Calcium is the most abundant cation in the human body.
Calcium accounts for approximately 1 kg in a 70 kg male.
Calcium is a major mineral in bones and teeth and regulates muscle contraction and relaxation. It activates enzymes in various metabolic pathways and aids in blood clotting.
Deficiency can result from a low dietary intake of calcium, reduction of stomach acid, high protein intake, low vitamin D status and increased GI motility.
The skeleton provides structural support for organs and muscles. It also stores essential minerals such as phosphorus and magnesium. Teeth and bones contain about 99% of the body's calcium and are dependent upon calcium for strength and structure. The remaining 1% circulated in blood.
Calcium as food or dietary supplements is ingested in the form of relatively insoluble salts.
Calcium is absorbed through both an active and a passive transport system in the small intestine. The active transport mechanism depends on the action of the activated form of vitamin D, 1-25-dihydroxycholecalciferol or 1,25-(OH)2D3. In vitamin D-induced calcium transport, a calcium-binding protein called calbindin is involved. Calbindin serves as a translocator and as a cytosolic calcium buffer. The passive transport of calcium involves the direct absorption of soluble calcium freed from complexes during digestion.
In January 2010, the health claim for calcium was expanded to include vitamin D by the U.S. Food and Drug Administration. Sample claims include "Adequate calcium throughout life, as a part of a well-balanced diet, may reduce the risk of osteoporosis." and "Adequate calcium and vitamin D as part of a healthful diet, along with physical activity, may reduce the risk of osteoporosis in later life."1
Calcium is essential for mineralization of bones and teeth. The primary mineral forming bones is hydroxyapatite [Ca10(PO4)6(OH)2]. Bones are continually remodeled throughout life by osteoclasts (cells that dissolve or resorb bone) and osteoblasts (cells that produce new bone). Calcium is essential for the formation of new bone.
Calcium helps regulate the contraction and relaxation of cardiac and skeletal muscle. Calcium also participates in the constriction and relaxation of blood vessels.
Calcium is essential for regulation of various enzymes, probably through the activity of the enzyme calmodulin.
Bone remodeling for the formation of sturdy skeletal mass during linear bone growth depends on the presence of sufficient calcium.
True calcium deficiency is rare but calcium insufficiency is much more common, particularly in developed countries. Calcium deficiencies are usually caused by medical problems (e.g. renal failure) or treatments (e.g. removal of the stomach or use of certain medications). Symptoms of long-term calcium deficiency include numbness, tingling of the fingers, muscle cramps, convulsions, lethargy, poor appetite, and abnormal heartbeat.
Calcium supplemental doses up to 2,500 mg/day are usually well tolerated. Doses that exceed this amount may increase the risk for kidney stones and soft tissue calcification. Neither of these conditions is solely linked to calcium supplements.
Individuals that suffer from hyperparathyroidism should not take calcium without the supervision of a healthcare professional.
Dairy products are good sources of calcium. Eight ounces of whole milk contains 291 mg of calcium and skim milk contains 302 mg of calcium. Other milk products, such as yogurt, ice cream and ice milk, all contain various amounts of calcium. A half-cup to 1 oz of ricotta cheese, cottage cheese, cheddar and mozzarella all contain between 155 to 337 mg of calcium. One cup or 8 oz of fruits and vegetables such as broccoli, turnip greens, mustard greens, legumes, and dried fruits contain between 56 to 300 mg of calcium. Fish, shellfish, and raw tofu are also good sources of calcium.
Fortified foods such as apple juice, orange juice, and cottage cheese provide
Calcium carbonate is more difficult to absorb on an empty stomach, it needs an acidic environment to enhance absorption. The percent of calcium absorbed decreases as the calcium load increases; therefore calcium carbonate absorption is greater in doses of 500 mg or less, with food.
Since calcium citrate is highly soluble in acid, it is better absorbed on an empty stomach. The citrate form does not need gastric acid for absorption. Similarly, calcium lactate can be absorbed at various pHs and does not need to be taken with food for absorption for these reasons.
Young infants and approximately 30% of elderly have low secretion of hydrochloric acid by gastric parietal cells. It has been established that low hydrochloric acid secretion can lead to decreased absorption of some minerals. Conflicting results have been reported in clinical studies on the effects of intraluminal gastric pH values on calcium absorption.
Elemental calcium refers to the amount of calcium found in a product because calcium alone is unstable.
Calcium phosphate is insoluble and is poorly absorbed.
