Calcitriol

What it is

Calcitriol is the hormone the body makes from vitamin D3 after two activation steps - one in the liver, one in the kidney. As a medicine it is a synthetic copy of that hormone, supplied as oral capsules and solution, an intravenous injection and a topical ointment. It is NOT cholecalciferol, the vitamin D in supplements and fortified food: cholecalciferol still has to be activated by the body, calcitriol is already active and bypasses that control. That is why it is prescribed in amounts measured in mcg and why the kidney failure that stops a person activating cholecalciferol is the main reason to prescribe it.

What the research says

It drives calcium absorption from the gut, mobilises calcium from bone with parathyroid hormone, increases calcium reabsorption in the kidney and suppresses parathyroid hormone. In chronic kidney disease, trials show it lowers parathyroid hormone but systematic reviews found no proven benefit on death, bone pain or parathyroidectomy, with more hypercalcaemia and hyperphosphataemia. In hypoparathyroidism it raises a low calcium, which is the point. Applied to the skin it clears mild-to-moderate plaque psoriasis in a minority of people. Hypercalcaemia is the harm that runs through all of it.

Evidence grade: Disputed.

How it works

Drug class: Active vitamin D hormone (vitamin D receptor agonist); the fully activated metabolite of vitamin D3, not a nutritional vitamin D supplement

Vitamin D3 is made in the skin when the sun's ultraviolet rays act on 7-dehydrocholesterol, and the label says man's natural supply of vitamin D depends mainly on that. It is inert until the liver turns it into 25-hydroxyvitamin D3 and the kidney then turns that into calcitriol. Calcitriol is the end product that actually does the work - it switches on calcium absorption in the intestine, acts on bone, kidney and the parathyroid gland, and directly suppresses parathyroid hormone. Giving calcitriol therefore skips both activation steps and the body's control over them. (Source 1)

What it is used for

• Vitamin D compounds lower parathyroid hormone in this group, but the Cochrane review of 16 trials in 894 patients found no effect on death or the need for dialysis, and found serum phosphorus and calcium went up. The reviewers say the balance of benefit and harm 'remain to be understood'. Evidence: disputed. (Source 2)
• Sixty trials in 2,773 patients found no formulation, route or schedule altered the risk of death, bone pain or parathyroidectomy; parathyroid hormone fell at the cost of higher serum phosphorus. All the trials were underpowered for clinical outcomes. Evidence: disputed. (Source 3)
• This is the use with the clearest rationale - the missing hormone's downstream effect is replaced - but the controlled evidence is thin. A randomised trial comparing calcitriol with alfacalcidol found calcium control equivalent and both left most patients with hyperphosphataemia and hypercalciuria. A retrospective cohort links cumulative calcitriol use to kidney function decline. Evidence: limited. (Source 4)
• In two 8-week vehicle-controlled trials, 23.4% versus 14.4% and 20.5% versus 6.6% of subjects reached clear or minimal disease with a two-grade improvement; those trials enrolled from age 13 upwards, although the ointment is labelled from age 2. The Cochrane review of topical psoriasis treatments found vitamin D analogues better than placebo but concluded corticosteroids perform at least as well with fewer local adverse events, while saying there is still no evidence on the risk of skin thinning with long-term corticosteroid use. Evidence: limited. (Source 5)
• A 953-man phase III trial was stopped early for excess deaths: median overall survival 17.8 months with high-dose calcitriol versus 20.2 months in the control arm. An earlier 250-man phase II trial had suggested a survival benefit, which this trial did not confirm. Evidence: not-supported. (Source 6)
• A meta-analysis pooling the prescription active vitamin D drugs calcitriol and alfacalcidol - which it calls 'D-hormones' - reported a halving of overall fracture rate, but the two trials that looked specifically at calcitriol and spinal fracture gave a non-significant result. The pooled figure is not calcitriol's own effect and is not evidence about ordinary vitamin D supplements. Evidence: disputed. (Source 7)
• A 128-patient double-blind trial comparing calcitriol with cholecalciferol found neither improved brachial artery flow-mediated dilation or markers of inflammation over 6 months, although each moved the blood test it was expected to move. Evidence: not-supported. (Source 8)

Interactions

• Calcium supplements (label): Calcitriol's whole job is to increase calcium absorption, so extra calcium on top of it can push blood calcium too high. The label says uncontrolled intake of additional calcium-containing preparations should be avoided. (Source 9)
• Vitamin D supplements (cholecalciferol, ergocalciferol) and other vitamin D derivatives (label): Taking a vitamin D supplement alongside calcitriol adds a second source of the same signal and can cause hypercalcaemia; the label says pharmacological doses should be withheld during treatment. (Source 9)
• Magnesium-containing preparations such as antacids (label): In people on chronic renal dialysis this combination can raise blood magnesium to dangerous levels, so the label says they should not be taken together. (Source 9)
• Phosphate-binding agents (label): Calcitriol itself changes how phosphate moves in the gut, kidney and bone, so the amount of binder has to be re-set against the measured serum phosphate. (Source 9)
• Thiazide diuretics (case reports): Thiazides make the kidney hold on to calcium. Added to calcitriol, which pushes calcium in from the gut, blood calcium can rise too far; the label cites reports of hypercalcaemia on the combination. (Source 9)
• Digitalis (digoxin and related drugs) (label): A high blood calcium makes the heart more sensitive to digitalis, so hypercalcaemia in someone on digitalis may set off an arrhythmia. (Source 9)
• Cholestyramine (label): It binds fat-soluble vitamins in the gut and may stop calcitriol being absorbed. (Source 9)
• Ketoconazole (pharmacokinetic study): Ketoconazole blocks the enzymes that both make and break down calcitriol; it lowered the body's own calcitriol in healthy men, but its effect on prescribed calcitriol has not been studied. (Source 9)
• Phenytoin and phenobarbital (and other enzyme-inducing anticonvulsants) (label): They speed up vitamin D breakdown, lowering the body's own 25-hydroxyvitamin D, so more calcitriol may be needed. (Source 9)
• Corticosteroids (label): Steroids block calcium absorption while calcitriol promotes it, so the two work against each other. (Source 9)
• Dietary calcium, especially a sudden increase in dairy products (label): An abrupt rise in calcium from food can trigger hypercalcaemia in someone taking calcitriol, which is why dietary calcium intake is estimated and adjusted rather than left free. (Source 10)
• Alcohol (no documented calcitriol-specific interaction found) (label): We found no interaction between calcitriol and alcohol in the labels parsed or the systematic reviews searched. The label's drug-interactions section names cholestyramine, phenytoin, phenobarbital, thiazides, digitalis, ketoconazole, corticosteroids, phosphate binders, vitamin D, calcium supplements and magnesium, and does not mention alcohol. (Source 9)

