Calcium is a divalent cation with an atomic weight of 40, one of the most abandoned elements in the Earth’s biosphere and it is present in both solid matter and in aqueous solutions. A solid, calcium carbonate, occurs in marble, chalk, limestone, and calcite, calcium sulfate in anhydrite and gypsum, calcium fluoride in fluorspar or fluorite and calcium phosphate occurs in apatite. Calcium also occurs in numerous silicates and aluminosilicates. Many organisms concentrate calcium compounds in their shells or skeletons. For example, calcium carbonate is formed in the shells of oysters and in the skeletons of coral, which are often used as a calcium source in dietary supplements. In soil, calcium usually is present as a cation in colloids. In plants, calcium is present in the leaves, stems, roots, and seeds in concentration ranging from 0.1% to almost 10%. In living cells, calcium is one of 21 elements occurring as mineral elements in biosphere and is essential for conducting cell functions. In mammals, calcium is present in all cells and accounts for up to 4% of total body weight.

In humans, it ranks fifth after oxygen, carbon, hydrogen, and nitrogen and it makes up 1.9% of the body by weight. Approximately 99% of calcium is contained in bones and teeth as calcium hydroxyapatite (Ca₁₀[PO₄]₆[OH]₂) and the remainder is inside the cells (0.9%) and extracellular fluid (0.1%). In the bone and teeth, calcium constitutes 25% of the dry weight and 40% of the ash weight. The extracellular fluid contains ionized calcium at concentrations of about 4.8 mg/100 mL (1.20 mmol L⁻¹) maintained by the parathyroid–vitamin D axis as well as complexed calcium at concentrations of about 1.6 mg/100 mL (0.4 mmol L⁻¹). The plasma contains a protein-bound calcium fraction at a concentration of 3.2 mg/100 mL (0.8 mmol L⁻¹). In the cellular compartment, the total calcium concentration is lower than in extracellular fluid by several orders of magnitude (Robertson and Marshall, 1981).

In bone and teeth, the most calcified structure in the animal and human body, the role of calcium is structural and mechanical, determining their hardness and strength (Abrams, 2011; Hill et al., 2013). The second most calcified structure is the vasculature. Once considered a passive process, vascular calcification has emerged as an actively regulated form of tissue biomineralization, in which skeletal morphogens and osteochondrogenic transcription factors are expressed by cells within the vessel wall, regulating the deposition of vascular calcium (Bithika and Dwight, 2012). Another physiological role of calcium is to act as an activator for several key cellular enzymes such as pancreatic lipase, acid phosphatase, cholinesterase, ATPase, and succinic dehydrogenase (Nicholls, 2002; Brownlee et al., 2010; Hung et al., 2010; Glancy and Balaban, 2012; Tarasov et al., 2012). Through its role in enzyme activation, calcium stimulates muscle contraction (i.e. promotes muscle tone and normal heartbeat) and regulates the transmission of nerve impulses from one cell to another through its control over acetylcholine production (Harnett and Biancani, 2003). Calcium is also essential for the normal clotting of blood, by stimulating the release of thromboplastin from the blood platelets (Østerud, 2010; Diamond, 2013). In conjunction with phospholipids, calcium plays a key role in the regulation of the permeability of cell membranes and consequently over the uptake of other nutrients by the cell (Brenner and Moulin, 2012; Kiselyov et al., 2012). On a molecular level, calcium is an important second messenger participating in many activities. For example, when physicochemical insults deregulate calcium delicate homeostasis, it acts as an intrinsic stressor producing or increasing cell damage (Cerella et al., 2010).

Dietary calcium comes from food sources associated with dairy products, other foods such as vegetables and cereals, foods fortified with inorganic or organic calcium, and from dietary supplements containing calcium.

Dairy foods are excellent sources of calcium and a major supplier of dietary calcium in the developed and majority of less developed countries (Table 1.1). For example, more than 40% of dietary calcium in North American and British diet come from milk, cheese, and yogurt and from foods to which dairy products have been added such as pizza, lasagna, and dairy desserts (Annonymous, 2011a).

A major nondairy source of calcium is green vegetables such as kale, turnip greens, bok choy, and Chinese cabbage, which provide approximately ∼7% of dietary calcium (Table 1.2).

