence is accumulating that adult bone loss is the result of insufficient consumption of bioavailable calcium. Several strategies for assaying calcium bioavailability are discussed. Information is presented supporting the rat as a model for predicting human calcium u t i l i z a t i o n . This cannot be fully evaluated, however, because animal data have been obtained using growing rats fed controlled amounts of calcium and human data have been obtained from adult subjects who have received liberal amounts of calcium. Calcium absorption data are needed from animal and human subjects having similar nutritional and physiological characteristics and which have consumed identical calcium sources. Adult bone loss i s one of the most d e b i l i t a t i n g health problems in modern western society f o r e l d e r l y people. Although bone i s l o s t by both men and women as they age ( 7 3 , 9 5 ) , women suffer from osteoporosis more frequently and severely than do men. Bone loss i s detected by radiodensity and photon absorption techniques. Because 20 to 50 percent of bone mineral may be l o s t before the loss i s detected by radiodensity techniques ( 1 , 2 ) , i t i s probable that bone mineral i s being l o s t much e a r l i e r than age 40 to 45 in women and age 60 in men as i s commonly thought ( 3 , 4 ) . Photon absorptiometry has a precision of 2 to 4 percent r e l a t i v e to bone mineral content of the same bone. Measurements on the r a d i i and ulnae are highly correlated (r = 0 . 8 5 ) with bone mineral content of the femoral neck {2). Using photon absorptiometry, Mazess et a l . (5) reported that bone mineral declines beginning approximately at age 50 f o r both men and women. It i s estimated that the average rate of t h i s bone loss amounts to approximately 10 mg calcium d a i l y f o r men and 20 mg calcium f o r women before menopause. After menopause t h i s loss i s 0097-6156/ 85/ 0275-0017506.00/ 0 © 1985 American Chemical Society

Kies; Nutritional Bioavailability of Calcium ACS Symposium Series; American Chemical Society: Washington, DC, 1985.


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N U T R I T I O N A L BIOAVAILABILITY O F C A L C I U M

approximately 4 0 to 1 2 0 mg calcium d a i l y { § ) . Calculating from the data reported by Mazess et a l . ( 5 J , approximately 5 0 mg of bone mineral i s l o s t d a i l y by women over age 5 0 . It i s generally believed that the larger the bone mass before age-onset bone loss occurs the less l i k e l y the development of d e b i l i t a t i n g bone loss a f t e r age 6 5 ( 3 , 6 , 7 ) . Bone strength however declines much e a r l i e r in l i f e beginning approximately age 2 0 f o r both men and women (8). In animals bone strength i s d i r e c t l y related with i t s mineral content ( 9 - 1 2 ) . These are related to the amounts of dietary calcium and phosphorus ( 1 1 , 1 2 ) or other factors a f f e c t i n g mineral metabolism ( 9 , 1 0 ) . In people, however, the ash, calcium and phosphorus concentrations of bones do not seem to change with age ( 1 3 ) even though human bone strength ( 8 ) and bone mass ( 3 , 1 4 ) clearTy do decline with aging. Havvi et a l . ( 1 3 ) also found descrepancies between bone densities and r a d i o l o g i c i T l y detected osteoporosis vs. bone mineral contents. In spite of these descrepancies, bone loss i s a major d i f f i c u l t y facing aging people. Evidence i s accumulating for dietary calcium deficiency being an e n t i t y in human n u t r i t i o n ( 6 , 7 , 1 5 , 1 6 ) . In a study of 1 3 0 normal perimenopausal women, Heany et a l . ( 1 5 J found that t h e i r calcium balance averaged - 2 5 to - 3 0 milligrams d a i l y . By regression analysis they determined that these women required an intake of 1241 mg (with a 95% confidence interval of 1 1 6 6 to 1 3 1 6 mg Ca) calcium d a i l y to maintain calcium balance. From other data, i t i s estimated that 3 5 mmol ( 1 4 0 0 mg) calcium d a i l y i s needed to maintain calcium balance in women aged 3 5 to 5 0 and postmenopausal women need 4 7 . 5 mmol ( 1 9 0 0 mg) calcium d a i l y {6). A l l of these values are well above the current Recommended Dietary Allowance of 8 0 0 mg calcium d a i l y f o r adult women. The average d a i l y calcium intakes of American women above age 2 3 vary from 5 1 5 to 6 0 4 milligrams for d i f f e r e n t age groups ( 1 7 ) . An average d a i l y calcium intake of 9 4 4 (Sd = 3 4 3 ) milligrams was found for 1 0 0 premenopausal Canadian women ( 1 8 ) . Calcium i s the only nutrient that i s associated with incidence of bone fracture ( 6 ) . Calcium intake i s highly correlated with the mineral content of the bones of experimental animals ( 1 1 ). Thus, calcium could be considered the most frequently d e f i c i e n t nutrient in the U.S.A. Anything that could r e s u l t in greater intakes of calcium and/or improved calcium b i o a v a i l a b i l i t y would be p o t e n t i a l l y important in preventing or delaying d e b i l i t a t i n g bone loss in the e l d e r l y . Approximately, 4 6 percent of a l l calcium consumed by Americans is from dairy products ( 1 7 ) . Scythes et a l . ( 1 8 ) found that dairy products contributed 66.7~percent of the calcium consumed by Canadian pre-menopausal women. Others suggest that dairy products contribute approximately 7 5 percent of the calcium consumed ( 1 9 ) . Neither data set includes calcium taken as supplements. About nine percent of the population consume calcium supplements ( 2 0 ) . Dairy products, however, contribute only 1 3 . 8 to 1 8 . 2 percent of the energy consumed ( 1 7 , 1 8 ) . C l e a r l y , dairy products are a r i c h source of dietary calcium (approximately 1 3 7 0 mg per 1 0 0 0 kcal) and can contribute major quantities of calcium to the diets of those who consume them.