Calcium absorption can be decreased by high intake of foods that contain oxalic acid (spinach, chard, beet greens), phytic acid in unleavened whole grains, large intake of phosphorus-containing foods (meat or soda), stress, lack of movement, diazide diuretics, laxatives or aluminum-containing medications.
Postmenopausal women have reduced estrogen levels. Lower estrogen levels are associated with increased rate of bone resorption and decreased rate of bone formation. Calcium supplements do not completely prevent bone loss but can help to moderate it, particularly in combination with other treatments.
People with lactose intolerance are at risk for calcium insufficiency because they avoid dairy products.
People who are allergic to cow's milk products are at risk for calcium insufficiency because they cannot include dairy products in the diet.
Vegetarians are at risk for calcium insufficiency. Oxalic and phytic acids present in plant products may limit the amount of calcium absorbed. Vegans are at particularly high risk for calcium insufficiency since they avoid dairy products entirely. Calcium intake of vegan diets is typically lower than other diets and calcium absorption may be further impeded by oxalic and phytic acids.
Calcium decreases absorption of biphosphonates (used to treat osteoporosis; including Actonel, Boniva, Fosamax, and others),fluoroquinolone (e.g. Cipro, Levaquin) and tetracycline antibiotics, levothyroxine, phenytoin (an anticonvulsant), and tiludronate disodium (used to treat Paget's disease). Doses should be separated by at least four hours.
Taking calcium supplements with gentamicin, an antibiotic, can increase the risk of harmful effects on the kidneys. This combination should be avoided.
The activity of cation exchange resins, such as those used to treat hyperkalemia (high levels of potassium in the blood), is blocked by calcium supplements when taken orally. This prevents neutralization of bicarbonate ion and removal of potassium from the bloodstream. System alkalosis can result. These drugs should not be taken together. Sodium polystyrene sulfonate is an example of a cation exchange resin.
Antacids containing aluminum should not be taken with calcium citrate supplements. The citrate in these supplements significantly increases the amount of aluminum absorbed into the bloodstream. People with kidney disease should be particularly cautious.
H2 blockers (such as cimetidine) and proton pump inhibitors (such as omeprazole) may decrease bioavailability of calcium supplements sush as calcium carbonate or calcium phosphate.
Bile acid sequestrants invrease loss of calcium in urine. Calcium supplements may help to prevent calcium insufficiency.
Beta blockers (e.g. acebutolol, atenolol, and bisoprolol) and calcium channel blockers (e.g. amlodipine, Diltiazem, and Nifedipine) are used for high blood pressure. Risk of abnormal heart rhythms is increased with the combination of calcium channel blockers and calcium supplements. Although the results of clinical trials are contradictory, efficacy of these medications may be decreased by supplemental calcium. Calcium supplements should not be taken with beta blockers or calcium channel blockers unless under the supervision of a healthcare provider.
Diuretics can influence absorption and excretion of calcium. Calcium levels in the blood can be increased by thiazide diuretics (such as hydrochlorothiazide). Calcium levels in the blood can be decreased by loop diuretics (such as furosemide and bumetanide). Certain potassium-sparing diuretics (such as amiloride) may decrease the amount of calcium excreted in the urine, especially in people with kidney stones.
The effect of calcium supplementation on bone loss in 32 controlled trials in postmenopausal women.
This meta-analysis evaluated the effect of calcium supplementation on bone loss in postmenopausal women. Thirty-two published controlled trials were included totaling 3,169 postmenopausal women. Supplemental calcium ranged from 700 to 2,000 mg per day with a median value of 1,000 mg. The median duration of the trials was 2 years. When comparing controls and supplemented participants, statistically different bone mass or density losses were noted. For controls, the average mean rate of change in bone mass or density was -1.07 % p.a. (P<0.001) while it was -0.27 % p.a. for supplemented participants (not significantly different from baseline) (for difference between control and supplemented P<0.001). Supplemental calcium less than 700 mg daily was not found to be effective. Significantly faster bone loss occurred for women taking less than 1,150 mg daily than those taking more than 1,350 mg daily. The effects seem to be held for at least four years. The author concluded that supplemental calcium would help to minimize bone loss in postmenopausal women.3
Effect of calcium and vitamin D supplementation on bone mineral density in women aged 65-71 years: a 3-year randomized population-based trial (OSTPRE-FPS).