Other nondairy sources of calcium are grains, legumes, fruits, meat, poultry, fish (Tables 1.3 and 1.4), and eggs each providing 1% to 5% of calcium in a typical Western-style diet (Annonymous, 2009).

Other excellent sources of calcium are nuts (Table 1.5) and spices (Table 1.6).

In African diet, calcium-rich foods include crabs, edible caterpillars, locust beans, millet, and cowpea, baobab, and amaranth leaves (Annonymous, 2000).

In several developed countries, an important source of dietary calcium are foods fortified with calcium, which do not naturally contain calcium such as orange juice, other beverages, soy milk and tofu and ready-to-eat cereals (Table 1.7) (Calvo et al., 2004; Rafferty et al., 2007; Poliquin et al., 2009).

In recent decades, dietary supplements became an important source of dietary calcium. The use of vitamin and mineral supplements that include calcium becomes commonplace in several populations, especially in the developed countries. For example, among the United States (US) population based on a national survey, about 40% of adults, but almost 70% of older women reported calcium intake from supplements (Bailey et al., 2010). Current estimates from the National Health and Nutrition Survey (NHANES) showed that in the US adult population between 2007 and 2010, dietary supplements users have approximately 10% higher calcium intake than nonusers (Wallace et al., 2014).

The most common forms of supplemental calcium are calcium carbonate and calcium citrate. Generally, less calcium carbonate is required to achieve a given dose of elemental calcium because calcium carbonate provides 40% of elemental calcium, compared with 20% for calcium citrate. However, compared with calcium citrate, calcium carbonate is more often associated with gastrointestinal side effects, including constipation, flatulence, and bloating (Straub, 2007). In contrast, calcium citrate is less dependent than calcium carbonate on stomach acid for absorption (Recker, 1985) and thus, can be taken without food. Other forms of calcium in dietary supplements include calcium lactate, gluconate, glucoheptonate, and hydroxyapatite and their relevance for life stage groups may vary. The health benefits of calcium supplements are still debatable. For example, in a 2013 update, the US Preventive Services Task Force concludes that the current evidence is insufficient to assess the balance of the benefits and harms of combined vitamin D and calcium supplementation for the primary prevention of fractures in premenopausal women or in men (Moyer, 2013). Some recent studies have raised concern about an increased cardiovascular risk with the use of calcium supplements, but the findings are considered inconsistent and inconclusive (Xiao et al., 2013).

Calcium is absorbed in the intestine by passive diffusion (paracellular) or by active transport (transcellular) across the intestinal mucosa (Bronner, 2009). The rate of paracellular calcium uptake is considered nonsaturable, while transcellular transport can be upregulated under conditions of dietary calcium constraints. The paracellular route is tied to a downhill concentration gradient between the luminal and the extracellular compartments throughout the entire intestine. Although canonically thought to be constant, the recent evidence suggests that paracellular calcium transport is regulated, at least in part, by 1,25(OH)₂ vitamin D (Christakos, 2012).

Transcellular calcium absorption can also take place against an uphill gradient, but requires molecular machinery in the form of distinct calcium transport proteins and energy from hydrolyzable adenosine triphosphate (ATP) (Auchère et al., 1998). The absorption occurs mostly in the duodenum and the jejunum (Pansu et al., 1983) and the process is activated by calcitriol and is dependent on the intestinal vitamin D receptor (VDR) and physiologic factors such as the presence of calcium-regulating hormones and the life stage (Whiting, 2010; Gallagher, 2013). Since a concentration gradient is not a prerequisite for this process, transcellular transport accounts for most of the absorption of calcium at low and moderate intake levels (Table 1.8).

The solubility of calcium salts is increased in the acid environment of the stomach, but the dissolved calcium ions to some extent reassociate and precipitate in the jejunum and ileum where the pH is closer to neutral. Recent observations indicate that a reduction of gastric acidity may impair effective calcium uptake throughout the entire intestine (Kopic and Geibel, 2013). In the neutral environment, the absorbability of calcium is determined mainly by the presence of other food components such as lactose, glucose, fatty acids, phosphorus, and oxalate, which can bind to soluble calcium, are released resulting in complex luminal interactions. For example, absorption of calcium supplements, and especially those that are less soluble, is substantially better if they are taken with a meal perhaps by food-stimulated gastric secretion and delayed emptying allowing dispersion and dissolution of calcium. In the gastrointestinal lumen, calcium can compete or interfere with the absorption of other minerals such as iron, zinc, and magnesium.

