View source for Calcium in biology

{{Short description|Use of calcium by organisms}}
{{Use dmy dates|date=December 2024}}
[[File:Shapes_of_the_cardiac_action_potential_in_the_heart.svg|thumb|430x430px|Calcium is used in many nerves in the [[voltage-gated calcium channel]] which is slightly slower than the [[voltage-gated potassium channel]]. It is most notably used in the [[cardiac action potential]].<ref>{{Cite journal |last1=Kléber |first1=André G. |last2=Rudy |first2=Yoram |date=1 April 2004 |title=Basic Mechanisms of Cardiac Impulse Propagation and Associated Arrhythmias |url=https://journals.physiology.org/doi/full/10.1152/physrev.00025.2003 |journal=Physiological Reviews |volume=84 |issue=2 |pages=431–488 |doi=10.1152/physrev.00025.2003 |pmid=15044680 |issn=0031-9333|url-access=subscription }}</ref>]]
[[Calcium]] ions  (Ca<sup>2+</sup>) contribute to the [[physiology]] and [[biochemistry]] of organisms' [[cell (biology)|cells]]. They play an important role in [[signal transduction]] pathways,<ref name="marisa" /><ref name="Brini" /> where they act as a [[second messenger]], in [[neurotransmitter]] release from [[neurons]], in contraction of all [[muscle]] cell types, and in [[fertilization]]. Many [[enzyme]]s require calcium ions as a [[Cofactor (biochemistry)|cofactor]], including several of the [[coagulation factor]]s. Extracellular calcium is also important for maintaining the [[potential difference]] across [[excitable cell]] [[cell membrane|membranes]], as well as proper bone formation.

Plasma calcium levels in mammals are tightly regulated,<ref name=marisa>{{cite book
|first1=Marisa
|last1= Brini
|first2= Denis
|last2= Ottolini
|first3= Tito
|last3= Calì
|first4= Ernesto
|last4= Carafoli
|chapter= Calcium in Health and Disease
|editor=Astrid Sigel, Helmut Sigel and Roland K. O. Sigel
|title=Interrelations between Essential Metal Ions and Human Diseases
|series=Metal Ions in Life Sciences
|volume=13
|year=2013
|publisher=Springer
|pages=81–137
|doi=10.1007/978-94-007-7500-8_4
|pmid= 24470090
|isbn= 978-94-007-7499-5
}}</ref><ref name=Brini>{{cite book
|last1=Brini |first1=Marisa |last2=Call |first2=Tito |last3=Ottolini |first3=Denis |last4=Carafoli |first4=Ernesto
|chapter=Intracellular Calcium Homeostasis and Signaling |editor1-first=Lucia|editor1-last=Banci |series=Metal Ions in Life Sciences |volume=12
|pages=119–68 |title=Metallomics and the Cell |year=2013 |publisher=Springer |isbn=978-94-007-5560-4|doi=10.1007/978-94-007-5561-1_5|pmid=23595672 }} electronic-book {{ISBN|978-94-007-5561-1}} {{ISSN|1559-0836}} electronic-{{ISSN|1868-0402}}</ref> with [[bone]] acting as the major [[mineral storage]] site. Calcium [[ion]]s, Ca<sup>2+</sup>, 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 [[bone resorption|resorption]] of Ca<sup>2+</sup> from bone, [[reabsorption]] in the kidney back into circulation, and increases in the activation of [[vitamin D3|vitamin D<sub>3</sub>]] to [[calcitriol]]. Calcitriol, the active form of vitamin D<sub>3</sub>, promotes [[small intestines#Absorptions|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 cell]]s 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 [[organelle]]s which repetitively release and then reaccumulate Ca<sup>2+</sup> ions in response to specific cellular events: storage sites include [[mitochondria]] and the [[endoplasmic reticulum]].<ref name="ncbi.nlm.nih.gov">{{cite journal | last1 = Wilson | first1 = C.H. | last2 = Ali | first2 = E.S. | last3 = Scrimgeour | first3 = N. | last4 = Martin | first4 = A.M. | last5 = Hua | first5 = J. | last6 = Tallis | first6 = G.A. | last7 = Rychkov | first7 = G.Y. | last8 = Barritt | first8 = G.J. | year = 2015 | title = Steatosis inhibits liver cell store-operated Ca(2)(+) entry and reduces ER Ca(2)(+) through a protein kinase C-dependent mechanism | journal = Biochem J | volume = 466 | issue = 2| pages = 379–90 | doi=10.1042/bj20140881 | pmid=25422863}}</ref>

