Calcitriol (1,25-dihydroxyvitamin D, the hormone)

In brief

What calcitriol is: the hormone at the end of the vitamin D pathway

Think of vitamin D as raw ore. Skin makes it from a cholesterol precursor under sunlight, or it arrives in food, and in that form it does almost nothing ^2,5. The liver refines it into 25-hydroxyvitamin D, the storage form that circulates in quantity and that the ordinary blood test measures ^5,32. The kidney then makes the finished product in small, controlled amounts: 1,25-dihydroxyvitamin D, calcitriol, the hormone ^5,22.

It is a hormone in the strict sense endocrinologists use. It is made in one organ in response to signals from others, chiefly parathyroid hormone from the glands in the neck and fibroblast growth factor 23 (FGF23), a hormone made in bone ^10,13. It travels in the blood to distant cells, binds a receptor of the steroid family inside them, and changes which genes they read ^16,19. And it suppresses its own production, both by turning down the enzyme that makes it and by turning up the enzyme that destroys it ^6,55. A review in Nature Reviews Cancer in 2014 put it plainly: vitamin D is not really a vitamin but the precursor of the steroid hormone calcitriol ⁴.

Chemically it is vitamin D3 carrying two extra hydroxyl groups, one at carbon 25 put on in the liver and one at carbon 1 put on in the kidney, in the orientation chemists call alpha ^2,5. Its formula, C27H44O3, was established by mass spectrometry in 1971 ¹. Chemists write it as 1alpha,25-dihydroxyvitamin D3 or 1,25-dihydroxycholecalciferol; calcitriol is its clinical name, and the international nomenclature commission issued formal naming rules for the whole family in 1981 ^2,3,56. Its own breakdown product, an acid made by trimming the side chain, was named calcitroic acid in 1979 ¹⁵.

The quantities are what make it a hormone rather than a nutrient. In healthy children from the age of three, calcitriol runs between 108 and 246 picomoles per liter, while the precursor that is judged sufficient for bone runs between 50 and 125 nanomoles per liter, hundreds of times more (for the precursor, 1 nanogram per milliliter is about 2.5 nanomoles per liter, so that range is 20 to 50 nanograms per milliliter), a range the 2024 Endocrine Society guideline declined to endorse as a target ^20,32,57. The precursor lasts weeks in the blood; calcitriol's plasma half-life is only several hours ^21,58. That is why the two numbers mean such different things, and why measuring the hormone tells you so little about whether someone has had enough vitamin D.

1971: three laboratories, one molecule

In the 1960s the field was split over whether vitamin D acted as itself or through something the body made from it. Egon Kodicek at the Dunn Nutritional Laboratory in Cambridge, after ten years of tracer experiments, concluded that it acted unchanged; in retrospect his radioactive vitamin was too weakly labeled to reveal its metabolites ². Hector DeLuca at Wisconsin, Harry Steenbock's last graduate student, made vitamin D with far higher radioactivity and found it converted to more polar, that is more water-soluble, products, the first being 25-hydroxyvitamin D from the liver ^2,64. It was a reversal in its own right, and it opened the search for the next step.

Three clues already pointed to a hormone. In 1966 Wasserman and Taylor found that vitamin D induced a calcium-binding protein in the intestine of rachitic chicks, chicks with rickets whose amount tracked calcium absorption, a protein that would turn out to be the product of a hormone-regulated gene ³⁴. In 1969 Mark Haussler and Anthony Norman at Riverside found a protein in chick intestinal chromatin, the DNA-protein complex of the nucleus, that bound an active vitamin D metabolite tightly, a receptor two years before anyone knew its ligand ⁶⁵. And in 1970 Fraser and Kodicek reported that the active metabolite was made in the kidney ⁶⁶.

The identification came from all three groups within four months of each other. Kodicek's group gave vitamin D labeled with radioactive carbon and with radioactive hydrogen at carbon 1, and noticed that the active metabolite had lost its hydrogen label, a clue that carbon 1 had been hydroxylated; their paper, dated 26 March 1971, called the molecule a new kidney hormone controlling calcium metabolism ^2,22. DeLuca's laboratory, in April, isolated what they called the peak V metabolite pure from chicken intestine and identified it as 1,25-dihydroxycholecalciferol by mass spectrometry, ultraviolet spectroscopy and chemical reactions, with Michael Holick as first author; their full paper followed in July ^3,67. Norman's group, on 2 July, gave its formula as C27H44O3, showed it was made in the kidney from 25-hydroxyvitamin D, and reported it 4 to 13 times as active as vitamin D3 at moving calcium across the intestine ¹.

The independent historical review in Endocrine Connections credits each group with a part: Kodicek's with the tracer clue and the kidney, Norman's with the chromatin link and the potency, and Holick in DeLuca's group with showing that the new hydroxyl pointed in the alpha direction ². DeLuca's own history tells the same story from inside one of the laboratories, and its account of priority should be read with that in mind ⁶⁴. The molecule was first synthesized chemically by Semmler, and a group led by Milan Uskokovic at Hoffmann-La Roche developed its commercial synthesis in the early 1970s; the clinical name calcitriol came with the drug ².

The kidney's switch: CYP27B1 and the signals that work it

The enzyme that makes calcitriol, CYP27B1, is a member of the cytochrome P450 family, enzymes that add oxygen to molecules, and the kidney is its principal site ^5,6. Its first known master was parathyroid hormone ¹⁰. In 1972, in rats on a low-calcium diet, removing the thyroid and parathyroid glands cut calcitriol production to negligible levels within 40 hours; 20 units a day of parathyroid extract prevented the fall, and 40 units restored production almost to normal within 36 hours, changes the authors showed could not be explained by calcium or phosphorus alone ¹⁰. They called parathyroid hormone a tropin, a stimulator, of the vitamin D hormone ¹⁰.

Calcium and phosphorus act on the same switch ^11,12. In 1971, the more calcium rats had in their diet and blood, the less calcitriol they made, which the authors read as the mechanism by which the gut adapts its calcium absorption to a low intake ¹¹. Two years later the same laboratory showed that inorganic phosphorus controls the kidney's handling of the precursor too ¹². The design is simple: when calcium or phosphate is short, make more of the hormone that brings them in from food; when they are plentiful, make less.

