Calcium Phosphate; Cholecalciferol

What it is

This is a fixed combination of two substances. Calcium phosphate is a calcium salt - in the licensed European product, 3100 mg of calcium phosphate supplying 1200 mg (30 mmol) of elemental calcium per sachet. Cholecalciferol (colecalciferol, vitamin D3) is the form of vitamin D made in skin from sunlight, supplied here as 20 micrograms, which is 800 international units. The licensed form is a granular powder stirred into water. In the United States the same pairing is generally sold as a dietary supplement rather than an FDA-approved medicine, so the regulatory position quoted here is the Irish/EU Summary of Product Characteristics for Calfovit D3, revised May 2017.

What the research says

Calcium is the raw material of bone and vitamin D3 is what allows it to be absorbed and what suppresses the overactive parathyroid gland that strips calcium out of bone in deficient older people. The combination's evidence splits sharply by who takes it. In frail, institutionalised, vitamin D-deficient elderly women - exactly the Decalyos trials, which used calcium phosphate and vitamin D3 - hip fractures fell by 43%. In community-dwelling older adults who are not deficient, a meta-analysis of 33 trials and 51,145 people found no reduction in fractures at all. The harms are modest but real: more hypercalcaemia, more gastrointestinal symptoms, more kidney stones and kidney disease. A possible increase in heart attacks with calcium supplements remains disputed.

Evidence grade: Disputed.

How it works

Drug class: Mineral and vitamin combination: a calcium salt plus vitamin D3 (ATC A12AX)

Vitamin D3 is converted in liver and kidney to the hormone that makes the gut absorb calcium. When vitamin D is low and calcium intake is poor, the parathyroid glands become overactive and pull calcium out of bone - secondary hyperparathyroidism. Giving calcium and vitamin D3 together switches that off, which is the stated rationale for the combination; the SmPC says this secondary hyperparathyroidism is effectively corrected by the combined effect of tribasic calcium phosphate and vitamin D3. (Source 1)

What it is used for

• In 583 institutionalised women aged about 85, both a fixed and a separate combination of 1200 mg calcium with 800 IU vitamin D3 raised serum 25-hydroxyvitamin D and brought raised parathyroid hormone back into the normal range within 6 months. This biochemical effect is the best-supported thing the combination does. Evidence: established. (Source 2)
• The Decalyos trial gave 3270 ambulatory women (mean age 84) tricalcium phosphate containing 1.2 g calcium plus 800 IU vitamin D3 for 18 months: hip fractures were 43% lower and all non-vertebral fractures 32% lower than placebo. Cochrane's pooled estimate for vitamin D plus calcium is a hip fracture risk ratio of 0.84, which in institutions means about nine fewer hip fractures per 1000 people per year. Evidence: established. (Source 3)
• A meta-analysis of 33 randomised trials and 51,145 community-dwelling adults over 50 found no reduction in hip, non-vertebral, vertebral or total fractures from calcium, vitamin D, or the two combined. The RECORD trial in 5292 people who had already fractured found no benefit either. Cochrane's own absolute figure for community residents is about one fewer hip fracture per 1000 people per year. Evidence: not-supported. (Source 4)
• The Institute of Medicine's 2011 review concluded the evidence for these non-skeletal outcomes was inconsistent, inconclusive as to causality and insufficient even to set intake requirements, and that randomised evidence was limited and generally uninformative. Higher vitamin D levels were not consistently better and some outcomes showed U-shaped risk. Evidence: not-supported. (Source 5)

