Calcium1
Connie M. Weaver
Robert P. Heaney
1Abbreviations: 1,25(OH)2D, 1,25-dihydroxyvitamin D; AI, adequate intake; ATP, adenosine triphosphate; ATPase, adenosine triphosphatase; Ca2+, calcium ion; CaSR, calcium-sensing receptor; CT, calcitonin; DAG, diacylglycerol; ECF, extracellular fluid; IGF-I, insulinlike growth factor-I; InsP3, inositol-1,4,5-triphosphate; Na+, sodium ion; NHANES, National Health and Nutrition Examination Survey; PIP2, phosphatidylinositol-4,5-bisphosphate; PTH, parathyroid hormone; RyR, ryanodine receptor; VDR, vitamin D receptor.
BIOLOGIC ROLES OF CALCIUM
In higher mammals, the most obvious role of calcium is structural or mechanical and is expressed in the mass, hardness, and strength of the bones and teeth. Calcium has another fundamental function, however: shaping key biologic proteins to activate their catalytic and mechanical properties. A significant portion of the regulatory apparatus of the body is concerned with the protection of this second function (e.g., all the activities and roles of parathyroid hormone [PTH], calcitonin [CT], and a key activity of vitamin D). Calcium is the most tightly regulated ion in the extracellular fluid (ECF). The structural role is discussed in greater detail in the chapter on osteoporosis, whereas the cell metabolic, regulatory, and nutritional aspects of this critical element are discussed in this chapter.
Calcium and the Cell
The calcium ion (Ca2+) has an ionic radius of 0.99 Å and is able to form coordination bonds with up to 12 oxygen atoms (1). The combination of these two features makes calcium nearly unique among all cations in its ability to fit neatly into the folds of the peptide chain. Cytoplasmic proteins are extremely flexible to the point of being literally floppy. They typically assume hundreds of different three-dimensional configurations each second. Some of these configurations have the capacity to bind critical ligands or to assume catalytic functions. Without calcium, these configurations are so short lived as to be of little functional significance. Calcium, when present in the cytosol in sufficient concentration, binds to, for example, aspartate and glutamate side chains on the peptide backbone and thus builds intramolecular linkages that bind together different folds of the peptide chain and “freeze” the protein into a functionally active, particular shape. Magnesium and strontium, which are chemically similar to calcium in the test tube, have different ionic radii and do not bond so well with protein. Lead and cadmium ions, by contrast, substitute quite well for calcium, and, in fact, lead binds to various calcium-binding proteins with greater avidity than does calcium itself. Fortunately, neither element is present in significant quantity in the milieu in which living organisms thrive. Nevertheless, the ability of lead to bind to the calcium-binding proteins is part of the basis for lead toxicity.
Binding of calcium to thousands of cell proteins triggers changes in protein shape that govern function (2). These proteins range from those involved with cell movement and muscle contraction to nerve transmission, glandular secretion, and even cell division. In most of these
situations, calcium acts both as a signal transmitter from the outside of the cell to the inside and as an activator or stabilizer of the functional proteins involved. In fact, ionized calcium is the most common signal transmitter in all of biology. It operates from bacterial cells all the way up to cells of highly specialized tissues in higher mammals.
situations, calcium acts both as a signal transmitter from the outside of the cell to the inside and as an activator or stabilizer of the functional proteins involved. In fact, ionized calcium is the most common signal transmitter in all of biology. It operates from bacterial cells all the way up to cells of highly specialized tissues in higher mammals.
When a cell is activated (e.g., a muscle fiber receives a nerve stimulus to contract), the first thing that happens is that calcium channels in the plasma membrane open up to admit a few calcium ions into the cytosol. These bind immediately to a wide array of intracellular activator proteins, which, in turn, release a flood of calcium from the intracellular storage vesicles (the sarcoplasmic reticulum, in the case of muscle). This second step very quickly raises cytosol calcium concentration and leads to activation of the contraction complex. Two of the many reactions involving calcium-binding proteins are of particular interest here: (a) troponin C, after it has bound calcium, initiates a series of steps that lead to the actual muscle contraction; and (b) calmodulin, a second and widely distributed calcium-binding protein, activates the enzymes that break down glycogen to release energy for contraction. In this way, calcium ions both trigger the contraction and fuel the process. When the cell has completed its assigned task, the various pumps quickly lower the cytosol calcium concentration, and the cell returns to a resting state. These processes are described in more detail later in this chapter.
