Calcium in biology

ions contribute to the physiology and biochemistry of organisms' cells. They play an important role in signal transduction pathways, where they act as a second messenger, in neurotransmitter release from neurons, in contraction of all muscle cell types, and in fertilization. Many enzymes require calcium ions as a cofactor, including several of the coagulation factors. Extracellular calcium is also important for maintaining the potential difference across excitable cell membranes, as well as proper bone formation.
Plasma calcium levels in mammals are tightly regulated, with bone acting as the major mineral storage site. Calcium ions, Ca²⁺, are released from bone into the bloodstream under controlled conditions. Calcium is transported through the bloodstream as dissolved ions or bound to proteins such as serum albumin. Parathyroid hormone secreted by the parathyroid gland regulates the resorption of Ca²⁺ from bone, reabsorption in the kidney back into circulation, and increases in the activation of vitamin D₃ to calcitriol. Calcitriol, the active form of vitamin D₃, promotes absorption of calcium from the intestines and bones. Calcitriol also plays a key role in upregulating levels of intracellular calcium, and high levels of this ion appear to be protective against cancers of the breast and prostate. The suppression of calcitriol by excessive dietary calcium is believed to be the major mechanism for the potential link between dairy and cancer. However, the vitamin D present in many dairy products may help compensate for this deleterious effect of high-calcium diets by increasing serum calcitriol levels. Calcitonin secreted from the parafollicular cells of the thyroid gland also affects calcium levels by opposing parathyroid hormone; however, its physiological significance in humans is in dispute.
Intracellular calcium is stored in organelles which repetitively release and then reaccumulate Ca²⁺ ions in response to specific cellular events: storage sites include mitochondria and the endoplasmic reticulum.
Characteristic concentrations of calcium in model organisms are: in E. coli 3 mM, 100 nM, in budding yeast 2 mM, in mammalian cell 10–100 nM and in blood plasma 2 mM.

Humans

Age	Calcium
1–3 years	700
4–8 years	1000
9–18 years	1300
19–50 years	1000
>51 years	1000
Pregnancy	1000
Lactation	1000

In 2022, it was the 277th most commonly prescribed medication in the United States, with more than 700,000 prescriptions.

Dietary recommendations

The US Institute of Medicine established Recommended Dietary Allowances for calcium in 1997 and updated those values in 2011. See table. The
European Food Safety Authority uses the term Population Reference Intake instead of RDAs and sets slightly different numbers: ages 4–10 800 mg, ages 11–17 1150 mg, ages 18–24 1000 mg, and >25 years 950 mg.
Because of concerns of long-term adverse side effects such as calcification of arteries and kidney stones, the IOM and EFSA both set Tolerable Upper Intake Levels for the combination of dietary and supplemental calcium. From the IOM, people ages 9–18 years are not supposed to exceed 3,000 mg/day; for ages 19–50 not to exceed 2,500 mg/day; for ages 51 and older, not to exceed 2,000 mg/day. The EFSA set UL at 2,500 mg/day for adults but decided the information for children and adolescents was not sufficient to determine ULs.

Labeling

For US food and dietary supplement labeling purposes, the amount in a serving is expressed as a percent of Daily Value. For calcium labeling purposes, 100% of the Daily Value was 1000 mg, but as of 27 May 2016, it was revised to 1300 mg to bring it into agreement with the RDA. A table of the old and new adult daily values is provided at Reference Daily Intake.

Health claims

Although as a general rule, dietary supplement labeling and marketing are not allowed to make disease prevention or treatment claims, the FDA has for some foods and dietary supplements reviewed the science, concluded that there is significant scientific agreement for a beneficial effect of dietary calcium on bone mineral density, and published specifically worded allowed health claims. An initial ruling allowing a health claim for calcium dietary supplements and osteoporosis was later amended to include calcium and vitamin D supplements, effective 1 January 2010. Examples of allowed wording are shown below. In order to qualify for the calcium health claim, a dietary supplement must contain at least 20% of the Reference Dietary Intake, which for calcium means at least 260 mg/serving.

"Adequate calcium throughout life, as part of a well-balanced diet, may reduce the risk of osteoporosis."
"Adequate calcium as part of a healthful diet, along with physical activity, may reduce the risk of osteoporosis in later life."
"Adequate calcium and vitamin D throughout life, as part of a well-balanced diet, may reduce the risk of osteoporosis."
"Adequate calcium and vitamin D as part of a healthful diet, along with physical activity, may reduce the risk of osteoporosis in later life."