Stopping it

• There is no withdrawal syndrome described for calcitriol. What the literature and the label describe is the opposite problem: stopping is the treatment for its main harm. The label instructs that treatment be stopped immediately if hypercalcaemia develops and that calcium and phosphate then be checked daily. (Source 10)
• Because calcitriol has a short biological half-life, a raised blood calcium normalises within a few days of stopping - much faster than after vitamin D3 preparations. That is a practical difference between the active hormone and a supplement. (Source 11)
• Switching the other way is slow: the label notes that after a change from ergocalciferol to calcitriol it may take several months for the ergocalciferol level in the blood to return to baseline. (Source 12)

What goes wrong

A phase III trial of high-dose calcitriol added to docetaxel in castration-resistant prostate cancer was stopped early because more men in the calcitriol arm died. (Source 6)

• Randomized trial, Moderate certainty.
• Size: 953 men randomised.
• Who: Men with metastatic castration-resistant prostate cancer.
• How long: median follow-up 11.7 months for those alive at last assessment.
• Result: Median overall survival 17.8 months (95% CI 16.0 to 19.5) with high-dose calcitriol versus 20.2 months (18.8 to 23.0) in the control arm (log-rank P = .002); hazard ratio 1.33 after adjustment (P = .019) - that is, an absolute loss of about 2.4 months of median survival. Docetaxel toxicity leading to dose modification was more frequent in the calcitriol arm (31% versus 15%).
• Funding: industry-funded (open-label trial of the DN-101 calcitriol formulation)

Limit of this finding: The arms differed in more than calcitriol: the calcitriol arm had weekly docetaxel and the control arm docetaxel every 3 weeks plus prednisone, and the authors say the difference 'might be due to either weekly docetaxel dosing ... or DN-101 therapy'. A reader should not conclude calcitriol alone shortened survival, nor that it is safe at these doses.

At an interim analysis, more deaths were noted in the ASCENT arm, and the trial was halted. The median-follow-up for patients alive at last assessment was 11.7 months. Median OS was 17.8 months (95% CI, 16.0 to 19.5) in the ASCENT arm and 20.2 months (95% CI, 18.8 to 23.0) in the control arm (log-rank P = .002). Survival remained inferior after adjusting for baseline variables (hazard ratio, 1.33; P = .019). The two arms were similar in rates of total and serious adverse events. The most frequent adverse events were GI (reported in 75% of patients), and blood and lymphatic disorders (48%). Docetaxel toxicity leading to dose modification was more frequent in the ASCENT (31%) than in the control arm (15%).

Hypercalcaemia is the central harm of calcitriol, occurring in about one in three patients in the hypoparathyroidism studies in the label, and chronic hypercalcaemia can calcify soft tissue. (Source 11)

• Expert review, not systematic, Low certainty.
• Size: not stated as a denominator in the label text.
• Who: People given calcitriol for hypoparathyroidism and pseudohypoparathyroidism in the registration studies.
• How long: not stated.
• Result: Hypercalcaemia on at least one occasion in about 1 in 3 patients, hypercalciuria in about 1 in 7, and raised serum creatinine in about 1 in 6 (about half of whom had normal levels at baseline). Early symptoms: weakness, headache, somnolence, nausea, vomiting, dry mouth, constipation, muscle and bone pain, metallic taste, anorexia. Late: polyuria, polydipsia, weight loss, pancreatitis, ectopic calcification, nephrocalcinosis, hypertension, cardiac arrhythmias and rarely overt psychosis.
• Funding: industry (manufacturer's label data)

Limit of this finding: The label gives these as '1 in 3', '1 in 7' and '1 in 6' without stating how many patients were studied or over how long, and there is no placebo comparison. A reader should not treat them as rates measured against an untreated group.

In clinical studies on hypoparathyroidism and pseudohypoparathyroidism, hypercalcemia was noted on at least one occasion in about 1 in 3 patients and hypercalciuria in about 1 in 7 patients. Elevated serum creatinine levels were observed in about 1 in 6 patients (approximately one half of whom had normal levels at baseline). In concurrent hypercalcemia and hyperphosphatemia, soft-tissue calcification may occur; this can be seen radiographically (see WARNINGS ).

Even applied to the skin, calcitriol raised blood calcium above normal in a quarter of monitored subjects, and caused hypercalciuria and kidney stones in a year-long study. (Source 13)

• Randomized trial, Low certainty.
• Size: 419 subjects on ointment versus 420 on vehicle in the pooled 8-week trials; 74 and 79 with laboratory monitoring; 324 in the 52-week open-label trial.
• Who: People aged 13 to 87 with mild to moderate chronic plaque psoriasis.
• How long: 8 weeks in the controlled trials; up to 52 weeks open-label.
• Result: Hypercalcaemia in 24% (18 of 74) on active drug versus 16% (13 of 79) on vehicle - an absolute difference of 8 percentage points - with elevations less than 10% above the upper limit of normal. In the open-label year: laboratory test abnormality 8%, urine abnormality 4%, hypercalciuria 3%, skin discomfort 3%. Kidney stones were reported in 3 subjects and confirmed in two. Skin discomfort 3% versus 2% and pruritus 1% versus 1% in the controlled trials.
• Funding: industry (manufacturer's label data)

Limit of this finding: The vehicle arm's hypercalcaemia rate was 16%, so most of the 24% is background: a reader should not read 24% as the drug's attributable rate. The trials in this section enrolled people aged 13 and over, while the product is labelled from age 2, and the sentence giving the size of the elevations carries a stray closing bracket in the label. The label's own arithmetic does not close: the 419 people in the pooled trials are split as mild (105) to moderate (313), which adds to 418, although the sex split (284 and 135) and the race split (372 and 47) both add to 419 correctly. The label also prints its table caption as 'Selected Averse Events', its own misspelling of 'Adverse', and leaves an unmatched closing bracket in the sentence giving the size of the calcium rises. All three are in the source and are quoted as printed. The section's own opening disclaimer, now included, says rates from one drug's trials cannot be compared directly with another drug's.

