Calcium storage

Calcium ions (Ca²⁺) 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, electronic-book electronic- 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. 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 dubious.

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 (bound), 100 nM (free), in budding yeast 2mM (bound), in mammalian cell 10-100nM (free) and in blood plasma 2mM.

Humans

In 2020, calcium was the 204th most commonly prescribed medication in the United States, with more than 2million prescriptions.

Dietary recommendations

The U.S. Institute of Medicine (IOM) established Recommended Dietary Allowances (RDAs) for calcium in 1997 and updated those values in 2011. See table. The
European Food Safety Authority (EFSA) uses the term Population Reference Intake (PRIs) 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 (ULs) 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 U.S. food and dietary supplement labeling purposes the amount in a serving is expressed as a percent of Daily Value (%DV). For calcium labeling purposes 100% of the Daily Value was 1000 mg, but as of May 27, 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, 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 January 1, 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, 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 (EFSA) 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 (USDA) web site has a very complete searchable table of calcium content (in milligrams) in foods, per common measures such as per 100 grams or per a normal serving.

Measurement in blood

The amount of calcium in blood (more specifically, in blood plasma) 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 (GFP) 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 ((40 minus the serum albumin in g/L) multiplied by 0.02). 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⁺ (mostly calcium phosphate and some calcium sulfate) is the most important (and specific) element of bone and calcified cartilage. In humans, the total body content of calcium is present mostly in the form of bone mineral (roughly 99%). 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 uM. 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.

Effects

The effects of calcium on human cells are specific, meaning that different types of cells respond in different ways. However, in certain circumstances, its action may be more general. Ca²⁺ ions are one of the most widespread second messengers used in signal transduction. They make their entrance into the cytoplasm either from outside the cell through the cell membrane via calcium channels (such as calcium-binding proteins or voltage-gated calcium channels), or from some internal calcium storages such as the endoplasmic reticulum and mitochondria. Levels of intracellular calcium are regulated by transport proteins that remove it from the cell. For example, the sodium-calcium exchanger uses energy from the electrochemical gradient of sodium by coupling the influx of sodium into cell (and down its concentration gradient) with the transport of calcium out of the cell. In addition, the plasma membrane Ca²⁺ ATPase (PMCA) obtains energy to pump calcium out of the cell by hydrolysing adenosine triphosphate (ATP). In neurons, voltage-dependent, calcium-selective ion channels are important for synaptic transmission through the release of neurotransmitters into the synaptic cleft by vesicle fusion of synaptic vesicles.

Calcium's function in muscle contraction was found as early as 1882 by Ringer. Subsequent investigations were to reveal its role as a messenger about a century later. Because its action is interconnected with cAMP, they are called synarchic messengers. Calcium can bind to several different calcium-modulated proteins such as troponin-C (the first one to be identified) and cal