The enzyme was cloned in 1997 by two routes that say a lot about it. Kato's group in Tokyo cloned it from the kidneys of mice lacking the vitamin D receptor, in which the enzyme ran unchecked, and showed that calcitriol suppressed it in normal mice but not in knockouts, proof that the hormone's feedback on its own synthesis runs through its receptor ⁶. Miller and Portale's group in San Francisco cloned the human enzyme from skin keratinocytes, because its expression in kidney was too low, mapped it to chromosome 12, and found two null mutations in a child with type 1 vitamin D-dependent rickets ⁹. Kato's group found four more mutated families the next year ²⁵.

The switch explains a fact that confuses many clinicians. When vitamin D intake falls, parathyroid hormone rises and drives CYP27B1 harder, so calcitriol stays normal or even rises: in records from 3,661 Australian patients, calcitriol and calcium absorption fell only when 25-hydroxyvitamin D dropped to about 10 nmol/L ⁴⁷. The same switch is opened wide in pregnancy, when the plasma pool of calcitriol is increased throughout most of the nine months and the mother's intestinal calcium absorption doubles to supply a fetus that lays down about 30 grams of calcium, 80 percent of it in the third trimester ^58,68.

The phosphatonin story: a bone hormone that brakes the kidney

For two decades after 1971 the control of calcitriol seemed complete: parathyroid hormone, calcium and phosphate. One disease did not fit ⁶⁹. Some patients with small, often hidden tumors wasted phosphate in their urine, developed soft bones, and had inappropriately low calcitriol, and they were cured when the tumor came out; in 1994 an editorial in the New England Journal of Medicine argued that the tumors must be secreting a hormone no one had yet identified ⁶⁹.

It was found in 2000 and 2001 ^44,70. An international consortium studying families with autosomal dominant hypophosphatemic rickets, an inherited rickets passed down from one affected parent in which the kidney wastes phosphate, traced the disease to mutations in a new member of the fibroblast growth factor family, FGF23, the first mutations ever found in a human FGF gene ⁷⁰. Months later, Takeyoshi Yamashita's group at the pharmaceutical laboratory of Kirin Brewery cloned FGF23 from a tumor that caused osteomalacia; recombinant FGF23 lowered blood phosphate in mice within 12 hours, and cells secreting it, implanted into mice, reproduced the whole disease, low calcitriol and rickets included ⁴⁴. The dominant rickets mutations, they showed, sat at the site where FGF23 is normally cut and inactivated ⁴⁴.

In rats, the same group then showed how directly FGF23 acts on calcitriol. After a single injection, calcitriol had fallen by 3 hours and reached its lowest point at 9 hours, the time phosphate first began to drop; FGF23 had cut the kidney's messenger RNA, the working copy of a gene that a cell reads to make protein, for CYP27B1 and raised that for CYP24A1 within an hour, and it did so in rats without parathyroid glands, so parathyroid hormone was not involved ¹³. Mice with the FGF23 gene deleted had high phosphate and high calcitriol from an overactive CYP27B1, grew poorly and died young ⁵⁹. And an injection of calcitriol raised FGF23 within 4 hours, closing a loop in which the hormone summons its own brake ¹³. In 2026 a Boston group found that lysophosphatidic acid, a lipid derived from a kidney metabolite, needs calcitriol's action to raise FGF23 in mouse bone ⁶⁰. In people the evidence that dietary phosphate pulls this brake is thinner: in a randomized crossover study of 10 healthy young men, 5 days of extra dietary phosphate raised plasma phosphate and intact FGF23, and a higher intact FGF23 went with a lower calcitriol, although calcitriol itself did not change significantly ⁷¹.

The last piece was the receptor. In 1997 Kuro-o's group in Tokyo described a mouse with a broken gene they named klotho, which aged early: short life, infertility, hardened arteries, thin skin, osteoporosis and emphysema ⁷². In 2006 the Kirin group showed that klotho converts an ordinary FGF receptor into a specific receptor for FGF23, and that blocking klotho with an antibody made mice deaf to FGF23 ¹⁴. Much of the early FGF23 science, it should be said, came from a company laboratory, and the same company's successor later co-funded the trial that brought an antibody against FGF23 to children ^44,73.

The discovery rewrote kidney medicine. In a cross-sectional study of 80 people with chronic kidney disease in 2005, FGF23 rose early, and once it was accounted for, neither kidney function nor phosphate still predicted calcitriol; the authors concluded that FGF23 may worsen calcitriol deficiency, which a one-time snapshot of 80 people can suggest but not prove ³⁵. In 3,879 adults with stage 2 to 4 kidney disease in the Chronic Renal Insufficiency Cohort (CRIC) study, a high FGF23 was more common than a high parathyroid hormone or a high phosphate at every level of kidney function ⁴². Rising phosphate and FGF23 in kidney disease also induce CYP24A1, so the hormone is both made less and destroyed faster ⁵⁵.

CYP24A1, the off switch

A hormone that can raise blood calcium needs a reliable way to be destroyed. That job belongs to CYP24A1, the 24-hydroxylase, which adds a hydroxyl at carbon 24 of both calcitriol and its precursor, the first step in breaking them down ⁵⁵. Successive oxidations shorten the side chain until the molecule becomes an acid; in 1979 DeLuca's group isolated that acid from rats given labeled calcitriol and named it calcitroic acid ¹⁵. Its first crystal structure, from the rat, was among the advances reviewed in 2012 ⁵⁵.

The enzyme's first product from the precursor, 24,25-dihydroxyvitamin D, was long suspected of having a job of its own, and as late as 2000 its physiological importance was described as unclear ⁷⁴. In 2000, mice with CYP24A1 deleted could not clear calcitriol and mineralized some of their bone poorly; crossing them with mice lacking the vitamin D receptor cured the defect, showing that excess calcitriol, not the missing 24,25-dihydroxyvitamin D, was responsible, and that 24,25-dihydroxyvitamin D was dispensable for bone development ⁷⁴. That verdict was partly reversed in 2018: the same Montreal group found that mice unable to make 24,25-dihydroxyvitamin D healed fractures with smaller, less stiff callus, that 24,25-dihydroxyvitamin D and not calcitriol corrected the defect, and that it acts by binding a protein named FAM57B2 ⁷⁵. A 2026 study of the same signal, under the protein's new name TLCD3B, found it dispensable for reproduction in mice ⁷⁶. None of this has been tested in people.