Among subjects having laboratory monitoring, hypercalcemia was observed in 24% (18/74) of subjects exposed to active drug and in 16% (13/79) of subjects exposed to vehicle, the elevations were less than 10% above the upper limit of normal ) [see Warnings and Precautions ( 5.1) ]. The open label trial enrolled 324 subjects with psoriasis who were treated for up to 52 weeks and included 239 subjects exposed for 6 months and 116 subjects exposed for one year. Adverse events reported at a rate of greater than or equal to 3% of subjects treated with VECTICAL Ointment were lab test abnormality (8%), urine abnormality (4%), psoriasis (4%), hypercalciuria (3%), and discomfort of skin (3%). Kidney stones were reported in 3 subjects and confirmed in two.

Cumulative calcitriol treatment for postsurgical hypoparathyroidism was associated with a measurable decline in kidney function. (Source 14)

• Cohort study, Very low certainty.
• Size: 101 patients with permanent postsurgical hypoparathyroidism.
• Who: People who had total thyroidectomy between 1996 and 2016 at one tertiary hospital in Brussels and were still on calcitriol; pre-existing renal insufficiency and active malignancy excluded.
• How long: up to 12 years of follow-up.
• Result: Renal function declined at a rate of 1.06 mL/min/1.73 m2 per year of calcitriol therapy (p=0.027) in a multivariate linear regression correcting for mean calcium-phosphate product and age.
• Funding: not stated.

Limit of this finding: A retrospective chart review in one hospital with no comparison group: the association cannot separate the drug from the hypoparathyroidism it treats. The authors call it the first such demonstration, which means it is unreplicated. The paper's title says calcitriol 'Leads to Renal Function Decline', which a retrospective look back at records cannot establish; the study found a statistical association. The abstract also gives 101 as the number of people identified, not the number analysed after its exclusions, so the 1.06 mL/min per year figure has no stated denominator.

We found a statistically significant (p=0.027) relationship between the duration of calcitriol treatment and renal function decline at a rate of 1.06 ml/min/1.73 m2 per year of calcitriol therapy. Our study, although being retrospective, is the first one to demonstrate a relationship between the cumulative use of calcitriol therapy and renal function decline.

What the evidence supports

Topical calcitriol cleared mild-to-moderate plaque psoriasis in about one in five subjects over 8 weeks, against 7% to 14% on vehicle ointment. (Source 5)

• Randomized trial, Moderate certainty.
• Size: 839 subjects across two trials (209, 209, 210 and 211 per arm)
• Who: Adults with plaque psoriasis rated mild or moderate; mean age 48, 66% male.
• How long: 8 weeks, twice daily.
• Result: Clear or minimal disease with at least a two-grade improvement: 23.4% versus 14.4% (study 1) and 20.5% versus 6.6% (study 2) - absolute differences of 9.0 and 13.9 percentage points, so roughly 11 and 7 people treated for one extra success.
• Funding: industry-funded (manufacturer's registration trials, in the label)

Limit of this finding: These two trials enrolled people from 13 years old upwards, while the ointment is labelled from age 2, so there is no trial evidence here for children aged 2 to 12. In the label's table the first two columns are Study 1 and the last two Study 2, so each ointment percentage must be read against the vehicle percentage beside it, not across studies.

Success was defined as "Clear or Minimal" (up to light red or pink in coloration, surface dryness with some white coloration, and slight elevation above normal skin) with at least a 2-grade change from baseline. The success rates are displayed in the Table 2. Table 2. Percentage of Subjects with Clear or Minimal Disease AND Two Grade Improvement at End of Treatment (8 weeks) Study 1 Study 2 VECTICAL Ointment (N = 209) Vehicle Ointment (N = 209) VECTICAL Ointment (N = 210) Vehicle Ointment (N = 211) 23.4% 14.4% 20.5% 6.6%

Calcitriol is not a vitamin D supplement and is not interchangeable with one: it is the hormone, and a review of the terminology states active metabolites are not nutrients. (Source 15)

• Expert review, not systematic, Certainty not rated.
• Size: not applicable - a terminology and physiology review.
• Who: not applicable.
• How long: not applicable.
• Result: The review states calcitriol is the hormone that upregulates active calcium transport from the gut and suppresses parathyroid hormone secretion, that calcidiol and calcitriol are not nutrients, and that cholecalciferol is the only form of vitamin D that should be considered for fortification or dietary supplementation.
• Funding: not stated.

Limit of this finding: This paper spells the 25-hydroxyvitamin D metabolite three different ways - 'calcifediol' in its title, 'calcidiol' in the body and 'Calcidol' in the sentence quoted here. All three mean the same compound; the spelling is reproduced as printed rather than corrected. It is also a narrative review stating its author's conclusion, not a trial result.

Calcidol is the major circulating metabolite of cholecalciferol, while calcitriol is the hormone that upregulates the active transport of calcium from the gut, and which suppresses parathyroid hormone secretion. Nutrition policy papers and guidelines leave unstated the obvious fact that calcidiol and calcitriol are not nutrients, and that those metabolites are not pertinent to food fortification or dietary supplementation. Recent evidence shows that ergocalciferol is not stable with storage, and it is far more susceptible to breakdown with cooking and baking than is cholecalciferol. Therefore, it must be concluded that cholecalciferol is the only form of vitamin D that should be considered in the context of the nutritional functions of fortification and supplementation.