2.

MAHONEY A N D HENDRICKS

A Model for

Assaying

Ca

Bioavailability

19

Calcium retention i s dependent on two f a c t o r s , absorption and excretion. Normal subjects have been observed to have apparent calcium absorptions of 2 3 (sd = 1 2 ) to 2 7 (sd = 1 7 ) percent of the calcium from normal diets ( 2 1 , 2 2 ) . For 2 0 women aged 5 5 to 6 5 consuming 6 2 9 (se = 9 2 ) milligrams dietary calcium d a i l y , the apparent absorption was 3 2 . 1 (se = 1 . 9 ) percent ( 2 3 ) . An apparent calcium absorption of 2 9 . 5 percent (n = 1 3 0 ) may be calculated from data published by Heaney et a l . ( 1 5 ) . Apparent absorption values from 2 9 to 4 2 percent may be calcûTated from data published by Linkswiler ( 2 4 , 2 5 ) . However, much lower apparent absorption values of 6 to 1 5 percent may also be calculated from data published from the same laboratory ( 2 6 ) . Although there i s considerable v a r i a b i l i t y in the apparent absorption values determined from many s t u d i e s , a conservative value of 2 5 percent seems r e a l i s t i c for normal people consuming typical d i e t s . Calcium retention i s also affected by variations in urinary excretion. Dietary factors a f f e c t i n g calcium b i o a v a i l a b i l i t y have been recently reviewed ( 1 9 ) . Linkswiler and her students have shown that dietary protein i s a major f a c t o r contributing to urinary calcium excretion ( 2 4 , 2 5 , 2 7 , 2 8 ) . Renal acid excretion increases with protein intake" Lutz ( 2 9 ) has found that sodium bicarbonate ingestion w i l l a l k a l i n i z e the urine and reverse the renal excretion of calcium by people treated with a high protein d i e t . Renal acid secretion and c a l c u r i a occur during short-term starvation ( 3 0 ) . Ingestion of 5 grams of calcium lactate ( 6 5 0 mg Ca) corrects the acidosis of short-term starvation and improves the calcium balance; however, sodium bicarbonate alone markedly reduces the starvation acidosis but does not improve the calcium balance ( 3 0 ) as i t did above ( 2 9 ) for people treated with high protein d i e t . Thus correction of acidosis does not seem to be the primary factor in c o n t r o l l i n g urinary calcium excretion. Dietary phosphorus also affects calcium metabolism. Polyphosphate decreases calcium absorption in young men while orthophosphate supplement does not ( 2 6 J . However, in the rat a l l forms of phosphate decrease calcium absorption about equally ( 3 1 ) . However, widely divergent dietary calcium:phosphorus ratios do not seem to a f f e c t calcium u t i l i z a t i o n by people as long as there i s adequate phosphorus intake ( 3 2 ) . In general phosphorus stimulates calcium retention in man ( 3 2 J 7 Many other dietary factors have been reported to a f f e c t calcium b i o a v a i l a b i l i t y . Phytate, f i b e r , c e l l u l o s e , uronic a c i d s , sodium a l g i n a t e , oxalate, fat (only in the presence of steatorrhea), and alcohol have been reported to decrease calcium b i o a v a i l a b i l i t y ( 1 5 ) . Lactose and medium chain t r i g l y c e r i d e increase i t ( 1 5 ) . FTïïoride also affects calcium retention primarily by stimulating bone formation thereby decreasing calcium excretion ( 3 3 - 3 8 ) . The effects of f l u o r i d e on calcium u t i l i z a t i o n have been variable (34,38,39).

