Ingredient review —Calcium
What is it?
Description
Calcium is an essential mineral that is commonly used to promote healthy bones and teeth. It is often found in dairy products, though various nuts, seeds, leafy greens, and cruciferous vegetables also contain calcium. Daily requirements for calcium vary by age and whether or not the individual is pregnant or lactating. Most guidelines indicate that individuals older than 19 years of age require between 1,000 to 1,300 mg per day. (37) In infants (0 to 12 months), the National Institute of Health recommends 200 to 260 mg as an adequate intake, whereas the recommended dietary allowance (RDA) rises to 700 mg and 1,000 mg in children 1 to 3 and 4 to 8 years of age, respectively. Older children and adolescents (ages 9 to 18) are recommended to consume 1,300 mg per day. (108)
In healthy individuals, approximately 99% of calcium is stored in bone, while circulating blood levels are maintained between 8.8 to 10.4 mg/dL (2.2–2.6 mmol/L). (142) The homeostatic-monitoring of calcium levels acts to regulate brain, cardiovascular, hormonal, muscular, nerve, and skeletal functions, (96)(163) and ensures that the intake of calcium from the diet or from supplements produces little variability in circulating levels. (135) However, calcium supplementation may be indicated in populations at risk for hypocalcemia due to low or non-existent intake from the diet or for individuals taking certain medications. Considering average intakes in Western countries are under the RDA at approximately 700 to 800 mg per day, (147) a proportion of the population may safely benefit from supplementation if increased dietary intake is unrealistic. In general, long-term supplementation of up to 500 mg per day of calcium may be most effectively and safely used with a meal, in combination with vitamin D, and when the dietary intake of calcium does not exceed 800 mg per day. (26) Higher divided doses may be required if intake is still below the recommended levels.
Please note that while calcium is often combined with other ingredients such as vitamin D or magnesium, this review will only detail evidence for the use of calcium supplementation on its own. It should be noted that a significant amount of evidence (e.g., calcium plus vitamin D in the treatment of osteoporosis) is omitted from this ingredient review.
Main uses
Blood pressure regulation
Bone health
Hypocalcemia and hyperphosphatemia regulation
Prenatal health
Formulations
Formulation
Characteristics
Calcium carbonate
Contains 40% elemental calcium
Most commonly used form, and regularly used in research
Least expensive, but requires stomach acid to be properly absorbed; should be taken with a meal to reduce the likelihood of adverse GI events (68)(144)(163)
It is unclear whether calcium carbonate provides better, (85) lesser, (86) or equivalent (20) effects on the suppression of bone resorption markers than calcium citrate when taken with a meal, but it does appear to be less effective when taken on an empty stomach (at bedtime) than calcium citrate-malate. (44)
Calcium citrate
Contains 21% elemental calcium
Commonly used form and regularly used in research
More expensive than calcium carbonate, but does not need to be taken with a meal; should be used in people using H2 blockers or proton pump inhibitors, or in individuals with achlorhydria (144)(163)
Calcium lysinate
Contains 30% elemental calcium
Provides greater bioavailability than calcium carbonate or calcium citrate-malate (138)
Calcium chloride
Calcium fumarate
Contains 26% elemental calcium
Provides equal bioavailability to calcium gluconate (110)
Calcium acetate
Calcium hydroxyapatite (microcrystalline hydroxyapatite complex, MCHC; ossein-hydroxyapatite complex, OHC)
Contains 21% elemental calcium; derived from animal bone and is therefore not appropriate for vegetarians or vegans
A complex containing calcium, phosphorus, and bone metabolism proteins including osteocalcin, type I collagen, insulin growth factor type I and II, & transforming growth factor-ꞵ (TGFꞵ).