Interactions

• Tetracycline antibiotics (label): Calcium binds tetracyclines in the gut so less antibiotic is absorbed. The SmPC says the two should be taken at least 3 hours apart. (Source 6)
• Ciprofloxacin and other fluoroquinolone antibiotics (pharmacokinetic study): Calcium salts cut how much ciprofloxacin reaches the bloodstream. In a randomised crossover study in 15 healthy volunteers, calcium acetate reduced ciprofloxacin's relative oral bioavailability by 51%, which the authors warn may reduce efficacy and promote resistance. (Source 7)
• Levothyroxine and other thyroid hormone (clinical trial): Calcium adsorbs thyroxine in the acid stomach so less is absorbed. Taking 1200 mg of calcium with levothyroxine for 3 months raised mean TSH from 1.6 to 2.7 mIU/L and pushed one in five patients above the normal range; TSH fell again when calcium stopped. The SmPC also lists thyroid hormones as inhibiting calcium absorption. (Source 8)
• Levothyroxine taken at the same time (acute effect) (pharmacokinetic study): A single-dose study in seven volunteers without thyroid disease showed the size of the effect directly: maximum levothyroxine absorption fell from 837 microg (83.7% of the dose) alone to 579 microg (57.9%) when 2.0 g of calcium was taken at the same moment, and total absorption over 6 hours was significantly lower with calcium (p = 0.02). This is an acute pharmacokinetic experiment at a single 1,000 mg-scale levothyroxine dose in people without thyroid disease, not a dosing study in treated patients. (Source 9)
• Iron (dietary or supplemental) (pharmacokinetic study): Calcium blocks non-haem iron absorption from the same meal. In 13 women with marginal iron status, 500 mg of calcium more than halved iron absorption from a single meal, from 10.2% to 4.8%. (Source 10)
• Thiazide diuretics (label): Thiazides make the kidney hold on to calcium, so combining them with a calcium and vitamin D supplement can tip someone into hypercalcaemia. The SmPC asks for serum calcium monitoring during prolonged treatment. (Source 6)
• Digoxin and other cardiac glycosides (label): Calcium and digitalis act in the same direction on the heart. The SmPC warns this synergism may cause severe disorders of cardiac function and calls for strict supervision, with ECG and calcium monitoring if needed. (Source 6)
• Bisphosphonates and sodium fluoride (label): Calcium stops these drugs being absorbed from the gut. The SmPC advises leaving at least two hours before taking the calcium and vitamin D product. (Source 6)
• Colestyramine, corticosteroids, mineral oils, phenytoin and barbiturates (label): The first three reduce absorption of vitamin D from the gut; phenytoin and barbiturates speed up its inactivation. Either way less active vitamin D is available. (Source 6)
• Loop diuretics (furosemide, ethacrynic acid) and aluminium-containing antacids (label): These inhibit calcium absorption and increase its loss in urine and stool, working against the supplement. (Source 6)
• Foods containing phosphate, oxalic acid or phytic acid (label): These bind calcium in the gut and reduce how much is absorbed. The SmPC names them explicitly as food interactions. (Source 6)
• High-oxalate foods such as spinach (size of the effect) (pharmacokinetic study): A crossover study in 13 adults measured it: calcium absorption averaged 27.6% from milk but only 5.1% from spinach, where oxalate had bound essentially all the calcium. (Source 11)
• Other vitamin D supplements and vitamin D-fortified foods (label): Doses stack, and the risk is hypercalcaemia. The SmPC says all other vitamin D compounds and derivatives, including vitamin D-fortified foods, should be withheld during treatment. (Source 12)

Stopping it

• There is no withdrawal syndrome, but the SmPC sets a monitoring-driven stopping rule: if urinary calcium exceeds 7.5 mmol (300 mg) in 24 hours, treatment should be temporarily interrupted. (Source 12)
• If hypercalcaemia develops, the treatment is to stop the supplement. The SmPC's overdose section says the treatment with calcium and vitamin D must be discontinued, along with thiazides, lithium, vitamin A and cardiac glycosides, with rehydration and further measures as needed. (Source 13)
• Benefit depends on continuing to take it. In the WHI trial, censoring women once they stopped adhering to the study medication moved the hip fracture hazard ratio from 0.88 to 0.71, which is an argument that stopping removes whatever effect exists rather than that the effect persists. (Source 14)
• What is reversed by stopping is the biochemical effect. In Decalyos II, parathyroid hormone and 25-hydroxyvitamin D normalised within 6 months of starting - the implication being that the correction is maintained by the supplement, not a permanent change. (Source 2)

What goes wrong

Calcium plus vitamin D increased the risk of kidney stones in the WHI trial. (Source 14)

• Randomized trial, High certainty.
• Size: 36,282 postmenopausal women.
• Who: healthy postmenopausal women aged 50 to 79.
• How long: average 7.0 years.
• Result: renal calculi HR 1.17 (95% CI 1.02 to 1.34)
• Funding: publicly funded (Women's Health Initiative)

The risk of renal calculi increased with calcium plus vitamin D (hazard ratio, 1.17; 95 percent confidence interval, 1.02 to 1.34).

Hypercalcaemia was more than twice as common with vitamin D with or without calcium, though usually mild. (Source 15)

• Systematic review, High certainty.
• Size: 21 trials, 17,124 participants.
• Who: post-menopausal women and older men.
• How long: varied.
• Result: RR 2.28 (95% CI 1.57 to 3.31); usually mild, 2.6 to 2.8 mmol/L; much higher for calcitriol (RR 4.41, 2.14 to 9.09)
• Funding: not stated.

