Calcium

Calcium is an essential mineral.

Calcium is most well known to serve as a major building block of bone in the human body, with there being anywhere from 1-2 kg of calcium in the human body that is 99% localized to bone tissue (skeleton and teeth).^[1][2] The calcium tends to be stored in the form of hydroxyapatite crystals (Ca¹⁰(OH)²(PO⁴)⁶) formed by bone cells known as osteoblasts.^[3]

The remaining calcium is in a soluble form, found in the bloodstream and cells across the body, where it serves a vital role in aiding cellular signalling.^[2][4]

The recommended daily intakes for calcium are the following:^[5][6]

• 700 mg for those 1-3 years of age
• 1,000 mg for those 4-8 years of age, as well as for adults between the ages of 19 and 50
• 1,300 mg for those between the ages of 9 and 18
• 1,200 mg for adults over the age of 71 and for women over the age of 50 (men between the ages of 50 and 70 only require 1,000 mg)

Infants less than a year old have minor calcium requirements of 200-260 mg whereas women who are pregnant or lactating require up to 1,300 mg of calcium daily.^[5][6]

While the condition of bone deformation known as Rickets is commonly attributed to be due to a Vitamin D deficiency,^[7] calcium also plays a pivotal role as the two are intricately linked when it comes to supporting the growth of bones (alongside other nutrients such as phosphorus and magnesium)^[8] and instances of rickets in the presence of adequate Vitamin D have been reported.^[9][10] While this condition affects children and youth exclusively, usually those under 18 months of age associated with lack of Vitamin D^[8][11] and potentially in early adolescence with very low calcium intake,^[12] adults don't experience any disease state specific to a lack of dietary calcium a lifetime of insufficient intake is one of the major risk factors in the promotion of osteoporosis.

Both Vitamin D and calcium deficiency can lead to rickets, usually with Vitamin D presenting rickets within 1-2 years of age and calcium deficiency presenting rickets in childhood to early adolescence. Adults don't have a disease state specifically associated to calcium deficiency but it plays a major role in the onset of osteoporosis

The tolerable upper limit (TUL) of calcium is between 2,000-3,000 mg depending on age group, the higher TUL being for adolescents and pregnant or lactating women and the lower TUL of 2,000 mg for adults over the age of 50. Young adults and children have a TUL of 2,500 mg.^[5][6]

Calcium phosphate (pentacalcium hydroxytriphosphate) is a form of calcium that is 2/3rds calcium by weight, and is an endogenous metabolite of calcium in the body (after forming with phosphorus in the intestines).^[13]

At 1,000mg (calcium equivalent) calcium phosphate supplementation is able to increase serum concentrations of calcium without affecting phosphorus levels in the postprandial state^[14] although it has been noted to not influence fasting levels of calcium nor phosphorus over six weeks at 1,500mg.^[15]

Calcium phosphate appears to be a viable form of calcium supplementation

Coral calcium is a dietary supplement from coral (Coral calx or Praval bhasma) that is claimed to be better absorbed when compared to other forms of calcium supplementation, referencing a small study comparing a 525 mg dose of calcium as carbonate versus the same dose of calcium from coral from the Ryukyu islands (a 2:1 calcium:magnesium).^[16] It's popularity as a supplement has at times been reported^[17] to be associated with how the long lifespan of Okinawans are, in turn, associated with water intake that may have its mineral contents modified by the presence of high amounts of coral reef.^[18]

Coral is also known to possess hydroxyapatite,^[19] a product of calcium in the human body that is very prominent in human bones and teeth. The relevance of orally ingested hydroxyapatite from coral calcium is currently unknown. Despite this, studies in rats do confirm that coral calcium is able to improve bone mineralization in models of bone loss.^[20][21]

Coral calcium is calcium derived from Coral calx. As it confers dietary calcium it appears to also work well as a bone health supplement (based on limited but coherent evidence). Whether it is better than traditional calcium supplements is unknown and there is no good evidence for any claim that cannot also be given for standard calcium supplements

Calcium-sensing receptors (CaSRs) are receptors that respond to changes in calcium concentrations. Expressed in the kidneys, thyroid and the parathyroid which serve as a link between fluctuating calcium concentrations and manipulating the actions of parathyroid hormone and Vitamin D to help mitigate abnormal levels of calcium.^[22] These receptors can be influenced by inflammation,^[22] as both IL-6^[23] and IL-1β^[24] are known to increase the trancription rates and, ultimately, the amount of receptors.