Strategies for determining calcium b i o a v a i l a b i l i t y The term b i o a v a i l a b i l i t y implies that f r a c t i o n of a n u t r i e n t , drug or toxicant that i s u t i l i z e d r e l a t i v e to the amount consumed. Calcium i s fed to the test subject in amounts below what the subject w i l l u t i l i z e . This ensures that a l l of the calcium provided can be absorbed and metabolized. Then, that f r a c t i o n



20


which i s u t i l i z e d r e l a t i v e to that given i s considered to be the amount of calcium in the source that i s metabolizable. There are two primary approaches to determining b i o availability: (a) Direct measurement of uptake into the body can be done using pharmacokinetic methods, quantitating the accumulation of radioactive n u t r i e n t s , or by quantitating the accumulation of a unique mineral or compound above an expected background l e v e l . The uptake into the body can be estimated i n d i r e c t l y by t r a d i t i o n a l metabolic balance methods (31,40). One can also use changes in blood concentrations of minerals, compounds or physiological markers in conjunction with body weight data to calculate an estimate of mineral or compound uptake (41-45). (b) The second approach i s to determine the uptake of a test mineral or compound r e l a t i v e to the uptake of a stable reference source of that mineral or compound (11,46). Calcium carbonate has frequently been used as a reference source in animal studies of calcium b i o a v a i l a b i l i t y . Nearly a l l of the calcium in the body i s located in bone. Bone i s very s e n s i t i v e to dietary factors such as the amount of calcium present in the d i e t and the a v a i l a b i l i t y of that calcium when a l l other nutrients are present in adequate amounts (46, 47). This i s e s p e c i a l l y true of the growing animal which i s u t i I i z e d in most b i o a v a i l a b i l i t y studies. Adult animals, however, may also be used. Krook et al (48) caused osteoporosis in adult dogs in 42 weeks by feeding a low-calcium high-phosphorus d i e t . The bones were r a d i o l o g i c a l l y normal a f t e r 28 weeks of calcium repletion (48). The ash contents of the vertebral bones of these dogs were much more responsive to dietary calcium and phosphorus manipulation than were the humeri and femora (48). The rat appears to be a good animal model that might be developed f o r predicting calcium b i o a v a i l a b i l i t y for human beings. Various dietary and physiological factors a f f e c t human and rat calcium absorption s i m i l a r l y (Table I ) . The greatest discrepancy among studies seems to be human and rat responses to changes in dietary phosphorus; increases in dietary phosphorus consistently decrease calcium absorption by the rat but does not consistently decrease i t in man. However, the calcium absorption response was s i m i l a r for rats.and humans for 8 of 9 dietary and physiological factors reviewed (Table I ) . This i s good evidence that the rat may be a p r a c t i c a l model for estimating human dietary calcium utilization. An attempt was made to c o l l a t e data on human and rat apparent calcium absorption values f o r several calcium sources. Absorption values were so variable within species and calcium sources that a c o r r e l a t i o n could not be j u s t i f i e d . Much of t h i s v a r i a b i l i t y may be due to methodological differences between the design of the rat and the human experiments. Most of the animal experiments were conducted using rapidly growing rats which were fed modest amounts of calcium but which have high calcium requirements. On the other hand, most of the human experiments were conducted using adult subjects consuming l i b e r a l amounts of calcium. Some degree of standardization of methodologies for rats and human experimentation must be done before a reasonable comparison can be made on the c o r r e l a t i o n between the calcium absorption responses of these two species.