If all the functional proteins of a cell were fully activated by calcium at the same time, the cell would rapidly self-destruct. For that reason, cells must keep free calcium ion concentrations in the cytosol at extremely low levels, typically on the order of 100 nmol. This is 10,000-fold lower than the concentration of calcium ion in the extracellular water outside of the cell. Cells maintain this concentration gradient by a combination of mechanisms: (a) a cell membrane with limited calcium permeability; (b) ion pumps that move calcium rapidly out of the cytosol, either to the outside of the cell or into storage vesicles within the cell; and (c) a series of specialized proteins in the storage vesicles that have no catalytic function in their own right but that serve only to bind (and hence sequester) large quantities of calcium. Low cytosolic [Ca2+] ensures that the various functional proteins remain dormant until the cell activates certain of them, and it does this simply by letting [Ca2+] rise in critical cytosolic compartments. In contrast to proteins that are activated by rising cytosolic [Ca2+] are enzymes such as several proteases and dehydrogenase, which are activated or stabilized by bound calcium independent of changes in [Ca2+]i.
OCCURRENCE AND DISTRIBUTION IN NATURE
Calcium is the fifth most abundant element in the biosphere (after iron, aluminum, silicon, and oxygen). It is the stuff of limestone and marble, coral and pearls, sea shells and egg shells, and antlers and bones. Because calcium salts exhibit intermediate solubility, calcium is found both in solid form (rocks) and in solution. It was probably present in abundance in the watery environment in which life first appeared. Today, seawater contains approximately 10 mmol calcium per liter (approximately eight times higher than the calcium concentration in the extracellular water of higher vertebrates); and even fresh waters, if they support an abundant biota, typically contain calcium at concentrations of 1 to 2 mmol. In most soils, calcium exists as an exchangeable cation in the soil colloids. It is taken up by plants, whose parts typically contain from 0.1% to as much as 8% calcium. Generally, calcium concentrations are highest in the leaves, lower in the stems and roots, and lowest in the seeds.
In land-living mammals, calcium accounts for 2% to 4% of gross body weight. A 60-kg woman typically contains approximately 1000 to 1200 g (25 to 30 mol) of calcium in her body. More than 99% of that total is in the bones and teeth. Approximately 1 g is in the plasma and ECF bathing the cells, and 6 to 8 g are in the tissues themselves (mostly sequestered in calcium storage vesicles inside of cells, as discussed earlier).
In the circulating blood, calcium concentration is typically 2.25 to 2.5 mmol. Approximately 40% to 45% of this quantity is bound to plasma proteins, approximately 8% to 10% is complexed with ions such as citrate, and 45% to 50% is dissociated as free ions. In the ECF outside of the blood vessels, total calcium is on the order of 1.25 mmol, which differs from plasma concentration because of the absence of most plasma proteins from the ECF. It is the calcium concentration in the ECF that the cells see and that is tightly regulated by the parathyroid, CT, and vitamin D hormonal control systems.
With advancing age, humans commonly accumulate calcium deposits in various damaged tissues, such as atherosclerotic plaques in arteries, healed granulomas, other scars left by disease or injury, and often in the rib cartilages as well. These deposits are called dystrophic calcification and rarely amount to more than a few grams of calcium. These deposits are not caused by dietary calcium but by local injury, coupled with the widespread tendency of proteins to bind calcium. Calcification in tissues other than bones and teeth is generally a sign of tissue damage and cell death. This process is greatly exaggerated in conditions such as end stage kidney disease, when the calcium × phosphorus product of the ECF exceeds 2.5 to 3.0 mmol2/L2.