Calcium-sensing receptors are the receptors where changing levels of calcium in the body are 'detected', which then signal for other changes to initiate to help regulate calcium levels in the body

Calcium is absorbed by one of two ways in the intestines; a transporter-mediated process and a paracellular process.^[25][26]

The transporter-mediated process occurs primarily in the first two segments of the intestines, the duodenum and jejunum.^[27][28] This is the stage of calcium absorption that has a rate-limit and can be regulated by both calcium levels in the body and Vitamin D^[28] (although paracellular is still somewhat regulated^[29]). It is an active transport system which starts with uptake through calcium channels (TRPV6 and TRPV5; previously known as CaT1 and CaT2 respectively) with TRPV6 being the variant favored in the intestines rather than the kidneys where TRPV5 dominates^[30][31] while an L-type channel known as Ca_v1.3 also exists in the intestines that can also help transport calcium from the intestines.^[32] The two receptors seem to have complementary roles with TRPV6 being more active in calcium reuptake during fasting and Ca_v1.3 being more active during feeding.^[26][32]

After initial uptake into the cell, calbindins (CBs) bind to calcium to carry it through the cell from the apical membrane to the basolateral membrane^[26][33] and also help support the cell they are in by acting as buffering agents.^[34] After the transfer, the calbindins pass calcium off to two proteins known as PMCA (mostly PMCA1b^[35]) and NCX1; a pump and a Na⁺/Ca²⁺ exchanger respectively where the former is generally responsible for 80% of the calcium efflux.^[36][37]

Unlike the transport-mediated process, the paracellular (between cells) process occurs at all points in the intestines. It does occur in the ileum (segment of the large intestine that calcium transporters don't work in)^[27] and also occurs throughout the entirety of the large intestine.^[38] Generally speaking, this route of absorption is more relevant when chyme (digested food) travels through the intestines at a slower rate^[39] and when the diet is sufficiently high in calcium.^[25]

Calcium absorption is affected by several factors. It varies based on environmental, age, and dietary considerations.^[40][41][42] Postmenopausal women absorb calcium less than premenopausal women and thus require a higher dose of calcium than premenopausal women.^[43][44] In healthy, premenopausal women, the proportion of dietary calcium absorbed varies from 17-58%, and is positively correlated with body mass index, dietary fat, serum vitamin D level, and parathyroid hormone concentrations. It is inversely correlated with total calcium intake, dietary fiber intake, alcohol consumption, physical activity, and symptoms of constipation.^[45] Elderly women have a resistance to Vitamin D action that can contribute to their negative calcium balance, secondary hyperparathyroidism, and bone loss.^[46] Additionally, weight loss is associated with elevated calcium requirement due to inadequate total calcium absorption. If this requirement is not met, it could activate the calcium-parathyroid hormone axis to absorb more calcium.^[47]

Calcium absorption increases from early to late pregnancy, decreases in early lactation, and then increases when weaning.^{[48][49][50][51][52]}

Calcium can be absorbed at any point in the intestines. Most absorption occurs quite soon after ingestion by active transports whereas there is a small concentration-dependent absorption that can occur for as long as chyme that contains calcium remains in the intestines. Absorption also differs according to age and environmental and dietary considerations.

There have been many drug interactions reported among users of the various dosage forms of calcium. The type of interaction encountered will be different for every medication.

Taking calcium with bisphosphonate drugs for osteoporosis or thyroid hormones like levothyroxine^[53] can cause reduced drug absorption most likely due to forming insoluble complexes.^[54].