Hypercalcaemia, which was usually mild (2.6 to 2.8 mmol/L), was more common in people receiving vitamin D or an analogue, with or without calcium (21 trials, 17,124 participants, RR 2.28, 95% CI 1.57 to 3.31)

Calcium plus vitamin D caused a small but statistically significant increase in gastrointestinal symptoms and in renal disease. (Source 15)

• Systematic review, High certainty.
• Size: gastrointestinal symptoms 15 trials/47,761 participants; renal disease 11 trials/46,548 participants.
• Who: post-menopausal women and older men.
• How long: varied.
• Result: gastrointestinal symptoms RR 1.04 (95% CI 1.00 to 1.08), for calcium plus vitamin D RR 1.05 (1.01 to 1.09); renal disease RR 1.16 (1.02 to 1.33)
• Funding: not stated.

There was also a small increased risk of gastrointestinal symptoms (15 trials, 47,761 participants, RR 1.04, 95% CI 1.00 to 1.08), especially for calcium plus vitamin D (four trials, 40,524 participants, RR 1.05, 95% CI 1.01 to 1.09), and a significant increase in renal disease (11 trials, 46,548 participants, RR 1.16, 95% CI 1.02 to 1.33).

A patient-level meta-analysis found calcium supplements given without vitamin D were associated with a 31% higher risk of myocardial infarction. (Source 16)

• Meta-analysis, Low certainty.
• Size: 15 trials; 5 with patient-level data (8151 participants), 11 with trial-level data (11,921 participants)
• Who: mean age over 40, calcium 500 mg/day or more.
• How long: median 3.6 years (patient level), mean 4.0 years (trial level)
• Result: myocardial infarction HR 1.31 (95% CI 1.02 to 1.67, P=0.035); stroke 1.20 (0.96 to 1.50); composite 1.18 (1.00 to 1.39); death 1.09 (0.96 to 1.23); trial-level pooled RR 1.27 (1.01 to 1.59)
• Funding: not stated; cardiovascular outcomes came from self-reports, hospital admissions and death certificates, not pre-specified endpoints.

In the five studies contributing patient level data, 143 people allocated to calcium had a myocardial infarction compared with 111 allocated to placebo (hazard ratio 1.31, 95% confidence interval 1.02 to 1.67, P=0.035).

The licensed product's own adverse-reaction list gives no frequencies, because the reactions come from postmarketing reports. (Source 17)

• Official position, Certainty not rated.
• Size: postmarketing reports of uncertain denominator.
• Who: users of the licensed calcium phosphate plus colecalciferol product.
• How long: not applicable.
• Result: hypercalcaemia, hypercalciuria, nausea, constipation, diarrhoea, epigastric pain, urticaria, allergic dermatitis and anaphylactic reaction, all with frequency not known.
• Funding: marketing authorisation holder (Menarini); SmPC revised May 2017.

Metabolism and nutrition disorders Hypercalcaemia, hypercalciuria Gastrointestinal Disorders Nausea, constipation, diarrhoea, epigastric pain

Overdose causes hypercalcaemia whose symptoms range from thirst and constipation to arrhythmia, coma and irreversible kidney damage. (Source 13)

• Official position, Certainty not rated.
• Size: not stated.
• Who: people taking calcium with vitamin D.
• How long: not applicable.
• Result: the stated intoxication threshold is 40,000 to 100,000 IU/day of vitamin D for 1 to 2 months with normal parathyroid function, and calcium in excess of 2000 mg per day.
• Funding: marketing authorisation holder (Menarini); SmPC revised May 2017.

Overdose can lead to hypervitaminosis D and hypercalcaemia. Symptoms of hypercalcaemia may include anorexia, thirst, nausea, vomiting, constipation, abdominal pain, muscle weakness, fatigue, mental disturbances, polidipsia, polyuria, bone pain, nephrocalcinosis, renal calculi and in severe cases, cardiac arrhythmias.

The licensed fixed combination is not indicated during pregnancy or breastfeeding, because its vitamin D content exceeds the daily ceiling the SmPC sets for those states. (Source 18)

• Official position, Certainty not rated.
• Size: not applicable - regulatory position.
• Who: pregnant and breastfeeding women.
• How long: not applicable.
• Result: the SmPC states the daily dose of vitamin D should not exceed 600 I.U. in pregnancy and lactation, which this 800 I.U. product exceeds.
• Funding: not applicable - national regulator.

Limit of this finding: The 600 I.U. figure is this product's own licensing rationale for not being indicated in pregnancy or breastfeeding, because each sachet delivers 800 I.U. of vitamin D together with 1200 mg of calcium. It is not a general upper limit for vitamin D in pregnancy, and should not be read as one. The SmPC also says there are no or limited data on the product's use in pregnant women, so this is a licensing restriction rather than a measured risk.

Due to its high vitamin D content, CALFOVIT D3 is not indicated for use during pregnancy and lactation as the daily dose of Vitamin D should not exceed 600 I.U. (see section 4.3).

