Calcium metabolism refers to the movements and regulation of calcium ions (Ca2+) in and out of

various body compartments, such as the gastrointestinal tract, the blood plasma,
the extracellular and intracellular fluids, and bone tissue. An important aspect of calcium metabolism
is plasma calcium homeostasis, the regulation of calcium ions in the blood plasma within narrow
limits.[1] In this process, bone tissue acts as a calcium storage center for deposits and withdrawals as
needed by the blood, via continual bone remodeling.[2]:276–277 Derangement of this mechanism leads
to hypercalcemia or hypocalcemia, both of which can have consequences for health. The level of the
calcium in humans' plasma is regulated by calcitonin and parathyroid hormone (PTH); calcitonin is
released by the thyroid gland when its plasma level is above its set normal point (in order to lower
calcium level); PTH is released by the parathyroid glands when calcium level falls below set point (in
order to raise it).

Contents

 1Calcium concentrations
 2Function
o 2.1Bones
o 2.2Muscles
o 2.3Normal plasma levels
 3Sources
o 3.1Bone storage
 4Absorption from the intestine
 5Reabsorption
o 5.1The kidneys
 6Excretion
 7Calcium metabolism regulation
o 7.1High plasma level
o 7.2Low plasma level
 8Pathology
 9Research into cancer prevention
 10See also
 11Footnotes
 12References
 13External links

Calcium concentrations[edit]
Calcium is the most abundant mineral in the human body.[citation needed] The average adult body contains
in total approximately 1 kg, 99% in the skeleton in the form of calcium phosphate salts[citation needed]. The
extracellular fluid (ECF) contains approximately 22 mmol, of which about 9 mmol is in
the plasma.[3] Approximately 10 mmol of calcium is exchanged between bone and the ECF over a
period of twenty-four hours.[4] The concentration of calcium ions inside the cells (in the intracellular
fluid) is more than 7,000 times lower than in the blood plasma (i.e. at <0.0002 mmol/L, compared
with 1.4 mmol/L in the plasma)

Function[edit]
Main article: Calcium in biology
Calcium has several main functions in the body. It readily binds to proteins, particularly those with
amino acids whose side chains terminate in carboxyl (-COOH) groups (e.g. glutamate residues).
When such binding occurs the electrical charges on the protein chain change, causing the protein's
tertiary structure (i.e. 3-dimensional form) to change. Good examples of this are several of
the clotting factors in the blood plasma, which are functionless in the absence of calcium ions, but
become fully functional on the addition of the correct concentration of calcium salts. The voltage
gated sodium ion channels in the cell membranes of nerves and muscle are particularly sensitive to
the calcium ion concentration in the plasma.[5] Relatively small decreases in the plasma ionized
calcium levels (hypocalcemia) cause these channels to leak sodium into the nerve cells or axons,
making them hyper-excitable (positive bathmotropic effect), thus causing spontaneous muscle
spasms (tetany) and paraesthesia (the sensation of "pins and needles") of the extremities and round
the mouth.[6] When the plasma ionized calcium rises above normal (hypercalcemia) more calcium is
bound to these sodium channels having a negative bathmotropic effect on them, causing lethargy,
muscle weakness, anorexia, constipation and labile emotions.[6]
Because the intracellular calcium ion concentration is extremely low (see above) the entry of minute
quantities of calcium ions from the endoplasmic reticulum or from the extracellular fluids, cause
rapid, very marked, and readily reversible changes in the relative concentration of these ions in
the cytosol. This can therefore serve as a very effective intracellular signal (or "second messenger")
in a variety of circumstances, including muscle contraction, the release of hormones
(e.g. insulin from the beta cells in the pancreatic islets) or neurotransmitters (e.g. acetylcholine from
pre-synaptic terminals of nerves) and other functions.

Bones[edit]
Calcium acts structurally as supporting material in bones as calcium
hydroxyapatite (Ca10(PO4)6(OH)2).

