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The Journal of Nutrition Vol. 129 No. 1 January 1999,
pp. 9-12
Department of BioStructure and Function, The University of Connecticut Health Center, Farmington, Connecticut 06030-3705 and * INSERM U45 and Ecole Pratique des Hautes Etudes, Hôpital E. Herriot, 69437 Lyon, France
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ABSTRACT |
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Abstract
Introduction
References
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The amount of calcium absorbed in the intestine depends on habitual calcium intake. When intake is low, active transcellular calcium transport in the duodenum is upregulated and a larger proportion of calcium is absorbed by the active process than by the passive paracellular process that prevails in the jejunum and ileum. Bioavailability of the calcium source
digestibility and solubilizationplays a role under conditions of low calcium intake but is relatively unimportant when calcium intakes are high (e.g. >800 mg/d in people). Vitamin D intake is a second factor, as active calcium transport is directly and proportionally dependent on the presence in the intestinal cell of calbindin D9k, the biosynthesis of which is totally vitamin D dependent. Passive absorption in jejunum and ileum is the major absorptive process when calcium intake is adequate or high. Passive calcium absorption is a complicated function of solubility in the distal small intestine, the length of sojourn of the chyme in a given intestinal segment, and the rate of paracellular diffusion from lumen to lymph and blood. Calcium that reaches the large intestine undergoes absorption there by both active and passive processes. Probably no more than 10% of total calcium absorption takes place in the large intestine, whether calcium intake is low or high. Calcium absorption by the large bowel can assume nutritional importance under conditions of significant small bowel resection.
The important role played by calcium in the mammalian organism is now well recognized. Calcium is the major cation of bone mineral. Its rate of deposition in the skeleton is highest in the newborn infant, decreasing to a very low level by the time people have stopped growing (Fig. 1). The rate of calcium removal from the skeleton tends to parallel the calcium deposition rate. The rate of calcium accumulation in the skeleton is the difference between deposition and removal rates and constitutes the bone calcium mass. Figure 2 shows that the bone calcium mass of the newborn infant is quite small and reaches a maximum in persons 35-45 y old. After that age, bone calcium mass decreases, gradually in men and abruptly in women for about a decade after their menopause. Thereafter, the rates at which bone calcium decreases are approximately comparable in both men and women, even though the bone calcium mass of women on average is markedly lower than that of men (Fig. 2).
As has become evident in the last 20 or so years, calcium also plays a major signaling role in the body. This is true for the closely regulated extracellular calcium, a decrease of which will trigger, among others, release of parathyroid hormone, a molecule that by its actions on bone tends to restore plasma calcium to 2.5 mmol/L, the concentration aimed for in calcium homeostasis (Bronner and Stein 1995 Calcium also plays an important role as intracellular messenger in many systems and cells (e.g., cardiac, renal, etc.).
The typical calcium content of the adult human body is 1 kg. Virtually all is found in the skeleton, with the amount in body fluids and cells of the soft tissues accounting for <1% of the body's total (Bronner 1997 If, for example, an individual accumulates 1 kg (25 mol) Ca in the first 40 y of life, this would be equivalent to a daily average of 106/40 × 365 mg/d or 68 mg/d (1.7 mmol/d). This average is what 20-y-old individuals typically retain. With daily calcium intakes between 600 (15 mmol) and 1200 mg (30 mmol), this would yield an average retention efficiency of 68/900 or 7.6%. These 20-y-old individuals therefore would have to consume 13 times more than what they end up storing in their skeleton.
The path of calcium in the body involves ingestion, digestion, intestinal transit during which calcium is absorbed transepithelially and fecal excretion. Absorbed calcium mixes rapidly with the body fluid calcium. When the plasma calcium is normal, i.e., ~2.5 mmol/L, some 50% of calcium ions in the plasma that circulates through the skeleton remains in the bone mineral and is replaced by calcium ions that had previously entered the bone mineral (Bronner and Stein 1992
Food is comminuted by chewing and after it has been swallowed, reaches the stomach. There the secreted gastric acid lowers the pH of the stomach contents substantially. When the stomach contents are expelled into the duodenum, the pH rises and continues to rise to alkaline levels in the lower half of the small intestine (Table 1). As a result of this change in pH, less calcium is solubilized and some may reprecipitate (Schedl et al. 1968
Recker (1985) Calcium Bioavailability.
It is obvious that calcium must be ionized and in solution to be absorbed. Even if a calcium salt is precipitated because of alkaline conditions Active and Passive Transepithelial Calcium Transport.
Active transport refers to the fact that this transcellular process requires metabolic energy. It essentially is localized to the upper duodenum and is totally dependent on vitamin D (Pansu et al. 1983 Calcium Absorption from the Colon.
It is of interest to know whether the large intestine contributes significantly to calcium absorption. Calcium absorption occurs in the cecum and the ascending colon (Petith and Schedl 1976
INTRODUCTION
Abstract
Introduction
References
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Fig 1.