The human consequences arrived in 2011. Karl Schlingmann, Martin Konrad and colleagues found recessive loss-of-function mutations in CYP24A1 in six children with familial idiopathic infantile hypercalcemia, a disease of severe hypercalcemia, failure to thrive, vomiting, dehydration and calcified kidneys, and in a second group of infants who became severely hypercalcemic after bolus vitamin D prophylaxis ²⁹. The authors connected their finding to the increased incidence of the disease in Britain in the 1950s, when milk products were heavily fortified with vitamin D ²⁹. Adults turned out to carry the same disease: two patients at the National Institutes of Health in 2013 had high calcitriol, normal 25-hydroxyvitamin D, low 24,25-dihydroxyvitamin D, high calcium, suppressed parathyroid hormone and kidney stones ⁴⁹. A 2016 review added that some patients with a single mutated copy are affected, and that first-time calcium stone formers as a group show signs of impaired 24-hydroxylation ³⁸.

The body has a reserve off switch ⁶³. CYP3A4, the liver enzyme that clears many drugs, can also inactivate vitamin D metabolites, and in 2017 a Philadelphia group gave rifampin, a tuberculosis drug that strongly induces CYP3A4, to two patients lacking CYP24A1; over up to 13 months their calcium, urine calcium and calcitriol normalized or improved ⁶³. The same enzyme can do too much: in 2018 the group found two unrelated children with rickets carrying a new mutation that made CYP3A4 destroy calcitriol ten times faster than normal, and twice as fast as CYP24A1 itself ²⁸.

The receptor: from a chromatin protein to a crystal structure

The receptor was found before the hormone ^1,65. In 1969 Haussler and Norman described a protein in the chromatin of chick intestine that bound an active vitamin D metabolite with high affinity, and purified it 167-fold ⁶⁵. Once calcitriol had been identified, Haussler's group showed the hormone itself bound to intestinal chromatin ⁷⁷. The independent history credits Haussler's laboratory with the clearest early evidence for the receptor protein and, later, with its purification and cloning ².

The human receptor was cloned in 1988 from intestine and a cultured cell line: a 1,281-base-pair coding sequence for a protein that belonged to the steroid-receptor gene family and was closest in size and sequence to the receptor for thyroid hormone ¹⁶. The first author worked for a biotechnology company, California Biotechnology ¹⁶. Within months the same circle of laboratories found the first disease-causing mutations in it, in children with rickets that did not respond to the hormone ²⁷.

Its shape came next. In 2000 Rochel, Moras and colleagues at the Institute of Genetics and Molecular and Cellular Biology in Illkirch, France, published the crystal structure of the receptor's ligand-binding domain, the part that holds the hormone, with calcitriol inside it, at a resolution of 1.8 angstroms, an angstrom being a ten-billionth of a meter, about the width of an atom; to get crystals they removed a variable insertion that turned out to be unnecessary for binding the hormone or activating genes ¹⁷. The structure showed the hormone's active shape inside its pocket and explained why some synthetic analogs bind differently ¹⁷. In 2012 the same group used cryo-electron microscopy, imaging of flash-frozen molecules with an electron beam, to picture the whole receptor, paired with its partner the retinoid X receptor, sitting on a DNA target, a complex of about 100 kilodaltons, a kilodalton being a unit of molecular mass, held in an open shape where other regulatory proteins can attach ¹⁸.

On DNA, the receptor reads short sequences called vitamin D response elements. One of the first defined, in 1989, was a 21-base-pair element in the gene for osteocalcin, a bone protein, that made the gene respond to calcitriol ⁶¹. Reviews now speak of thousands of receptor binding sites regulating hundreds of genes in a pattern that differs from one cell type to another ^2,5. In one genome-wide map, made in 2010 by chromatin immunoprecipitation and sequencing, calcitriol-stimulated receptor occupied 2,776 sites in human cells and changed the expression of 229 genes, and the sites were enriched near genes that genome-wide studies had linked to autoimmune diseases and cancers ¹⁹. That enrichment is an association between maps; it does not show that the hormone changes the risk of those diseases.

Not every effect is slow. In 1984 Norman's group found that calcitriol at 130 picomolar raised calcium transport across perfused chick duodenum within 14 minutes, too quickly for new proteins to be made, through mechanisms they called unknown ⁷⁸. Such rapid, non-genomic actions have been proposed to run through a receptor in the cell membrane, but the 2022 history notes that this protein has never been fully characterized at the molecular level ². The receptor has been counted in at least 36 cell types, which is the basis for most claims about calcitriol outside bone; a count of cells that carry a receptor is not a measure of what the receptor does in them ⁷⁹.

What the knockout mice proved: the gut is the main job

In 1997 two groups deleted the receptor in mice ^62,80. Demay's group in Boston found the mice normal at birth, hypocalcemic by 21 days of age, with rising parathyroid hormone, and rachitic by day 35; from four weeks they lost their hair, which dietary vitamin D deficiency never does ⁶². Kato's group in Tokyo saw the same pattern after weaning, with infertility and uterine underdevelopment in females, and most of their mice died within 15 weeks ⁸⁰.

The decisive experiment came a year later. Fed a diet known to prevent secondary hyperparathyroidism in vitamin D-deficient rats, the receptor-knockout mice kept normal blood calcium, never developed hyperparathyroidism, and did not get rickets or osteomalacia; they still went bald ³³. The skeleton, in other words, can be built without the receptor if the minerals reach it some other way ³³. Most of what calcitriol does for bone it does at the intestine, by inducing the transport machinery whose first known part, a calcium-binding protein, had been found in rachitic chicks in 1966 ^33,34. People confirm it. In 1986 a child with hereditary resistance to the hormone, whose calcitriol ran about 100 times normal and who no longer responded to any vitamin D drug, was given calcium infusions at night for 7 months: the rickets healed and bone biopsies showed normal mineralization, although her bone cells still could not respond to calcitriol ⁸¹. It is one patient, but it is the human version of the rescue diet. The hair is a separate story: the receptor is needed for normal hair growth even when minerals are normal ³³.