2.



Table I.

A Model for Assaying

Ca

Comparison of Various Dietary and Physiological Factors on Apparent Calcium Absorption by Rats and Humans

Factor

Human Beings

Ca absorption decreases with age

True True (over age 60) True (over age 30)

Gastric a c i d i t y necessary for absorption of poorly soluble Ca source Ortho phosphate

True True in B i l l r o t h II patient False (Total gastrectomy) No change S l i g h t decrease Decrease

Rat

True False

True

Decrease Polyphosphate

Decrease

Increased dietary protein

Increase

Intestine adapts True to Low CA intake by increasing absorption Lactose Increase No change Pregnancy

Increase

Lactation

Increase?

a

Ca

-47

21

Bioavailability

Decrease

Reference 59,60 61 16 62,63 64 65-67 68 69 9,10,31 26,70-72 28 27,73 31,74,75 26 31 25,27,76 & 77

Increased absorptive cap 78 No change in absorptive cap 79 No change 81 Increase 80,82 16,83 True 84,85,99 · 68 ,86 87 Increase 88 No change 89-91 92-93 Increase 94,95 Increase

uptake in serum.


94,96,97


22


Although present data cannot be used to determine the c o r r e l a t i o n between human and rat calcium absorption responses, Bressani (49) found a high c o r r e l a t i o n between nitrogen balance index in children and nitrogen growth index in r a t s . Using published data, a high correlation (r = 0.94) f o r percent iron u t i l i z a t i o n between rats and human beings was found (Mahoney & Hendricks, unpublished data). A l s o , iron absorption by rats and humans responded s i m i l a r l y to 18 of 19 dietary and physiological factors reviewed which are known to a f f e c t iron u t i l i z a t i o n (Mahoney & Hendricks, unpublished data). Again, phosphorus seemed to be the d i f f e r i n g factor for these two species. We believe that t h i s evidence along with that presented in Table I i s i n d i c a t i v e of the potential u t i l i t y of the rat for quantitative preduction human u t i l i z a t i o n of many nutrients including calcium. This w i l l require much concerted research to determine. Metabolic Balance Methods. T h e o r e t i c a l l y , the amount of mineral retained in the body should be determinable by balance methods. Heroux and Peter (50) attempted to do t h i s f o r calcium and magnesium in rats fed three d i e t s . For rats fed t h e i r stock d i e t , they predicted from balance data that the carcasses would contain 23.8 g calcium and 605 mg magnesium. By a n a l y s i s , the carcasses contained 4.45 g calcium and 152 mg magnesium. However, the relationship between calcium balance data (X) and carcass data (Y) were c l o s e l y related (Y = 1.05X - . 0 3 , r = 0.99 f o r group mean data) in the rat data of Whittemore et a l . (51). The metabolic balance technique has received much c r i t i c i s m (40,50,52-54). The intake and c o l l e c t i o n errors are usually not random, the intake usually being s l i g h t l y overestimated and the output being s l i g h t l y underestimated, seldom the reverse (53). As a r e s u l t a s l i g h t positive error in the balance of nutrients is usually encountered (50). Thus, alternate methods f o r determining the b i o a v a i l a b i l i t y of nutrients are sought. The most meaningful methods, however, w i l l be those that present the b i o a v a i l a b i l i t y of test sources in terms of the amount of the nutrient u t i l i z e d r e l a t i v e to that consumed. C e r t a i n l y , meticulously executed balance studies w i l l continue to be very valuable for evaluating nutrient u t i l i z a t i o n . Isotope Methods. The isotopes of calcium have r e l a t i v e l y short h a l f - l i v e s and are r e a d i l y counted using l i q u i d s c i n t i l l a t i o n or gamma counters as appropriate to the nuclide. Calcium isotopes may be quantitated in the excreta, blood, tissues or in the whole body. This has made them useful f o r many n u t r i t i o n a l metabolic studies. However, because of safety concerns, radioactive isotopes are cumbersome to work with and many researchers are unwilling to administer them to human beings. This has limited the use of isotopes to those studies in which alternate methods are not a v a i l a b l e or are imprecise. Methodologies f o r stable isotopes of calcium, which may be safely used in human being, are becoming available for use in metabolism s t u d i e s . These w i l l be p r a c t i c a l alternatives to radioactive isotopes in the future. Isotopic methods f o r estimating calcium absorption have been evaluated by several researchers (49,55-58). From the human data of Harrison et a l . (55), the relationship between percent calcium absorption determined by isotope d i l u t i o n (Y) and excreta counting



