Calcium is an essential mineral.
In the UK, the average diet provides: for men, 1007mg daily; women, 774mg daily.
Calcium has a structural role in bones and teeth. Some 99% of calcium is found in the skeleton. Bone density increases during the ﬁrst three decades of life, reaching its peak about the age of 30. After this age, bone density declines, and the decline increases more rapidly in women after the menopause. However, bone density also declines in older men. Calcium is also essential for cellular structure, blood clotting, muscle contraction, nerve transmission, enzyme activation and hormone function.
Calcium is absorbed in the duodenum, jejunum and ileum by an active saturable process that involves vitaminD.At high intakes, some calcium Is absorbed by passive diffusion (independent of vitamin D). It can also be absorbed from the colon.
More than 99% of the body’s calcium is stored in the bones and teeth. The physiologically active form of calcium is the ionised form (in the blood). Blood calcium levels are controlled homeostatically by parathyroid hormone, calcitonin and vitamin D and a range of other hormones.
Excretion of calcium occurs in the urine, although a large amount is reabsorbed in the kidney tubules, the amount excreted varying with the quantity of calcium absorbed and the degree of bone loss. Elimination of unabsorbed andendogenouslysecretedcalciumoccursinthe faeces. Calcium is also lost in the sweat and is excreted in breast milk.
Bioavailability is dependent to some extent on vitamin D status. Absorption is reduced by phytates (present in bran and high-ﬁbre cereals), but high-ﬁbre diets at currently recommended levels of intake do not signiﬁcantly affect calcium absorption in the long term. Absorption is reduced by oxalic acid (present in cauliﬂower, spinach and rhubarb). High sodium intake may reduce calcium retention.
The efﬁciency of absorption is increased during periods of high physiological requirement (e.g. in childhood, adolescence, pregnancy and breast-feeding) and impaired in the elderly.
Simple calcium deﬁciency is not a recognised clinical disorder. However, low dietary intake during adolescence and young adulthood may reduce peak bone mass and bone mineral content and increase the risk of osteoporosis in later life.
However, requirements may be increased and/or and supplements may be necessary in:
children, adolescents, pre- and post-menopausal women pregnant and breast-feeding women vegans and others who avoid milk and milk products; and those with lactose intolerance (because of avoidance of milk and milk products).
The role of calcium has been investigated in a number of conditions, including osteoporosis, hypertension, colon cancer, obesity, menstrual symptoms and pre-eclampsia.
Calcium supplements may have a role in the prevention of osteoporosis. Most of the available evidence has been obtained from studies looking at three different population groups (i.e. children and adolescents, pre-menopausal women and post-menopausal women).
Children and adolescents
Adequate intake of calcium is important throughout life, but seems to be particularly important during skeletal growth and development of peak bone mass. There are also data to show that high intake of milk and dairy produce increases bone mineralisation and bone growth in adolescence – effects that may not be due entirely to the high calcium content of milk. In addition to other minerals, such as magnesium, phosphorus and zinc (which are themselves important for bone health),milk also provides energy and protein,both of which may stimulate bone growth through their inﬂuence on insulin growth factor 1 (IGF-1).
Several controlled intervention studies using calcium supplements in children and adolescents have shown that calcium intakes above the current British Reference Nutrient Intake are effective in increasing bone mineral accretion, particularly in those youngsters with habitually low calcium intakes. However, another study has demonstrated that calcium supplementation (500mg daily) has only a modest effect on bone mineral density (BMD) in girls aged 12–14, and this effect was independent of habitual calcium intake.
Whether any beneﬁts are sustained if calcium intake is reduced is not clear. However, a follow-up study of a trial in which 1000mg calcium was given to adolescent girls for 1year has shown that increased bone mineral accretion may be sustained for a period of 3.5years after supplementation has been discontinued. A further RCT has demonstrated that calcium supplementation given from childhood young adulthood signiﬁcantly improved bone accretion during the pubertal growth spurt with a diminishing effect thereafter.
A Cochrane review, including 19 trials,has assessed effectiveness of calcium supplementation for improving BMD in children. There was no effect of calcium supplementation on femoral neck or lumbar spine BMD.There was a small effect on total body bone mineral content and upper limb BMD, but only the effect in the upper limb persisted after supplementation stopped. This effect is unlikely to result in a clinically signiﬁcant reduction in fracture risk and there view concluded that the results do not support the use of calcium supplementation in healthy children public health intervention.
In pre-menopausal women, results from studies examining the relationship between dietary calcium intake and bone mass and also those from calcium supplementation studies are contradictory.Some show a positive effect of calcium on BMD, but others do not.