Muscles[edit]
In skeletal and heart muscle calcium ions, released from the sarcoplasmic
reticulum (the endoplasmic reticulum of striated muscles) binds to the troponin C protein present on
the actin-containing thin filaments of the myofibrils. The troponin's 3D structure changes as a result,
causing the tropomyosin to which it is attached to be rolled away from the myosin-binding sites on
the actin molecules that form the back-bone of the thin filaments. Myosin can then bind to the
exposed myosin-binding sites on the thin filament, to undergo a repeating series of conformational
changes called the cross-bridge cycle, for which ATP provides the energy. During the cycle, each
myosin protein ‘paddles’ along the thin actin filament, repeatedly binding to myosin-binding sites
along the actin filament, ratcheting and letting go. In effect, the thick filament moves or slides along
the thin filament, resulting in muscle contraction. This process is known as the sliding filament
model of muscle contraction.[7][8][9][10][11]

Normal plasma levels[edit]

The plasma total calcium concentration is in the range of 2.2-2.6 mmol/L (9-10.5 mg/dL), and the
normal ionized calcium is 1.3-1.5 mmol/L (4.5-5.6 mg/dL).[3] The amount of total calcium in the blood
varies with the level of plasma albumin, the most abundant protein in plasma, and therefore the main
carrier of protein-bound calcium in the blood. The biologic effect of calcium is, however, determined
by the amount of ionized calcium, rather than the total calcium. It is therefore the
plasma ionized calcium level which is tightly regulated to remain within very narrow limits by
homeostatic negative feedback systems.
Between 35-50% of the calcium in plasma is protein-bound, and 5-10% is in the form of complexes
with organic acids and phosphates. The remainder (50-60%) is ionized. The ionized calcium can be
determined directly by colorimetry, or it can be read off from nomograms, though the usefulness of
the latter is limited when the pH and protein content of the plasma deviate widely from the normal.[3]
Sources[edit]
Not all the calcium in the diet can be readily absorbed from the gut. The calcium that is most readily
absorbed is found in dairy product and eggs, as well as in tinned fish products. The calcium
contained in vegetable matter is often complexed with phytates,[12] oxalates,[13] citrate and other
organic acids, such as the long-chained fatty acids (e.g. palmitic acid), with which calcium binds to
form insoluble calcium soaps.[14]

Bone storage[edit]
Although calcium flow to and from the bone is neutral, about 5–10 mmol is turned over a day. Bone
serves as an important storage point for calcium, as it contains 99% of the total body calcium.
Calcium release from bone is regulated by parathyroid hormone in conjunction
with calcitriol manufactured in the kidney under the influence of PTH. Calcitonin (a hormone
secreted by the thyroid gland when plasma ionized calcium levels are high or rising; not to be
confused with "calcitriol" which is manufactured in the kidney) stimulates incorporation of calcium
into bone.

Absorption from the intestine[edit]