Bone does receive direct signals ⁸². In rat bone-tumor cells, physiological concentrations of calcitriol, half-maximal at 0.04 ng/mL, raised production of the vitamin K-dependent bone protein osteocalcin sixfold, the first bone protein shown to be specifically switched on by the hormone ⁸². But the knockout and rescue experiments set the order of importance, and that order matters for every argument that extra vitamin D strengthens bone directly.

The receptor gene was also expected to explain who gets osteoporosis. A 1994 Nature paper from Sydney reported that common variants in the receptor gene predicted bone density and accounted for up to 75 percent of its genetic component in healthy people ⁸³. That claim did not survive ⁸⁴. In 2006 the GENOMOS consortium pooled 26,242 participants from nine European research teams and found that the FokI, BsmI, ApaI and TaqI variants made differences in bone density smaller than 0.011 g/cm2 and none in fractures, with odds ratios between 0.98 and 1.02; only one promoter variant, Cdx2, carried a 9 percent lower risk of vertebral fracture, of borderline significance ⁸⁴. The question has not quite closed. In a 2026 genetic analysis of 2,098 people with prediabetes from the D2d trial, 4,000 IU of vitamin D3 a day lowered the risk of diabetes by 19 percent in carriers of the ApaI C allele (hazard ratio 0.81, 95 percent confidence interval 0.66 to 0.99) and not at all in AA carriers (1.02); it is a subgroup analysis made after the data were seen, and it needs replication ⁸⁵.

Made outside the kidney: granulomas, tumors and the placenta

The first hint came from one patient. In 1979 Papapoulos and colleagues followed a 36-year-old man with sarcoidosis, a disease of clustered inflammatory cells called granulomas, who had four episodes of high calcium in seven years, all in summer; his calcitriol ran 26 to 62 pg/mL when calcium was normal and up to 137 pg/mL when it was high, and 3,000 units of vitamin D3 a day reproduced the pattern ⁴⁸. In 1981 a man with sarcoidosis and no kidneys at all became hypercalcemic with calcitriol in his blood, which settled where it was coming from: somewhere other than the kidney ³⁷. In 1983 lung macrophages taken from five of seven patients with sarcoidosis made a calcitriol-like metabolite in culture, most of it from the patient who was hypercalcemic ⁷.

Why macrophages make the hormone became clear in 2006. When human macrophages sense a bacterium through their Toll-like receptors, they switch on both CYP27B1 and the vitamin D receptor, make calcitriol from the precursor in the blood, and use it to induce cathelicidin, an antimicrobial peptide that killed intracellular Mycobacterium tuberculosis in culture ⁸⁶. Calcitriol made this way is a local defense signal; it escapes the kidney's feedback, which is why granulomas can flood the blood with it ³⁸.

A 2016 review lists the causes of calcitriol-driven hypercalcemia: granulomatous diseases such as sarcoidosis and tuberculosis, lymphomas and other tumors that carry CYP27B1, and failures of the off switch ³⁸. The rare causes keep appearing. A 2026 report described a retroperitoneal liposarcoma making the hormone and counted only three earlier sarcoma cases ⁸⁷. Another described a 77-year-old woman whose silicone implant material had migrated into lymph nodes and formed granulomas, with suppressed parathyroid hormone and a calcitriol that was only inappropriately normal ⁸⁸. A third described a man who came home from a sunny holiday in Portugal severely hypercalcemic and was found to have sarcoidosis, the old seasonal story retold ^48,89.

Treatment aims at the granuloma. Corticosteroids are the usual first step, as in the 2026 holiday case, and chloroquine lowered calcitriol and calcium in sarcoidosis in a 1989 report ^89,90. The diagnosis needs care in both directions. In electronic records from 117,395 US adults with sarcoidosis published in 2026, 31.3 percent had a high calcium at some point, only 30.5 percent of those had parathyroid hormone measured, and 3.0 percent met biochemical criteria for primary hyperparathyroidism, three quarters of them never coded as such; sarcoidosis does not protect anyone from a parathyroid adenoma ⁹¹.

The placenta is the other organ that makes the hormone ⁸. Human decidua, the lining of the pregnant uterus, and placenta synthesized calcitriol in culture in 1979 ⁸. In pregnancy the circulating pool of calcitriol is increased through most of gestation and intestinal calcium absorption doubles ^58,68. A 2008 review concluded that these maternal and fetal adaptations supply the fetus with calcium relatively independently of the mother's vitamin D status ⁹². How much of the pregnancy rise comes from the placenta, and how much from the mother's kidney, the culture experiments cannot say. A 2026 review of hypercalcemia in pregnancy notes that in sarcoidosis the two sources add up, the kidney's extra production in pregnancy on top of the granulomas' ⁹³. How much tissue outside the kidney can contribute was seen again in 2025: in 44 people on hemodialysis, whose kidneys make almost no calcitriol, raising the precursor with extended-release calcifediol lifted calcitriol from 9.4 to 50.7 pg/mL, into the normal range in 93 percent of them; most of the authors worked for OPKO Health, which sells the drug ⁹⁴.

The wrong test for deficiency, and the right test in a few situations

Measuring calcitriol to diagnose vitamin D deficiency is like checking a thermostat's setting to see whether the oil tank is empty. When the precursor runs low, parathyroid hormone rises and drives the kidney harder, and calcitriol stays normal or high; in records from 3,661 patients, the hormone and calcium absorption fell only once 25-hydroxyvitamin D reached about 10 nmol/L, the edge of true depletion ⁴⁷. The hormone's plasma half-life is hours, so it swings with the day's signals, while the precursor's is weeks ^21,58. The Endocrine Society's 2011 guideline named serum 25-hydroxyvitamin D, by a reliable assay, as the initial test in people at risk of deficiency, and a 2017 international conference called it the critical measurement of status ^32,95. The society's 2024 guideline went further: finding no trial evidence that screening helps and no clear evidence for an optimal target level, it suggested against routine 25-hydroxyvitamin D testing in every population it considered, so the precursor test too is now reserved for people with an established reason for it ⁵⁷.