2.



Ca

Bioavailability

23

(X) may be expressed as: Y = 0.83 X + 2 . 4 , r = 0.77. Also from t h e i r data, the relationship between percent calcium absorption by isotope d i l u t i o n (Y) and absorption determined by whole body counting plus urine was: Y = 0.90 X + 3 . 9 , r = 0.96. From the human data of Agnew et a l . (56), the relationship between calcium retention determined by whole body counting (Y) or by excreta counting (X) was: Y = 0.87 X - 2 . 0 , r = 0.93. From human data (58), the relationship between percent calcium absorption determined by isotope d i l u t i o n (Y) and absorption determined by fecal counting (X) was e x c e l l e n t : Y = 0.99 X + 1.04, r = 0.99. S i m i l a r l y , the relationship between percent calcium absorption determined by isotope d i l u t i o n (Y) and calcium balance (X) was e x c e l l e n t : Y = 0.92 X - . 0 2 , r = 0.97 calculated from rat data (51). It is c l e a r from the above that calcium retention determined by balance data consistently are greater than when determined by carcass analysis or whole body counting; however, there i s a good c o r r e l a t i o n between the two methods. This i s e s p e c i a l l y true when the calcium i s quantitated by isotope counting in the excreta in the balance method. Relati ye Cal c i urn Bi oavai1abi1i t y . Determination of the b i o a v a i l a b i l i t y of calcium in low-calcium food sources i s d i f f i c u l t using metabolic balance techniques. It can be done, however, using changes in bone composition in growing animals fed test sources compared with animals fed a reference source such as calcium carbonate. A dose-response curve for the reference calcium source is created by feeding diets containing d i f f e r e n t amounts of calcium; and, the bone response i s determined. The bone response of the animals fed the test calcium source may then be compared with the response expected f o r an equal dose of calcium from the reference source. This i s done by determining the equation f o r the l i n e a r portion of the dose-response curve f o r the reference substance by the method of least squares. Using t h i s equation, one can then calculate the response anticipated for the reference substance at the actual dose of the test substance. Relative b i o a v a i l a b i l i t y (RB) may then be calculated as f o l l o w s : d o _ Actual Response of test d i e t Response estimated from CaC0

y 3

i A

n

n

, u u

If t h i s model i s s e l e c t e d , one must then decide what variables to use for the ordinate and the abscissa. The parameters must be d o s e - s e n s i t i v e , free of confounding v a r i a b l e s , e a s i l y determined and preferably l i n e a r . We have evaluated t h i s approach for estimating the b i o a v a i l a b i l i t y of calcium in mechanically deboned meat products (11 ). T y p i c a l l y , correlations between various bone parameters and dietary calcium are very high (r = 0.943 to 0.999). This i s consistent with what others have found for s i m i l a r parameters (46,47). These correlations are also s i m i l a r to the those (r = 0.947 to 0.982) between the amount of calcium consumed and calcium retained (11) a good index procedure. A very important advantage of the r e l a t i v e b i o a v a i l a b i l i t y assay i s that experimental parameters may be selected which are e a s i l y quantitated. Thus, Tso et a l . (11) determined the r e l a t i o n s h i p between dietary calcium concentration (X, g/kg) and