What the evidence does not support

Vitamin D compounds including calcitriol lower parathyroid hormone in chronic kidney disease without any proven benefit on outcomes patients feel, and with more hypercalcaemia and hyperphosphataemia. (Source 16)

• Meta-analysis, Low certainty.
• Size: 3,667 participants across 76 trials.
• Who: People with chronic kidney disease, on and off dialysis.
• How long: varies by trial.
• Result: No reduction in risk of death, bone pain, vascular calcification or parathyroidectomy. Established vitamin D sterols versus placebo: hypercalcaemia relative risk 2.37 (95% CI 1.16 to 4.85) and hyperphosphataemia RR 1.77 (1.15 to 2.74), with no consistent reduction in parathyroid hormone. Newer analogues: hypercalcaemia RR 5.15 (1.06 to 24.97), parathyroid hormone weighted mean difference -10.77 pmol/L (-20.51 to -1.03).
• Funding: not stated in the abstract.

Limit of this finding: Only 8 of 76 trials reported mortality, so 'no reduction in risk for death' means the trials could not detect one, not that one was excluded. The review pools calcitriol with alfacalcidol and 24,25(OH)2 vitamin D3 under 'established sterols', so the hypercalcaemia relative risk is not calcitriol-specific, and relative risks are given without the underlying event rates. The hypercalcaemia figure for the newer analogues, a relative risk of 5.15, has a confidence interval running from 1.06 to 24.97 - up to roughly a 24-fold difference - so it is far too imprecise to quote as a risk number.

Vitamin D compounds did not reduce the risk for death, bone pain, vascular calcification, or parathyroidectomy. Compared with placebo, established vitamin D sterols were associated with an increased risk for hypercalcemia (relative risk, 2.37 [95% CI, 1.16 to 4.85]) and hyperphosphatemia (relative risk, 1.77 [CI, 1.15 to 2.74]) but did not show a consistent reduction in parathyroid hormone (PTH) levels. Compared with placebo, more recently developed vitamin D analogues were associated with hypercalcemia (relative risk, 5.15 [CI, 1.06 to 24.97]) but not hyperphosphatemia, and levels of PTH were reduced (weighted mean difference, -10.77 pmol/L [CI, -20.51 to -1.03 pmol/L]). For suppression of PTH, intravenous administration was superior to oral vitamin D, but higher intravenous doses were used. LIMITATIONS: Few studies reported patient-level outcomes, including mortality (8 of 76 trials), and only 5 trials directly compared the effects of treatment with newer vitamin D compounds versus established ones. Heterogeneity in some comparisons remained unexplained by metaregression analyses. CONCLUSION: Vitamin D compounds do not consistently reduce PTH levels, and beneficial effects on patient-level outcomes are unproven.

In 60 trials in dialysis patients, no form or schedule of vitamin D compound changed the risk of death, bone pain or parathyroidectomy. (Source 3)

• Systematic review, Low certainty.
• Size: 2,773 patients across 60 studies.
• Who: People with chronic kidney disease requiring dialysis.
• How long: varies by trial.
• Result: No altered risk of death, bone pain or parathyroidectomy. Against placebo, vitamin D compounds lowered parathyroid hormone at the cost of raised serum phosphorus. Trends toward increased hypercalcaemia and serum calcium did not reach statistical significance. The reviewers state all studies were inadequately powered for clinical outcomes.
• Funding: not stated (Cochrane review)

Limit of this finding: The review says 'marked heterogeneity in reporting of outcomes resulted in few data available for formal meta-analysis', so most of these statements rest on narrative synthesis rather than pooled estimates. A reader should not read 'no altered risk' as a demonstration of no effect.

No formulation, route, or schedule of administration was associated with altered risks of death, bone pain, or parathyroidectomy. Marked heterogeneity in reporting of outcomes resulted in few data available for formal meta-analysis. Compared with placebo, vitamin D compounds lowered serum PTH at the expense of increasing serum phosphorus. Trends toward increased hypercalcaemia and serum calcium did not reach statistical significance but may be clinically relevant.

The earlier randomised trial that suggested high-dose calcitriol improved survival in prostate cancer did not meet its own primary endpoint. (Source 17)

• Randomized trial, Low certainty.
• Size: 250 patients randomised.
• Who: Men with progressive metastatic androgen-independent prostate cancer.
• How long: PSA response within 6 months of enrolment.
• Result: PSA response within 6 months - the primary endpoint - 58% with calcitriol versus 49% with placebo (P = .16); overall PSA response 63% versus 52% (P = .07). The hazard ratio for death of 0.67 (P = .04) came from a multivariate analysis of a secondary outcome.
• Funding: industry-funded (DN-101 formulation, ASCENT Investigators)

Limit of this finding: Survival was not this trial's primary endpoint and the authors say so. DN-101 is a high-dose weekly oral calcitriol formulation used in cancer trials, not the marketed calcitriol used for kidney and bone disease. The 24.5-month figure was never observed: the median had not been reached, and the number was calculated back from a hazard ratio, so it is a projection and must not be read as a measured survival benefit. The confirmatory phase III trial of the same regimen, ASCENT-II, was then stopped early because more men died on the drug, so this 2007 signal was not confirmed but reversed. The paper also reports grade 3/4 side effects as less common on the drug (58%) than on placebo (70%), and two different pairs of PSA response rates for the same trial; both are its own figures and neither supports a benefit.

Within 6 months, PSA responses were seen in 58% in DN-101 patients and 49% in placebo patients (P = .16). Overall, PSA response rates were 63% (DN-101) and 52% (placebo), P = .07. Patients in the DN-101 group had a hazard ratio for death of 0.67 (P = .04) in a multivariate analysis that included baseline hemoglobin and performance status. Median survival has not been reached for the DN-101 arm and is estimated to be 24.5 months using the hazard ratio, compared with 16.4 months for placebo.