The normal adult diet contains about 25 mmol of calcium per day. Only about 5 mmol of this is
absorbed into the body per day (see below).[15]
Calcium is absorbed across the intestinal epithelial cell's brush border membrane. The TRPV6
channel was proposed to be the major player in intestinal Ca2+ uptake [16]. However, Trpv6 KO mice
didn’t display significant reduction of serum calcium levels and showed only slightly reduced [16] or
even unchanged intestinal Ca2+absorption [17][18], indicating that other absorption pathways must exist.
Recently, TRPM7 was linked to intestinal calcium uptake. The authors could show that intestinal
deletion of TRPM7 results in strongly reduced calcium levels in serum and bones, [19] and intensively
increased levels of calcitriol and PTH, indicating that TRPM7 is essential for the intestinal bulk
uptake of calcium. After the cellular uptake, calcium is immediately bound to calbindin, a vitamin D-
dependent calcium-binding protein. Calbindin transfers the calcium directly into the epithelial
cell's endoplasmic reticulum, through which the calcium is transferred to the basal membrane on the
opposite side of the cell, without entering its cytosol or intracellular fluid. From there calcium pumps
(PMCA1) actively transport calcium into the body.[20] Active transport of calcium occurs primarily in
the duodenum portion of the intestine when calcium intake is low; and through passive paracellular
transport in the jejunum and ileum parts when calcium intake is high, independently of Vitamin D
level.[21]
The active absorption of calcium from the gut is regulated by the calcitriol (or
1,25 dihydroxycholecalciferol, or 1,25 dihydroxyvitamin D3) concentration in the blood. Calcitriol is a
cholesterol derivative. Under the influence of ultraviolet light on the skin, cholesterol is converted to
previtamin D3 which spontaneously isomerizes to vitamin D3 (or cholecaliferol). It is then converted
from cholecaliferol to calcifediol in the liver.[22] Under the influence of parathyroid hormone,
the kidneys convert calcifediol into the active hormone calcitriol, which acts on the epithelial cells
(enterocytes) lining the small intestine to increase the rate of absorption of calcium from the
intestinal contents. In short the cycle is following:
Cholesterol ultraviolet→ Previtamin D3 isomerization→ Vitamin D3 Liver→ Calcifediol PTH +
Kidneys→ Calcitriol

Low PTH levels in the blood (which occur under physiological conditions when the plasma
ionized calcium levels are high) inhibit the conversion of cholecalciferol into calcitriol, which in
turn inhibits calcium absorption from the gut. The opposite happens when the plasma ionized
calcium levels are low: parathyroid hormone is secreted into the blood and the kidneys convert
more calcifediol into the active calcitriol, increasing calcium absorption from the gut.[23]

Reabsorption[edit]
Since about 15 mmol of calcium is excreted into the intestine via the bile per day,[3] the total
amount of calcium that reaches the duodenum and jejunum each day is about 40 mmol
(25 mmol from the diet plus 15 mmol from the bile), of which, on average, 20 mmol is absorbed
(back) into the blood. The net result is that about 5 mmol more calcium is absorbed from the gut
than is excreted into it via the bile. If there is no active bone building (as in childhood), or
increased need for calcium during pregnancy and lactation, the 5 mmol calcium that is absorbed
from the gut makes up for urinary losses that are only partially regulated.[15]

The kidneys[edit]
The kidney filters 250 mmol of calcium ions a day in pro-urine (or glomerular filtrate), and
resorbs 245 mmol, leading to a net average loss in the urine of about 5 mmol/d. The quantity of
calcium ions excreted in the urine per day is partially under the influence of the
plasma parathyroid hormone (PTH) level - high levels of PTH decreasing the rate of calcium ion
excretion, and low levels increasing it.[note 1] However, parathyroid hormone has a greater effect
on the quantity of phosphate ions(HPO42−) excreted in the urine.[24] Phosphates form insoluble
salts in combination with calcium ions. High concentrations of HPO42− in the plasma, therefore,
lower the ionized calcium level in the extra-cellular fluids. Thus, the excretion of more phosphate
than calcium ions in the urine raises the plasma ionized calcium level, even though the total
calcium concentration might be lowered. The kidney influences the plasma ionized calcium
concentration in yet another manner. It processes vitamin D3 into calcitriol, the active form that is
most effective in promoting the intestinal absorption of calcium. This conversion of vitamin
D3 into calcitriol, is also promoted by high plasma parathyroid hormone levels.[23][25]

Excretion[edit]
Most excretion of excess calcium is via the bile and feces, because the plasma calcitriol levels
(which ultimately depend on the plasma calcium levels) regulate how much of the biliary calcium
is reabsorbed from the intestinal contents. Urinary excretion of calcium is relatively modest
(about 5 mmol/day) in comparison to what can be excreted via the feces (15 mmol/day).

Calcium metabolism regulation[edit]

 Calcium regulation in the human body.[26]

The plasma ionized calcium concentration is regulated within narrow limits (1.3–1.5 mmol/L).
This is achieved by both theparafollicular cells of the thyroid gland, and the parathyroid
glands constantly sensing (i.e. measuring) the concentration of calcium ions in the blood flowing
through them.