What the evidence supports

Calcium phosphate with vitamin D3 reduced hip fractures by 43% and all non-vertebral fractures by 32% in very old ambulatory women. (Source 3)

• Randomized trial, Moderate certainty.
• Size: 3270 women (1634 active, 1636 double placebo)
• Who: healthy ambulatory French women, mean age 84 (SD 6), living in sheltered accommodation.
• How long: 18 months.
• Result: hip fractures 43% lower (P=0.043); total non-vertebral fractures 32% lower (P=0.015); mean parathyroid hormone fell 44% from baseline.
• Funding: not stated in the abstract; the trial product was a marketed combination (Decalyos)

Among the women who completed the 18-month study, the number of hip fractures was 43 percent lower (P = 0.043) and the total number of nonvertebral fractures was 32 percent lower (P = 0.015) among the women treated with vitamin D3 and calcium than among those who received placebo.

The Decalyos trial used tricalcium phosphate as the calcium source, so this evidence applies directly to the calcium phosphate plus cholecalciferol combination. (Source 3)

• Randomized trial, Moderate certainty.
• Size: 3270 women.
• Who: ambulatory elderly women, mean age 84.
• How long: 18 months.
• Result: 1.2 g elemental calcium as tricalcium phosphate plus 20 micrograms (800 IU) vitamin D3 daily versus double placebo.
• Funding: not stated in the abstract.

Each day for 18 months, 1634 women received tricalcium phosphate (containing 1.2 g of elemental calcium) and 20 micrograms (800 IU) of vitamin D3, and 1636 women received a double placebo.

A confirmatory trial showed both fixed and separate calcium plus vitamin D3 combinations normalised parathyroid hormone within 6 months. (Source 2)

• Randomized trial, Moderate certainty.
• Size: 583 women (199 fixed combination, 190 separate, 194 placebo)
• Who: ambulatory institutionalised women, mean age 85.2 (SD 7.1)
• How long: 2 years.
• Result: serum 25-hydroxyvitamin D rose and intact parathyroid hormone fell into the normal range after 6 months in both active groups.
• Funding: not stated in the abstract; a confirmatory study of a marketed fixed combination.

Limit of this finding: The paper's title and its closing sentence say the combination reduces hip fracture risk, but the only hip-fracture figure it reports is a relative risk of 1.69 with a 95% confidence interval of 0.96 to 3.0, and an interval that includes 1 means the difference could have arisen by chance. Read this trial as evidence that the parathyroid hormone and vitamin D changes were real and that the hip-fracture difference pointed in the expected direction; it is not on its own evidence that the combination prevents hip fractures.

Both types of calcium-vitamin D3 regimens increased serum 25-hydroxyvitamin D and decreased serum intact parathyroid hormone to a similar extent, with levels returning within the normal range after 6 months.

Cochrane found vitamin D plus calcium gives a small reduction in hip fracture risk on high quality evidence. (Source 15)

• Systematic review, High certainty.
• Size: 9 trials, 49,853 participants (within a review of 53 trials and 91,791 participants)
• Who: post-menopausal women and older men in community, nursing home and hospital settings.
• How long: varied.
• Result: hip fracture RR 0.84 (95% CI 0.74 to 0.96, P=0.01); any fracture RR 0.95 (0.90 to 0.99)
• Funding: not stated; 40% of trials at low risk of bias for sequence generation, 53% unclear.

There is high quality evidence that vitamin D plus calcium results in a small reduction in hip fracture risk (nine trials, 49,853 participants; RR 0.84, 95% confidence interval (CI) 0.74 to 0.96; P value 0.01).

The absolute size of that benefit depends entirely on baseline risk: about one fewer hip fracture per 1000 per year in the community, about nine fewer per 1000 per year in institutions. (Source 15)

• Systematic review, High certainty.
• Size: 9 trials, 49,853 participants.
• Who: community residents (8 hip fractures per 1000/year) versus institution residents (54 per 1000/year)
• How long: per year.
• Result: one fewer per 1000 per year (95% CI 0 to 2) in the community; nine fewer per 1000 per year (95% CI 2 to 14) in institutions.
• Funding: not stated.

In low-risk populations (residents in the community: with an estimated eight hip fractures per 1000 per year), this equates to one fewer hip fracture per 1000 older adults per year (95% CI 0 to 2). In high risk populations (residents in institutions: with an estimated 54 hip fractures per 1000 per year), this equates to nine fewer hip fractures per 1000 older adults per year (95% CI 2 to 14).

The same Cochrane review found no increase in death from taking calcium and vitamin D. (Source 15)

• Systematic review, High certainty.
• Size: 29 trials, 71,032 participants.
• Who: post-menopausal women and older men.
• How long: varied.
• Result: mortality RR 0.97 (95% CI 0.93 to 1.01)
• Funding: not stated.