Neither calcitriol nor cholecalciferol improved blood-vessel function in chronic kidney disease, and the two moved different blood tests - the clearest demonstration that they are not interchangeable. (Source 8)

• Randomized trial, Moderate certainty.
• Size: 128 randomised, 115 completed.
• Who: Adults with eGFR 15-44 mL/min per 1.73 m2 and 25-hydroxyvitamin D below 30 ng/mL at one US centre.
• How long: 6 months.
• Result: Flow-mediated dilation did not improve in either arm (calcitriol 4.8 plus or minus 3.1% to 5.1 plus or minus 3.6%; cholecalciferol 5.2 plus or minus 5.2% to 4.7 plus or minus 3.6%). 25-hydroxyvitamin D rose 11.0 plus or minus 9.5 ng/mL on cholecalciferol versus -0.8 plus or minus 4.8 on calcitriol (P<0.001); parathyroid hormone fell -22.1 pg/mL on calcitriol versus -0.3 on cholecalciferol (P=0.004).
• Funding: not stated in the abstract (University of Colorado investigator trial)

Limit of this finding: Two printing problems in the published record, left as the source has them. 'per 1.73 m2and serum' is a lost superscript: it means 'per 1.73 m2 and serum', with the 2 as a square. And the interquartile ranges printed as '[-48.7-3.5]' and '[-22.6-16.9]' mean -48.7 to 3.5 and -22.6 to 16.9, with the hyphen doing duty both as a minus sign and as the word 'to'.

After 6 months, neither calcitriol nor cholecalciferol treatment resulted in a significant improvement in flow-mediated dilation (mean±SD percentage flow-mediated dilation; calcitriol: baseline 4.8±3.1%, end of study 5.1±3.6%; cholecalciferol: baseline 5.2±5.2%, end of study 4.7±3.6%); 25-hydroxyvitamin D levels increased significantly in the cholecalciferol group compared with the calcitriol group (cholecalciferol: 11.0±9.5 ng/ml; calcitriol: -0.8±4.8 ng/ml; P<0.001). Parathyroid hormone levels decreased significantly in the calcitriol group compared with the cholecalciferol group (median [interquartile range]; calcitriol: -22.1 [-48.7-3.5] pg/ml; cholecalciferol: -0.3 [-22.6-16.9] pg/ml; P=0.004). CONCLUSIONS: Six months of therapy with calcitriol or cholecalciferol did not improve vascular endothelial function or improve inflammation in patients with CKD.

Where the evidence is mixed

In pre-dialysis chronic kidney disease, vitamin D compounds lowered parathyroid hormone substantially but raised serum phosphorus and calcium, with no effect on mortality or progression to dialysis. (Source 2)

• Systematic review, Low certainty.
• Size: 894 patients across 16 studies.
• Who: People with chronic kidney disease not requiring dialysis.
• How long: varies by trial.
• Result: Parathyroid hormone mean difference -49.34 pg/mL (95% CI -85.70 to -12.97) across 4 studies and 153 patients; more than 30% reduction in parathyroid hormone from baseline, risk ratio 7.87 (4.87 to 12.73) in 264 patients. End-of-treatment serum phosphorus rose by 0.37 mg/dL (0.09 to 0.66) and serum calcium by 0.20 mg/dL (0.17 to 0.23). No formulation, route or schedule altered mortality risk or need for dialysis.
• Funding: not stated (Cochrane review)

Limit of this finding: Calcitriol is one of several 'established' compounds pooled here alongside alfacalcidol and 24,25(OH)2 vitamin D3; the parathyroid hormone estimate rests on 4 studies and 153 patients. A reader should not read these as calcitriol-specific figures. One of these estimates is incompletely reported in the review itself: the figure for a more than 30% fall in parathyroid hormone names 264 patients but no number of studies, so it cannot be placed against the 16 studies and 894 patients in the headline.

Sixteen studies (894 patients) were included. No formulation, route, or schedule of vitamin D compound was found to alter the mortality risk or need for dialysis. Vitamin D compounds significantly lowered serum PTH (4 studies, 153 patients: MD -49.34 pg/mL, 95% CI -85.70 to -12.97 (-5.6 pmol/L, 95% CI -9.77 to -1.48)) and were more likely to reduce serum PTH > 30% from baseline value (264 patients: RR 7.87, 95% CI 4.87 to 12.73). Vitamin D treatment was associated with increased end of treatment serum phosphorus (3 studies, 140 patients: MD 0.37 mg/dL, 95% CI 0.09, 0.66 (0.12 mmol/L, 95% CI 0.03, 0.21)) and serum calcium (5 studies, 184 patients: MD 0.20 mg/dL, 95% CI 0.17 to 0.23 (0.05 mmol/L, 95% CI 0.04 to 0.06)).

Across 177 trials of topical psoriasis treatments, vitamin D analogues beat placebo but corticosteroids worked at least as well and caused fewer local adverse events. (Source 18)

• Systematic review, Moderate certainty.
• Size: 34,808 participants across 177 randomised controlled trials.
• Who: People with chronic plaque psoriasis, including scalp and inverse psoriasis.
• How long: trials of varying length; long-term defined as at least 24 weeks.
• Result: Vitamin D analogues on the body: standardised mean difference ranging from -0.67 (95% CI -1.04 to -0.30) to -1.66 (-2.66 to -0.67), which the review translates to 0.8 to 1.9 points on a 6-point global improvement scale. Potent corticosteroids SMD -0.89 (-1.06 to -0.72) and very potent -1.56 (-1.87 to -1.26), or 1.0 and 1.8 points. On the scalp, vitamin D was significantly less effective than potent and very potent corticosteroids.
• Funding: not stated (Cochrane review)

Limit of this finding: This review covers the whole class of vitamin D analogues - calcipotriol, becocalcidiol, paricalcitol and others - and the individual estimates quoted rest on single small studies (119 and 11 participants). A reader should not read these as calcitriol-specific effects. The review does not give corticosteroids a clean bill of health: its conclusion goes on to say that for people on long-term corticosteroid treatment there is still a lack of evidence about the risk of skin thinning, and that safety data are needed - and its own results note that only 25 of the 177 trials assessed skin thinning at all, using measurements that detect only the most severe cases. One of the published confidence intervals also has an unmatched bracket, which is the journal's own typographical error.