A randomized, population-based, open trial investigated vitamin D and calcium supplements to support bone mineral density in postmenopausal women. Five-hundred-ninety-three women completed bone mineral density measurements and were therefore eligible to participate in the trial, a subset of a larger trial of these supplements for fracture prevention (n=3,432). Participants were aged 66 to 71 years. Participants were randomly assigned to receive daily vitamin D (800 IU cholecalciferol) plus calcium (1,000 mg calcium from 1,250 mg calcium carbonate) or no supplement for the three year trial. Total body bone mineral density increased significantly more in the intervention group than in the control group (0.84% vs. 0.19%, p = 0.011). Analyses of the change differences in bone mineral density failed to reach significance (lumbar spine, p = 0.372; femoral neck, p = 0.188; trochanter, p = 0.085; total proximal femur, p = 0.070). The results of this study indicate that calcium plus vitamin D supplements benefit total bone mineral density for ambulatory postmenopausal women.4
Calcium plus vitamin D supplementation has limited effects on femoral geometric strength in older postmenopausal women: the Women's Health Initiative.
The Women’s Health Initiative studies included a subgroup of calcium plus vitamin D supplemented women. Data from these supplemented women and the placebo group were evaluated to investigate the efficacy of these supplements on preservation of bone mineral density. One-thousand-nine-hundred-seventy women were included in the trial, women from the supplemented and placebo groups who completed two DXA scans at the femoral narrow neck, intertrochanter, and shaft. Women in the supplemented group consumed 1,000 mg elemental calcium (from calcium carbonate) and 400 IU vitamin D (cholecalciferol) daily for at least six years. Women were randomly assigned to receive the supplement or a placebo. Hip BMD at the narrow neck declined less with calcium plus vitamin D supplements compared to placebo over 6 years. The underlying cross-sectional geometry at the femoral narrow neck was increased with calcium plus vitamin D (suggesting greater strength) relative to placebo. The results of the Women’s Health Initiative suggest that calcium plus vitamin D may support bone mineral density for postmenopausal women.5
Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis.
A meta-analysis of 29 randomized trials including 63,897 people was conducted to evaluate calcium or calcium plus vitamin D for fractures and bone loss. Trials with people aged 50 years or older were eligible. Calcium or calcium plus vitamin D was associated with a 12% risk reduction in fractures of all types (risk ratio 0.88, 95% CI 0.83-0.95; p=0.0004) using pooled data from 17 trials reporting fracture as an outcome (52,625 participants). For the 23 trials reporting bone mineral density as an outcome (41,419 participants), calcium or calcium plus vitamin D was associated with a reduced rate of bone loss of 0.54% (0.35-0.73; p<0.0001) at the hip and 1.19% (0.76-1.61%; p<0.0001) in the spine. For trials with calcium doses of 1,200 mg or more, treatment was more effective (treatment effect 0.80 vs 0.94; p=0.006) than for those with less than 1,200 mg. Similarly, treatment was more effective for trials with vitamin D doses of 800 IU or more compared to doses less than 800 IU (treatment effect 0.84 vs 0.87; p=0.03). The results of this meta-analysis support the conclusion that calcium or calcium plus vitamin D prevent fractures and bone loss for people over 50. The authors suggest that 1,200 mg calcium and 800 IU of vitamin D or higher have better efficacy than lower amounts.6
Randomized controlled trial of calcium supplementation in healthy, nonosteoporotic, older men.
A randomized, double-blind, placebo-controlled trial was completed to evaluate the effects of calcium supplements on bone mineral density (BMD) in men over the age of 40 years. Participants were randomly assigned to consume 600 mg calcium per day, 1,200 mg/day, or a daily placebo for a 2-year period. Three-hundred-twenty-three healthy men (mean age, 57 years) participated in the trial. For those consuming 1,200 mg/day, BMD increased at all sites by 1% to 1.5% more than those receiving placebo. BMD was not different from placebo at any site for the 600 mg/day group. In the 1,200 mg/day group, sustained decreases in serum parathyroid hormone (25%, P<0.001), total alkaline phosphatase activity (8%, P=0.01), and procollagen type 1 N-terminal propeptide (20%, P<0.001) were identified. Calcium supplementation did not affect tooth loss, constipation, or cramps. Although falls tended to be less frequent in the group receiving 1,200 mg/day calcium (not significant), vascular events tended to be more common in the groups receiving calcium compared to the group receiving placebo (not significant). The results of this study suggest that 1,200 mg calcium/day improved BMD in healthy men over the age of 40 years. These effects were similar to those seen in women.7
Comment: three recent meta-analyses and the early termination of a calcium supplement trial have instigated significant debate and concern in the medical community. The meta-analyses produced conflicting results. Concerns have been raised about the methods and data used in these meta-analyses. Further studies are needed to clarify these results and determine their significance. In the meantime, there is not sufficient evidence to change recommendations regarding calcium supplements.
Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis.
This meta-analysis investigated the risk of myocardial infarction and other cardiovascular events with respect to calcium supplements. Five trials with patient-level data (8,151 participants, median follow-up 3.6 years, interquartile range 2.7-4.3 years) and 11 trials with trial-level data (11,921 participants, mean duration 4.0 years) were identified and included in the analysis. In the trials with patient level data, 143 people taking calcium supplements suffered myocardial infarction compared with 111 in the placebo groups (hazard ratio 1.31, 95% confidence interval 1.02 to 1.67, P=0.035). Increased risk for stroke (1.20, 0.96 to 1.50, P=0.11), the composite end point of myocardial infarction, stroke, or sudden death (1.18, 1.00 to 1.39, P=0.057), and death (1.09, 0.96 to 1.23, P=0.18) were noted but did not reach statistical significance. In trials contributing trial-level data, 296 people suffered a myocardial infarction (166 consuming calcium supplements and 130 in the placebo group). This constitutes an increased incidence of myocardial infarction in the calcium supplemented group (pooled relative risk 1.27, 95% confidence interval 1.01 to 1.59, P=0.038). The results of this meta-analysis suggest that calcium supplements without vitamin D increase risk of myocardial infarction. These results warrant further study to determine the significance and the cause of the association.8
Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women's Health Initiative limited access dataset and meta-analysis.
A meta-analysis of the Women’s Health Initiative calcium plus vitamin D study and eight other calcium plus vitamin D studies was conducted. In addition to the calcium and vitamin D assigned during these randomized trials, the effect of personal calcium supplements was evaluated. Forty-six percent of women in the WHI study were not taking personal calcium supplements; the hazard ratios for cardiovascular events for those assigned to the calcium plus vitamin D group ranged from 1.13 to 1.22 (P=0.05 for clinical myocardial infarction or stroke, P=0.04 for clinical myocardial infarction or revascularization). Relative to placebo (three studied trials), calcium plus vitamin D increased risk of myocardial infarction (relative risk 1.21, 95% CI 1.01 to 1.44, P=0.04), stroke (RR 1.20, 95% CI 1.00 to 1.43, P=0.05), and the composite of myocardial infarction or stroke (RR 1.16, 95% CI 1.02 to 1.32, P=0.02). Of the 28,072 women not taking personal calcium supplements in all nine trials, 1,384 experienced a myocardial infarction or stroke; calcium alone or with vitamin D increased relative risk of myocardial infarction (RR 1.24, 95% CI 1.07 to 1.45, P=0.004) and increased combined risk for myocardial infarction or stroke (RR 1.15, 95% CI 1.03 to 1.27, P=0.009). The results of this meta-analysis suggest that calcium alone or in combination with vitamin D increases risk for myocardial infarction and stroke. Further analysis is warranted.9
Systematic review: Vitamin D and calcium supplementation in prevention of cardiovascular events.
A meta-analysis was conducted including seventeen prospective studies and randomized trials investigating vitamin D, calcium, and cardiovascular events. Vitamin D supplements were studied in five prospective trials of dialysis patients and one study of the general population. Cardiovascular disease mortality was reduced in these populations with vitamin D supplements. Secondary analysis of eight randomized trials revealed a slight but nonsignificant reduction in cardiovascular disease risk with vitamin D supplements (approximately 1,000 IU/day; pooled relative risk, 0.90 [95% CI, 0.77 to 1.05]). Calcium supplements were not found to increase risk of cardiovascular disease in four prospective studies of healthy people. Secondary of eight randomized trials revealed that calcium supplementation and calcium with vitamin D supplements did not alter risk for cardiovascular disease relative to placebo (pooled relative risk, 1.14 [CI, 0.92 to 1.41]; pooled relative risk, 1.04 [CI, 0.92 to 1.18]; respectively). The results of this meta-analysis suggest that vitamin D may reduce risk for cardiovascular events at moderately high doses while calcium does not appear to alter risk for cardiovascular disease.10
Calcium/vitamin D supplementation and cardiovascular events.