This review found that there was no increased risk of death from taking calcium and vitamin D.

What the evidence does not support

In Decalyos II the difference in hip fracture risk between placebo and active treatment did not reach statistical significance. (Source 2)

• Randomized trial, Low certainty.
• Size: 583 institutionalised women randomised (199 fixed combination, 190 separate, 194 placebo)
• Who: ambulatory institutionalised women, mean age 85.2 (SD 7.1)
• How long: 2 years.
• Result: relative risk of hip fracture in the placebo group compared with the active treatment group 1.69 (95% CI = 0.96, 3.0); the earlier Decalyos I estimate was RR 1.7 (95% CI = 1.0, 2.8)
• Funding: not stated in the abstract; a confirmatory study of a marketed fixed combination.

Limit of this finding: The paper's title and its closing sentence say the combination reduces hip fracture risk, but the only hip-fracture figure it reports is a relative risk of 1.69 with a 95% confidence interval of 0.96 to 3.0, and an interval that includes 1 means the difference could have arisen by chance. Read this trial as evidence that the parathyroid hormone and vitamin D changes were real and that the hip-fracture difference pointed in the expected direction; it is not on its own evidence that the combination prevents hip fractures.

The relative risk (RR) of HF in the placebo group compared with the active treatment group was 1.69 (95% CI = 0.96, 3.0), which is similar to that found in Decalyos I (RR = 1.7; 95% CI = 1.0, 2.8).

Vitamin D on its own, without calcium, does not prevent hip fracture - high quality evidence. (Source 15)

• Systematic review, High certainty.
• Size: 11 trials, 27,693 participants.
• Who: post-menopausal women and older men.
• How long: varied.
• Result: hip fracture RR 1.12 (95% CI 0.98 to 1.29); any new fracture RR 1.03 (0.96 to 1.11)
• Funding: not stated.

There is high quality evidence that vitamin D alone, in the formats and doses tested, is unlikely to be effective in preventing hip fracture (11 trials, 27,693 participants; risk ratio (RR) 1.12, 95% confidence intervals (CI) 0.98 to 1.29)

In community-dwelling older adults, combined calcium and vitamin D supplements were not associated with fewer fractures of any kind. (Source 4)

• Meta-analysis, Moderate certainty.
• Size: 33 randomised trials, 51,145 participants.
• Who: community-dwelling adults older than 50.
• How long: varied.
• Result: hip fracture RR 1.09 (95% CI 0.85 to 1.39), absolute risk difference 0.00 (95% CI -0.00 to 0.00); no association for non-vertebral, vertebral or total fracture; results consistent regardless of dose, sex, fracture history, dietary calcium intake or baseline 25-hydroxyvitamin D.
• Funding: not stated.

There was no significant association of combined calcium and vitamin D with hip fracture compared with placebo or no treatment (RR, 1.09 [95% CI, 0.85 to 1.39]; ARD, 0.00 [95% CI, -0.00 to 0.00]).

The RECORD trial found no reduction in new low-trauma fractures from calcium, vitamin D3, or both combined, in people who had already fractured. (Source 19)

• Randomized trial, High certainty.
• Size: 5292 people (4481 women), 698 had a new low-trauma fracture.
• Who: aged 70 or older, mobile before a low-trauma fracture, 21 UK hospitals.
• How long: 24 to 62 months.
• Result: combination versus placebo 165/1306 (12.6%) vs 179/1332 (13.4%); calcium HR 0.94 (95% CI 0.81 to 1.09); vitamin D3 HR 1.02 (0.88 to 1.19)
• Funding: publicly funded UK trial (funder not stated in the abstract)

between those allocated combination treatment and those assigned placebo (165 [12.6%] of 1306 vs 179 [13.4%] of 1332; HR for interaction term 1.01 [0.75-1.36]). The groups did not differ in the incidence of all-new fractures, fractures confirmed by radiography, hip fractures, death, number of falls, or quality of life.

In 36,282 postmenopausal women, calcium plus vitamin D did not significantly reduce hip, spine or total fractures by intention to treat. (Source 14)

• Randomized trial, High certainty.
• Size: 36,282 postmenopausal women aged 50 to 79.
• Who: healthy postmenopausal women already in a WHI trial.
• How long: average 7.0 years.
• Result: hip fracture HR 0.88 (95% CI 0.72 to 1.08); clinical spine 0.90 (0.74 to 1.10); total 0.96 (0.91 to 1.02); hip bone density 1.06% higher (P<0.01)
• Funding: publicly funded (Women's Health Initiative, National Institutes of Health)

Intention-to-treat analysis indicated that participants receiving calcium plus vitamin D supplementation had a hazard ratio of 0.88 for hip fracture (95 percent confidence interval, 0.72 to 1.08), 0.90 for clinical spine fracture (0.74 to 1.10), and 0.96 for total fractures (0.91 to 1.02).