When used on the body, most vitamin D analogues were significantly more effective than placebo, with the standardised mean difference (SMD) ranging from -0.67 (95% CI -1.04 to -0.30; 1 study, 119 participants) for twice-daily becocalcidiol to SMD -1.66 (95% CI -2.66 to -0.67; 1 study, 11 participants) for once-daily paricalcitol. On a 6-point global improvement scale, these effects translate into 0.8 and 1.9 points, respectively. Most corticosteroids also performed better than placebo; potent corticosteroids (SMD -0.89; 95% CI -1.06 to -0.72; I² statistic = 65.1%; 14 studies, 2011 participants) had smaller benefits than very potent corticosteroids (SMD -1.56; 95% CI -1.87 to -1.26); I² statistic = 81.7%; 10 studies, 1264 participants). On a 6-point improvement scale, these benefits equate to 1.0 and 1.8 points, respectively. Dithranol, combined treatment with vitamin D/corticosteroid, and tazarotene all performed significantly better than placebo.Head-to-head comparisons of vitamin D for psoriasis of the body against potent or very potent corticosteroids had mixed findings. For both body and scalp psoriasis, combined treatment with vitamin D and corticosteroid performed significantly better than vitamin D alone or corticosteroid alone. Vitamin D generally performed better than coal tar, but findings relative to dithranol were mixed. When applied to psoriasis of the scalp, vitamin D was significantly less effective than both potent corticosteroids and very potent corticosteroids. Indirect evidence from placebo-controlled trials supported these findings.For both body and scalp psoriasis, potent corticosteroids were less likely than vitamin D to cause local adverse events, such as burning or irritation.

A randomised trial found calcitriol and alfacalcidol controlled calcium equally in hypoparathyroidism, and both left most patients with high phosphate and high urinary calcium. (Source 4)

• Randomized trial, Low certainty.
• Size: 45 patients (20 continued alfacalcidol, 25 switched to calcitriol)
• Who: People with idiopathic hypoparathyroidism already at optimal calcium control, at a tertiary centre.
• How long: 6 months.
• Result: Serum calcium at 6 months 8.7 plus or minus 0.4 versus 8.9 plus or minus 0.4 mg/dL (P = 0.13). A majority in both arms had hyperphosphataemia (75% versus 76%), hypercalciuria (75% versus 72%) and elevated FGF23.
• Funding: not stated in the abstract.

Limit of this finding: An open-label trial - nobody was blinded - in 45 people at a single tertiary centre over 6 months, in idiopathic hypoparathyroidism. It compares two prescription active vitamin D drugs with each other and says nothing about vitamin D supplements.

Patients receiving alfacalcidol and calcitriol had comparable serum calcium at 6 months (8.7 ± 0.4 vs 8.9 ± 0.4 mg/dL, P = 0.13). Their median [interquartile range (IQR)] dose at 6 months was 2.0 (1.0-2.5) and 0.75 (0.5-1.0) µg/d, respectively. Serum 1,25(OH)2D levels were physiological in both (35.3 ± 11.6 and 32.3 ± 16.9 pg/mL). Serum phosphate and calcium excretion were comparable in 2 arms. A majority had hyperphosphatemia (75% vs 76%), hypercalciuria (75% vs 72%), and elevated FGF23

A meta-analysis reported that calcitriol and alfacalcidol together halve fracture rates, but the calcitriol-specific spinal fracture result was not statistically significant. (Source 7)

• Meta-analysis, Low certainty.
• Size: 17 randomised controlled trials meeting inclusion criteria.
• Who: Healthy, osteopenic or osteoporotic patients, with and without corticosteroid exposure.
• How long: varies by trial.
• Result: Pooled 'D-hormone' effect on bone loss in patients not on corticosteroids: effect size 0.39 (p<0.001). Overall fracture relative risk 0.52 (0.46; 0.59), vertebral 0.53 (0.47; 0.60), non-vertebral 0.34 (0.16; 0.71). But only two studies addressed calcitriol and spinal fracture rate specifically: 'None of them provided significant results', global RR 0.33 (0.07; 1.51).
• Funding: not stated in the abstract.

Limit of this finding: 'D-hormones' in this paper means the prescription active vitamin D drugs alfacalcidol and calcitriol pooled together. It does not mean ordinary vitamin D - cholecalciferol or ergocalciferol - so the halving of fracture rate (RR 0.52) is not calcitriol's own effect and is not evidence about vitamin D supplements of any kind. The two trials that did isolate calcitriol gave RR 0.33 with a confidence interval of 0.07 to 1.51, which crosses 1 and therefore shows no effect; the review says as much itself. Trial quality scores ranged from 20% to 100%. In the quoted text 'CS' is corticosteroids and 'ES' is effect size; 'DH' is never spelled out anywhere in the source.

D-hormones significantly reduced the overall fracture rates: RR=0.52 (0.46; 0.59) and both vertebral and non-vertebral fractures: RR=0.53 (0.47; 0.60) and RR=0.34 (0.16; 0.71), respectively. No statistical difference in response was observed between results from studies on healthy and osteoporotic patients or depending on the fact that controls were allowed to calcium supplementation. Treatment with D-hormones was evaluated for maintaining spinal bone mass in five trials of patients with CS-induced osteoporosis, and provided ES=0.43 at p<0.001. Only two studies specifically addressed the effects of calcitriol on spinal fracture rate. None of them provided significant results, and the global RR did not reach the significance level as well: RR=0.33 (0.07; 1.51).

Where the research disagrees

Whether 'vitamin D' means calcitriol or cholecalciferol when the two are discussed together

• Vieth, European Journal of Clinical Nutrition, narrative review of terminology and physiology: Nutrition policy papers and guidelines leave unstated the obvious fact that calcidiol and calcitriol are not nutrients, and that those metabolites are not pertinent to food fortification or dietary supplementation. (Source 15)
• Kendrick and colleagues, randomised double-blind trial in chronic kidney disease, randomised controlled trial, 128 patients, 6 months: 25-hydroxyvitamin D levels increased significantly in the cholecalciferol group compared with the calcitriol group (cholecalciferol: 11.0±9.5 ng/ml; calcitriol: -0.8±4.8 ng/ml; P<0.001). Parathyroid hormone levels decreased significantly in the calcitriol group compared with the cholecalciferol group (median [interquartile range]; calcitriol: -22.1 [-48.7-3.5] pg/ml; cholecalciferol: -0.3 [-22.6-16.9] pg/ml; P=0.004). (Source 8)

Whether high-dose calcitriol helps or harms in castration-resistant prostate cancer