Characteristic concentrations of calcium in model organisms are: in ''E.&nbsp;coli'' 3&nbsp;[[Millimolar|mM]] (bound), 100&nbsp;[[Nanomolar|nM]] (free), in budding yeast 2&nbsp;mM (bound), in mammalian cell 10–100&nbsp;nM (free) and in blood plasma 2&nbsp;mM.<ref>{{cite web|url = http://book.bionumbers.org/what-are-the-concentrations-of-different-ions-in-cells/|title =Cell Biology by the Numbers: What are the concentrations of different ions in cells? |website =book.bionumbers.org|first1= Ron|last1= Milo|first2= Rob |last2=Philips|access-date=24 March 2017}}</ref>

{{TOC limit}}

==Humans==

{| class="wikitable" style="float:right; margin-left:15px"
|+ Age-adjusted daily calcium recommendations (from U.S. Institute of Medicine RDAs)<ref name="DRItext">{{cite book | title = Dietary Reference Intakes for Calcium and Vitamin D, Chapter 5 Dietary Reference Intakes pages 345–402 | publisher = National Academies Press | location = Washington, D.C. | year = 2011 | isbn = 978-0-309-16394-1 | url = https://www.nap.edu/read/13050/chapter/7| doi = 10.17226/13050 | pmid = 21796828 | author1 = Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D Calcium | last2 = Ross | first2 = A. C. | last3 = Taylor | first3 = C. L. | last4 = Yaktine | first4 = A. L. | last5 = Del Valle | first5 = H. B. | s2cid = 58721779 }}</ref>
|-
! Age
! Calcium (mg/day)
|-
| 1–3 years
| 700
|-
| 4–8 years
| 1000
|-
| 9–18 years
| 1300
|-
| 19–50 years
| 1000
|-
| >51 years
| 1000
|-
| Pregnancy
| 1000
|-
| Lactation
| 1000
|}
[[File:Calcium_intake_world_map.svg|thumb|upright=1.4|Global dietary calcium intake among adults (mg/day)<ref>{{cite journal|vauthors=Balk EM, Adam GP, Langberg VN, Earley A, Clark P, Ebeling PR, Mithal A, Rizzoli R, Zerbini CA, Pierroz DD, Dawson-Hughes B|date=December 2017|title=Global dietary calcium intake among adults: a systematic review|journal=Osteoporosis International|volume=28|issue=12|pages=3315–24|doi=10.1007/s00198-017-4230-x|pmc=5684325|pmid=29026938}}</ref>{{Div col|small=yes|colwidth=10em}}
{{legend|#f51d1e|<400}}{{legend|#aa2b2c|400–500}}{{legend|#fa7929|500–600}}{{legend|#a46e2c|600–700}}{{legend|#fee940|700–800}}{{legend|#829d29|800–900}}{{legend|#84fc5a|900–1000}}{{legend|#2d621d|>1000}}
{{div col end}}]]

In 2022, it was the 277th most commonly prescribed medication in the United States, with more than 700,000 prescriptions.<ref>{{cite web | title=The Top 300 of 2022 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=30 August 2024 | archive-date=30 August 2024 | archive-url=https://web.archive.org/web/20240830202410/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Calcium Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Calcium | access-date = 30 August 2024 }}</ref>

===Dietary recommendations===
The US Institute of Medicine (IOM) established [[Recommended Dietary Allowances]] (RDAs) for calcium in 1997 and updated those values in 2011.<ref name="DRItext" /> 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&nbsp;mg, ages 11–17 1150&nbsp;mg, ages 18–24 1000&nbsp;mg, and >25 years 950&nbsp;mg.<ref>{{cite web | title = Overview on Dietary Reference Values for the EU population as derived by the EFSA Panel on Dietetic Products, Nutrition and Allergies| year = 2017| url = https://www.efsa.europa.eu/sites/default/files/assets/DRV_Summary_tables_jan_17.pdf}}</ref>

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 level|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&nbsp;mg/day; for ages 19–50 not to exceed 2,500&nbsp;mg/day; for ages 51 and older, not to exceed 2,000&nbsp;mg/day.<ref>{{cite book | title = Dietary Reference Intakes for Calcium and Vitamin D, Chapter 6 Tolerable Upper Intake Levels pages 403–56 | publisher = National Academies Press | location = Washington, D.C. | year = 2011 | isbn = 978-0-309-16394-1 | url = https://www.nap.edu/read/13050/chapter/8| doi = 10.17226/13050 | pmid = 21796828 | author1 = Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D Calcium | last2 = Ross | first2 = A. C. | last3 = Taylor | first3 = C. L. | last4 = Yaktine | first4 = A. L. | last5 = Del Valle | first5 = H. B. | s2cid = 58721779 }}</ref> The EFSA set UL at 2,500&nbsp;mg/day for adults but decided the information for children and adolescents was not sufficient to determine ULs.<ref>{{citation| title = Tolerable Upper Intake Levels For Vitamins And Minerals| publisher = European Food Safety Authority| year = 2006| url = http://www.efsa.europa.eu/sites/default/files/efsa_rep/blobserver_assets/ndatolerableuil.pdf}}</ref>