The mistake is common enough that laboratories now police it. In 2025 nine laboratories in a test-stewardship network agreed on a benchmark of 50 orders for 25-hydroxyvitamin D for every order of calcitriol; a laboratory below that ratio is probably seeing calcitriol ordered by mistake for vitamin D status, and one above it suggests the hormone is being saved for the questions it can answer ⁹⁶. Low values in acute illness need the same caution: in 185 patients hospitalized in Istanbul in spring 2020, reported in 2026, low calcitriol was independently associated with severe disease, an association that cannot say whether the low hormone was a cause or a consequence of being very ill ⁹⁷.

The hormone is the right test when the question is about the loop itself. In high calcium with suppressed parathyroid hormone, a high calcitriol points to granulomas, lymphoma or a broken off switch ³⁸. In rickets that does not respond to vitamin D, a low calcitriol points to a missing CYP27B1, and a very high calcitriol to a broken receptor; the first patient described with the receptor form had 137 pg/mL ^36,98. In phosphate-wasting disease, a low or inappropriately normal calcitriol points to excess FGF23 ⁴⁴. And when calcitriol is high with normal 25-hydroxyvitamin D, a low 24,25-dihydroxyvitamin D points to CYP24A1 loss ^49,50.

The number itself is harder to measure than the precursor ^32,99. Concentrations are in the picomolar range, and pediatric reference intervals from one immunoassay, published in 2018, ran from 77 to 471 pmol/L in the first year of life, narrowing to 108 to 246 pmol/L from age three, with some infant values possibly inflated by a cross-reacting substance ²⁰. In 2025 a Norwich group found an immunoassay and a mass spectrometry method in close agreement in 80 young adults but not in 422 children, where the correlation fell to 0.65 ⁹⁹. Laboratories report calcitriol either in picograms per milliliter or in picomoles per liter; because the molecule weighs 416.64 grams per mole, 1 pg/mL equals 2.4 pmol/L, so the childhood range of 108 to 246 pmol/L is about 45 to 102 pg/mL ²⁰. Every number on this page should be read against the method and the units that produced it.

• Serum 1,25-dihydroxyvitamin DMeasured by immunoassay, which captures the hormone with antibodies, or by liquid chromatography with tandem mass spectrometry, which weighs it, after antibodies have first pulled it out of the sample; in 80 young adults the two agreed closely, in 422 children they did not ⁹⁹.Calcium that is high while parathyroid hormone is low (granulomatous disease, lymphoma, CYP24A1 loss); suspected inherited rickets; FGF23 disorders; research in kidney diseaseGood in adults on a well-run assay, with values in the picomolar range; pediatric reference intervals were set in 2018 and are method-specific ^20,99. A 2017 international conference listed calcitriol among the markers that still need standardization ³².It does not measure vitamin D status: deficiency raises parathyroid hormone, which keeps calcitriol normal or high until the precursor is almost gone ⁴⁷. Nine laboratories in 2025 set a benchmark of 50 precursor tests for every calcitriol test, because the wrong one is so often ordered ⁹⁶. A normal value does not exclude granuloma-driven hypercalcemia, which can run with a calcitriol that is only inappropriately normal ⁸⁸.
• Parathyroid hormone with calciumThe first question in any high calcium is whether parathyroid hormone is high or suppressed; calcitriol-driven hypercalcemia suppresses it ³⁸.Sorting hypercalcemia into parathyroid-driven and calcitriol-driven causesDecisive when done; in 117,395 US adults with sarcoidosis, only 30.5 percent of those with high calcium had parathyroid hormone measured, and 3.0 percent met biochemical criteria for primary hyperparathyroidism ⁹¹.Two causes can coexist, and attributing every high calcium in sarcoidosis to granulomas misses the parathyroid adenoma ⁹¹.
• 25-hydroxyvitamin D to 24,25-dihydroxyvitamin D ratioWhen CYP24A1 is missing, its product 24,25-dihydroxyvitamin D is low while the precursor is normal or high ⁴⁹.Screening for loss of the off switch in hypercalcemia or kidney stones with high calcitriolA biochemical marker; one 2026 report calls a ratio above 80 useful, with genetic testing the gold standard ⁵⁰.It does not detect the second inherited cause, loss of the phosphate transporter SLC34A1, which raises calcitriol by a different route ³⁰.
• Genetic testingCYP27B1 (type 1 rickets), the receptor gene (type 2), CYP3A4 (type 3), CYP24A1 and SLC34A1 (infantile hypercalcemia) ^{25,27,28,29,30}.Early-onset rickets resistant to vitamin D; familial or recurrent hypercalcemia; adults with unexplained stones and high calcitriolDefines the disease when a variant known to disable the gene is found ^25,29.Prevalence and penetrance, meaning how often people who carry the faulty genes actually become ill, are uncertain: a French protocol estimates infantile hypercalcemia at 1 in 33,000, while a database estimate suggested predicted deleterious CYP24A1 genotypes in 4 to 20 percent of people ^49,138.

Calcitriol as a drug: Rocaltrol and its descendants

Hoffmann-La Roche's chemists developed the commercial synthesis in the early 1970s, and the company sold the drug as Rocaltrol ^2,23. It was in controlled clinical use by 1978: in a randomized blinded comparison with vitamin D3 in 22 hemodialysis patients published that May, a mean 0.579 microgram a day raised calcium from 8.7 to 10.25 mg/dL and lowered alkaline phosphatase, and the hypercalcemia it caused in 2 of 13 patients, as high as 13.2 mg/dL, reversed promptly when the dose was cut ¹⁰¹. By June 1979 the independent Medical Letter was reviewing calcitriol for the low calcium of patients on long-term dialysis, the obvious first use for a hormone made by the organ those patients had lost ²⁴. Its short half-life, only hours in plasma, made it controllable: an excess could be stopped and would clear quickly, unlike an overdose of vitamin D itself ^21,58,101. The first warning arrived in the same year as the first use. In a Danish controlled trial in 18 people with advanced kidney failure not yet on dialysis, published in September 1978, kidney function fell faster during calcitriol treatment than before it in every patient on the drug, and 7 of 8 became hypercalcemic; the authors called deteriorating kidney function a major limitation of the drug before dialysis ¹⁰².