METABOLISM
Calcium metabolism and transport, as affected by age, race, and sex, on intakes approximating requirements (1000 to 1300 mg/day), are given in Table 7.1. Part of dietary calcium is absorbed into the bloodstream where it is in intimate exchange with ECF calcium. Part of the absorbed calcium is returned as endogenous secretion to the gut, where it is excreted along with unabsorbed
calcium. Part is excreted in the urine through the kidney, and part enters the slower exchange pools of soft tissue and bone. Dietary calcium influences calcium absorption and, consequently, fecal calcium and, to a lesser extent, urinary calcium excretion. An obligatory loss of calcium occurs through endogenous secretion, urine, and skin. Gender, age, and racial differences in calcium metabolism exist. Adolescents are more efficient at using calcium than are young adults, and elderly persons are the least efficient. Boys are more efficient at calcium metabolism than girls, and blacks are more efficient than whites.
calcium. Part is excreted in the urine through the kidney, and part enters the slower exchange pools of soft tissue and bone. Dietary calcium influences calcium absorption and, consequently, fecal calcium and, to a lesser extent, urinary calcium excretion. An obligatory loss of calcium occurs through endogenous secretion, urine, and skin. Gender, age, and racial differences in calcium metabolism exist. Adolescents are more efficient at using calcium than are young adults, and elderly persons are the least efficient. Boys are more efficient at calcium metabolism than girls, and blacks are more efficient than whites.
TABLE 7.1 CALCIUM (Ca) METABOLISM AS INFLUENCED BY RACE AND AGE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Homeostatic Regulation
Plasma calcium is tightly regulated at approximately 2.5 mM (9 to 10 mg/dL). When serum calcium is more than 10% away from the population mean, one has reason to suspect disease. The regulation of serum calcium concentration involves a system of controlling factors and feedback mechanisms (Fig. 7.1).
Plasma calcium concentrations are detected by surface calcium-sensing receptors (CaSRs) found in parathyroid and the clear cells of thyroid glands, kidney, intestine, bone marrow, and other tissues. When plasma calcium concentrations are elevated, PTH release is inhibited and CT release is stimulated.
When plasma calcium concentration falls, the parathyroid gland is stimulated to release PTH. PTH increases renal phosphate clearance and renal tubular reabsorption of calcium; it activates bone resorption loci, augments osteoclast activity at existing resorption loci, and activates vitamin D to enhance intestinal calcium absorption. Activation of vitamin D occurs in two steps. An initial hydroxylation is catalyzed by vitamin D-25-hydroxylase (CYP27), a microsomal cytochrome P-450 enzyme system in the liver. The second hydroxylation by 25-OH D-1-α-hydroxylase (CYP27B1) in the proximal convoluted tubule cells of the kidney converts the vitamin to its active potent form, 1,25-dihydroxyvitamin D [1,25(OH)2D] or calcitriol. (See the chapter on vitamin D for additional details.) This latter step is stimulated by PTH and is augmented by a fall in serum phosphate. PTH and 1,25(OH)2D act synergistically to enhance renal tubular reabsorption of calcium and to mobilize calcium stores from bone. PTH acts in a classical negative feedback loop to raise the ECF [Ca2+], thereby closing the loop and reducing PTH release. Some evidence indicates that the intestine also has CYP27B1 activity that could produce 1,25(OH)2D for local use; this would explain observations of increased calcium absorption with increased serum 25(OH)D levels without change in serum 1,25(OH)2D levels (3).
 Fig. 7.1. Homeostatic regulation of calcium (Ca2+) depicting the changes in vitamin D and parathyroid hormone (PTH) when plasma calcium falls to less than 2.5 mM. CaSR, calcium sensing receptor; Pi, inorganic phosphate; PO43-, phosphate. |
Although the sophisticated regulatory mechanism described earlier allows a rapid response that corrects transient hypocalcemia, in the presence of a chronically calcium-deficient diet, it maintains ECF [Ca2+] at the cost of depleting the skeleton. The three tissues supporting serum calcium levels (i.e., gut, kidney, and bone) operate independently of one another, and altered responsiveness of any of these can increase bone fragility. For example, low fractional calcium absorption capacity was associated with increased hip fracture risk in elderly postmenopausal women (4).
When plasma calcium concentration rises in response to increased calcium absorption or increased bone resorption, extracellular Ca2+ binds to CaSR on the surface of parathyroid cells and thus stimulates a conformational change in the receptors leading to an inhibition of PTH secretion from the parathyroid (5). PTH augments tubular reabsorption of calcium. That reabsorption has a maximum (the TmCa), and when that maximum is exceeded, additional filtered calcium is excreted.