Calcium can also reduce the efficacy of some antivirals (e.g. amprenavir and zalcitabine), aspirin, several antibiotics (e.g. several fluoroquinolones, tetracycline, and several cephalosporins), and some antifungals (e.g. ketoconazole) can cause reduced drug efficacy.^[54] Efficacy is also reduced for some drugs used for gastrointestinal issues (e.g. hyoscyamine, bisacodyl, and bismuth subcitrate), the antiplatlet drug ticlopidine, the calcium channel blocker verapamil, and the beta-blocker atenolol.^[54] Efficacy of iron is also reduced by calcium.^[54] Phosphate absorption is also reduced when calcium is taken concurrently.^[54]

Taking long-term lithium may cause hypercalcemia in 10%-60% of patients^[55] and taking it concurrently can theoretically increase this risk. Serious interactions between calcium and the thiazide (such as hydrochlorothiazide) and thiazide-like (e.g. clopamide and chlorthalidone) can also occur. Taking these drugs together with calcium can cause milk-alkali syndrome, which is characterized by hypercalcemia, metabolic alkalosis, and renal failure.^[54]

Another serious interaction between calcium and digitoxin or digoxin can occur, leading to cardiotoxicity.^[54]

Calcium has many drug interactions, each of which can cause a different effect. While some interactions may be mild, calcium can cause more serious complications such as renal failure and reduced plasma concentration or efficacy of other drugs. Some of the more common drug interactions include aspirin, atenolol, bisacodyl, bismuth subcitrate, ciprofloxacin, doxycycline, tetracycline, and digoxin.

Consumption of milk products with additional calcium (10-fold higher than normal) is able to increase fecal lipids by 139% and free fatty acids by 195%.^[56]

Calcium phosphate is known to be produced in the gut from calcium and phosphorus^[13] where it appears able to precipitate intestinal substances such as bile acids or fatty acids.^[57][58] Supplementation of 1,000mg calcium has been demonstrated to increase fecal bile acids while reducing fecal cholesterol concentrations.^[58]

Dietary calcium intake has once been noted to be inversely related to clotting activity of platelets in farmers^[59] and studies in research animals have noted dietary calcium to be associated with less platelet calcium responses^[60] and handling^[61] in hypertensive rats; thought to indicate a protective effect.

While dietary calcium seems to have a facilitative role in platelets that reduces their overall aggregatory potential it is uncertain as to what effect high or low calcium intake in the diet or supplementation results in

Fatty acid binding protein (FABP), specifically FABP4, is both a cytosolic and plasma protein involved in trafficking fatty acids. It appears to have an additive effect on lipids and atherosclerotic buildup due to knockout mice being resistant to these states^[62][63] and its release from adipocytes (and macrophages) is known to be partially dependent on calciums action as assessed by 0.5-3µM ionomycin.^[64] Increases in FABP4 levels have been detected in vitro with other agonists that stimulate calcium release such as capsaicin.^[65] There are currently no human studies assessing dietary calcium supplementation and it's relation to serum FAB4.

Calcium is involved in the release of FABP4 but an interaction with this protein and supplementation of calcium itself is not yet known

The presence of calcium in arteries (Coronary artery calcium; CAC) is known to be predictive of cardiovascular disease and coronary heart disease even in adults without cardiovascular diseases.^[66][67] This is thought to be related to arterial stiffness related to calcium, related to both Vitamin D intake^[68] and proteins influenced by Vitamin K intake.^[69]

Calcium's role in the adipocyte is that of an intracellular messenger, being released in response to various agonists such as capsaicin.^[65]

Osteoporosis, a weakening of skeletal bones due to loss of bone mass, is a relatively common bone ailment in the first world with one study noting an estimated 10.3% prevalence of osteoporosis in those above the age of 50 in the USA (2010) and a further 43.9% prevalence of low bone mass without osteoporosis.^[70] Calcium is investigated in its role in osteoporosis due both to its pivotal role in being a large constituent of bone mass but also due to generally low intake of calcium in populations which suffer from osteoporosis and reduced bone mass.^[71][72]

Fractured bones are known to be a large risk during advancing age due to a combination of reduced bone integrity and diminishing muscular strength,^[73] largely tied in to osteoporotic pathology.^[74] Beyond other preventative measures such as resistance training which is effectively preventative^[75] calcium supplementation is also investigated due to aiding in bone integrity during osteoporosis.