Calcium is excreted in urine, feces, and body tissues and fluids, such as sweat. Calcium excretion in the urine is a function of the balance between the calcium load filtered by the kidneys and the efficiency of reabsorption from the renal tubules. Most of the calcium (∼98%) is reabsorbed by either passive or active processes occurring at four sites in the kidney, each contributing to maintaining neutral calcium balance. The majority of the filtered calcium (∼70%) is reabsorbed passively in the proximal tubule and the remaining 30% actively in the ascending loop of Henle, the distal tubule, and collecting duct (Allen and Woods, 1994).

Regulation of calcium homeostasis during a lifetime is a complex process reflecting a balance among intestinal calcium absorption, bone calcium influx and efflux, and renal calcium excretion. Maintaining the level of circulating ionized calcium within a narrow physiological range between 8.5 and 10.5 mg dL⁻¹ (2.12 and 2.62 mmol L⁻¹) is critical for normal body function (Jeon, 2008). Homeostasis of serum calcium level is maintained through an endocrine system comprised of controlling factors, epithelial calcium channels, and feedback mechanisms that includes vitamin D metabolites, primarily calcitriol, and parathyroid hormone (PTH) (Peacock, 2010). Any perturbations in calcium homeostasis can result in hypocalcemia or hypercalcemia and adaptations in calcium handling must occur during a lifetime that include growth and aging (Felsenfeld et al., 2013).

Calcium systemic balance is essential for a multitude of physiological processes, ranging from cell signaling to maintenance of bone health. A systemic calcium balance (positive, neutral, or negative) is the measure derived by taking the difference between the total intake and the sum of the urinary, fecal, and sweat calcium excretion. These measures have some limitations and are generally cross-sectional in nature, and their precision differs. Long-term balance studies for calcium are rarely carried out because of the difficult study protocol. Calcium balance can also be estimated by using stable isotopes to trace the amount of calcium absorbed from a single feeding. In general, a positive calcium balance is indicative of calcium accretion also termed net calcium retention, neutral balance suggests maintenance of bone, and a negative balance indicates bone loss.

The relevance of the calcium balance state varies depending upon the developmental stage. Infancy through late adolescence periods are characterized by positive calcium balance due to enhanced bone formation. In female adolescents and adults, even within the normal menstrual cycle, there are measurable fluctuations in calcium balance owing to the effects of fluctuating sex steroid levels and other factors on the basal rates of bone formation and resorption. Later in life, menopause and age-related bone loss lead to a net loss of calcium due to enhanced bone resorption.

In an average adult human, daily calcium intake is approximately 800–1000 mg per day (20–25 mmol). From this amount, about 25–50% is absorbed and passes into the exchangeable calcium pool (Figure 1.1). This pool consists of the small amount of calcium in the blood, lymph, and other body fluids, and accounts for 1% of the total body calcium. Calcium located in bones and teeth (99%) is inaccessible to most physiological processes. Approximately 150 mg per day (3.75 mmol) of calcium enter the intestinal lumen in intestinal secretions such as digestive enzymes and bile, but about 30% of this calcium is reabsorbed (Allen and Woods, 1994). The kidneys filter about 8.6 g per day (215 mmol) of calcium, almost all (∼98%) of which is reabsorbed so that only 100 to 200 mg per day (2.5 to 5 mmol) is excreted in approximately equal amounts in the urine and stool. Calcium loss from the skin is about 15 mg per day (0.4 mmol) depending on sweating. In the adult human, the extracellular calcium pool turns over approximately 20 to 30 times per day, while the bone pool turns over every 5 to 6 years.

Calcium availability from diet varies with form of calcium ingested. In general, bioavailability is increased when calcium is well solubilized and inhibited in the presence of agents that bind calcium or form insoluble calcium salts. The absorption of calcium is about 30% from dairy and fortified foods (e.g., orange juice, tofu, and soymilk) and nearly twice as high from certain leafy green vegetables and calcium supplements (Table 1.9).