A guideline panel reviewing the same question concluded there is moderate-quality evidence of no cardiovascular relationship either way. (Source 20)

• Official position, Moderate certainty.
• Size: expert panel using an independent Tufts University evidence report.
• Who: generally healthy adults.
• How long: not applicable.
• Result: B-level (moderate-quality) evidence of no relationship, beneficial or harmful, to cardiovascular or cerebrovascular disease, mortality or all-cause mortality; intake up to the upper level of 2000 to 2500 mg/d considered cardiovascularly safe.
• Funding: National Osteoporosis Foundation and American Society for Preventive Cardiology.

The National Osteoporosis Foundation and American Society for Preventive Cardiology adopt the position that there is moderate-quality evidence (B level) that calcium with or without vitamin D intake from food or supplements has no relationship (beneficial or harmful) to the risk for cardiovascular and cerebrovascular disease, mortality, or all-cause mortality in generally healthy adults at this time.

Vitamin D3 2000 IU daily did not reduce fractures in 25,871 generally healthy midlife and older adults. (Source 21)

• Randomized trial, High certainty.
• Size: 25,871 participants, 1991 confirmed incident fractures in 1551 people.
• Who: US men 50+ and women 55+, not selected for vitamin D deficiency, low bone mass or osteoporosis.
• How long: median 5.3 years.
• Result: total fractures 769/12,927 vs 782/12,944, HR 0.98 (95% CI 0.89 to 1.08, P=0.70); non-vertebral HR 0.97 (0.87 to 1.07); hip HR 1.01 (0.70 to 1.47)
• Funding: publicly funded (National Institute of Arthritis and Musculoskeletal and Skin Diseases)

Supplemental vitamin D3, as compared with placebo, did not have a significant effect on total fractures (which occurred in 769 of 12,927 participants in the vitamin D group and in 782 of 12,944 participants in the placebo group; hazard ratio, 0.98; 95% confidence interval [CI], 0.89 to 1.08; P = 0.70), nonvertebral fractures (hazard ratio, 0.97; 95% CI, 0.87 to 1.07; P = 0.50), or hip fractures (hazard ratio, 1.01; 95% CI, 0.70 to 1.47; P = 0.96).

The Institute of Medicine concluded the evidence for non-skeletal benefits of calcium and vitamin D was inconsistent and insufficient. (Source 5)

• Official position, Moderate certainty.
• Size: comprehensive evidence review by an IOM committee.
• Who: North American population.
• How long: not applicable.
• Result: evidence for cancer, cardiovascular disease, diabetes and autoimmune disorders inconsistent, inconclusive as to causality and insufficient to inform requirements; randomised evidence limited and generally uninformative.
• Funding: Institute of Medicine (now National Academy of Medicine)

For extraskeletal outcomes, including cancer, cardiovascular disease, diabetes, and autoimmune disorders, the evidence was inconsistent, inconclusive as to causality, and insufficient to inform nutritional requirements.

Where the evidence is mixed

In Decalyos II the femoral neck bone density difference versus placebo did not reach statistical significance. (Source 2)

• Randomized trial, Low certainty.
• Size: subgroup of 114 patients within 583 randomised.
• Who: institutionalised women, mean age 85.2.
• How long: 2 years.
• Result: between-group difference 2.65% (95% CI -0.44 to 5.75%); femoral neck BMD -2.36%/year on placebo versus +0.29%/year on treatment.
• Funding: not stated in the abstract.

Limit of this finding: The paper's title and its closing sentence say the combination reduces hip fracture risk, but the only hip-fracture figure it reports is a relative risk of 1.69 with a 95% confidence interval of 0.96 to 3.0, and an interval that includes 1 means the difference could have arisen by chance. Read this trial as evidence that the parathyroid hormone and vitamin D changes were real and that the hip-fracture difference pointed in the expected direction; it is not on its own evidence that the combination prevents hip fractures.

The difference between the two groups was 2.65% (95% CI = -0.44, 5.75%) with a trend in favor of the active treatment group.

Which calcium salt a supplement uses has little effect on how much calcium is absorbed, because solubility barely predicts absorbability. (Source 22)

• Blood level study, Low certainty.
• Size: seven chemically defined calcium sources plus four food sources.
• Who: normal adult women under standardised load conditions.
• How long: single-load absorption tests.
• Result: no detectable effect of solubility on absorption across 0.1 to 10 mM, the range into which most supplement sources fall.
• Funding: not stated.