A review^[76] found only two interventions using 800mg calcium (one with Vitamin D using milk^[77] and the other supplementation^[78]) and 50 publications assessing correlations between calcium intake and fracture rates predominately in the elderly; the authors found that, overall, there was no significant and consistent relationship between fracture rates and dietary calcium, milk intake, or intake of dairy overall.^[76] Despite this, meta-analyses assessing the usage of calcium in conjunction with Vitamin D do support the preventative benefits of supplementing both to assist in reducing the risk of fractures showing a 15% reduction of total fractures (Summary relative risk estimate (SRRE) of 0.85; 95% CI 0.73-0.98) with a 30% reduction in hip fractures specifically (SRRE 0.70; 95% CI 0.56-0.87).^[79]

While supplementing calcium alone does not appear to be sufficient enough to prevent the risk of fractures in the elderly, combining calcium and Vitamin D supplementation does appear to be effective

Four week supplementation of calcium in active and sedentary males (35mg/kg calcium as gluconate) failed to increase testosterone in sedentary men relative to their own baseline, and while an increase in testosterone was seen in the active group supplemented with calcium it was not significantly different than the active group given no supplement.^[80]

No significant influence on testosterone concentrations

Soluble bile acids (rather than total fecal bile acids) contributes to colonic epithelium toxicity^[81][82] and are thought to underlie colonic DNA damage and genotoxicity;^[83][84] due to the ability of calcium to precipitate these bile acids^[85][56][86] secondary to forming amorphous calcium phosphate^[87] it is thought to be protective against colon cancer.

Supplementation of 1,000mg calcium for four weeks in otherwise healthy adults has failed to alter the genotoxicity of fecal water, which may be due to barely affecting bile acids in fecal water (despite significantly reducing insoluble bile acids).^[58]

Hypertension has been estimated to complicate 5% of worldwide pregnencies and 11% of first time pregnancies;^[88] due to this being associated with morbidity safe interventions to prevent hypertension and a related condition, pre-eclampsia, are sought after. Calcium is investigated as an inverse relationship between calcium intake and blood pressure during pregnancy is known^[89] which extends to pre-eclampsia.^[90] Low blood calcium also appears to be a useful predictor of both hypertension^[91] and pre-eclampsia^[92] during pregnancy.

A Cochrane review on the topic of calcium supplementation during pregnancy has found that, in 13 studies that assess high dose calcium supplementation (1,000mg or greater) the average risk of high blood pressure appeared to be reduced (RR 0.65; 95% CI of 0.53-0.81) alongside a significant reduction in the risk of developing pre-eclampsia (RR 0.45; 95% CI of 0.31-0.65);^[93] the effect was most significant in women who were at greater risk of pre-eclampsia as assessed by other factors and women who had low dietary calcium intake.^[93]

It appears that supplementation of 1,000mg calcium during pregnancy is able to reduce the risk of developing high blood pressure and pre-clampsia with particular potency in people who have a low dietary calcium intake. Increasing calcium intake from food products is also able to confer this protective effect.