In infants and children, a principal defense against hypercalcemia is release of CT by the C cells of the thyroid gland. CT is a peptide hormone with binding sites in the kidney, bone, and central nervous system. Absorption of calcium from an 8-oz feeding in a 6-month-old infant dumps 150 to 220 mg calcium into the ECF. This is enough, given the small size of the ECF compartment at that age (1.5 to 2 L), to produce fatal hypercalcemia if other adjustments are not made. Instead, CT is released, in part in response to the rise in serum calcium, but even before that, in response to gut hormones signaling coming absorption. This burst of CT slows or halts osteoclastic resorption, thus stopping bony release of calcium. Then, later, when absorption stops, CT levels also fall, and osteoclastic resorption resumes. By contrast, CT has little significance in adults because absorption is lower to begin with, and the ECF is vastly larger. As a result, absorptive calcemia from a high-calcium diet raises ECF [Ca2+] by only a few percentage points, and the absence of CT (as with thyroid ablation) has little impact on calcium homeostasis.
Absorption
Calcium usually is freed from complexes in the diet during digestion and is released in a soluble and typically ionized form for absorption. However, small-molecular-weight complexes such as calcium oxalate and calcium carbonate can be absorbed intact (6).
 Fig. 7.2. Calcium (Ca) absorption showing active, transcellular absorption and passive, paracellular absorption. Paracellular absorption is bidirectional; transcellular absorption is unidirectional. Ca enters the cytosol down a concentration gradient. Ca enters the cell through CaT1 and is transported across the enterocyte against an uphill gradient with the aid of vitamin D-induced calbindin, probably at least partially through endosomes and lysosomes. Finally, it is extruded at the basolateral membrane primarily by the plasma membrane calcium adenosine triphosphatase (ATPase) pump (PMCA) and secondarily by the sodium (Na+)/Ca2+ exchanger or by exocytosis. ADP, adenosine diphosphate; VDR, vitamin D receptor. |
Fractional calcium absorption (absorptive efficiency) generally varies approximately inversely with the logarithm of intake, but the absolute quantity of calcium absorbed increases with intake (7, 8). However, only 20% of the variation in calcium absorption can be accounted for by usual calcium intake (9). Rather, individuals seem to have preset absorptive efficiencies; approximately 60% of the variance in calcium absorption among individuals can be accounted for by their individual fractional calcium absorption (10).
Mechanisms of Absorption
Calcium absorption occurs by two pathways (Fig. 7.2):
Transcellular: This saturable (active) transfer involves a calcium-binding protein, calbindin.
Paracellular: This nonsaturable (diffusional) transfer is a linear function of calcium content of the chyme.
The relationship between calcium intake and absorbed calcium is shown in Figure 7.3. At lower calcium intakes, the active component contributes most to absorbed calcium. The Michaelis-Menten constant (Km) for the active component in adults is calculated to be 3.2 to 5.5 mM (equivalent to a calcium load of 230 to 400 mg) (3). As calcium intakes increase and the active component becomes saturated, an increasing proportion of calcium is absorbed by passive diffusion.
 Fig. 7.3. Calcium is absorbed by both saturable and nonsaturable pathways. Total calcium transport (the sum of a saturable component [A] defined by the Michaelis-Menten equation and a concentrationdependent, nonsaturable component [B] defined by a linear equation) is described by a curvilinear function. |
Active absorption is most efficient in the duodenum and next in the jejunum, but total calcium absorbed is greatest in the ileum, where residence time is the longest. In one rat study, net calcium absorption was distributed as 62% in the ileum, 23% in the jejunum, and 15% in the duodenum (11). Absorption from the colon accounts for approximately 5% to 23% (or ˜1% of ingested calcium) of the total absorption in normal individuals, but it may be important in patients with small bowel resections and when colonic bacteria break down dietary complexes.
Transcellular Calcium Transport.