24

NUTRITIONAL BIOAVAILABILITY O F C A L C I U M

bone weight (Y, mg): Y = 8.88 X + 6 6 . 7 , r = 0.99. Relative b i o a v a i l a b i l i t i e s determined with t h i s relationship were s i m i l a r to those determined by calcium retained compared with the calcium consumed or by percent bone ash r e l a t i v e to dietary calcium concentration. They found that bone breaking strength was also a good parameter f o r determining r e l a t i v e b i o a v a i l a b i l i t y . Similar results were found on r e c a l c u l a t i n g the rat data reported by Wong and LaCroix (57). Using t h e i r data, r e l a t i v e calcium b i o a v a i l a b i l i t i e s determined by using bone weight (Y, mg) vs. dietary calcium (X, g/kg) were s i m i l a r in two experiments to those computed by s l o p e - r a t i o . There was a good c o r r e l a t i o n (r = 0.92) between r e l a t i v e b i o a v a i l a b i l i t i e s determined by bone weight (Y, mg) or bone calcium (Y, mg) vs. dietary calcium (X, g/kg). Thus, r e l a t i v e b i o a v a i l a b i l i t i e s are readily determined using e a s i l y quantitated parameters of calcium metabolism. Furthermore, r e l a t i v e b i o a v a i l a b i l i t i e s determined as described above may be used to evaluate calcium b i o a v a i l a b i l i t y in sources having low calcium concentrations. From the foregoing, i t i s clear that r e l a t i v e b i o a v a i l a b i l i t i e s f o r various sources may be determined using e a s i l y analyzed parameters of calcium metabolism. Determining the amount of calcium consumed (X, mg) and the dry weight of some e a s i l y dissected bone (Y, mg) seem l o g i c a l parameters for evaluating r e l a t i v e calcium b i o a v i l a b i l i t y . By doing t h i s on an individual animal b a s i s , one accounts for variations in food intake and weight gain which i s not done when calcium dose i s expressed as concentration in diet or bone. This i s p a r t i c u l a r l y important when evaluating calcium b i o a v a i l a b i l i t i e s of food sources which can cause marked variations in animal acceptance of test d i e t s . The data may then be analyzed with appropriate s t a t i s t i c a l models f o r determining r e l a t i v e b i o a v a i l a b i l i t i e s . Relative b i o a v a i l a b i l i t y determinations are l i m i t e d by what i s known about the quantitative absorption of the reference substance. One cannot confidently predict absorption of the test substances based on r e l a t i v e b i o a v a i l a b i l i t y data. Relative b i o a v a i l a b i l i t y data, however, can be used to rank the test sources and to provide a basis for comparison among experiments. Acknowledgments Paper 2975 of the Utah State University Experiment S t a t i o n .

Agricultural

Literature Cited 1. Lutwak, L. J . Am. Dietet. Assoc. 1964, 44, 173-175. 2. Mazess, R.B. In: Barzel, U.S., Ed., "Osteoporosis II", Grune & Stratton, Inc., New York, NY, 1979. 3. Garn, S.M. "The Earlier Gain and the Later Loss of Cortical Bone in Nutritional Perspective", Charles C. Thomas, Publisher, Springfield, IL 1970. 4. P a r f i t t , A.M. Medical Times 1981, November. 5. Mazess, R.B.; Peppler, W.W.; Chesney, R.W.; Lange, Τ . Α . ; Lindgren, U.; Smith, E., Jr. Calcif Tissue Int. 1984, 36, 8-13. 6. P a r f i t t , A.M. Lancet 1983, 2, 1181-1184. 7. A v i o l i , L.V. Fed. Proc. 1981, 40, 2418-2422. 8. Lindhal, O. Acta Orthop. Scand. 1976, 47, 11-19. Kies; Nutritional Bioavailability of Calcium ACS Symposium Series; American Chemical Society: Washington, DC, 1985.

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15. 16. 17.

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Ca

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26

38. 39. 40. 41. 42. 43. 44.


45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67.

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2.


68. 69. 70.

71. 72. 73.


74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99.


Ca

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27

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Nutritional Bioavailability of Calcium - American Chemical Society

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