It is known that the risk of pre-eclampsia is increased with high BMI during pregnancy (greater than 35) and with high blood pressure before pregnancy,^[94] calcium supplementation of 2g a day for the second half of pregnancy appears to be unable of normalizing this risk.^[95]

While calcium reduces the risk of pre-eclampsia related to low dietary calcium intake, it does not appear to significantly the risk of pre-eclampsia caused by other factors such as excessive body weight

Based on observational studies suggesting that increased maternal calcium intake is associated with reduced blood pressure in the child^[96][97] the topic has been reviewed^[98] assessing four trials using calcium supplementation^{[99][100][101][102]} which found that, when assessing the mother's intake of calcium during pregnancy, that the child's blood pressure in youth appeared to be inversely associated with the mother's calcium intake.

This effect may only persist in women who were hypertensive during pregnancy^[101] as one of these trials in women with low dietary calcium intake (West Africa) given 1,500 mg calcium during the second half of pregnancy failed to find an effect of supplementation when the mothers had normal blood pressure.^[102]

Supplemental calcium during pregnancy may have a beneficial effect on the blood pressure of the offspring during youth, potentially related to alleviating the high blood pressure of the mother

In studies assessing the delivery of the child, it was found that supplementation of calcium (1.8g) throughout the second half of pregnancy was associated with less usage of antenatal corticosteroids^[103] and less complications with preterm birth (rupture of membranes and admittance for threatened preterm labour).^[103]

In women who just gave birth (5 days postpartum) given calcium either through dairy products (932mg calcium) or via supplementation (1000mg) for six months, both groups were associated with increased bone mineral density and bone mineral content and were not significantly different.^[104]

Past research has suggested that soluble fatty acids and secondary bile acids, which act as surfactants in the intestines, may have a role in the promotion of cancer due to stimulating colonic crypt cells^[105] which may be indicative of increased risk of colon cancer.^[106] Calcium has been investigated in regards to colon cancer as it has a negative correlation with the prevalence of this form of cancer^[107] and has shown a suppressive effect when tested in mice subject to a combination of fatty acids and intestinal inflammation.^[105] It is thought that excess calcium administration can combine with these soluble lipids and form inert calcium soaps for elimination^[105] which has been noted in humans given milk with an increased calcium content (10-fold more than normal) which successfully increased elimination of fatty and bile acids in the feces.^[56]

Studies in humans using supplemental calcium in various instances of intestinal inflammation have found a reduction in intestinal hyperproliferation following intestinal bypass (2,400 or 3,600mg calcium carbonate for twelve weeks)^[108] and in subjects with a familial history of colon cancer given 700mg calcium carbonate supplementation (1.3-1.5g calcium daily in conjunction with diet).^[109] In both cases the level of crypt cell proliferation has reduced.

It is thought that soluble fatty acids in the intestines may damage intestinal tissue which subsequently play a role in promoting colon cancer. Calcium supplementation, or higher than normal calcium intake, seems to protect against this effect

In Japanese men who were subject to dietary analysis, low dietary calcium appeared to be associated with increased arterial stiffness (assessed by ba-PWV); while vitamin D itself has no relation it appeared that there was even less arterial stiffness in those who consumed high levels of calcium and vitamin D.^[68]

In vitro, sugar alcohols appear to enhance the absorption of calcium in the small intestine (ileum and jejunum) as well as in the large intestine.^[110] Tested sugar alcohols (Erythriol, xylitol, maltitol, lactitol, sorbitol, and palatinit) all appear to enhance absorption of calcium overall with some differences in where they affect absorption.^[110]

This effect has also been noted with oligosaccharides^{[111][112][113]} and is thought to be related to changes in the solubility of calcium;^[114][115] fermentation of these molecules and production of SCFAs can alter the acidity of the lumen which is known to increase passive (paracellular) calcium absorption.^[116]

Absorption of calcium appears to be increased by fermentable and partially fermentable carbohydrates, possibly related to the reduced colonic pH increasing the solubility of calcium