====Labeling====
For US 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&nbsp;mg, but as of 27 May 2016, it was revised to 1300&nbsp;mg to bring it into agreement with the RDA.<ref name="FedReg">{{cite web|url=https://www.gpo.gov/fdsys/pkg/FR-2016-05-27/pdf/2016-11867.pdf |title=Federal Register May 27, 2016 Food Labeling: Revision of the Nutrition and Supplement Facts Labels. FR page 33982.}}</ref><ref>{{cite web | title=Daily Value Reference of the Dietary Supplement Label Database (DSLD) | website=Dietary Supplement Label Database (DSLD) | url=https://www.dsld.nlm.nih.gov/dsld/dailyvalue.jsp | access-date=16 May 2020 | archive-date=7 April 2020 | archive-url=https://web.archive.org/web/20200407073956/https://dsld.nlm.nih.gov/dsld/dailyvalue.jsp }}</ref> 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 (along with vitamin D to facilitate its absorption), 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&nbsp;mg/serving.<ref>[https://www.regulations.gov/document?D=FDA-2004-P-0205-0006 Food Labeling: Health Claims; Calcium and Osteoporosis, and Calcium, Vitamin D, and Osteoporosis] U.S. Food and Drug Administration.</ref>

*"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.<ref>[https://wayback.archive-it.org/7993/20170111181617/http://www.fda.gov/Food/IngredientsPackagingLabeling/LabelingNutrition/ucm073030.htm Qualified Health Claims: Letter of Enforcement Discretion – Calcium and Hypertension; Pregnancy-Induced Hypertension; and Preeclampsia (Docket No. 2004Q-0098)] U.S. Food and Drug Administration (2005).</ref> 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.<ref>[https://wayback.archive-it.org/7993/20171114023216/https://www.fda.gov/Food/IngredientsPackagingLabeling/LabelingNutrition/ucm072771.htm Qualified Health Claims: Letter Regarding Calcium and Colon/Rectal, Breast, and Prostate Cancers and Recurrent Colon Polyps (Docket No. 2004Q-0097)] U.S. Food and Drug Administration (2005).</ref> Proposals for QHCs for calcium as protective against kidney stones or against menstrual disorders or pain were rejected.<ref>[https://wayback.archive-it.org/7993/20171115122114/https://www.fda.gov/Food/IngredientsPackagingLabeling/LabelingNutrition/ucm073348.htm Qualified Health Claims: Letter of Denial – Calcium and Kidney Stones; Urinary Stones; and Kidney Stones and Urinary Stones (Docket No. 2004Q-0102)] U.S. Food and Drug Administration (2005).</ref><ref>[https://wayback.archive-it.org/7993/20171115122115/https://www.fda.gov/Food/IngredientsPackagingLabeling/LabelingNutrition/ucm073387.htm Qualified Health Claims: Letters of Denial - Calcium and a Reduced Risk Of Menstrual Disorders (Docket No. 2004Q-0099)] U.S. Food and Drug Administration (2005)</ref>

The [[European Food Safety Authority]] (EFSA) concluded that "Calcium contributes to the normal development of bones."<ref>[https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2016.4587 Calcium and contribution to the normal development of bones: evaluation of a health claim] {{Webarchive|url=https://web.archive.org/web/20191220053447/https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2016.4587 |date=20 December 2019 }} European Food Safety Authority (2016).</ref> 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.<ref>[https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2011.2201 Scientific Opinion on the substantiation of health claims related to calcium and potassium and maintenance of normal acid-base balance] {{Webarchive|url=https://web.archive.org/web/20190901144900/https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2011.2201 |date=1 September 2019 }} European Food Safety Authority (2011).</ref> The EFSA also rejected claims for calcium and nails, hair, blood lipids, premenstrual syndrome and body weight maintenance.<ref>[https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2010.1725 Scientific Opinion on the substantiation of health claims related to calcium and maintenance of normal bone and teeth (ID 2731, 3155, 4311, 4312, 4703), maintenance of normal hair and nails (ID 399, 3155), maintenance of normal blood LDL-cholesterol concentrations (ID 349, 1893), maintenance of normal blood HDL-cholesterol concentrations (ID 349, 1893), reduction in the severity of symptoms related to the premenstrual syndrome (ID 348, 1892), "cell membrane permeability" (ID 363), reduction of tiredness and fatigue (ID 232), contribution to normal psychological functions (ID 233), contribution to the maintenance or achievement of a normal body weight (ID 228, 229) and regulation of normal cell division and differentiation] {{Webarchive|url=https://web.archive.org/web/20190901144900/https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2010.1725 |date=1 September 2019 }} EFSA Journal 2010;8(10):1725.</ref>