Calcium entry into the epithelial cells occurs primarily through a calcium channel, TRPV6 (CaT1) (12), although it is not a ratelimiting step (13). Calcium transfer occurs down a steep electrochemical gradient and does not require energy. The main regulator of transport across the epithelial cell against the energy gradient is 1,25(OH)2D. As illustrated in Figure 7.2, 1,25(OH)2D, which is responsive to serum calcium levels, regulates the synthesis of calbindin by binding with vitamin D receptor (VDR) in the cytoplasm and translocating to the nucleus, where it binds to response elements to initiate transcription of calbindin mRNA. The essentiality of VDR and 1,25(OH)2D in the control of calcium absorption was established with transgenic mice (14). Intestinal calbindin, a 9-kDa protein in mammals and a 28-kDa protein in birds, is capable of binding 2 Ca2+ per molecule. Calbindin operates by binding Ca2+ on the surface of the cell and then internalizes the ions through endocytic vesicles that may fuse with lysosomes. After release of the bound calcium in the acidic lysosomal interior, the calbindin returns to the cell surface, and the Ca2+ ions exit the cell through the basolateral membrane (15). Using ion microscopic imaging of injected 44Ca2+, calcium entry into the villus was observed in vitamin D-deficient chicks, but the rapid transfer of Ca2+ through the cytoplasm to the basolateral pole did not occur in the absence of the ability to synthesize calbindin (16). Thus, calbindin serves both as a Ca2+ translocator and a cytosolic Ca2+ buffer to resist toxicity in chick intestine (17), but its role in mammalian intestinal epithelial cells has been questioned (3). Much remains to be understood about calcium transport across the intestine because in a doublecalbindin D9k/TRPV6 knockout mouse model, calcium absorption still responded to 1,25(OH)2D, although that response was reduced by 60% compared with wild-type mouse (18).
Vitamin D-induced calcium transport also involves activation of a Ca2+-dependent adenosine triphosphate (ATP) pump (PMCAlb) to effect extrusion of calcium against an electrochemical gradient into the ECF (19). Relative Ca2+-binding capacities across the enterocyte are brush border, 1, calbindin, 4, and the ATP-dependent Ca2+ pump, 10; this gradient ensures unidirectional transfer of Ca2+ (20). A rapid increase in calcium absorption resulting from transcaltachia, which involves 1,25(OH)2D-mediated (but not transcriptional) events, also appears to be at work (3).
Paracellular Calcium Transport.
In the paracellular pathway, calcium transfer occurs between the cells. Theoretically, this transfer can occur in both directions, but normally the predominant direction is from lumen into blood because much of the transfer is by solute drag, which is predominantly from lumen into ECF. The rate of transfer depends on ingested calcium load and tightness of the junctions. Calcitriol also enhances flux of ions including Ca2+ (21). Water probably carries calcium through the junctions by solvent drag, which is stimulated by 1,25(OH)2D through induction of tight junction proteins (22).
Physiologic Factors Affecting Absorption
Various host factors affect fractional calcium absorption. Vitamin D status, intestinal transit time, and mucosal mass are the best established (23). Phosphorus deficiency, as may occur through prolonged use of aluminum- containing antacids, can cause hypophosphatemia, increased circulating levels of 1,25(OH)2D, and elevated calcium absorption.
Stage of life also influences calcium absorption. In infancy, absorption is dominated by diffusion. Therefore, the vitamin D status of the mother does not affect fractional calcium absorption of young breast-fed infants. Both active and passive calcium transport is increased during pregnancy and lactation. Calbindin and plasma 1,25(OH)2 and PTH levels increase during pregnancy. From midlife onward, absorption efficiency declines by approximately 0.2 absorption percentage points per year, and at menopause, an additional 2% decrease occurs (24). Decreased calcium absorption efficiency with age is related to increased intestinal resistance to 1,25(OH)2D, as illustrated by a steeper slope in the relationship between fractional calcium absorption and serum 1,25(OH)2D3 in elderly postmenopausal women than
in young premenopausal women (25). The age-related decrease in calcium absorption from intestinal resistance to 1,25(OH)2D3 has been associated with decreased VDR levels (26), as well as with reduced estrogen levels (23).
in young premenopausal women (25). The age-related decrease in calcium absorption from intestinal resistance to 1,25(OH)2D3 has been associated with decreased VDR levels (26), as well as with reduced estrogen levels (23).
Decreased stomach acid, as occurs in achlorhydria, reduces the solubility of insoluble calcium salts (e.g., carbonate, phosphate) and thus could, in theory, reduce absorption of calcium unless fed with a meal (27). Absorption of calcium supplements improves when they are taken with food irrespective of gastric acid status, perhaps by slowing gastric emptying and thereby extending the time in which the calcium-containing chyme is in contact with the absorptive surface.