After the menopause, bone loss occurs at an increasing rate, and while calcium may help to slow the loss, it does not prevent it. Moreover, theinﬂuenceofcalciumatthisstageoflifeseems to vary with the length of time that has passed since the menopause.Moststudiesfailtoshowa relationship between calcium intake,from either food or supplements, and bone loss during the 5 years immediately following the menopause. The rapid loss of oestrogen causes a very high rate of bone resorption, which increases serum calcium concentrations and inhibits intestinal absorption of calcium.
In one study,19 women who had undergone the menopause within the last 5 years had rapid bone loss that was not affected by a calcium supplement of 500mg a day. However, one RCT in women over 45 showed that calcium and vitamin D supplementation during a 30 month period showed a positive effect on BMD in both peri- and post-menopausal subjects.
In women who were more than 6 years after the menopause (and had a calcium intake of <400mg a day), the same supplement signiﬁcantly reduced bone loss. Another study in women 10 years after the menopause showed that a calcium supplement of 1000mg a day had a beneﬁt on both total and site-speciﬁc bone mass even though their habitual calcium intake was satisfactory, and that this effect of supplementation could last for 4 years and result in fewer fractures.
Using fracture rather than bone loss as the end point, some recent studies have demonstrated a beneﬁt of calcium given with vitamin D in older people. A French study (Decalyos I),23 showed considerable reduction in fracture rates in a large group of elderly people (mean age 84±6) who were living in a nursing home and given 1200 mg calcium with 800 units of vitamin D. Protection became apparent after 6–12 months, and after 3 years the probability of hip fractures was reduced by 29%.
In a more recent study, also in elderly people, similar results were obtained from calcium supplementation alone, but the subjects were vitamin D replete. Researchers in the USA looked at the effects of 500mg of calcium plus 700 units of vitamin D for 3 years in 176 men and 213 women aged 65 or older who were living at home. The supplemented group had a reduced incidence of non-vertebral fracture and lower bone loss in the femoral neck and the total body than the non-supplemented group.
A further study conducted by the French group (Decalyos II) has conﬁrmed the results of Decalyos I and found that calcium (1200mg) plus vitamin D (800units) reduces both hip bone loss and the risk of hip fracture in elderly institutionalised women. Analysis of the Decalyos data showed that this supplementation strategy is cost-saving.
A recent meta-analysis has conﬁrmed that calcium supplementation slows bone loss in post-menopausal women with a trend towards a reduction in vertebral fractures.
A trial involving 36282 post-menopausal women aged 50–79 randomised participants to receive 1000mg of elemental calcium with 400 units of vitamin D3 daily or placebo. There was a small but signiﬁcant 1% improvement in hip bone density for those taking calcium combined with vitamin D compared with those taking placebo.There was also a 12% reduction in hip fracture, but this was non-signiﬁcant.
However,womenwhoconsistentlytookthefull supplement dose experienced a 29% decrease in hip fracture. Women older than 60 had a signiﬁcant 21% reduction in hip fracture. The supplements had no signiﬁcant effect on spine or total fractures and were associated with an increased risk of kidney stones.
A 5-year, double-blind, placebo-controlled study involving 1460 women over the age of 70 found that 1200mg calcium daily is effective in preventing fracture in those who are compliant,but as a public health intervention in the ambulatory elderly population is ineffective because of poor long-term compliance.
Steroids cause bone loss and it has been suggested that patients on steroids should receive preventive treatment(e.g.calcium,vitamin D, bisphosphonates, oestrogens). A Cochrane meta-analysis of ﬁve trials involving 274 patients found a clinically and statistically signiﬁcantpreventionofbonelossatthelumbar spine and forearm with vitamin D and calcium in corticosteroid treated patients. The authors recommended that because of low toxicity and low cost, all patients being started on corticosteroids should receive prophylactic therapy with calcium and vitamin D.
Epidemiological studies support an inverse relationship between the amount of calcium in the diet and blood pressure. However, based on multivariate analyses, the absolute contribution of calcium is very small. Some clinical intervention studies have reported reduction in blood pressure in normotensive and hypertensive subjects or no effect. A meta-analysis of 33 RCTs concluded that calcium(800–2000mg daily) may lead to a small reduction in systolic blood pressure. Another meta-analysis of 22 randomised clinical trials showed that calcium supplements (500–1000mg daily) produced a signiﬁcant decrease in systolic but not diastolic blood pressure, but the authors concluded that the effect was too small to support the use of calcium supplementation in hypertension. Calcium may be most effective in patients with hypertension who are Afro-Caribbean or who are responsive to manipulation of dietary sodium.