A meta-analysis shows that calcium hydroxyapatite users had 1.02% higher BMD (mainly via an attenuation of bone loss) than calcium carbonate. (30)
Comparative studies published since the release of the above meta-analysis have continued to support this relationship, with a similar if not slightly better (~5% difference) adverse effect profile; (29)(36) calcium hydroxyapatite may provide a greater analgesic effect in osteopenia than calcium carbonate. (31)
Calcium hydroxyapatite increased serum calcium to a lesser extent than calcium carbonate or citrate, but produced greater phosphate and calcium-phosphate concentrations. However, it also resulted in equivalent reductions in bone resorption markers and bone turnover. (20) Calcium citrate, carbonate, pidolate, and gluconolactate reduced PTH to a greater extent than calcium hydroxyapatite. (46)
Calcium hydroxyapatite provided similar benefits to bone turnover (statistically equivalent) as tricalcium phosphate, but may provide a small clinical advantage for BMD over tricalcium phosphate. (1)
Calcium pidolate
Calcium lactate
Contains 13% elemental calcium
Provides similar bioavailability to calcium carbonate, calcium citrate, calcium gluconate, calcium lactate, and calcium acetate in a fasted state (139)
Calcium lactate gluconate
Contains 12% elemental calcium
Provides similar bioavailability to calcium carbonate, citrate, and pidolate, but lower PTH suppression than carbonate and citrate in a fasted state (46)
Calcium citrate-malate
Calcium gluconate
Other forms without comparative evidence
Calcium phosphate: contains 38% elemental calcium
Calcium aspartate: contains 23% elemental calcium
Calcium malate: contains 23% elemental calcium
Calcium glycinate: contains 21% elemental calcium
Calcium butyrate: contains 19% elemental calcium
Calcium-D-glucarate: contains 16% elemental calcium
Calcium caprylate: contains 12% elemental calcium
Calcium undecylenate: contains 10% elemental calcium
Calcium ascorbate: contains 9% elemental calcium
Calcium folinate: contains 8% elemental calcium
Calcium pantothenate: contains 8% elemental calcium
Dosing & administration
Blood pressure
Dosing & administration
>1,000 mg per day to healthy normotensive Px
Outcomes
SBP (1.14 mmHg) & DBP (0.71 mmHg), and effects were higher with intakes >1,500 mg per day (2.79 mmHg and 1.43 mmHg, respectively) (38)
Class of evidence
a
Dosing & administration
800-1,000 mg (from calcium carbonate or lactate) per day for 5-14 weeks to Px with normo- or hypertension
Outcomes
Class of evidence
b
Bone mineral density
General outcomes from A-level evidence
bone mineral density (small effect, 0.7-1.8%) within one year (i.e., no further increases observed with greater durations) in older adults and may mitigate further bone loss for up to four years, but this is unlikely to translate to clinically significant reductions in fracture risk (3.5-10%); (109)(147)(141) addition of resistance exercise may provide further benefit (101)
bone mineral density in children (1.1%), (97) with potentially greater benefits when combined with exercise (1.5-3.7%) (143)
Note: No effect of calcium supplementation was observed on BMD in lactating women (27)
Dosing & administration
1,000 mg per day over four years to postmenopausal women
Outcomes
Prevents annual bone loss observed in control groups (~1%) (109)
Class of evidence
a
Dosing & administration
400-600 mg (from calcium carbonate or citrate) 1-4 times per day for up to four years to postmenopausal women
Outcomes
Reduces bone loss and improves markers of bone resorption compared to placebo via:
total rate of bone loss per year (43%); loss in total BMD (0.4-1.1%), lumbar spine BMD (1.8-2.0%), femur BMD (0.7-1.6%), & hip BMD (2.1%)
parathyroid hormone (13-19%), osteocalcin (12-17%), undercarboxylated osteocalcin (22%), & pyridinoline (32%) (32)(92)(123)(126)(129)
Improvements in BMD may begin to attenuate after one year of use (127)
Note: Decision on dosing magnitude may depend on the Px’s baseline dietary intake of calcium to avoid excessive intake.
Class of evidence
b
Dosing & administration
500-1,000 mg (from calcium carbonate, lactogluconate-carbonate, or citrate) per day for 2-3 years in perimenopausal women
Outcomes
rate of spinal bone loss (1.2-4.8%), femoral bone loss (1%), & metacarpal cortical thickness (1%) by decreasing markers of bone turnover compared to placebo
Class of evidence
b
Dosing & administration
1,200 mg (from calcium citrate) per day over two years to healthy older men
Outcomes
Class of evidence
b
Dosing & administration
500-1,000 mg (from calcium citrate-malate, lactate gluconate, or carbonate) per day for up to seven years in adolescent girls
Outcomes
total BMD (0.73-1.3%), spine BMD (0.66-2.90%), & hip BMD (1.27%) compared to placebo
Class of evidence
b
Dosing & administration
300-1,000 mg (from calcium carbonate) per day for up to one and a half years to children with low dietary calcium intakes
Outcomes
radius BMD (4.5-7.0%) and BMC (2.5-5.5%) & lumbar BMC (4.5%)
Class of evidence
b
Cardiometabolic profile
Dosing & administration
>1,000 mg per day for minimum of 12 weeks
Outcomes
LDL-C (3.1-5.8 mg/dl) (45)
Class of evidence
a
Dosing & administration
500 mg (from calcium citrate) twice per day for one year to postmenopausal women
Outcomes
HDL-C (8%, equal to ~3.5 mg/dL) & HDL:LDL ratio
LDL-C (6%, equal to 6.12 mg/dL but borderline stat. significance)(128)
Class of evidence
b
Chronic kidney disease (CKD)
General outcomes from A-level evidence
Dosing & administration
Titrated between ~170-510 mg (from calcium acetate) based on serum phosphate three times per day for 12 weeks to Px with CKD or on hemodialysis
Outcomes
Class of evidence
b
Fractures
General outcomes from A-level evidence
relative risk of total fractures (10-11%) and vertebral fractures (14%), but not hip or forearm fractures in older adults (evidence is weak and inconsistent), (17) & osteoporotic fractures in postmenopausal women (25-75%); (42) greater efficacy may be observed in Px with low baseline dietary calcium intake, living in institutions, & with lower bodyweight. The addition of vitamin D did little to change the effect (148)
Dosing & administration
>1,200 mg per day to Px aged 50 years and older
Outcomes
relative risk of any fracture by 10% with any dose, effect was greater with >1,200 mg per day, particularly in Px with low dietary calcium intake, living in institutions, & with lower bodyweight
Note: The addition of vitamin D provided a small additional benefit. (148)
Class of evidence
a
Polycystic ovary syndrome (PCOS)
General outcomes from A-level evidence
No data currently available.