The maximum dose of elemental calcium that should be taken at a time is 500 mg to prevent unwanted effects on absorption of calcium and parathyroid hormone.More specifically, absorption of calcium decreases two-fold when calcium is overused, which may lead to bone resorption and increase in parathyroid hormone levels. ^[117] In other words, calcium supplements might interfere with how well our bones absorb calcium. ^[118] Natural calcium products have also been reported to contain measurable lead content. ^[119] While minimum calcium intake varies by age group and pregnancy, maximum calcium intake is consistently 2500 mg per day for everyone. Calcium intake that exceeds the recommended maximum daily dose can result in adverse effects and can interfere with absorption of other minerals, such as zinc, phosphorus, and magnesium.^[117]

In a small observational study, elderly women taking calcium supplementation for five or more years had increased odds of developing dementia (OR 2.10), including vascular and mixed-dementia, but not Alzheimer’s dementia. However, the dose is not mentioned in this study.^[120]

When taking large amounts of calcium carbonate (>20 g/day) for a prolonged period of time, there may be a risk of hypercalcemia, milk-alkali syndrome, nephrocalcinosus, and renal insufficiency.^[121]

Fatal prostate cancer has also been associated with calcium intakes from food or supplementation in amounts 1500 mg per day.^[117] Other studies suggest consuming 2000 mg/day might increase risk for prostate cancer.^[122][123] However, there is contradictory research that indicates no association between calcium intake and overall prostate cancer risk..^[124][125] One of these studies found an increased risk of advanced or fatal prostate cancer, however, while overall risk of prostate cancer was unaffected.^[124]

In one meta-analysis, the authors claimed a possible increased risk of cardiovascular disease with calcium use, although the results of the analysis were not statistically significant.^[126] In a different meta-analysis, calcium supplementation of 500 mg or greater per day without coadministered vitamin D was linked with an increased risk of myocardial infarction.^[127] Furthermore, a re-analysis of one study, where postmenopausal women were taking 1 g of calcium and 400 IU of vitamin D daily, found that there was interaction between personal calcium use or allocated calcium and vitamin D use and cardiovascular events. Two meta-analyses of 11 placebo controlled trials found that calcium or calcium with vitamin D modestly increased the risk of cardiovascular events, specifically myocardial infarction and stroke.^[128]

Meta-analyses of calcium supplementation suggest that it may be linked to increased risk of cardiovascular disease. Possible links with dementia and prostate cancer exist, but more research is needed to confirm this correlation.

Calcium supplementation has been reported to cause belching, flatulence, nausea, gastrointestinal discomfort, constipation, excessive abdominal cramping, bloating, severe diarrhea, and abdominal pain.^[129][121]

There is evidence that support that the benefits from calcium supplementation disappear after consistent use is withdrawn.^[130][131]

A handful of case reports have shown that adults who take calcium supplementation can potentially experience side effects; one person acquired acute pancreatitis after taking 1800 mg calcium carbonate daily due to having their thyroid removed,^[132] another developed kidney stones due to 3000-5000 mg of calcium phosphate for osteoporosis prevention, ^[133] and a final report of 3 patients developed hypercalcemia taking various doses of calcium carbonate for osteoporosis and heart burn.^[134]

One case study found an elderly woman who used calcium carbonate 500 my two-three times daily for osteoporosis suffered from red, hot, swollen joints that was found to be connected to her calcium intake leading the author to conclude “some people are peculiarly sensitive to oral calcium supplementation”.^[135] An additional case report found that a lactating woman who used calcium carbonate in moderate doses suffered from hypercalcemia.^[136] Lastly a case report on 3 premature infants who were given 195.3 mg of calcium lactate and 290.7 mg calcium glycerophosphate, developed blockage of a part of their intestines.^[137]

There have been reports of severe hypercalcemia in Williams-Beuren syndrome patients. This is caused by a deleted gene, which is responsible for regulating the intestinal absorption of calcium.^[138] Calcium supplementation may be cautioned in people who suffer from this condition.

Additionally, in patients with renal impairment, doses as low of 4g/day of calcium may cause hypercalcemia and milk-alkali syndrome^[139]

There has also been evidence that calcium supplementation is linked with the severity of pseudoxanthoma elasticum (PXE) lesions in people affected by this condition.^[140]