In the range from 0.1 to 10 mM, within which most calcium supplement sources fall, there was no detectable effect of solubility on absorption.

Where the research disagrees

Whether calcium supplements raise the risk of myocardial infarction

• Bolland and colleagues, patient-level and trial-level meta-analysis, BMJ (2010), meta-analysis of 15 randomised placebo-controlled trials; cardiovascular events were not pre-specified primary endpoints and came from self-reports, hospital admissions and death certificates: Calcium supplements (without coadministered vitamin D) are associated with an increased risk of myocardial infarction. (Source 16)
• National Osteoporosis Foundation and American Society for Preventive Cardiology (2016), expert guideline panel grading an independent systematic evidence report; moderate-quality (B level) evidence: The National Osteoporosis Foundation and American Society for Preventive Cardiology adopt the position that there is moderate-quality evidence (B level) that calcium with or without vitamin D intake from food or supplements has no relationship (beneficial or harmful) to the risk for cardiovascular and cerebrovascular disease, mortality, or all-cause mortality in generally healthy adults at this time. (Source 20)
• Cochrane review of 53 trials (2014), systematic review; found no mortality increase but acknowledged other reviews reporting increased myocardial infarction: This review found that there was no increased risk of death from taking calcium and vitamin D. (Source 15)

Whether calcium plus vitamin D prevents fractures

• Cochrane review of 53 trials, 91,791 participants (2014), systematic review with GRADE; high quality evidence, but the absolute benefit depends on baseline risk: There is high quality evidence that vitamin D plus calcium results in a small reduction in hip fracture risk (nine trials, 49,853 participants; RR 0.84, 95% confidence interval (CI) 0.74 to 0.96; P value 0.01). (Source 15)
• Zhao and colleagues, JAMA (2017), 33 trials and 51,145 community-dwelling adults, meta-analysis restricted to community-dwelling adults over 50, reporting absolute risk differences: In this meta-analysis of randomized clinical trials, the use of supplements that included calcium, vitamin D, or both compared with placebo or no treatment was not associated with a lower risk of fractures among community-dwelling older adults. (Source 4)
• Chapuy and colleagues, Decalyos, NEJM (1992), 3270 women of mean age 84, randomised double-placebo-controlled trial in a deficient, institution-dwelling, very old population using calcium phosphate: Among the women who completed the 18-month study, the number of hip fractures was 43 percent lower (P = 0.043) and the total number of nonvertebral fractures was 32 percent lower (P = 0.015) among the women treated with vitamin D3 and calcium than among those who received placebo. (Source 3)

How much

• Reference intake: Dosing of a licensed product is set by the prescriber. As a position, the Calfovit D3 SmPC (HPRA, revised May 2017) gives one sachet a day for adults and the elderly, each sachet containing 3100 mg calcium phosphate (1200 mg elemental calcium) and 20 micrograms (800 IU) colecalciferol. As a separate position, the Institute of Medicine's 2011 dietary reference intakes set calcium RDAs of 700 to 1300 mg daily and vitamin D RDAs of 600 IU/day to age 70 and 800 IU/day from 71. (Source 23)
• Upper limit: Position of the Institute of Medicine, 2011, as summarised for practitioners: the Tolerable Upper Intake Level for calcium ranges from 1000 to 3000 mg daily depending on age, based on calcium excretion and kidney stone formation, and for vitamin D from 1000 to 4000 IU daily, based on hypercalcaemia. The product SmPC adds that vitamin D intoxication occurs above about 40,000 IU/day for 1 to 2 months. (Source 24)
• Studied: Decalyos gave 1634 women tricalcium phosphate containing 1.2 g of elemental calcium plus 20 micrograms (800 IU) of vitamin D3 daily for 18 months. (Source 3)
• Studied: Decalyos II gave 1200 mg calcium and 800 IU vitamin D3 daily, as a fixed combination or separately, for 2 years. (Source 2)
• Studied: The WHI calcium and vitamin D trial gave 1000 mg of elemental calcium as calcium carbonate with 400 IU of vitamin D3 daily for an average of 7 years. (Source 14)
• Studied: RECORD gave 800 IU vitamin D3 and/or 1000 mg calcium daily for 24 to 62 months. (Source 19)
• Studied: VITAL gave vitamin D3 2000 IU per day, without calcium, for a median of 5.3 years. (Source 21)

A common belief, and what the research shows

The belief: Everyone over a certain age should take calcium with vitamin D to prevent fractures.