High plasma level[edit]

When the concentration rises the parafollicular cells of the thyroid gland increase their secretion
of calcitonin (a proteinaceous hormone) into the blood. At the same time the parathyroid glands
reduce their rate of parathyroid hormone (or PTH, also a proteinaceous hormone) secretion into
the blood. The resulting high levels of calcitonin in the blood stimulate the skeleton to remove
calcium from the blood plasma, and deposit it as bone.
The reduced levels of PTH inhibit removal of calcium from the skeleton. The low levels of PTH
have several other effects: they increase the loss of calcium in the urine, but more importantly
inhibit the loss of phosphate ions via that route. Phosphate ions will therefore be retained in the
plasma where they form insoluble salts with calcium ions, thereby removing them from the
ionized calcium pool in the blood. The low levels of PTH also inhibit the formation
of calcitriol (not to be confused with calcitonin) from cholecalciferol (vitamin D3) by the kidneys.
The reduction in the blood calcitriol concentration acts (comparatively slowly) on the epithelial
cells (enterocytes) of the duodenum inhibiting their ability to absorb calcium from the intestinal
contents.[1][4][27][28] The low calcitriol levels also act on bone causing the osteoclasts to release
fewer calcium ions into the blood plasma.[24]

Low plasma level[edit]

When the plasma ionized calcium level is low or falls the opposite happens. Calcitonin secretion
is inhibited and PTH secretion is stimulated, resulting in calcium being removed from bone to
rapidly correct the plasma calcium level. The high plasma PTH levels inhibit calcium loss via the
urine while stimulating the excretion of phosphate ions via that route. They also stimulate the
kidneys to manufacture calcitriol (a steroid hormone), which enhances the ability of the cells
lining the gut to absorb calcium from the intestinal contents into the blood, by stimulating the
production of calbindin in these cells. The PTH stimulated production of calcitriol also causes
calcium to be released from bone into the blood, by the release of RANKL (a cytokine, or local
hormone) from the osteoblasts which increases the bone resorptive activity by the osteoclasts.
These are, however, a relatively slow processes[1][4][24][27][28]
Thus fast short term regulation of the plasma ionized calcium level primarily involves rapid
movements of calcium into or out of the skeleton. Longer term regulation is achieved by
regulating the amount of calcium absorbed from the gut or lost via the feces.[1][4][27][28]

Pathology[edit]
Main article: Disorders of calcium metabolism
Hypocalcemia (low blood calcium) and hypercalcemia (high blood calcium) are both serious
medical disorders. Osteoporosis, osteomalacia and rickets are bone disorders linked to calcium
metabolism disorders and effects of vitamin D. Renal osteodystrophy is a consequence
of chronic renal failure related to the calcium metabolism.
A low calcium intake may be a risk factor in the development of osteoporosis in later life. In
one meta-analysis, the authors found that in fifty out of the fifty-two studies that they reviewed, a
diet adequately rich in calcium reduced calcium loss from bone with advancing (post-
menopausal) age.[29] A diet with sustained adequate amounts of calcium reduced the risk of
osteoporosis.

Research into cancer prevention[edit]

The role that calcium might have in reducing the rates of colorectal cancer has been the subject
of many studies. However, given its modest efficacy, there is no current medical
recommendation to use calcium for cancer reduction. Several epidemiological studies suggest
that people with high calcium intake have a reduced risk of colorectal cancer. These
observations have been confirmed by experimental studies in volunteers and in rodents. One
large scale clinical trial shows that 1.2 g calcium each day reduces, modestly, intestinal polyps
recurrence in volunteers.[30] Data from the four published trials are available.[31] Some forty
carcinogenesis studies in rats or mice, reported in the Chemoprev.Database, also support that
calcium could prevent intestinal cancer.[32]