Dietary fiber has an adverse effect on calcium absorption in humans and can impair the calcium balance significantly. The majority of marked adverse effects of dietary fiber could be explained by the calcium-binding capacity of phytic acid. However, other constituents of dietary fiber also have the ability to bind calcium. For example, uronic acids present in hemicellulose can bind calcium strongly and may explain the inhibition of dietary fiber calcium absorption from cellulose-containing foods. Pectin present in dietary fiber especially in fruits and vegetables do not affect calcium absorption most likely because 80% of uronic acids in pectin are methylated and cannot bind calcium (Allen and Woods, 1994).

Other food compounds such as oxalic acid that also bind calcium could significantly interfere with absorption and decrease calcium bioavailability. The poor absorption of calcium from spinach (5% compared to 27% absorption from milk) has been attributed to its binding to oxalic acid in spinach. However, other factors may also be involved because calcium absorption from calcium oxalate is twice as high as that from that the plant. It has been documented that during the absorption of calcium oxalate there is no tracer exchange, suggesting that absorption occurs without dissociation of the molecule (Heaney and Weaver, 1989). Similarly, solubility of salts such as citrate or citrate-malate is not related to their absorbability. Thus, the form in which the calcium approaches the mucosal brush border and in which it is transported by the paracellular mechanism may be a better predictor of its bioavailability than the solubility of the salt.

Some food constituents increase calcium bioavailability. For example, lactose enhances the absorption of calcium in animals and human infants. Lactose increases the diffusional component of calcium and perhaps of phosphorus, especially in the ileum, and probably acts osmotically to alter the junctions between the epithelial cells (Kobayashi et al., 1975). Solubility of the dominant chemical form of calcium in specific foods, or of calcium supplements, has a negligible effect on calcium absorption after lactase treatment can be ascribed to the fact that most metabolizable sugars enhance calcium absorption. However, it is doubtful that lactose improves the absorbability of calcium from dairy products beyond infancy. For example, in adults the absorption of calcium from yogurt is the same as that from milk, even though the lactose in yogurt is hydrolyzed in the stomach by lactase originating from the bacteria in the yogurt (Smith et al., 1985).

Dark green, leafy vegetables are often relatively high in calcium. Absorption from many of these is expected to be good, if they are low in oxalic acid (e.g., kale, broccoli, turnip and mustard greens, and collard). For example, absorption from kale is as good as from milk. Other factors may also be involved because calcium absorption from calcium oxalate is twice as high as that from spinach (Heaney and Weaver, 1989). There is no interference of calcium oxalate with the absorption of calcium in milk when the two are consumed together.

Protein intake stimulates acid release in the stomach, and this, in turn, enhances calcium absorption. However, it has long been known that protein also increases urinary calcium excretion. The effect of protein on calcium retention and hence bone health has been controversial (Allen and Woods, 1994). Sodium and potassium in the diet may also affect the calcium balance. High intakes of sodium increase urinary calcium excretion. In contrast, adding more potassium to a high-sodium diet might help decrease calcium excretion, particularly in postmenopausal women (Sellmeyer et al., 2002; Annonymous, 2011b). Phosphate in food is a mixture of inorganic and organic and similarly to calcium, the portion of phosphorus absorption is due to saturable, active transport facilitated by calcitriol. However, fractional phosphorus absorption is virtually constant across a broad range of intakes, suggesting that absorption occurs primarily by a passive, concentration-dependent process. Interestingly, several observational studies have suggested that the consumption of carbonated soft drinks with high levels of phosphate is associated with reduced bone mass and increased fracture risk. However, it is likely that the effect is due to replacing milk with soda, rather than to phosphorus itself (Heaney and Rafferty, 2001).

Alcohol intake can affect calcium nutriture by reducing calcium absorption although the amount of alcohol required to cause an effect and whether moderate alcohol consumption is helpful or harmful to bone are unknown (Hirsch and Peng, 1996). Caffeine from coffee and tea modestly increases calcium excretion and reduces absorption (Heaney and Recker, 1982). Other studies have indicated that caffeine intake from two to three cups of coffee per day might result in bone loss, but only in individuals with low milk or low total calcium intake (Harris and Dawson-Hughes, 1994).