The risk of coronary and cerebrovascular events was evaluated in the Women's Health Initiative, a randomized trial of calcium (1,000 mg/day) plus vitamin D (400 IU/day) supplements compared to placebo. In all, 36,282 postmenopausal women (aged 50 to 79 years) participated in the trial. Participants were randomly assigned to receive calcium plus vitamin D daily (twice daily 500 mg calcium as calcium carbonate with 200 IU vitamin D) or a placebo; participants were followed for a minimum of 7 years. Four-hundred-ninety-nine women were confirmed to die from myocardial infarction or coronary heart disease in the calcium plus vitamin D group and 475 women in the placebo group (hazard ratio, 1.04; 95% confidence interval, 0.92 to 1.18). Stroke was confirmed among 362 women assigned to calcium plus vitamin D group and 377 assigned to the placebo group (hazard ratio, 0.95; 95% confidence interval, 0.82 to 1.10). Women with higher total calcium intake (diet plus supplements) at baseline were not at higher risk for coronary events (P=0.91 for interaction) or stroke (P=0.14 for interaction). The results of this analysis do not support the hypothesis that calcium supplements increase risk for coronary or cerebrovascular events; calcium plus vitamin D neither increased nor decreased risk for coronary or cerebrovascular events in this study.11
Calcium supplementation and the risks of atherosclerotic vascular disease in older women: results of a 5-year RCT and a 4.5-year follow-up.
The risk of atherosclerotic vascular disease in older women was assessed using data from the Calcium Intake Fracture Outcome Study (CAIFOS). This five year randomized, double blind, placebo-controlled trial included 1,460 women aged 75.1 years (± 2.7 years) and 4.5 years of posttrial follow-up data was available. Participants were randomized to receive 1,200 mg of calcium carbonate daily or an identical placebo. The calcium supplemented group of women did not have a higher risk of death or first-time hospitalization from atherosclerotic vascular disease during the 5-year trial (HR=0.938, 95% confidence interval (CI) 0.690-1.275) or during 4.5 years of posttrial observation (HR=0.919, 95% CI 0.737-1.146). Although not reaching significance, these data suggest that calcium supplementation may reduce risk of hospitalization for atherosclerotic vascular events for this population. The data indicate that 1,200 mg supplemental calcium daily does not significantly increase the risk of atherosclerotic vascular disease in elderly women.12
Blood pressure response to calcium supplementation: a meta-analysis of randomized controlled trials.
A meta-analysis of randomized controlled trials was conducted to determine the effects of calcium supplements on hypertension in non-pregnant people. Forty clinical trials met the inclusion criteria for a total of 2,492 participants. Systolic and diastolic blood pressure was reduced with calcium supplementation (mean daily dose: 1,200 mg; systolic BP: -1.86 mmHg, 95% confidence interval -2.91 to -0.81; diastolic BP: -0.99 mmHg, 95% confidence interval -1.61 to -0.37). People with relatively low calcium intake (up to 800 mg per day) demonstrated larger BP reductions: -2.63 mmHg (-4.03 to -1.24) for systolic BP and -1.30 mmHg (-2.13 to -0.47) for diastolic BP. This study suggests that adequate intake of calcium is essential for prevention of hypertension. Additional studies are necessary to further evaluate these results.13
Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial.
A double-blind, placebo-controlled, randomized population-based trial investigated the efficacy of calcium or calcium plus vitamin D on cancer risk. Participants were randomly selected from the population and included 1,179 healthy postmenopausal women (at least 55 years old at the beginning of the trial) in a 9-county rural area of Nebraska. Participants were randomly assigned to consume 1,400-1,500 mg supplemental calcium daily (Ca-only), calcium plus 1,100 IU vitamin D3 daily (Ca + D), or a placebo. Cancer incidence was lower in the Ca + D women than in the placebo control subjects (P<0.03). The unadjusted relative risks (RR) of incident cancer in the Ca + D and Ca-only groups were 0.402 (P=0.01) and 0.532 (P=0.06), respectively. When analysis was confined to cancers diagnosed after the first 12 mo, RR for the Ca + D group fell to 0.232 (CI: 0.09, 0.60; P<0.005) but did not change significantly for the Ca-only group. The results of this study indicate that calcium or calcium plus vitamin D reduced risk for all types of cancer. Further study is needed to ascertain the mechanisms and the efficacy of these supplements for particular cancers.14
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