• Beer and colleagues, ASCENT phase II investigators, double-blind randomised trial, 250 patients; survival was a secondary outcome: This study suggests that DN-101 treatment was associated with improved survival, but this will require confirmation because survival was not a primary end point. (Source 17)
• Scher and colleagues, ASCENT-2 phase III investigators, open-label randomised phase III trial, 953 men, halted at interim analysis: Median OS was 17.8 months (95% CI, 16.0 to 19.5) in the ASCENT arm and 20.2 months (95% CI, 18.8 to 23.0) in the control arm (log-rank P = .002). Survival remained inferior after adjusting for baseline variables (hazard ratio, 1.33; P = .019). The two arms were similar in rates of total and serious adverse events. The most frequent adverse events were GI (reported in 75% of patients), and blood and lymphatic disorders (48%). Docetaxel toxicity leading to dose modification was more frequent in the ASCENT (31%) than in the control arm (15%). CONCLUSION: ASCENT treatment was associated with shorter survival than the control. (Source 6)

How much

• Reference intake: Dosing is set by the prescriber and titrated against blood calcium and phosphate, not chosen by the reader. As a position, the FDA label cited here (DailyMed SPL for CALCITRIOL capsules, effective 2026-07-10) states that the effectiveness of calcitriol therapy is predicated on each patient receiving an adequate daily intake of calcium, and advises a dietary calcium intake of at least 600 mg daily. (Source 19)
• Upper limit: There is no upper intake level for calcitriol in the sense used for nutrients, because it is a hormone, not a nutrient. As a position, the label's ceiling is biochemical rather than numerical: it instructs that treatment stop immediately if hypercalcaemia develops, that the product of serum calcium and phosphate not be allowed to exceed 70 mg2/dL2 - that is, 70 in units of milligrams per decilitre squared - and that pharmacological doses of vitamin D be withheld during treatment. (Source 12)
• Studied: The Colorado trial gave calcitriol 0.5 mcg daily or cholecalciferol 2000 IU daily for 6 months in chronic kidney disease. (Source 8)
• Studied: The ASCENT phase III trial used DN-101, a high-dose calcitriol formulation, at 45 mcg weekly with weekly docetaxel - an amount far above anything used for kidney or bone disease. (Source 6)
• Studied: The hypoparathyroidism trial reported a median calcitriol dose at 6 months of 0.75 mcg per day (interquartile range 0.5-1.0) against alfacalcidol 2.0 mcg per day. (Source 4)
• Studied: The topical trials applied calcitriol ointment twice daily for 8 weeks. (Source 5)

A common belief, and what the research shows

The belief: Calcitriol is just a strong vitamin D supplement, so it can be taken alongside the vitamin D in a multivitamin.

What the research shows: They are not the same thing and are not interchangeable. Cholecalciferol is the inactive nutrient; the liver and then the kidney have to convert it, and the kidney step is regulated. Calcitriol is the end hormone, so it bypasses that regulation entirely - which is why the label says pharmacological doses of vitamin D and its derivatives should be withheld during calcitriol treatment to avoid additive effects and hypercalcaemia. A trial that gave the two head to head found cholecalciferol raised 25-hydroxyvitamin D while calcitriol did not, and calcitriol lowered parathyroid hormone while cholecalciferol did not: different drugs with different effects.

Questions and answers

What is it?

Calcitriol is the active vitamin D hormone - 1,25-dihydroxyvitamin D3, also written 1,25-dihydroxycholecalciferol. It is the molecule the body makes from vitamin D3 after the liver and then the kidney each add a hydroxyl group. As a medicine it is a synthetic copy of that hormone, sold as capsules, an oral solution, an intravenous injection and an ointment. It is not the cholecalciferol sold as a vitamin D supplement. (Source 1)

What does it do in the body?

It drives calcium absorption from the gut, works with parathyroid hormone to release calcium from bone, makes the kidney reabsorb more calcium, and directly suppresses the parathyroid gland. In chronic kidney disease the point is that suppression of parathyroid hormone, because a failing kidney cannot make calcitriol itself; in hypoparathyroidism the point is raising a low blood calcium. Giving the finished hormone skips both activation steps and the body's control over them, which is why hypercalcaemia is the harm that follows it everywhere. (Source 1)

Is it good or bad for you?

Good where the body cannot make its own and bad where it is not needed. In hypoparathyroidism and in dialysis-related hypocalcaemia it replaces a missing signal. But in chronic kidney disease the meta-analysis of 76 trials and 3,667 participants found no reduction in death, bone pain, vascular calcification or parathyroidectomy, and an increased risk of hypercalcaemia (relative risk 2.37, 95% CI 1.16 to 4.85) and hyperphosphataemia (1.77, 1.15 to 2.74). At high doses in prostate cancer it was associated with shorter survival. It is a hormone with a narrow margin, not a supplement. (Source 16)

How do you get more of it?

Calcitriol itself is prescription-only and no food or supplement contains it in a usable amount. The body's own supply comes from sunlight on the skin making vitamin D3, the liver converting it to 25-hydroxyvitamin D3, and the kidney converting that to calcitriol, with the body's own synthesis and breakdown regulating the level. The label puts normal daily production at 0.5 to 1.0 mcg, somewhat higher when bone is being built, as in growth or pregnancy. The practical consequence is that a vitamin D supplement raises the precursor, not the hormone - which a trial confirmed when cholecalciferol raised 25-hydroxyvitamin D and calcitriol did not. (Source 1)

If it is harmful, what reduces it?

When calcitriol has done too much, the problem is the high blood calcium it causes, and the remedy is to stop the drug. The label says treatment should be stopped immediately if hypercalcaemia develops and that calcium and phosphate be checked daily until they come back. Because calcitriol has a short biological half-life, a raised calcium normalises within a few days of withdrawal - much faster than after a vitamin D3 preparation, which can take months. Dietary calcium is estimated and adjusted, and extra calcium and vitamin D preparations are kept out. (Source 10)

Why might someone be low in it or missing it?