In 2005, the FDA approved a Qualified Health Claim for calcium and hypertension in light of the evidence available at that time, with suggested wording "Some scientific evidence suggests that calcium supplements may reduce the risk of hypertension. However, FDA has determined that the evidence is inconsistent and not conclusive." Evidence for pregnancy-induced hypertension and preeclampsia was considered inconclusive. The same year, the FDA approved a QHC for calcium and colon cancer, with suggested wording "Some evidence suggests that calcium supplements may reduce the risk of colon/rectal cancer, however, FDA has determined that this evidence is limited and not conclusive." Evidence for breast cancer and prostate cancer was considered inconclusive. Proposals for QHCs for calcium as protective against kidney stones or against menstrual disorders or pain were rejected.
The European Food Safety Authority concluded that "Calcium contributes to the normal development of bones." The EFSA rejected a claim that a cause-and-effect relationship existed between the dietary intake of calcium and potassium and maintenance of normal acid-base balance. The EFSA also rejected claims for calcium and nails, hair, blood lipids, premenstrual syndrome and body weight maintenance.

Food sources

The United States Department of Agriculture web site has a very complete searchable table of calcium content in foods, per common measures such as per 100 grams or per a normal serving.

Food, calcium per 100 grams

parmesan = 1140 mg

milk powder = 909 mg

goat hard cheese = 895 mg

Cheddar cheese = 720 mg

tahini paste = 427 mg

molasses = 273 mg

sardines = 240 mg

almonds = 234 mg

collard greens = 232 mg

kale = 150 mg

goat milk = 134 mg

sesame seeds = 125 mg

nonfat cow milk = 122 mg

plain whole-milk yogurt = 121 mg

Food, calcium per 100 grams

hazelnuts = 114 mg

tofu, soft = 114 mg

beet greens = 114 mg

spinach = 99 mg

ricottas = 90 mg

lentils = 79 mg

chickpeas = 53 mg

rolled oats = 52 mg

eggs, boiled = 50 mg

orange = 40 mg

human milk = 33 mg

rice, white, long-grain = 19 mg

beef = 12 mg

cod = 11 mg

Measurement in blood

The amount of calcium in blood can be measured as total calcium, which includes both protein-bound and free calcium. In contrast, ionized calcium is a measure of free calcium. An abnormally high level of calcium in plasma is termed hypercalcemia and an abnormally low level is termed hypocalcemia, with "abnormal" generally referring to levels outside the reference range.
The main methods to measure serum calcium are:

O-Cresolphalein Complexone Method; A disadvantage of this method is that the volatile nature of the 2-amino-2-methyl-1-propanol used in this method makes it necessary to calibrate the method every few hours in a clinical laboratory setup.
Arsenazo III Method; This method is more robust, but the arsenic in the reagent is a health hazard.

The total amount of Ca²⁺ present in a tissue may be measured using Atomic absorption spectroscopy, in which the tissue is vaporized and combusted. To measure Ca²⁺ concentration or spatial distribution within the cell cytoplasm in vivo or in vitro, a range of fluorescent reporters may be used. These include cell permeable, calcium-binding fluorescent dyes such as Fura-2 or genetically engineered variant of green fluorescent protein named Cameleon.

Corrected calcium

As access to an ionized calcium is not always available a corrected calcium may be used instead. To calculate a corrected calcium in mmol/L one takes the total calcium in mmol/L and adds it to. There is, however, controversy around the usefulness of corrected calcium as it may be no better than total calcium. It may be more useful to correct total calcium for both albumin and the anion gap.

Other animals

Vertebrates

In vertebrates, calcium ions, like many other ions, are of such vital importance to many physiological processes that its concentration is maintained within specific limits to ensure adequate homeostasis. This is evidenced by human plasma calcium, which is one of the most closely regulated physiological variables in the human body. Normal plasma levels vary between 1 and 2% over any given time. Approximately half of all ionized calcium circulates in its unbound form, with the other half being complexed with plasma proteins such as albumin, as well as anions including bicarbonate, citrate, phosphate, and sulfate.
Different tissues contain calcium in different concentrations. For instance, Ca²⁺ is the most important element of bone and calcified cartilage. In humans, the total body content of calcium is present mostly in the form of bone mineral. In this state, it is largely unavailable for exchange/bioavailability. The way to overcome this is through the process of bone resorption, in which calcium is liberated into the bloodstream through the action of bone osteoclasts. The remainder of calcium is present within the extracellular and intracellular fluids.
Within a typical cell, the intracellular concentration of ionized calcium is roughly 100 nM, but is subject to increases of 10- to 100-fold during various cellular functions. The intracellular calcium level is kept relatively low with respect to the extracellular fluid, by an approximate magnitude of 12,000-fold. This gradient is maintained through various plasma membrane calcium pumps that utilize ATP for energy, as well as a sizable storage within intracellular compartments. In electrically excitable cells, such as skeletal and cardiac muscles and neurons, membrane depolarization leads to a Ca²⁺ transient with cytosolic Ca²⁺ concentration reaching around 1 μM. Mitochondria are capable of sequestering and storing some of that Ca²⁺. It has been estimated that mitochondrial matrix free calcium concentration rises to the tens of micromolar levels in situ during neuronal activity.