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Calcium

1.   Introduction

Unless otherwise stated, the information provided in this section was taken from the EFSA Scientific Opinion on Dietary Reference Values for calcium, 2015.

1.1      Chemistry

Calcium is the fifth most abundant element in the earth’s crust, sea water and the human body. It has an atomic mass of 40.08, and it belongs to the group of the alkaline earth elements and forms a stable divalent cation. Calcium salts are generally water soluble, with the exception of calcium sulphate, carbonate and phosphates, which are soluble in acids.

1.2      Biochemical functions

Calcium is an integral component of the skeleton; approximately 99 % of total body calcium is found in bones and teeth, where it is mainly present as calcium hydroxyapatite [Ca10(PO4)6(OH)2]. It has a structural role, and is needed for tissue rigidity, strength and elasticity. Bone is a reservoir for calcium and other inorganic nutrients, and participates in whole-body mineral homeostasis through the processes of bone formation and resorption. It is a dynamic tissue that is continuously remodelled throughout the life course under the control of osteocytes (Bonewald, 2011). Osteoblasts are responsible for the formation of new bone tissue and osteoclasts for bone resorption. In infants and children, the rate of formation exceeds that of resorption and new bone tissue is laid down as part of the process of growth, whereas in later life the rate of bone resorption exceeds formation, resulting in bone loss and microarchitectural changes that compromise bone strength and increase the risk of fracture.

The remaining 1 % of calcium found in the body acts as an essential intracellular messenger in cells and tissues. It has a critical role in many physiological functions involved in the regulation of metabolic processes, including vascular contraction and vasodilation, muscle contraction, enzyme activation, neural transmission, membrane transport, glandular secretion and hormone function. Owing to its ability to complex with anions such as citrate and bicarbonate, ionized calcium is the most common signal transduction element in the human body (IOM, 2011).

1.3      Dietary sources and intake data

1.3.1       Dietary sources

Rich food sources of calcium include

·        dairy products

·        selected vegetables (such as spinach, purslane, chard, endive, and broccoli)

·        legumes

·        nuts

·        fish with soft bones (e.g. tinned sardines)

·        and calcium-fortified foods.

The main dietary sources of calcium in different European countries vary, although dairy products are generally the most important food group (Welch et al., 2009); water may also contribute significantly to the daily intake in hard water areas.

1.3.2       Recommended dietary intake

An overview of dietary reference values for calcium in newborn, children and adults are shown below. These data were reported in the WHO report on vitamin and mineral requirements in human nutrition- Second edition, 2004. More recent recommendations about calcium intake from the US Institute of Medicine (IOM, 2011), German-speaking countries (D-A-CH, 2015) or Nordic Council of Ministers (NCM, 2014) are in the same range.

Group

Recommended calcium intake (mg/day)

Infants and children

 

0-6 month

 

Human milk

300

Cow milk

400

7-12 month

400

1-3 years

500

4-6 years

600

7-9 years

700

Adolescents

 

10-18 years

1300

Adults

 

Females

 

19 years to menopause

1000

Postmenopause

1300

Males

 

19-65 years

1000

65+ years

1300

Pregnant women (last trimester)

1200

Lactating women

1000

 

1.4      Toxicokinetics

1.4.1       Absorption

1.4.1.1      Intestinal absorption

Intestinal calcium absorption occurs through both an active, saturable, transcellular process and a non-saturable, passive process. Active transport involves entry of calcium into the enterocyte and is controlled by 1,25-dihydroxy-calciferol (1,25(OH)2D or calcitriol). This is the hydroxylated form of vitamin D (25-hydroxy-calciferol or calcidiol), the synthesis of which is regulated by PTH. It has been proposed that the epithelial calcium-selective channel TRPV6 mediates 1,25(OH)2D-dependent uptake of calcium across the brush border (Christakos, 2012). Calcium is then moved to the interior of the enterocyte by calcium-binding protein (CaBP), calbindin, the synthesis of which is dependent on 1,25(OH)2D. Finally, calcium is extruded from the basolateral membrane against a concentration gradient by the intestinal plasma pump, PMCA1b, again controlled by 1,25(OH)2D and also by dietary calcium intake (Christakos, 2012). Passive transport is paracellular, taking place through the tight junctions and structures present within intercellular spaces throughout the entire length of the intestine, although it predominates in the more distal regions.