A Cochrane review of 13 RCTs found that calcium supplementation was associated with a statistically signiﬁcant reduction in systolic blood pressure (mean difference: –2.5mmHg; 95% CI, –4.5 to –0.6) but not diastolic blood pressure(mean difference:–0.8mmHg;95%CI, 2.1 to 0.4). The review concluded that evidence in favour of causal association between calcium supplementation and blood pressure reduction is weak and that longer duration, better quality studies are needed.
Calcium supplementation may reduce the occurrence of colorectal cancer, but study results are inconsistent. High calcium intake (1200–1400mg daily) has been linked with reduced colon cancer risk in epidemiological studies, and high dietary and supplemental calcium have been associated with reduced recurrence of adenomatous polyps, and reduced colorectal cancer risk. Other studies have shown no signiﬁcant effects of calcium supplementation on colorectal cell proliferation in subjects at high risk for colorectal cancer. There is also evidence that vitamin D acts with calcium in reducing risk of colorectal adenomal recurrence. A pooled analysis of 10 cohort studies found that higher consumption of calcium is associated with lower risk of colorectal cancer.
Evidence from the Calcium Polyp Prevention Study, which involved patients with recent colorectal adenoma,showed that calcium (1200mg daily) may have a more pronounced antineoplastic effect on advanced colorectal lesions than on other types of polyps. In the Polyp Prevention Trial, calcium and vitamin D intake was inversely associated with recurrence of adenomatous polyps in the large bowel. A recent Cochrane review concluded that evidence from two RCTs suggests that calcium supplementation might contribute to a moderate degree to the prevention of colorectal adenomatous polyps, but that this does not constitute sufﬁcient evidence to recommend the general use of calcium supplements to prevent colorectal cancer. A systematic review and meta-analysis of three trials also suggested that calcium supplementation prevents recurrent colorectal adenomas.
Calcium has been associated with increased risk of prostate cancer.In the Physician’s Health Study, men consuming >600mg calcium a day from dairy products had a 32% higher risk of prostate cancer compared with men consuming <150mg daily.55 However, in a recent RCT involving 672 men, calcium 1200mg daily was not associated with increased prostate cancer risk. A meta-analysis of 12 studies found that high intake of dairy products and calcium may be associated with an increased risk of prostate cancer, although the effect appeared to be small.
Calcium supplementation (1200mg daily for three menstrual cycles) was effective in reducing premenstrual but not menstrual pain in a prospective, randomised, double-blind, placebo-controlled trial. In another trial, when given with manganese, calcium (1336mg daily) reduced menstrual pain and undesirable behavioural symptoms. A further trial showed that calcium (1000mg daily) reduced both premenstrual and menstrual symptom scores, and there was a signiﬁcant effect of calcium on menstrual pain.
Use of calcium supplements during pregnancy may reduce the risk of pre-eclampsia. An analysis of clinical trials that examined the effects of calcium intake on pre-eclampsia and pregnancy outcomes in 2500 women found that those who consumed 1500–2000 mg of calcium a day were 70% less likely to suffer from hypertension in pregnancy. However, a large study involving 4589 healthy ﬁrst-time mothers found that calcium supplementation (2000mg daily) had no effect on the incidence of hypertension, protein excretion or complications of childbirth. A Cochrane systematic review of pregnancy induced hypertension identiﬁed nine placebo controlled RCTs. Calcium signiﬁcantly reduced the relative risk of hypertension, especially in women at high risk of hypertension and with low dietary
Dietary calcium plays a pivotal role in the regulation of energy metabolism. High-calcium diets reduce adipose tissue accretion and weight gain during periods of over consumption and increase fat break down top reserve thermogenesis during energy restriction, thereby accelerating weight loss. A review analysing data from six observational studies and three controlled trials has shown that high calcium intakes are associated with lower weight gain at midlife. An RCT looking at the effect of calcium supplementation(1000mg daily) in 100 women found no signiﬁcant differences between body weight or fat mass changes between the placebo and calcium-supplemented groups. However, there was a trend to increased loss of body weight in the calcium group, which the authors suggested to be consistent with a small effect.
Calcium supplements should be avoided in conditions associated with hypercalcaemia and hypercalcuria, and in renal impairment (chronic). They should be used with caution and with medical supervision in hypertension because blood pressure control may be altered.