Bone calcium deposition rate, vo+, expressed on a body weight basis, kg, plotted as a function of age in 118 children, aged 0 to 18 y. The units of vo+/weight are mg Ca/kg body weight. Data, adapted from Abrams et al. (1992, 1994) and Bronner and Abrams (1998) 
, were provided by S. A. Abrams and reproduced with permission.
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Fig 2.
Bone mineral content as a function of age, determined by photon absorptiometry. Unpublished data kindly provided by C. Christiansen, Center for Clinical and Basic Research, Ballerup, Denmark, and reproduced with permission.
).
). It is thus obvious that almost all calcium that is ingested and retained is found in the skeleton. Interestingly enough, calcium accumulation by the body is a relatively inefficient process.
). Of the plasma calcium ions that circulate through the kidney, approximately half are filtered into the renal tubule, and some 70% of these are reabsorbed as the fluid passes through the various parts of the nephron (Bronner 1997). Calcium ions that enter the intestine with the body fluids (succus entericus, bile, etc.) or as cell debris mix with intestinal content and are reabsorbed at the rate at which the chyme is absorbed. Figure 3 provides a diagrammatic representation of these statements.
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Fig 3.
Schematic diagram of the flow of calcium through the body. The Ca pool includes calcium in solution in blood plasma, in the extracellular fluid, and in, or associated with, bone, described in units of mass, e.g., mmol. vi = Ca, ingested in food; va = Ca absorbed from food; vndo = endogenous Ca lost in stool; vu = Ca excreted in urine; vF = Ca excreted in stool; vmisc = Ca lost from the body via sweat, semen, menstrual fluid, milk; vo+ = Ca deposited in bone; vo 
= Ca resorbed from bone. v's, i.e. rates, described in units of mass per unit time, e.g., mmol/d. vT = rate at which Ca enters or leaves the pool, i.e., equal to va + vo = vu + vendo + vo+ + vmisc. In a nonlactating mammal or persons, vmisc is generally negligibly small. The body Ca balance = bone Ca balance = vo+ 
vo. Reproduced from Bronner (1997) with permission.
). For this reason, calcium carbonate, when ingested alone, is a relatively poor source of calcium (Fujita et al. 1995) and, in patients with achlorhydria, is absorbed very poorly (Recker 1985).
View this table:
Table 1.
pH and sojourn time in segments of the intestine of rats fed a high-calcium diet1
also reports that when calcium carbonate was given with skim milk, achlorhydric patients absorbed as much calcium as control subjects with normal stomach acidity. The labeled calcium was from calcium carbonate, but exchange between 45Ca and milk Ca is likely to have taken place. Therefore all one can conclude is that achlorhydria affects calcium absorption only to a minor degree, if any, when sufficient solubilized calcium is available.
as prevail in the ileum (Table 1)some calcium ions are in solution. As these are absorbed, other calcium ions will go into solution, and the total absorbed is a complicated function of local solubility, the rate of tryansepithelial movement (i.e. absorption) and the sojourn time in the particular intestinal segment (Duflos et al. 1995). Moreover, calcium found in vegetables or other nonfluid foods cannot go into solution until at least some part of the vegetable (or food) has been digested. Therefore foods with high fiber content are likely to be poorer sources of calcium than foods that contain less or no fiber but an equivalent amount of calcium (cereals vs. milk, Weaver et al. 1991). These theoretically valid considerations notwithstanding, studies with vegetables grown with labeled calcium have indicated unexpectedly high absorption levels for some, probably because effective digestibility is hard to assess (kale vs. spinach, Heaney and Weaver 1990, Heaney et al. 1988).
), casein phosphopeptides (Hansen et al. 1997), or by the addition of highly soluble salts such as calcium gluconate (Pansu et al. 1993) or calcium gluconate-glycerophosphate (Schanler and Abrams 1995). Other studies have dealt with the question of whether certain diet components, e.g., rice cereal added to infant formula (Lifschitz and Abrams 1998) or increasing dietary fiber in weaning cereals (Davidson et al. 1996), have adversely affected calcium bioavailability and/or absorption. In a review such as this, individual reports cannot be analyzed in detail. Nevertheless it is apparent that when calcium intake is adequate, differences in bioavailability, as from increased solubilization, play no or only a minor role in the amount of calcium that is absorbed or deposited in the skeleton (Deroisy et al. 1997, Tsugawa et al. 1995). When, however, the dietary calcium content is low and in the form of poorly soluble or poorly digestible sources (e.g., spinach, Peterson et al. 1995), the decrease in calcium absorption compared to a source like milk becomes nutritionally significant. The high absorbability of calcium in milk has been related to the presence of lactose (Fournier 1954), phosphopeptides (Mykkänen and Wasserman 1980) and amino acids (Wasserman et al. 1956), the latter perhaps derived from hydrolysis of casein in the intestinal lumen. It is of interest that some milk substitutes, though otherwise nutritionally equivalent (Cioccia et al. 1995) are, compared to milk, a poorer source for calcium and phosphorus (Barrera et al. 1995). On the other hand, milk and dairy products have all the same effective bioavailability (Nickel et al. 1996).
found that when synthetic triglycerides (with 73.9% of the palmitate in the Sn-2 position) were added to a formula diet, palmitate and calcium absorption were improved significantly (Ca from some 42 to 57%) and the percentage of milk fat excreted as fatty acid calcium soaps reduced by about half to 3.3%. It would be interesting to know whether and to what extent these findings also apply to the diets of children and adults whose total fat intake may differ from that of the infants (4.2 g/100 g milk).