Digested food (chyme) travels down the lumen of the small intestine for approximately 3 hours, passing through the duodenum in a few minutes and taking 2–3 hours to travel through the distal half of the small intestine (Christakos, 2012). Transcellular (active) transport is the major route of calcium absorption, with paracellular (passive) transport being responsible for an estimated 8–23 % of total calcium absorbed (McCormick, 2002). However, when calcium intake is high, paracellular transport accounts for a higher proportion of absorbed calcium because CaBP is rate-limiting and down-regulated when exposed to high concentrations of calcium (Bronner, 2003). Although the efficiency of absorption is highest in the duodenum (Wasserman, 2004), most calcium is absorbed in the ileum, presumably because the exposure time of the chyme is much longer than that in the proximal intestine. Calcium can also be taken up in the colon by passive absorption: with a habitual estimated intake of 620 mg/day, the percentage of colonic absorption (i.e. absorption > seven hours post ingestion) was calculated to be 4.2 % (Barger-Lux et al., 1989) and, at intakes of about 900 mg/day, colonic absorption was 5.7 % (Abrams et al., 2007).

Fractional calcium absorption is inversely related to the concentration of calcium present in the gut lumen (Ireland and Fordtran, 1973) and dietary load (Heaney et al., 1990). For example, absorption from a meal containing 15 or 500 mg of calcium was 64 and 28 %, respectively (Heaney et al., 1990). In order to obtain reproducible data for calcium absorption at different levels of intake, a period of adaptation is required, which should be a minimum duration of one week (Dawson-Hughes et al., 1993).

Calcium absorption is affected by vitamin D status (Seamans and Cashman, 2009). It has been shown to be low in patients with vitamin D deficiency (Nordin, 1997). Additionally, calcium absorption varies throughout the lifespan, being higher during periods of rapid growth and lower in old age. It has been estimated that in children 3–3.5 % of the variability in absorption appears to be associated with height (Abrams et al., 2005), which presumably reflects the calcium requirement for bone growth.

Absorption of calcium from food supplements depends on when they are consumed and the dose: smaller doses taken with meals are better absorbed (Heaney, 1991). The solubility, chemical form and particle size of calcium does not greatly affect absorption (Nowak et al., 2008; Elble et al., 2011), although there are reports of higher percentages of absorption from calcium citrate malate (Reinwald et al., 2008) and from “nanonised” pearl powder (Chen et al., 2008).

 

1.4.2       Distribution

1.4.2.1      Transport in blood

Calcium is present in the blood in three different forms:

·        45 % as free Ca2+ions (ionized)

·        45 % bound to proteins (about 45 %) and

·        10 % complexed to citrate, phosphate, sulphate and carbonate.

Calcium in the blood (and in extracellular fluid) is kept constant at 2.5 mmol/L (range 2.25–2.6 mmol/L), and ionized calcium (between 1.1 and 1.4 mmol/L) is controlled by the interrelated action of three hormones, namely PTH, 1,25(OH)2D and calcitonin.

1.4.2.2      Distribution to tissues

Calcium deposition into bone is an on-going process during periods of growth, with maximal accretion during the pubertal growth spurt (Matkovic et al., 1994). Maternal and foetal calcium metabolism are different: in the foetus, serum calcium, phosphorus and ionized calcium are higher than maternal values, whilst PTH and 1,25(OH)2D are lower (IOM, 2011). Foetal requirements for calcium are met through physiological changes in the mother, including increased efficiency of absorption and a decrease in maternal bone mineral, predominantly from trabecular bone; calcium is actively transported across the placenta from the mother to the foetus (Olausson et al., 2012). Maternal serum calcium concentrations fall owing to plasma volume expansion (Pedersen et al., 1984) and higher 1,25(OH)2D (Seely et al., 1997), but ionized serum calcium remains within the normal range (Seely et al., 1997).