Kidney doctors soon wanted it for a second purpose, to suppress the overactive parathyroid glands of kidney failure ¹⁰³. In 1984 Slatopolsky's group found that oral calcitriol, at doses that kept calcium at the top of normal, did not lower parathyroid hormone in dialysis patients, whereas intravenous calcitriol suppressed it by 70.1 percent in all 20 patients, part of the effect appearing before calcium rose ¹⁰³. Rat and clinical data suggested the gland's response outlasted the hormone's hours in the blood, the rationale for pulse dosing; the review that set out the argument held that the spacing could be wider still, one or two pulses a week rather than the three then usual ²¹.

The problem was calcium. Every dose that suppressed the parathyroid glands also drove intestinal calcium and phosphate absorption, so a generation of analogs was designed to separate the two ^104,105. Paricalcitol, a modified hormone built on vitamin D2 (ergocalciferol, the form made by fungi and plants), produced at least a 30 percent fall in parathyroid hormone in 68 percent of 40 dialysis patients against 8 percent of 38 on placebo in three trials published in 1998, with no hypercalcemia before the target was reached; the sponsor is not stated in the indexed record ¹⁰⁵. Doxercalciferol, 1-alpha-hydroxyvitamin D2, a prohormone, lowered parathyroid hormone by 55 percent at 16 weeks in 138 dialysis patients in 2000, with calcium above 11.2 mg/dL in 3.26 percent of measurements against 0.46 percent on placebo, in a trial whose sponsor is also not stated in the indexed record ¹⁰⁶. Alfacalcidol, a vitamin D3 molecule already hydroxylated at carbon 1, is only active after the liver converts it to calcitriol ¹⁰⁴. A 2023 network meta-analysis, a method that compares drugs indirectly through trials that each tested one of them against a common comparator, of nine trials in 1,426 patients with kidney disease not on dialysis found paricalcitol and extended-release calcifediol, a slow-release form of the precursor, lowered parathyroid hormone similarly, with paricalcitol raising calcium by about 0.2 mg/dL more; there were no head-to-head trials ¹⁰⁷. Whether the separation worked in people was tested in 2007: a meta-analysis of 76 trials in 3,667 patients found that vitamin D compounds did not reduce death, bone pain, vascular calcification or parathyroid surgery, that the newer analogs, against placebo, still raised the risk of hypercalcemia (relative risk 5.15, 95 percent confidence interval 1.06 to 24.97), and that only 5 trials had compared newer with older compounds directly ¹⁰⁸.

Osteoporosis was tried and divided. In 1992, 622 New Zealand women with vertebral fractures took calcitriol 0.25 microgram twice a day or calcium for three years; new vertebral fractures in the third year ran 9.9 against 31.5 per 100 patient-years in the whole cohort, a benefit the authors found only in the women with five or fewer fractures at entry, where the third-year rates were 4.2 against 31.0; the trial was single-blind and the comparison was with calcium, not placebo ¹⁰⁹. A smaller double-blind trial three years earlier, 86 women against placebo for two years, had found no gain in bone and new fractures in 26 percent on calcitriol against 16 percent on placebo, a difference that was not significant either way ¹¹⁰. In Japan the analog eldecalcitol reduced vertebral fractures against alfacalcidol in 1,054 patients, 13.4 against 17.5 percent over three years, a comparison of two active vitamin D drugs with each other; its sponsor is not stated in the indexed record ¹¹¹.

One hoped-for side benefit was ruled out. A 2024 pooling of the individual records of 411 people from placebo-controlled calcitriol trials, an individual-participant meta-analysis, found no effect on body weight, waist, fat or lean mass, though none of those trials had been designed to test weight ¹¹².

Kidney disease: a laboratory number that did not become an outcome

The argument for giving active vitamin D more widely in kidney disease rested on an observational study. In 2003 a historical cohort, a study that looks back at the records of patients already treated, of 67,399 American hemodialysis patients found mortality of 0.180 per person-year among those started on paricalcitol against 0.223 among those started on calcitriol, 16 percent lower after adjustment, with an advantage in 28 of 42 subgroups ¹¹⁷. The authors wrote that a prospective randomized study was critical to confirm it; the first author worked for Fresenius Medical Care, a dialysis provider, and the comparison was between drugs chosen by doctors, not by chance ¹¹⁷. Observational studies that compared treated with untreated patients pointed the same way, and the J-DAVID investigators later cited them as the reason for their trial ⁴¹.

The trials that tested the idea used two kinds of endpoint. Two tested whether the receptor could shrink the thickened heart muscle common in kidney disease ^51,113. PRIMO, in 2012, randomized 227 patients in 11 countries with moderately reduced kidney function to paricalcitol 2 micrograms a day or placebo for 48 weeks: parathyroid hormone normalized within four weeks, left ventricular mass did not change, and hypercalcemia was more frequent on the drug ⁵¹. OPERA, in 2014, gave 60 patients with stage 3 to 5 disease paricalcitol 1 microgram a day or placebo for 52 weeks, with the same result for the heart; cardiovascular hospitalizations, a secondary endpoint in a small trial, were fewer ¹¹³. The sponsor of neither trial is stated in the indexed record ^51,113.

The third tested the outcome itself. J-DAVID, published in 2018, randomized 976 Japanese hemodialysis patients without secondary hyperparathyroidism to alfacalcidol 0.5 microgram a day or no active vitamin D and followed them for a median of four years: cardiovascular events occurred in 21.1 percent against 17.9 percent, a hazard ratio of 1.25 with a confidence interval from 0.94 to 1.67, and deaths in 18.2 against 16.8 percent ⁴¹. The authors concluded that the findings did not support active vitamin D for patients like these ⁴¹. The observational survival advantage did not appear when chance, not doctors, decided who got the drug ^41,117.

The guidelines moved accordingly. Kidney doctors now group these problems under one name, chronic kidney disease-mineral and bone disorder, or CKD-MBD: the linked disturbances of calcium, phosphate, parathyroid hormone and vitamin D, the bone disease that follows, and the calcification of blood vessels ^118,119. The 2017 update of the international guideline from Kidney Disease: Improving Global Outcomes (KDIGO) revised 15 recommendations, emphasized treating trends rather than single values, and urged caution to avoid hypercalcemia when treating secondary hyperparathyroidism ^100,120. The US Kidney Disease Outcomes Quality Initiative (KDOQI) work group of the National Kidney Foundation agreed with most of it but raised concerns about the advice on calcium and on treating abnormal parathyroid hormone, a sign that the right use of these drugs in kidney disease is still argued over ¹¹⁸. A 2023 meta-analysis of 128 randomized trials in 11,270 adults with stage 3 to 5 kidney disease found that vitamin D compounds, the plain vitamin and the active forms together, probably had no effect on death (relative risk 1.04, 95 percent confidence interval 0.84 to 1.24), had uncertain effects on fracture and cardiovascular death, and lowered parathyroid hormone while raising calcium ¹¹⁹. The associations keep coming: in 2026, lower calcitriol was linked to poorer response to anemia drugs in 363 Korean patients with kidney disease, an observation that, like Teng's, needs a trial before it means anything for treatment ¹²¹.