===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.<ref>{{cite web |url=https://ndb.nal.usda.gov/ndb/nutrients/report/nutrientsfrm?max=25&offset=0&totCount=0&nutrient1=301&nutrient2=&nutrient3=&subset=0&sort=f&measureby=g |archive-url=https://archive.today/20171129203327/https://ndb.nal.usda.gov/ndb/nutrients/report/nutrientsfrm?max=25&offset=0&totCount=0&nutrient1=301&nutrient2=&nutrient3=&subset=0&sort=f&measureby=g |archive-date=29 November 2017 |title=Food Composition Databases Show Nutrients List |publisher= United States Department of Agriculture: Agricultural Research Service |work=USDA Food Composition Databases |access-date=29 November 2017 }}</ref><ref>{{cite web |title=SR Legacy Nutrient Search |url=https://www.ars.usda.gov/northeast-area/beltsville-md-bhnrc/beltsville-human-nutrition-research-center/methods-and-application-of-food-composition-laboratory/mafcl-site-pages/sr-legacy-nutrient-search/ |website=usda.gov |access-date=7 April 2020}}</ref>
<div style="float:left; padding: 1em;">
{| class="wikitable"
|-
!Food, calcium per 100 grams
|-
|[[parmesan]] ([[cheese]]) = 1140&nbsp;mg
|-
|[[milk powder]] = 909&nbsp;mg
|-
|goat hard cheese = 895&nbsp;mg
|-
|[[Cheddar cheese]] = 720&nbsp;mg
|-
|[[tahini]] paste = 427&nbsp;mg
|-
|[[molasses]] = 273&nbsp;mg
|-
|[[Sardines as food|sardines]] = 240&nbsp;mg
|-
|[[almond]]s = 234&nbsp;mg
|-
|[[collard greens]] = 232&nbsp;mg
|-
|[[kale]] = 150&nbsp;mg
|-
|goat milk = 134&nbsp;mg
|-
|[[sesame]] seeds (unhulled) = 125&nbsp;mg
|-
|[[nonfat]] [[cow milk]] = 122&nbsp;mg
|-
|plain whole-milk [[yogurt]] = 121&nbsp;mg
|-
|}
</div>
<div style="float:left; padding: 1em;">
{|class="wikitable"
|-
!Food, calcium per 100 grams
|-
|[[hazelnut]]s = 114&nbsp;mg
|-
|[[tofu]], soft = 114&nbsp;mg
|-
|[[beet]] greens = 114&nbsp;mg
|-
|[[spinach]] = 99&nbsp;mg
|-
|[[ricotta]]s (skimmed milk cheese) = 90&nbsp;mg
|-
|[[lentil]]s = 79&nbsp;mg
|-
|[[chickpea]]s = 53&nbsp;mg
|-
|[[Rolled oats|rolled oat]]s = 52&nbsp;mg<ref>{{cite web | url=https://fdc.nal.usda.gov/food-details/173904/nutrients | title=FoodData Central | access-date=29 November 2022 | archive-date=3 April 2019 | archive-url=https://web.archive.org/web/20190403171801/https://fdc.nal.usda.gov/fdc-app.html#/food-details/173904/nutrients | url-status=live }}</ref>
|-
|[[egg (food)|eggs]], boiled = 50&nbsp;mg
|-
|[[Orange (fruit)|orange]] = 40&nbsp;mg
|-
|human [[milk]] = 33&nbsp;mg
|-
|[[rice]], white, long-grain = 19&nbsp;mg
|-
|[[beef]] = 12&nbsp;mg
|-
|[[Cod as food|cod]] = 11&nbsp;mg
|-
|}
</div>{{Clear}}

===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]].