However, the extent to which these food compounds affect calcium absorption varies, and food combinations affect overall absorption efficiency. For example, eating spinach with milk at the same time reduces the absorption of the calcium in the milk (Weaver and Heaney, 1991). In contrast, wheat products (with the exception of wheat bran) do not appear to have a negative impact on calcium absorption (Weaver et al., 1991). Nevertheless, calcium from foods of plant origin is less bioavailable than calcium from foods of animal origin such as milk and dairy products (Weaver, 2009).

The calcium salts most commonly used for food fortification or as supplements exhibit similar absorbability when tested in pure chemical form (Rafferty et al., 2007). In contrast, the absorbability of calcium from pharmaceutical preparations is usually lower than predictions from studies of pure salts (Weaver and Heaney, 2006). Calcium citrate appears to be better absorbed than calcium carbonate when they are taken with food (Harvey et al., 1988). Other research suggests similar bioavailability of the forms of calcium carbonate and citrate (Heaney et al., 1999). Another form of supplemental calcium, calcium formate, showed a better ability to deliver calcium to the bloodstream after oral administration than both calcium carbonate and calcium citrate (Hanzlik et al., 2005).

• This chapter focuses on calcium in the context of dietary sources and providing bases of calcium metabolism in the human body.

• Calcium is an inorganic element essential to living cells present in the Earth’s biosphere as a solid matter and aqueous solution.

• In humans, calcium is an essential constituent of bones and teeth, participates in vascular calcification, and is necessary for activation catalytic and mechanical properties of proteins in key enzymes.

• Dietary sources of calcium include dairy and nondairy foods, fortified foods, and supplements.

• Calcium is readily absorbed through the gastrointestinal tract (through vitamin D₃ action) and calcium absorption is facilitated by some food components by forming calcium complexes with some food components and by high gastric acidity through aiding solubilization of the calcium salts.

• The calcium balance is measured as the difference between calcium absorbed and excreted is essential for many physiological processes, ranging from cell signaling to maintenance of bone health.

• Regulation of calcium homeostasis is based on the interrelationship among intestinal calcium absorption, bone influx and efflux of calcium, and renal calcium excretion.

Key facts about calcium and its forms in biosphere, lists calcium roles in living cells, and describes calcium physiological role in the human body.

1. Calcium is a mineral widely abandoned in the biosphere and occurs mostly as calcium salts such as carbonate, sulfate, fluorite, and phosphate.

2. Calcium is present in all living cells including plant cells.

3. In humans, 99% of the body’s calcium is stored in the bones and teeth where it supports their structure and functions.

4. The remaining 1% of supports critical metabolic functions such as vascular contraction and vasodilation, muscle function, nerve transmission, blood clotting, and intracellular signaling and hormonal secretion.

Key facts about calcium sources of dietary calcium. Key facts about major sources of calcium that include dairy and dairy products, nondairy foods such as vegetables, grains and soy foods, foods fortified with calcium such as juices and cereals, and calcium supplements such calcium carbonate and citrate.

1. The major source of calcium in the diet is dairy milk, milk products, and food sources associated with dairy products.

2. Major nondairy foods containing calcium include green leafy vegetables, grains, cereals, and legumes.

3. Other sources of calcium include foods fortified with inorganic or organic calcium such as fruit juices, beverages, and cereals.

4. Dietary supplements containing calcium are becoming important sources of dietary calcium especially in older adults.

5. Calcium carbonate and calcium citrate are major sources of calcium in dietary supplements.

Key facts about calcium absorption and excretion. Key facts about intestinal calcium absorption by two independent pathways and calcium excretion from the human body mainly in urine and stools.

1. Calcium absorption occurs across the intestinal mucosa via either passive nonsaturable diffusion (paracellular) or by active transport (transcellular) pathways.

2. Transcellular active transport takes place against an uphill gradient and requires calcium-transport proteins, energy from ATP. The process is activated by calcitriol, dependent on the intestinal vitamin D receptor (VDR) and the presence of calcium-regulating hormones.

3. The paracellular passive transport depends primarily on calcium quantity and availability in the diet.

4. The solubility of calcium salts is increased in the acid environment of the stomach and the intestine absorbs between 25 and 35% of the ingested calcium.