Hypoparathyroidism: standing in for the missing tropin

Parathyroid hormone is the kidney's main signal to make calcitriol, so when the parathyroid glands are lost, after neck surgery or for other reasons, the hormone runs short ^10,39,43. The logical replacement is the end product itself ³⁹. The First International Conference on the management of hypoparathyroidism, held in Florence in May 2015, published its summary statement and guidelines in 2016 ¹²². The 2022 international guideline, from a panel of 50 experts, kept calcium with active vitamin D, calcitriol or alfacalcidol, as first-line treatment, calling it a weak recommendation resting on low-quality evidence, with parathyroid hormone reserved for when conventional therapy fails ³⁹; a 2026 review by members of the same circle still calls conventional therapy the mainstay, with parathyroid hormone replacement for patients who do not respond to it ¹²³.

The cost of that substitution shows in the urine and the kidneys. Among 120 Boston patients followed between 1988 and 2009, 38 percent of those with a 24-hour collection had urine calcium above 300 mg a day at least once, 31 percent of those imaged had kidney calcifications, and stage 3 kidney disease or worse was 2 to 17 times more common than expected for their age ⁵⁴. A chart review cannot separate the disease from its treatment, but the 2022 guideline lists the same complications ^39,54.

Replacing the missing hormone is older than it looks. In 1996, in a randomized crossover trial of 10 patients at the National Institutes of Health, once-daily injections of the parathyroid hormone fragment PTH 1-34 kept calcium in the normal range with lower urine calcium than calcitriol with calcium ¹²⁴; a three-year randomized trial in 27 adults found urine calcium within the normal range on the hormone and above normal on calcitriol, with no difference in bone mineral density ¹²⁵. In the REPLACE trial of 2013, full-length recombinant parathyroid hormone let 48 of 90 patients, 53 percent, halve their calcium and active vitamin D while keeping their serum calcium, against 1 of 44, 2 percent, on placebo; two of the authors worked for the developer, NPS Pharmaceuticals ¹²⁶. That drug's production is now being halted because of manufacturing problems ¹²⁷. The newest form, palopegteriparatide, arrived in the 2020s and was approved by the US Food and Drug Administration in 2024 ^127,128. In the PaTHway trial, 84 adults with hypoparathyroidism were randomized three to one to palopegteriparatide, a slowly released form of parathyroid hormone, or placebo for 26 weeks; 79 percent on the drug against 5 percent on placebo kept normal calcium without active vitamin D, and 93 percent became independent of conventional therapy ¹²⁹. By two years, 97 percent of those remaining in the open extension were off active vitamin D, average 24-hour urine calcium was 158.8 mg, and estimated kidney function had risen by 9.0 mL/min/1.73 m2, a post hoc finding ¹³⁰. A 2026 review argues that the drug works partly by restoring the kidney's own calcitriol production, which stayed within normal limits for 3.5 years ⁴³. These reports were written in large part by employees of Ascendis Pharma, the drug's developer, and the long-term kidney comparison with conventional therapy has not been randomized ^43,129,130.

The skin: from a bone drug to a psoriasis ointment

Skin is both a source and a target. Keratinocytes carry CYP27B1, abundantly enough that the human enzyme was cloned from them, and they respond to calcitriol by making antimicrobial peptides ^9,131. The clinical use came by another route. In 1986 Morimoto and colleagues reported 40 patients with psoriasis treated in open studies: 13 of 17 improved on oral alfacalcidol, 1 of 4 on oral calcitriol, and 16 of 19 on calcitriol ointment, with no side effects recorded ¹³². The studies were uncontrolled, but they pointed at a hormone acting directly on the overgrowing cells of psoriatic skin ¹³². Calcitriol ointment itself was put to a controlled test much later, in two vehicle-controlled randomized trials in 839 people with mild to moderate plaque psoriasis: 3 micrograms per gram twice daily for 8 weeks beat its vehicle from week 2 onward, with no effect on calcium ¹³³.

The obstacle was the same as everywhere else: calcium. Leo Pharmaceutical Products in Denmark designed calcipotriol, called calcipotriene in the United States, an analog that matched calcitriol's effects on cell growth and differentiation in culture but was at least 100 times less active on calcium in rats ¹⁰⁴. The company's pharmacologists showed why: in rats it was cleared more than 100 times faster than calcitriol and broken down into metabolites more than 100 times weaker ¹¹⁴. A drug that works where it is put and disappears before it reaches the gut in quantity is a near-ideal topical treatment ¹¹⁴.

The pivotal comparison was elegant. In 1991, 345 patients with symmetrical psoriasis treated one side of the body with calcipotriol ointment and the other with the corticosteroid betamethasone valerate for six weeks, without knowing which was which: severity scores fell 68.8 percent with calcipotriol against 61.4 percent with the steroid, skin irritation was slightly more common on the calcipotriol side, and serum calcium did not change ¹¹⁵. Today the most used topical treatment for psoriasis combines calcipotriene with the potent corticosteroid betamethasone dipropionate, in several formulations approved by the US Food and Drug Administration ¹³⁴.

The ointment found a second life in 2017. In a randomized trial of 131 people with actinic keratoses, the scaly sun-damaged patches that can become squamous cell cancer, four days of calcipotriol plus 5-fluorouracil cleared 87.8 percent of lesions against 26.3 percent for 5-fluorouracil, a chemotherapy cream, with petroleum jelly, with a dense infiltrate of CD4 (helper) T cells, the immune cells that coordinate an attack, in the treated skin; in mice the effect depended on thymic stromal lymphopoietin (TSLP), an alarm signal released by skin cells ¹³⁵. The endpoint was a precancer, not cancer itself, and the trial was investigator-initiated ¹³⁵.