{| class="wikitable"
 |+ [[Reference ranges for blood tests]] for calcium
 |'''Target''' || '''Lower limit'''||'''Upper limit'''||'''Unit'''
 |-
 |rowspan=2| Ionized calcium || 1.03,<ref name=Larsson>{{cite journal |vauthors=Larsson L, Ohman S |title=Serum ionized calcium and corrected total calcium in borderline hyperparathyroidism |journal=Clin. Chem. |volume=24 |issue=11 |pages=1962–65 |date=November 1978 |pmid=709830 |doi=10.1093/clinchem/24.11.1962 |url=http://www.clinchem.org/cgi/pmidlookup?view=long&pmid=709830 |access-date=21 October 2011 |archive-url=https://web.archive.org/web/20191212193954/http://www.clinchem.org/cgi/pmidlookup?view=long&pmid=709830 |archive-date=12 December 2019 |doi-access=free |url-access=subscription }}</ref> 1.10<ref name=uppsala>Reference range list from Uppsala University Hospital ("Laborationslista"). Artnr 40284 Sj74a. Issued on 22 April 2008</ref> || 1.23,<ref name=Larsson /> 1.30<ref name=uppsala /> || mmol/L
 |-
 | 4.1,<ref name="calcium-molar">Derived from molar values using molar mass of 40.08  g•mol−1</ref> 4.4<ref name="calcium-molar" /> || 4.9,<ref name="calcium-molar" /> 5.2<ref name="calcium-molar" /> || mg/dL
 |-
 |rowspan=2| Total calcium || 2.1,<ref name=firstaid>Last page of {{cite book |author1=Deepak A. Rao |author2=Le, Tao |author3=Bhushan, Vikas |title=First Aid for the USMLE Step 1 2008 (First Aid for the Usmle Step 1) |publisher=McGraw-Hill Medical |year=2007 |isbn=978-0-07-149868-5 |url-access=registration |url=https://archive.org/details/firstaidforusmle00taol }}</ref><ref name="calcium-mass">Derived from mass values using molar mass of 40.08  g•mol−1</ref> 2.2<ref name=uppsala /> || 2.5,<ref name=uppsala /><ref name="calcium-mass" /> 2.6,<ref name="calcium-mass" /> 2.8<ref name=firstaid /> || mmol/L
 |-
 | 8.4,<ref name=firstaid /> 8.5<ref name=bloodbook>[http://www.bloodbook.com/ranges.html Blood Test Results – Normal Ranges] {{Webarchive|url=https://web.archive.org/web/20121102092931/http://www.bloodbook.com/ranges.html |date=2 November 2012 }} Bloodbook.Com</ref> || 10.2,<ref name=firstaid /> 10.5<ref name=bloodbook /> || mg/dL
|}

The main methods to measure serum calcium are:<ref>Clin Chem. 1992 Jun;38(6):904–08. Single stable reagent (Arsenazo III) for optically robust measurement of calcium in serum and plasma. Leary NO, Pembroke A, Duggan PF.</ref>
* 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 Ca<sup>2+</sup> present in a tissue may be measured using [[Atomic absorption spectroscopy]], in which the tissue is vaporized and combusted.  To measure Ca<sup>2+</sup> 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 (protein)|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).<ref name=BMJ2015>{{cite journal|last1=Minisola|first1=S|last2=Pepe|first2=J|last3=Piemonte|first3=S|last4=Cipriani|first4=C|s2cid=28462200|title=The diagnosis and management of hypercalcaemia.|journal=BMJ (Clinical Research Ed.)|date=2 June 2015|volume=350|article-number=h2723|pmid=26037642|doi=10.1136/bmj.h2723}}</ref> There is, however, controversy around the usefulness of corrected calcium as it may be no better than total calcium.<ref>{{cite book |last1=Thomas |first1=Lynn K. |last2=Othersen |first2=Jennifer Bohnstadt |title=Nutrition Therapy for Chronic Kidney Disease |date=2016 |publisher=CRC Press |isbn=978-1-4398-4950-7 |page=116 |url=https://books.google.com/books?id=o3bRBQAAQBAJ&dq=corrected+calcium+not+recommended&pg=PA116 |language=en}}</ref> It may be more useful to correct total calcium for both albumin and the [[anion gap]].<ref name =JALM2020>{{cite journal|last1=Yap|first1=E|last2=Roche-Recinos|first2=A|last3=Goldwasser|first3=P|title=Predicting Ionized Hypocalcemia in Critical Care: An Improved Method Based on the Anion Gap|journal= The Journal of Applied Laboratory Medicine|date=30 December 2019|volume=5|issue=1|pages=4–14|doi=  10.1373/jalm.2019.029314|pmid=32445343|doi-access=free}}</ref><ref name =CCA2022>{{cite journal|last1=Yap|first1=E|last2=Ouyang|first2=J|last3=Puri|first3=I|last4=Melaku|first4=Y|last5=Goldwasser|first5=P|title=Novel methods of predicting ionized calcium status from routine data in critical care: External validation in MIMIC-III|journal=Clinica Chimica Acta|date=1 June 2022|volume=531|pages=375–381|doi=10.1016/j.cca.2022.05.003|pmid=35526587|s2cid=248568849}}</ref>