Traditionally,a low-calcium diet was advised in patients with or at risk of kidney stones. Recent studies have suggested that the risk of kidney stones is not increased by calcium. In two studies, however, supplemental calcium was positively associated with risk.
A recent review on developments in stone prevention states: ‘Calcium should not be restricted. There is clear evidence from clinical and experimental studies that a normal or high calcium supply is appropriate in calcium stone disease. Only in absorptive hypercalcuria calcium restriction remains beneﬁcial in combination with thiazide and citrate therapy.’
Pregnancy and breast-feeding
No problems have been reported. Calcium supplements may be required during pregnancy and breast-feeding. Some studies have shown that the use of calcium supplements in pregnancy may lower the risk of pre-eclampsia, while another has not (see above).
Reported adverse effects with supplements include nausea, constipation and ﬂatulence (usually mild). Calcium metabolism is under such tight control that accumulation in blood or tissues from excessive intakes is almost unknown; accumulation is usually due to failure of control mechanisms. Toxic effects and hypercalcaemia areunlikelywithoraldosesof < 2000mgdaily. However, in young children, calcium supplements should be used under medical supervision because of a risk of bowel perforation.
Alcohol: excessive alcohol intake may reduce calcium absorption.
Aluminium-containing antacids: may reduce calcium absorption. Anticonvulsants: may reduce serum calcium levels.
Bisphosphonates: calcium may reduce absorption of etidronate; give 2h apart.
Cardiac glycosides: concurrent use with parenteral calcium preparations may increase risk of cardiac arrhythmias (ECG monitoring recommended).
Corticosteroids: may reduce serum calcium levels.
Laxatives: prolonged use of laxatives may reduce calcium absorption.
Loop diuretics: increased excretion of calcium.
4-Quinolones: may reduce absorption of 4-quinolones; give 2h apart.
Tamoxifen: calcium supplements may increase the risk of hypercalcaemia (a rare side-effect of tamoxifen therapy); calcium supplements are best avoided.
Tetracyclines: may reduce absorption of tetracyclines; give 2h apart. Thiazide diuretics: may reduce calcium excretion.
Fluoride:mayreduceabsorptionofﬂuorideand vice versa; give 2h apart.
Iron: calcium carbonate or calcium phosphate may reduce absorption of iron; give 2h apart (absorption of iron in multiple formulations containing iron and calcium is not signiﬁcantly altered).
Vitamin D: increased absorption of calcium and increased risk of hypercalcaemia; may be advantageous in some individuals.
Zinc: may reduce absorption of zinc.
Calcium is available in the form of tablets and capsules. A review of 35 US calcium supplements showed that four brands contained lower levels of calcium than claimed on the label. However, none of the products failed testing for exceeding contamination levels for lead and other heavy metals. Another survey showed that calcium supplements may contain lead, but levels were not high enough to cause concern.
The dose for potential prevention of osteoporosis is 1000–1200mg (as elemental calcium) daily with 800 units of cholecalciferol.Patient who may require Supplementation include: those aged 65 and over who are conﬁned to their homes and care institutes; post-menopausal women below the age of 65, where lifestyle modiﬁcation is unsustainable; secondary prevention of osteoporotic fractures in post-menopausal women; prevention of osteoporotic fractures in patients taking glucocorticoids. Note: doses are given in terms of elemental calcium.Patients should be advised that Calcium supplements are not identical; they provide different amounts of elemental calcium.
Upper safety levels
The UK Expert Group on Vitamins and minerals(EVM) has identiﬁed a likely safe total intake of calcium for adults from supplements alone of 1500 mg daily. The Tolerable Upper Intake Level (UL) for calcium, the highest total amount from diet and supplements unlikely to pose no risk for most people, is 2500 mg daily for adults and children from the age of 12 months.
Conclusion There is evidence that calcium supplementation can improve bone density in adolescents. Calcium may also help to reduce the decline in bone density in post-menopausal women, particularly when given in conjunction with vitamin D. However, there is less evidence that calcium supplementation attenuates the reduction in bone density around the time of the menopause. Calcium supplementation may lower blood pressure, but the effect is too small to recommend its use in hypertension. Evidence linking calcium to colon cancer and prostate cancer is conﬂicting. There is preliminary evidence that calcium supplementation may help symptoms of premenstrual syndrome (PMS), particularly pain, and may also reduce the risk of pre-eclampsia. Evidence of the value of calcium supplements in obesity is limited.
(extracted from) Dietary Supplements, Third Edition, by Pamela Mason, BSc, MSc, PhD, MRPharmS, published by Pharmaceutical Press, London, 2007.