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EC number: 218-235-4
CAS number: 2090-05-3
Unless otherwise stated, the
information provided in this section was taken from the EFSA Scientific
Opinion on Dietary Reference Values for calcium, 2015.
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.
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).
Rich food sources of calcium include
vegetables (such as spinach, purslane, chard, endive, and broccoli)
with soft bones (e.g. tinned sardines)
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.
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.
Recommended calcium intake (mg/day)
Infants and children
19 years to menopause
Pregnant women (last trimester)
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
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).
Calcium is present in the blood in
three different forms:
% as free Ca2+ions (ionized)
% bound to proteins (about 45 %) and
% 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
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).
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
% 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
% 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
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
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
1.4.4 Calcium as cation is
absorbed, stored and eliminated in human physiology, but no further
metabolism is known to occur.
Unabsorbed dietary calcium is lost in
the faeces. The main routes of endogenous calcium excretion are urine,
faeces and skin and sweat (dermal losses).
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.
% is reabsorbed passively in the proximal tubule and
% is under homeostatic regulation by the CaSR of the ascending loop of
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,
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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