== Other animals ==

=== Vertebrates ===
{{Main|Calcium metabolism}}
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 [[Blood plasma|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]].<ref>{{cite book
|first1=Marisa
|last1=Brini
|first2=Denis
|last2=Ottolini
|first3=Tito
|last3=Calì
|first4=Ernesto
|last4=Carafoli
|chapter=Calcium in Health and Disease
|editor=Astrid Sigel, Helmut Sigel and Roland K. O. Sigel
|title=Interrelations between Essential Metal Ions and Human Diseases
|series=Metal Ions in Life Sciences
|volume=13
|year=2013
|publisher=Springer
|pages=81–138
|doi=10.1007/978-94-007-7500-8_4
|pmid=24470090
|isbn=978-94-007-7499-5
}}</ref>

[[File:Calcium regulation.png|thumb|250px|[[Human homeostasis#Calcium|Calcium regulation]] in the human body<ref>{{cite book |chapter=The Parathyroid Glands and Vitamin D |author1=Boron, Walter F. |author2=Boulpaep, Emile L |title=Medical Physiology: A Cellular And Molecular Approach |publisher=Elsevier/Saunders |year=2003 |isbn=978-1-4160-2328-9 |page=1094}}</ref>]]

Different [[biological tissue|tissues]] contain calcium in different concentrations. For instance, Ca<sup>2+</sup> (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 pump]]s that utilize [[Adenosine triphosphate|ATP]] for energy, as well as a sizable storage within intracellular compartments. In [[electrically excitable cell]]s, such as skeletal and cardiac muscles and neurons, membrane depolarization leads to a Ca<sup>2+</sup> transient with cytosolic Ca<sup>2+</sup> concentration reaching around 1 μM.<ref>{{Cite journal|doi=10.1016/j.cell.2007.11.028|title=Calcium Signaling|year=2007|last1=Clapham|first1=David E.|journal=Cell|volume=131|issue=6|pages=1047–1058|pmid=18083096|s2cid=15087548|doi-access=free}}</ref> Mitochondria are capable of sequestering and storing some of that Ca<sup>2+</sup>. It has been estimated that mitochondrial matrix free calcium concentration rises to the tens of micromolar levels ''in situ'' during neuronal activity.<ref>{{cite journal | author = Ivannikov, M.| title = Mitochondrial Free Ca<sup>2+</sup> Levels and Their Effects on Energy Metabolism in Drosophila Motor Nerve Terminals | journal = [[Biophys. J.]] | volume = 104 | issue = 11 | pages = 2353–61 | year = 2013 | pmid=23746507 | doi=10.1016/j.bpj.2013.03.064 | pmc=3672877| bibcode = 2013BpJ...104.2353I |display-authors=etal}}</ref>

==== 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. Ca<sup>2+</sup> ions are one of the most widespread [[second messenger]]s 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 protein]]s or voltage-gated calcium channels), or from some internal [[calcium storage]]s such as the [[endoplasmic reticulum]]<ref name="ncbi.nlm.nih.gov" /> and [[mitochondria]]. Levels of intracellular calcium are regulated by [[transport protein]]s 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|plasma membrane Ca<sup>2+</sup> ATPase]] (PMCA) obtains energy to pump calcium out of the cell by [[hydrolysis|hydrolysing]] [[adenosine triphosphate]] (ATP). In [[neuron]]s, [[Voltage-dependent calcium channel|voltage-dependent, calcium-selective ion channels]] are important for [[Synapse|synaptic]] transmission through the release of [[neurotransmitters]] into the [[synaptic cleft]] by [[vesicle fusion]] of [[synaptic vesicle]]s.

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 [[cyclic AMP|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 [[calmodulin]], proteins that are necessary for promoting contraction in muscle.

In the endothelial cells which line the inside of blood vessels, Ca<sup>2+</sup> ions can regulate several signaling pathways which cause the smooth muscle surrounding blood vessels to relax.{{citation needed|reason=Calcium normally causes muscles to contract; is this a special case or a typo|date=January 2016}}  Some of these Ca<sup>2+</sup>-activated pathways include the stimulation of eNOS to produce nitric oxide, as well as the stimulation of K<sub>ca</sub> channels to efflux K<sup>+</sup> and cause hyperpolarization of the cell membrane.  Both nitric oxide and hyperpolarization cause the smooth muscle to relax in order to regulate the amount of tone in blood vessels.<ref>Christopher J Garland, C Robin Hiley, Kim A Dora.  EDHF: spreading the influence of the endothelium. ''British Journal of Pharmacology''.  164:3, 839–52. (2011).</ref>  However, dysfunction within these Ca<sup>2+</sup>-activated pathways can lead to an increase in tone caused by unregulated smooth muscle contraction.  This type of dysfunction can be seen in cardiovascular diseases, hypertension, and diabetes.<ref>Hua Cai, David G. Harrison.  Endothelial Dysfunction in Cardiovascular Diseases: The Role of Oxidant Stress. ''Circulation Research''.  87, 840–44. (2000).</ref>