What the research shows: The benefit is concentrated in people who are deficient and at high fracture risk, and disappears in healthy community-dwelling adults. Cochrane's own absolute figures make this explicit: "In low-risk populations (residents in the community: with an estimated eight hip fractures per 1000 per year), this equates to one fewer hip fracture per 1000 older adults per year (95% CI 0 to 2). In high risk populations (residents in institutions: with an estimated 54 hip fractures per 1000 per year), this equates to nine fewer hip fractures per 1000 older adults per year (95% CI 2 to 14)." A meta-analysis of 33 trials and 51,145 community-dwelling adults concluded the supplements were "not associated with a lower risk of fractures among community-dwelling older adults". Meanwhile the harms do not depend on baseline risk: hypercalcaemia RR 2.28, renal disease RR 1.16, and kidney stones HR 1.17 in the WHI trial.

Questions and answers

What is it?

It is two things in one dose: a calcium salt (calcium phosphate) and vitamin D3 (colecalciferol). In the licensed European product each sachet holds 3100 mg of calcium phosphate, which supplies 1200 mg of elemental calcium, together with 20 micrograms - 800 international units - of vitamin D3. It is a granular powder stirred into water, usually taken with the evening meal. (Source 25)

What does it do in the body?

Vitamin D3 lets the gut absorb calcium and switches off the overactive parathyroid gland that strips calcium from bone when vitamin D is low. The calcium supplies the mineral. The SmPC states that this secondary hyperparathyroidism is effectively corrected by the combined effect of tribasic calcium phosphate and vitamin D3, and the Decalyos II trial measured exactly that: parathyroid hormone back in the normal range within 6 months. (Source 1)

Is it good or bad for you?

It depends entirely on who takes it. In institutionalised, vitamin D-deficient women in their eighties it cut hip fractures by 43%. In community-dwelling older adults who are not deficient, 33 trials in 51,145 people found no fracture reduction. The harms do not vary the same way: hypercalcaemia was more than twice as common, gastrointestinal symptoms and kidney disease slightly more common, and kidney stones rose in the WHI trial. (Source 4)

How do you get more of it?

Calcium comes from dairy foods, fortified products and some vegetables, and vitamin D from sunlight, oily fish and fortified foods; supplements supply both. How much is needed is a position rather than a recommendation from us: the Institute of Medicine set calcium RDAs of 700 to 1300 mg daily and vitamin D RDAs of 600 IU/day to age 70 and 800 IU/day from 71, assuming minimal sun exposure. Which calcium salt a supplement uses makes little difference to absorption. (Source 24)

If it is harmful, what reduces it?

When calcium or vitamin D goes too high, the first step is to stop taking them. The SmPC's overdose section says the treatment with calcium and vitamin D must be discontinued, and that thiazide diuretics, lithium, vitamin A and cardiac glycosides should also be stopped, with rehydration and, depending on severity, loop diuretics, bisphosphonates, calcitonin or corticosteroids. A urinary calcium above 7.5 mmol/24 hours is the SmPC's trigger for interrupting treatment. (Source 13)

Why might someone be low in it or missing it?

The two shortfalls travel together. Decalyos II opens by stating that vitamin D insufficiency and low calcium intake contribute to increased parathyroid function and bone fragility in elderly people. Little sunlight, low dairy intake, age-related loss of skin synthesis and institutional living all push in that direction. Medicines matter too: colestyramine, corticosteroids and mineral oils reduce vitamin D absorption, while phenytoin and barbiturates speed its inactivation. (Source 2)

Which whole foods contain it or feed it?

Dairy is the most absorbable common source of calcium; oily fish and fortified foods supply vitamin D. Some plant foods contain calcium that is largely unavailable: a crossover study found calcium absorption averaged 27.6% from milk but only 5.1% from spinach, because oxalate had bound it. The SmPC names phosphate, oxalic acid and phytic acid in food as reducing calcium absorption. (Source 11)

What happens if you do not have it?

Sustained shortage of both drives secondary hyperparathyroidism, in which parathyroid hormone rises and bone is broken down to release calcium. Decalyos opens by noting that hypovitaminosis D and low calcium intake contribute to increased parathyroid function in elderly persons; in that trial the untreated group had 43% more hip fractures and 32% more non-vertebral fractures than the treated group over 18 months. (Source 3)

How can you test for it?

Three measurements are used: serum calcium, 24-hour urinary calcium, and serum 25-hydroxyvitamin D. The SmPC requires calcaemia and calciuria to be monitored in people with kidney problems or a tendency to stones, and sets an interruption threshold at urinary calcium above 7.5 mmol/24 hours. The 25-hydroxyvitamin D test is less settled than it looks: the Institute of Medicine concluded that vitamin D inadequacy in North America has been overestimated and called for the laboratory ranges to be reassessed. (Source 12)

References

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