VDR polymorphisms have been studied for their relationship with calcium absorption efficiency. One study showed a significant association between the VDR Fok1 polymorphism and calcium absorption in children (28).
Excretion
Loss of calcium from the body occurs in urine, feces, and sweat. Differences in losses between adult women and adolescent girls on equal and adequate calcium intakes are given in Table 7.1. This table demonstrates the conservation of calcium at the kidney for building bone during the rapid period of skeletal growth during puberty. African- American girls absorb more calcium and excrete less calcium than do white girls, and this characteristic results in greater net bone deposition (29). African-American women average 10% higher bone mineral content than do white women (30).
Turnover of the miscible calcium pool in healthy adults is approximately 16%/day, and the rapidly exchanging component (of which the ECF is a part) is approximately 40%/day. The filtered load of the kidney is determined by the glomerular filtration rate and the plasma concentration of ultrafiltrable calcium (ionized plus that bound to small-molecular-weight anions). In adults, this is approximately 175 to 250 mmol/day (7 to 10 g/day). More than 98% of this calcium is reabsorbed by the renal tubule as the filtrate passes through the nephron, but 2.5 to 5 mmol (100 to 200 mg) are excreted in the urine daily. Endogenous fecal excretory loss is similar to the amount excreted in the urine. Loss in the sweat is typically 0.4 to 0.6 mmol (16 to 24 mg)/day (31); and additional diurnal losses occur from shed skin, hair, and nails, thus bringing the total to as much as 1.5 mmol (60 mg)/day. Cutaneous losses from children average 1.3 mmol (52 mg)/day (32). Moderate exercise can increase calcium loss (33).
Endogenous Fecal Calcium
Fecal calcium includes that calcium that is unabsorbed from the diet plus calcium that enters the gut from endogenous sources, including shed mucosal cells and digestive secretions. Endogenous fecal calcium losses are approximately 2.5 to 3.0 mmol (100 to 120 mg)/day. These losses are inversely proportional to absorption efficiency and are directly related to gut mass (and hence to food intake). Urinary calcium increases during childhood up to adolescence. Endogenous fecal calcium values in adolescent girls do not differ significantly from those of young women (as shown in Table 7.1).
Urinary Excretion
In the kidney, an increase in ECF calcium ion concentration decreases the glomerular filtration rate, has a diuretic action in the proximal tubule, and inhibits the actions of antidiuretic hormone (34). Machinery for calcium transport described earlier for the intestinal epithelial cells is also present in the nephron. Paracellular transport dominates in the proximal tubule as reabsorption occurs across a concentration gradient, and it also occurs in the thick ascending limb of the loop of Henle, the distal nephron, and the collecting ducts.
Both active transport and passive transport depend on calcium load, are detected through CaSR, are stimulated by PTH and 1,25(OH)2D, and have a microvillar myosin I-calmodulin complex that could serve as a calcium transporter (35). PTH acts on proximal tubular cells to upregulate CYP1α expression. Calcium enters renal epithelial cells through a calcium channel, ECaC or CaT2 (36). Active transport occurs in the distal convoluted tubule against a concentration gradient. In the mammalian kidney, vitamin D regulation works through calbindin-D28k, which binds 4 Ca2+ per molecule and shares no sequence homology with calbindin-D9k of the intestine. This calcium-binding protein has been cloned and is regulated by both transcriptional and posttranscriptional mechanisms. Administration of 1,25(OH)2D to rats induces calbindin- D28k mRNA and VDR mRNA in vitamin D-sufficient animals (37). However, in the absence of vitamin D, hypercalciuria is not observed, as would be predicted if mechanisms were similar to the gut. A fall in filtered load is associated with slight reductions in urine calcium. Even so, renal calcium clearance is reduced in vitamin D deficiency and is increased in PTH deficiency—findings indicating that the major effect on conservation of calcium is exerted by PTH.
During the rapid growth of adolescence, urinary calcium is little influenced by load. Absorbed calcium is diverted to bone growth at calcium intakes typically ingested, except for obligatory losses in urine, skin, and endogenous secretions. Tubular reabsorption decreases in postmenopausal women.
DIETARY CONSIDERATIONS
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