Calcium coordination plays an important role in defining the structure and function of proteins. An example a protein with calcium coordination is [[von Willebrand factor]] (vWF) which has an essential role in blood clot formation process. It was discovered using single molecule [[optical tweezers]] measurement that calcium-bound vWF acts as a shear force sensor in the blood. Shear force leads to unfolding of the A2 domain of vWF whose refolding rate is dramatically enhanced in the presence of calcium.<ref>Jakobi AJ, Mashaghi A, Tans SJ, Huizinga EG. Calcium modulates force sensing by the von Willebrand factor A2 domain. Nature Communications 2011 Jul 12;2:385.  [http://www.nature.com/ncomms/journal/v2/n7/full/ncomms1385.html]</ref>

==== Adaptation ====
Ca<sup>2+</sup> ion flow regulates several secondary messenger systems in [[neural adaptation]] for visual, auditory, and the olfactory system. It may often be bound to [[calmodulin]] such as in the olfactory system to either enhance or repress cation channels.<ref>{{cite journal|pmid=16027364|pmc=1180786|year=2005|last1=Dougherty|first1=D. P.|title=Computational model of the cAMP-mediated sensory response and calcium-dependent adaptation in vertebrate olfactory receptor neurons|journal=Proceedings of the National Academy of Sciences|volume=102|issue=30|pages=10415–20|last2=Wright|first2=G. A.|last3=Yew|first3=A. C.|doi=10.1073/pnas.0504099102|bibcode=2005PNAS..10210415D|doi-access=free}}</ref> Other times the calcium level change can actually release [[guanylyl cyclase]] from inhibition, like in the photoreception system.<ref>{{cite journal|pmid=1962979|year=1990|last1=Pugh|first1=E. N. Jr.|title=Cyclic GMP and calcium: The internal messengers of excitation and adaptation in vertebrate photoreceptors|journal=Vision Research|volume=30|issue=12|pages=1923–48|last2=Lamb|first2=T. D.|doi=10.1016/0042-6989(90)90013-b|s2cid=22506803|doi-access=free}}</ref> Ca<sup>2+</sup> ion can also determine the speed of adaptation in a neural system depending on the receptors and proteins that have varied affinity for detecting levels of calcium to open or close channels at high concentration and low concentration of calcium in the cell at that time.<ref>{{cite journal|pmid=14977412|year=2004|last1=Gillespie|first1=P. G.|title=Myosin-1c, the hair cell's adaptation motor|journal=Annual Review of Physiology|volume=66|pages=521–45|last2=Cyr|first2=J. L.|doi=10.1146/annurev.physiol.66.032102.112842}}</ref>

{|class="wikitable sortable".
![[Cell type]]
!Effect
|-
| [[Endothelial cell]]s || ↑Vasodilation
|-
| [[Secretory cell]]s (mostly) || ↑Secretion ([[vesicle fusion]])
|-
| [[Juxtaglomerular cell]] || ↓Secretion<ref name=boron867>{{cite book |author1=Boron, Walter F. |author2=Boulpaep, Emile L |title=Medical Physiology: A Cellular And Molecular Approach |publisher=Elsevier/Saunders |year=2003 |isbn=978-1-4160-2328-9 |page=867}}</ref>
|-
| [[Parathyroid chief cell]]s || ↓Secretion<ref name=boron867 />
|-
| [[Neuron]]s || Transmission ([[vesicle fusion]]), [[neural adaptation]]
|-
| [[T cell]]s || Activation in response to antigen presentation to the [[T cell receptor]]<ref name=lange>{{cite book |author=Levinson, Warren |title=Review of medical microbiology and immunology |publisher=McGraw-Hill Medical |year=2008 |page=414 |isbn=978-0-07-149620-9 }}</ref>
|-
|[[Myocytes]] ||
* Contraction
* Activation of [[protein kinase C]]
|-
|Various || Activation of [[protein kinase C]] <br /> ''Further reading: [[Function of protein kinase C]]''
|-
|}

[[File:Blood values sorted by mass and molar concentration.png|thumb|center|600px|[[Reference ranges for blood tests]], showing calcium levels in purple at right]]

==== Negative effects and pathology ====
Substantial decreases in extracellular Ca<sup>2+</sup> ion concentrations may result in a condition known as [[hypocalcaemia|hypocalcemic]] [[tetany]], which is marked by spontaneous [[motor neuron]] discharge. In addition, severe [[hypocalcaemia]] will begin to affect aspects of [[blood coagulation]] and signal transduction.