5. Calcium leaves the body mainly in urine and feces, but also in other body tissues and fluids, such as sweat.

6. Calcium excretion in the urine is a function of the balance between calcium load and reabsorption from the renal tubules (∼98%).

Key facts about calcium homeostasis and systemic balance in the human body.

1. Regulation of calcium homeostasis during a lifetime is a complex process reflecting a balance among intestinal calcium absorption, bone calcium influx and efflux, and renal calcium excretion.

2. Homeostasis of serum calcium level is maintained through an endocrine system comprised of controlling factors, epithelial calcium channels, and feedback mechanisms that includes calcitriol and parathyroid hormone (PTH).

3. Exchangeable calcium pool accounts for ∼1% of calcium in the human body and turnovers 20–30 times a day.

4. Systemic calcium balance (positive, neutral, or negative) is the measure derived by taking the difference between the total intake and the sum of the urinary, fecal, and sweat calcium excretion.

Key facts about calcium bioavailability from food sources and calcium salts and dietary factors affecting its absorption such as fiber, oxalic acid, lactose, and protein.

1. Calcium availability from diet varies with form of calcium ingested.

2. The absorption of calcium is about 30% from dairy and fortified foods (e.g., orange juice, tofu, and soymilk) and nearly twice as high from certain leafy green vegetables and calcium supplements.

3. Dietary fiber has an adverse effect on calcium absorption in humans and can impair significantly calcium balance.

4. Other food compounds that bind calcium (e.g. oxalic acid) could significantly interfere with calcium absorption and decrease calcium bioavailability from some foods (e.g. spinach).

5. Lactose from milk increases calcium bioavailability especially in infants.

6. Other food components affecting calcium bioavailability include protein, sodium and potassium, phosphates, caffeine, and alcohol.

7. The calcium salts most commonly used for food fortification or as supplements exhibit similar absorbability.

1. Vitamin D₃. This is a fat-soluble vitamin that could be either provided with the diet or synthesized from 7-dehydrocholesterol with adequate sunlight exposure in humans.

2. Calcitriol. This is the hormonally active form of vitamin D, also termed 1,25-dihydroxyvitamin D₃, that increases the level of calcium (Ca²⁺) in the blood by increasing the uptake of calcium from the gut into the blood. Calcitriol is used to treat and prevent low levels of calcium in the blood of patients whose kidneys or parathyroid glands are not working normally.

3. Parathyroid Hormone (PTH). This is an 84 amino acid peptide acting primarily in kidney. PTH major physiological functions to raise plasma calcium via bone resorption and renal calcium reabsorption and to stimulate the metabolism of vitamin D to its active hormonal form 1,25-dihydroxyvitamin D_3.

4. NHANES. The National Health and Nutrition Examination Survey (NHANES) is a program of studies designed to assess the health and nutritional status of adults and children in the United States since early 1960s. The survey is unique in that it combines interviews and physical examinations. Findings from NHANES are used to determine the prevalence of major diseases and risk factors for diseases.

5. Calcitonin. This is a hormone (32 amino acid peptide) produced by the thyroid gland under conditions of hypercalcemia that lowers the levels of calcium and phosphate in the blood and promotes bone formation. Calcitonin inhibits bone removal by the osteoclasts and at the same time promotes bone formation by the osteoblasts.

6. Bone remodeling. This is a process by which bone is renewed to maintain strength and mineral homeostasis. The bone remodeling unit is composed of a tightly coupled group of highly specialized osteoclasts and osteoblasts that sequentially carry out resorption of old bone and formation of new bone.

7. Osteoclasts. These are large bone-resorbing cells triggered by parathyroid hormone (PTH) in response to hypocalcemia. Osteoclasts are formed from the conjoining of several cells created by the bone marrow and travel in the circulatory system working in perfect synchronization with osteoblasts to maintain the skeletal system.

8. Osteoblasts. These are bone-forming connective tissue cells found at the bone surface that can be stimulated to proliferate and differentiate as osteocytes.

9. Osteocytes. These are cells enclosed in bone that manufacture type 1 collagen and other substances that make up the bone extracellular matrix.