). Transcellular movement can be described as involving three sequential steps: entry, intracellular diffusion, and extrusion. Entry across the brush border into the cell is down an electrochemical gradient via calcium channels that are not voltage gated (Bronner 1997). Intracellular diffusion of the calcium ion, i.e., movement from brush border to the basolateral pole of the duodenal cell, is the rate-limiting step (Bronner et al. 1986). In the absence of the vitamin-D-dependent, cytosolic calcium-binding protein (calbindin, Mr
9 kDa) (Wasserman et al. 1968), self-diffusion of the calcium ion in the intestinal cell is only ~1/70 of the measured transport rate (Bronner et al. 1986). Indeed transcellular calcium transport varies directly with the cellular content of calbindin (Bronner et al. 1986, Pansu et al. 1989). Wasserman and Fullmer (1995) have shown that calcium enters the vitamin-D-deficient cell but remains localized to the brush border region, whereas calcium ions are found throughout the cell cytoplasm in vitamin-D-replete enterocytes. Stein (1992) and Feher et al. (1992) have described in detail how calbindin facilitates intracellular calcium diffusion. Effectively calbindin D9k, by binding calcium, raises the intracellular calcium concentration and then acts like a bucket brigade, with calcium diffusion increased to equal the experimentally evaluated transport rate (Bronner et al. 1986, Feher et al. 1992, Stein 1992). Thus the major role of vitamin D in transcellular calcium transport involves biosynthesis of calbindin D9k (Perret et al. 1988). The vitamin also seems to modulate entry and extrusion (Bronner et al. 1986, Wasserman et al. 1992).
; Wasserman et al. 1992), but does not appear to be rate limiting (Bronner et al. 1986).
). In rats on low calcium intakes, active transport in the duodenum can account for ~50% of the total absorbed (Bronner et al. 1986), but the fraction accounted for by active transport diminishes rapidly as calcium intake increases (Pansu et al. 1993). In premature infants the transcellular, vitamin-D-dependent active transport of calcium is not yet expressed; with intakes ranging from 40 to 130 mg Ca/d, the average absorbed is 58%, all of which moves paracellularly (Bronner et al. 1992).
). There absorption is by the passive, paracellular process exclusively (Pansu et al. 1983). The situation in the human is not likely to be very different.
), but not in the transverse colon (Escoffier 1996). (The experimental studies that culminated in the doctoral thesis of C. Duflos (1994) and the master's thesis of L. Escoffier (1996) were carried out in the laboratory and under the supervision of Dr. Danielle Pansu.) Of the total soluble calcium found in the entire intestinal tract, some 15% is found in the large intestine (Duflos 1994). Table 1 shows that the sojourn time in the cecum and ascending colon is 142 min compared with 187 min in the small intestine. If we assume that the rate of paracellular movement is similar in the small and large intestines, then one can calculate that 0.15 × 142/187 or 11% of calcium absorbed by the paracellular route throughout the entire tract is absorbed in the large intestine. Comparable figures are unavailable for humans but may not be drastically different.
). Inasmuch as active calcium transport is directly proportional to calbindin D9k content (Bronner et al. 1986), cecum and colon would account for ~7% of total active calcium transport. One may therefore reasonably conclude that the large intestine accounts for some 10% of total calcium transport in the rat.
have shown that when patients had extensive small-intestinal resection ( ms150 cm), calcium absorption was 13% in patients with at least half the colon preserved, significantly higher than in patients with ileostomy. A subsequent study (Hylander et al. 1990) confirmed these findings, patients with ileostomy absorbing 10% of 800 mg Ca/d, whereas patients with preserved colon absorbed 14% (P < 0.001). Clearly significant resection of the small bowel permits a larger amount of unabsorbed calcium to reach the large bowel, a portion of which then can be absorbed. But in the normal situation, even with very efficient active absorption (Karbach and Feldmeier 1993), the cecum and colon together contribute only a little to the overall calcium economy.
) to permit transepithelial calcium movement to proceed relatively independently of intrinsic bioavailability.
), as it is in the small intestine, there is no augmentation in the scavenging function of the large intestine, with large bowel calcium absorption probably still accounting for <10% of total intestinal absorption.
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FOOTNOTES |
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LITERATURE CITED |
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Abstract
Introduction
References
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an old problem revisited.
J. Nutr.
1995;
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