Ca<sup>2+</sup> ions can damage cells if they enter in excessive numbers (for example, in the case of [[excitotoxicity]], or over-excitation of [[neural circuit]]s, which can occur in [[neurodegenerative disease]]s, or after insults such as [[Traumatic brain injury|brain trauma]] or [[stroke]]). Excessive entry of [[calcium]] into a cell may damage it or even cause it to undergo [[apoptosis]], or death by [[necrosis]]. Calcium also acts as one of the primary regulators of osmotic stress ([[osmotic shock]]). Chronically elevated plasma calcium ([[hypercalcemia]]) is associated with [[cardiac arrhythmias]] and decreased neuromuscular excitability. One cause of hypercalcemia is a condition known as [[hyperparathyroidism]].

=== Invertebrates ===
Some [[invertebrate]]s use calcium compounds for building their [[exoskeleton]] ([[Exoskeleton|shells]] and [[carapace]]s) or [[endoskeleton]] ([[echinoderm]] plates and [[porifera]]n calcareous [[spicule (sponge)|spicules]]).

== Plants ==

=== Stomata closing ===
[[File:Calcium in Pollen.jpg|thumb|Calcium GCaMP reporter in tomato pollen tube]]
When [[abscisic acid]] signals the guard cells, free Ca<sup>2+</sup> ions enter the cytosol from both outside the cell and internal stores, reversing the concentration gradient so the K+ ions begin exiting the cell. The loss of solutes makes the cell flaccid and closes the stomatal pores.

=== Cellular division ===
Calcium is a necessary ion in the formation of the [[mitotic spindle]]. Without the mitotic spindle, [[cellular division]] cannot occur. Although young leaves have a higher need for calcium, older leaves contain higher amounts of calcium because calcium is relatively immobile through the plant. It is not transported through the [[phloem]] because it can bind with other nutrient ions and [[precipitate]] out of liquid solutions.

=== Structural roles ===
Ca<sup>2+</sup> ions are an essential component of plant [[cell walls]] and [[cell membranes]], and are used as [[cations]] to balance [[organic compound|organic]] [[anions]] in the plant [[vacuole]].<ref>{{cite journal | last = White | first = Philip J. |author2=Martin R. Broadley | year = 2003 | title = Calcium in Plants | journal = Annals of Botany | volume = 92 | issue = 4 | pages = 487–511 | url= | doi = 10.1093/aob/mcg164 | pmid = 12933363| pmc = 4243668 }}</ref>  The Ca<sup>2+</sup> concentration of the vacuole may reach millimolar levels.  The most striking use of Ca<sup>2+</sup> ions as a structural element in algae occurs in the marine [[coccolithophores]], which use Ca<sup>2+</sup> to form the [[calcium carbonate]] plates, with which they are covered.

Calcium is needed to form the [[pectin]] in the [[middle lamella]] of newly formed cells.

Calcium is needed to stabilize the permeability of cell membranes. Without calcium, the cell walls are unable to stabilize and hold their contents. This is particularly important in developing fruits. Without calcium, the cell walls are weak and unable to hold the contents of the fruit.

Some [[plant]]s accumulate Ca in their tissues, thus making them more firm. Calcium is stored as Ca-[[oxalate]] crystals in [[plastid]]s.

=== Cell signaling ===
Ca<sup>2+</sup> ions are usually kept at nanomolar levels in the [[cytosol]] of [[plant cells]], and act in a number of signal transduction pathways as [[second messenger]]s.

== See also ==

* [[:Category:Biology and pharmacology of chemical elements|Biology and pharmacology of chemical elements]]
* {{annotated link|Iodine in biology}}
* {{annotated link|Magnesium in biology}}
* {{annotated link|Osteoporosis}}
* {{annotated link|Potassium in biology}}
* {{annotated link|Selenium in biology}}
* {{annotated link|Sodium in biology}}
* {{annotated link|Vitamin D}}

== References ==
{{reflist}}

== External links ==
* [https://www.nal.usda.gov/fnic/vitamin-d-and-calcium United States Department of Agriculture: Vitamin D and Calcium] {{Webarchive|url=https://web.archive.org/web/20200520092003/https://www.nal.usda.gov/fnic/vitamin-d-and-calcium |date=20 May 2020 }}
* [https://www.nof.org/patients/treatment/calciumvitamin-d/ National Osteoporosis Foundation: Calcium and vitamin D]

{{Clinical biochemistry blood tests}}
{{Nitric oxide signaling}}
{{Elements in biology}}
[[Category:Biological systems]]
[[Category:Biology and pharmacology of chemical elements]]
[[Category:Calcium|Biology]]
[[Category:Calcium signaling]]
[[Category:Dietary minerals]]
[[Category:Signal transduction]]