Dosing & administration
1,000 mg per day for eight weeks to overweight and obese women with PCOS and vitamin D deficiency
Outcomes
Class of evidence
b
Pregnancy outcomes and preeclampsia
General outcomes from A-level evidence
relative risk of preeclampsia by 38-62%, gestational hypertension by 9-47%, maternal death or serious morbidity by 20%, preterm birth by 12-24%, and neonatal mortality by 30%, especially in women at high risk of preeclampsia and on low calcium diets (4)(22)(24)(75)(76)(77)(80)(87)(114)(145)(149)(159)
Dosing & administration
>1,000 mg per day to pregnant women starting no later than the 34-35th week of gestation
Outcomes
relative risk of preeclampsia by 52-55%, high blood pressure by 30-35%, maternal death or serious morbidity by 20%, & preterm birth by 24%
Effects are particularly prevalent in women at high risk for preeclampsia or with low serum calcium (76)(77)
Note: Lower doses (500 mg per day) also reduced risk of preeclampsia by 62% and high blood pressure by 47%, but did not influence maternal death, serious morbidity, or preterm birth. (77)
Class of evidence
a
Dosing & administration
>1,000 mg per day to pregnant women in the 11-24th week of pregnancy
Outcomes
relative risk of gestational hypertension (9%) (4)
Class of evidence
a
Dosing & administration
600-1,200 mg per day to pregnant women starting at 20 weeks gestation to delivery
Outcomes
Note: Moderate doses (600-1,200 mg) reduced the relative risk of preeclampsia and gestational hypertension (68% and 60%), higher doses (1,200-2,000 mg) reduced risk (41% and 26%), while lower doses (<600 mg) reduced risk of preeclampsia only (57%). However, the comparative risk reduction between doses using statistical analysis was not performed. (145)
Class of evidence
a
Dosing & administration
Up to 1,000 mg per day to pregnant women
Outcomes
relative risk of preeclampsia by 64% (75)
Class of evidence
a
Dosing & administration
1,800-2,000 mg (from calcium carbonate) per day from starting between 12-25 weeks gestation to delivery to healthy pregnant women
Outcomes
relative risk of preeclampsia (56-87%), preterm birth (45-56%), & pregnancy-induced hypertension and gestational hypertension (34-72%) (10)(40)(89)(118)
Note: Supplementation during pregnancy may also reduce SBP (1.4 mmHg) and risk for high SBP (41%) in children, particularly in children with greater BMI (~5.8-6.3 mmHg & 67% risk reduction) compared to placebo. (9)
Class of evidence
b
Dosing & administration
500 mg (from calcium carbonate) three times per day starting at less than 20 weeks gestation to delivery to healthy pregnant women on low calcium diets
Outcomes
risk of eclampsia (32%), severe gestational hypertension (29%), preeclamptic complications (24%), maternal mortality (20%) and neonatal mortality (30%) (158)
Class of evidence
b
Dosing & administration
500-1,200 mg (from calcium carbonate) per day starting from less than 16 weeks gestation to delivery and up to one month postpartum to healthy pregnant women
Outcomes
Class of evidence
b
Dosing & administration
2,000 mg (from calcium carbonate) per day starting from the 20-23rd week of gestation to delivery to pregnant adolescents
Outcomes
Class of evidence
b
Premenstrual syndrome
General outcomes from A-level evidence
incidence and symptoms (5)
Dosing & administration
500 mg (from calcium carbonate) once or twice per day for two to three months to women experiencing PMS
Outcomes
Class of evidence
b
Rickets
General outcomes from A-level evidence
No data currently available.