The body's own calcitriol falls when the kidney cannot make it. The label describes a vitamin-D-resistant state in people with kidney failure, caused by the kidney failing to convert the precursors into the active compound - which is the whole reason the drug exists. Other routes to a low level are loss of the parathyroid signal that switches the kidney enzyme on, poor absorption of fat-soluble vitamins (cholestyramine is named in the label), and drugs that speed vitamin D breakdown such as phenytoin, phenobarbital and carbamazepine. (Source 9)

Which whole foods contain it or feed it?

No whole food supplies calcitriol. Oily fish, egg yolk, liver and fortified foods supply cholecalciferol, the inactive precursor - and a review of the terminology makes the point sharply: calcidiol and calcitriol are not nutrients and are not relevant to food fortification or dietary supplementation. What food does matter for is calcium: the label singles out an abrupt increase in dietary calcium, such as more dairy products, as something that can trigger hypercalcaemia in someone taking calcitriol. (Source 15)

What happens if you do not have it?

Without calcitriol, calcium is not absorbed properly from the gut and parathyroid hormone is not suppressed. That is the state the drug is prescribed for: in moderate-to-severe chronic renal failure the consequence is secondary hyperparathyroidism and the bone disease that follows it, and in dialysis patients it is hypocalcaemia with metabolic bone disease, including the histological changes of osteitis fibrosa cystica and defective mineralisation. In hypoparathyroidism the consequence is hypocalcaemia and its symptoms. (Source 20)

How can you test for it?

Blood 1,25-dihydroxyvitamin D can be measured, but it is not what guides treatment and it is not the same test as the common vitamin D test, which measures 25-hydroxyvitamin D. What is actually monitored is the consequence: serum calcium twice weekly early on while the amount is being adjusted, daily during any episode of hypercalcaemia, plus phosphate, alkaline phosphatase, creatinine and intact parathyroid hormone. In dialysis patients a fall in alkaline phosphatase usually precedes hypercalcaemia and can warn of it. (Source 10)

References

1. DailyMed (FDA Structured Product Label), Validus Pharmaceuticals LLC. ROCALTROL (calcitriol) capsule and oral solution, DESCRIPTION and CLINICAL PHARMACOLOGY. 2023. Read the source
2. Cochrane Database of Systematic Reviews. Vitamin D compounds for people with chronic kidney disease not requiring dialysis.. 2009. PMID 19821446, DOI 10.1002/14651858.CD008175. Read the source
3. Cochrane Database of Systematic Reviews. Vitamin D compounds for people with chronic kidney disease requiring dialysis.. 2009. PMID 19821349, DOI 10.1002/14651858.CD005633.pub2. Read the source
4. The Journal of Clinical Endocrinology and Metabolism. Alfacalcidol vs Calcitriol in the Management of Patient With Hypoparathyroidism: A Randomized Controlled Trial.. 2021. PMID 33616655, DOI 10.1210/clinem/dgab114. Read the source
5. DailyMed (FDA Structured Product Label), Galderma Laboratories, L.P.. VECTICAL (calcitriol) ointment, section 14 Clinical Studies. 2024. Read the source
6. Journal of Clinical Oncology. Randomized, open-label phase III trial of docetaxel plus high-dose calcitriol versus docetaxel plus prednisone for patients with castration-resistant prostate cancer.. 2011. PMID 21483004, DOI 10.1200/JCO.2010.32.8815. Read the source
7. Osteoporosis International. Efficacy of alphacalcidol and calcitriol in primary and corticosteroid-induced osteoporosis: a meta-analysis of their effects on bone mineral density and fracture rate.. 2004. PMID 14740153, DOI 10.1007/s00198-003-1570-5. Read the source
8. Clinical Journal of the American Society of Nephrology. Cholecalciferol, Calcitriol, and Vascular Function in CKD: A Randomized, Double-Blind Trial.. 2017. PMID 28784657, DOI 10.2215/CJN.01870217. Read the source
9. DailyMed (FDA Structured Product Label), Validus Pharmaceuticals LLC. ROCALTROL (calcitriol) capsule and oral solution, PRECAUTIONS: Drug Interactions. 2023. Read the source
10. DailyMed (FDA Structured Product Label), Hikma Pharmaceuticals USA Inc.. CALCITRIOL capsule, PRECAUTIONS: General. 2026. Read the source
11. DailyMed (FDA Structured Product Label), Validus Pharmaceuticals LLC. ROCALTROL (calcitriol) capsule and oral solution, ADVERSE REACTIONS. 2023. Read the source
12. DailyMed (FDA Structured Product Label), Validus Pharmaceuticals LLC. ROCALTROL (calcitriol) capsule and oral solution, WARNINGS. 2023. Read the source
13. DailyMed (FDA Structured Product Label), Galderma Laboratories, L.P.. VECTICAL (calcitriol) ointment, section 6.1 Clinical Trials Experience. 2024. Read the source
14. Hormone and Metabolic Research. Long-Term Treatment with Calcitriol in Postsurgical Hypoparathyroidism Leads to Renal Function Decline.. 2019. PMID 31207657, DOI 10.1055/a-0902-8476. Read the source
15. European Journal of Clinical Nutrition. Vitamin D supplementation: cholecalciferol, calcifediol, and calcitriol.. 2020. PMID 32704098, DOI 10.1038/s41430-020-0697-1. Read the source
16. Annals of Internal Medicine. Meta-analysis: vitamin D compounds in chronic kidney disease.. 2007. PMID 18087055, DOI 10.7326/0003-4819-147-12-200712180-00004. Read the source
17. Journal of Clinical Oncology. Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT Investigators.. 2007. PMID 17308271, DOI 10.1200/JCO.2006.06.8197. Read the source
18. Cochrane Database of Systematic Reviews. Topical treatments for chronic plaque psoriasis.. 2013. PMID 23543539, DOI 10.1002/14651858.CD005028.pub3. Read the source
19. DailyMed (FDA Structured Product Label), Hikma Pharmaceuticals USA Inc.. CALCITRIOL capsule, PRECAUTIONS: Information for Patients. 2026. Read the source
20. DailyMed (FDA Structured Product Label), Validus Pharmaceuticals LLC. ROCALTROL (calcitriol) capsule and oral solution, INDICATIONS AND USAGE. 2023. Read the source