1.4.2.3      Storage and liberation

The skeleton and teeth contain 99 % of total body calcium and bone provides a reservoir for other essential calcium-dependent functions in the body. There are two types of bone in the skeleton:

·        80 % is cortical bone, the outer part of the skeletal structures, which is dense and compact with a high resistance to impact and a slow turnover rate, and

·        20 % is trabecular bone, which is found inside the long bones, vertebrae, pelvis and other large flat bones, which is less dense and has a higher turnover rate.

However, the amount of calcium taken up into bone is age (and growth) dependent. Bone mass increases substantially during the first two decades of life, reaching a plateau, referred to as peak bone mass (PBM), when BMD (bone mineral density) is stable. The precise timing of this is uncertain, and the rate of bone accrual varies by site (Hui et al., 1999; Ohlsson et al., 2011).

The remaining 1 % of total body calcium is present in soft tissues, with only 0.1 % in the extracellular fluid. Intracellular calcium storages include mitochondria and the endoplasmic reticulum.

Serum concentrations of calcium are homeostatically regulated to remain within a narrow range of 2.25–2.6 mmol/L (ionized calcium 1.1–1.4 mmol/L) and concentrations of soft tissue calcium are maintained at the expense of bone. When insufficient calcium is provided from the diet to balance obligatory losses and requirements for growth, calcium is taken from the bone. This mechanism is achieved through the interaction of three major calcium-regulating hormones, PTH, 1,25(OH)2D and calcitonin. The latter two determine how much calcium moves out of or into the body, whilst PTH determines how calcium moves between the extracellular fluid and bone. A decrease in serum concentrations of calcium induces the release of PTH via the calcium-sensing receptor (CaSR) which is located on the cell surface of the parathyroid glands. PTH stimulates 1,25(OH)2D synthesis in the kidney, bone resorption and renal reabsorption of calcium (Perez et al., 2008). Synthesis of 1,25(OH)2D is also stimulated by low serum phosphorus concentrations and decreases with high phosphorus concentrations. An increase in serum concentrations of calcium inhibits PTH secretion via the CaSR and 1,25(OH)2D synthesis, and stimulates calcitonin secretion by the parafollicular C cells of the thyroid gland. Other locations of the CaSR include the intestine, kidney, thyroid gland, lung, brain, skin, bone marrow and osteoblasts.

1.4.3       Metabolism

1.4.4     Calcium as cation is absorbed, stored and eliminated in human physiology, but no further metabolism is known to occur.

1.4.4       Elimination

Unabsorbed dietary calcium is lost in the faeces. The main routes of endogenous calcium excretion are urine, faeces and skin and sweat (dermal losses).

1.4.4.1      Urine

Urinary calcium is the fraction of the filtered plasma water calcium which is not reabsorbed in the renal tubules. At a normal glomerular filtration rate of 120 mL/min and an ultrafiltrable calcium concentration of 6.4 mg/100 mL (1.60 mmol/l), the filtered load of calcium is about 8 mg/min (0.20 mmol/min) or 11.6 g/day (290 mmol/day). Because the average 24-hour calcium excretion in subjects from developed countries is about 160–200 mg (4–5 mmol), it follows that” approximately 98 % of filtered calcium is reabsorbed.

·        ̴70 % is reabsorbed passively in the proximal tubule and

·        ̴30 % is under homeostatic regulation by the CaSR of the ascending loop of Henle.

Urinary calcium comprises absorbed calcium that is lost from the body after the requirements for bone and endogenous faecal and dermal excretion have been met. In adults, a positive association has been reported between urinary calcium excretion and calcium intake (Matkovic et al., 1995), but higher calcium intakes (with daily intakes ranging from 700 to 1,800 mg/day) are associated with only small increases in urinary calcium (Taylor and Curhan, 2009) because of a lower calcium absorption (also taken from the WHO report on vitamin and mineral requirements in human nutrition- Second edition, 2004).

1.4.4.2      Faeces

Faecal calcium is derived from a mixture of unabsorbed calcium, sloughed mucosal cells and intestinal secretions. Endogenous (obligatory) losses vary with body size (and possibly calcium intake), but are unrelated to age or sex (Charles et al., 1991). Stable isotope techniques have to be used to measure endogenous faecal losses of calcium and results are expressed per kg body weight. In adults, early isotope studies indicate a mean loss of 2.1 mg/kg body weight per day (Heaney and Skillman, 1964).

 

 

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