Dosing & administration
1,000 mg (from calcium carbonate) per day for at least 24 weeks to children with nutritional rickets
Outcomes
Class of evidence
c
Thyroidectomy-induced hypocalcemia
General outcomes from A-level evidence
Dosing & administration
3,000 mg per day for two weeks post-thyroidectomy
Outcomes
risk of post-thyroidectomy hypocalcemia (46%) compared to no intervention (2)
Class of evidence
a
Type II diabetes
General outcomes from A-level evidence
No data currently available.
Dosing & administration
1,000 mg (from calcium carbonate) per day for eight weeks to Px with type II diabetes with vitamin D insufficiency
Outcomes
serum leptin (~66 ng/mL), IL-6 (5 pg/mL), & TNF-ɑ (3.2 pg/mL) compared to placebo (146)
Class of evidence
b
Dosing & administration
1,500 mg (from calcium lactate-gluconate and carbonate) per day for eight weeks to Px with type II diabetes
Outcomes
insulin sensitivity compared to control (115)
Class of evidence
c
Adverse effects
Calcium supplementation may induce gastrointestinal-related effects. Supplementation with calcium increased the relative risk of constipation, cramping, bloating, diarrhea, pain, or other symptoms by 43 to 47% compared with placebo. (94)(117)
It should be noted that controversy related to whether or not calcium supplementation increases the risk of cardiovascular events, fractures, or kidney stones exists. (12)(34)(150) Some analyses indicate that supplementation increases the risk of cardiovascular events, (15)(16)(95)(165)(167) while others do not. (7)(35)(93)(161) Similarly, an increased risk for kidney stones has been observed in some analyses, (81) but not in others. (28)(83)
Overall, supplementation with calcium may need to be more closely monitored to avoid unnecessary use in excess of recommended dietary intakes to reduce the risk of negative outcomes or adverse events. (150) In general, total daily intake of calcium (from diet and supplements) should not exceed the tolerable upper intakes levels of 2,000 to 2,500 mg per day to reduce the risk of adverse cardiovascular outcomes, (35)(88) as well as to avoid reducing the uptake of other nutrients such as iron, zinc, or phosphorus. (99)(144)
Calcium is also one of the most documented nutrients with interactions with other drugs. (156) Detailing these interactions is outside the scope of this review, but healthcare practitioners should evaluate the risks and benefits of adding calcium supplements to a treatment plan containing other pharmaceuticals.
Pharmacokinetics
Absorption
- The body can absorb up to 500 mg of calcium at a time, with very little further absorption with higher doses. (66)
- The average absorption of calcium intake is ~25%; (79) however, absorption can be highly variable (e.g., varying between 15 to 58% in healthy women). (18)
- Several factors can influence calcium absorption; estrogen deficiencies and fibre intake (reducing intestinal transit time) may reduce absorption, while increased absorption may occur with an adequate vitamin D status or when supplementation is taken with food (increasing transit time). (18)
- While adding vitamin D to improve calcium absorption is common practice, there was no better or very little improvement in calcium absorption with the addition of vitamin D in some trials. (58)(74)(105)
- The majority (95%) of calcium is absorbed in the duodenum and proximal jejunum via saturable active transport (limiting large single amounts from being absorbed). (18)
- Approximately 5% is absorbed via passive diffusion, and absorption occurs throughout the entire intestine. (18)
- Intake of calcium from dairy products, mineral waters, or supplements produce equivalent bioavailability. (14)(61)(74)(105)
Distribution
Metabolism
- In a state where serum-free calcium levels are low, reduced calcium-sensing receptor activity in the parathyroid gland stimulates secretion of parathyroid hormone (PTH).
- PTH stimulates PTH receptors in the kidney to reabsorb calcium.
- PTH stimulates 25-hydroxyvitamin D 1α hydroxylase to convert vitamin D to calcitriol, which increases intestinal calcium levels.
- PTH also stimulates resorption of calcium from bone.
- These actions ultimately increase calcium levels in the blood and provide negative feedback to reduce further parathyroid gland activity.
- In a state where serum-free calcium levels are high, increased calcium-sensing receptor activity inhibits the release of PTH (reducing the above effects) and stimulates the thyroid gland to secrete calcitonin.
- Calcitonin reduces intestinal absorption and renal reabsorption of calcium and increases calcium bone deposition, thereby reducing circulating calcium levels. (96)(142)
Excretion
- On average, 22% of calcium is lost in urine and 75% in feces, though some can be lost via the skin, hair, and sweat. (79)
- Between 100 to 250 mg of calcium can be lost in the urine, and 100 to 200 mg is excreted in the feces every day. (18)
- Estrogen deficiencies and caffeine can also increase calcium excretion. (18)
References
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