When a part breaks: the inherited disorders

Every component of the loop has an inherited disease, and each one taught something. Vitamin D-dependent rickets type 1A, rickets that appears in infancy despite normal vitamin D intake, was shown in 1973 to be a failure to convert 25-hydroxyvitamin D into calcitriol, two years after the hormone was found ³⁶. The enzyme's gene was cloned in 1997 and mutations confirmed in one child and then in four unrelated families, every mutation abolishing its activity ^9,25. What such a child lacks is the hormone, not vitamin D ³⁶. A second, rarer failure of activation sits one step upstream: in 2004 a child with low 25-hydroxyvitamin D and classic signs of deficiency proved to carry two broken copies of CYP2R1, the liver's 25-hydroxylase, which is why that gene's loss is now called type 1B ^26,31. Seven patients in two families, described in 2017, showed the pattern that makes it easy to miss: a very low 25-hydroxyvitamin D with a normal or high calcitriol, read for years as ordinary deficiency ¹³⁶.

Type 2A is the opposite: the hormone is made but cannot act ⁹⁸. In 1978 a 22-year-old woman with rickets, low calcium and secondary hyperparathyroidism had a calcitriol of 137 pg/mL, far above normal, and the authors proposed the name vitamin D-dependent rickets type II ⁹⁸. In 1988 the cause was traced to single-letter mutations in the receptor's zinc fingers, the parts that grip DNA, which left the receptor able to bind the hormone but not the gene ²⁷. Some families with the receptor form lose their hair, a feature the knockout mice reproduced and that no diet could prevent ^33,62. Some children with the receptor form are managed with very high doses of oral calcium together with calcitriol ¹³⁷.

Type 3 was found in 2018 and turned the drug-clearing enzyme CYP3A4 into a cause of rickets: two unrelated children with the same new mutation had low levels of both the precursor and the hormone and resisted treatment with either, because their CYP3A4 destroyed calcitriol ten times faster than normal ²⁸.

The disorders of excess run the other way. Loss of CYP24A1 causes idiopathic infantile hypercalcemia, described in 2011, and later a disease of adults with stones ^29,49. Loss of the kidney phosphate transporter NaPi-IIa, encoded by SLC34A1, causes a second form, described in 2016 in 4 index patients, the first affected member identified in each family, and 12 sporadic cases: the wasted phosphate suppresses FGF23 and releases CYP27B1, so calcitriol rises inappropriately, and the hypercalcemia persists when vitamin D is stopped but responds to phosphate supplements ³⁰. A French national protocol published in 2026 put the prevalence of infantile idiopathic hypercalcemia at about 1 in 33,000 and called its natural history poorly understood ¹³⁸. The CYP24A1 form has been treated in case reports with rifampin and, in a 2026 series of three adults, with the antifungal fluconazole; neither has been tested in a trial ^63,139. In X-linked hypophosphatemia, the most common inherited form of FGF23 excess, conventional treatment has been oral phosphate with an active vitamin D such as calcitriol; in 2019 an open-label trial in 61 children found that switching to burosumab, an antibody against FGF23, healed rickets better by week 40, in a trial funded by the drug's makers ⁷³.

Calcitriol and cancer: the laboratory promise, and the trials that reversed it

The cancer story began in culture dishes in 1981. Suda's group found that calcitriol turned mouse myeloid leukemia cells into macrophage-like cells at concentrations from 0.12 nanomolar, and at 12 nanomolar as strongly as the most potent known stimulator ¹⁴⁰. The same year, Feldman's group found high-affinity receptors in malignant melanoma and slower growth of human melanoma cells exposed to the hormone, which they called the first demonstration of a calcitriol action on tumor cells ¹⁴¹. A hormone that made cancer cells mature and stop dividing looked like a drug waiting to be used.

The first clinical test, in 1985, set out the problem that has followed the field ever since. Leukemia cells taken from patients differentiated at 1 micromolar calcitriol and not at 1 nanomolar; 18 patients with myelodysplastic syndrome, a preleukemic marrow disease, given 2 micrograms a day had a few minor blood responses but no lasting benefit, 7 progressed to leukemia, and 9 became hypercalcemic, which prevented higher doses ⁵³. The concentrations that work in a dish cannot be reached in a person without raising calcium dangerously ⁵³. A 2026 paper on ovarian cancer cells states the same obstacle in its own opening lines, forty-one years on ¹⁴². Analogs were the proposed answer; one of them, seocalcitol, produced 2 complete responses among 33 evaluable patients with inoperable liver cancer in an uncontrolled trial in 2003, with hypercalcemia as its main toxicity ¹¹⁶.

Prostate cancer was the serious attempt. In 2003 Tomasz Beer's group in Portland gave 37 men with metastatic prostate cancer that no longer responded to hormone treatment weekly high-dose Rocaltrol, 0.5 microgram per kilogram, the day before weekly docetaxel chemotherapy: prostate-specific antigen (PSA), the blood marker of prostate cancer activity, fell by half in 30 of them, 81 percent, and median survival was 19.5 months, promising against earlier studies of docetaxel alone; the sponsor is not stated in the indexed record ¹⁴³. ASCENT, the Androgen-Independent Prostate Cancer Study of Calcitriol Enhancing Taxotere, Taxotere being docetaxel's brand name, was a double-blind trial in 250 men using DN-101, a high-dose formulation of calcitriol: it missed its primary endpoint, with a PSA response of 58 against 49 percent, but a multivariate analysis suggested a hazard ratio for death of 0.67, which the investigators said needed confirmation because survival had not been a primary endpoint; its sponsor is not stated in the indexed record either ¹⁴⁴.

The confirmation trial reversed it. ASCENT-2 randomized 953 men to weekly docetaxel with DN-101 or to the standard three-weekly docetaxel with prednisone, and was halted at an interim analysis because more men were dying in the calcitriol arm: median survival 17.8 against 20.2 months, an adjusted hazard ratio of 1.33 ⁴⁰. The two arms differed in docetaxel schedule as well as calcitriol, and the authors could not say which caused the harm; the sponsor is not stated in the indexed record ⁴⁰. What they could say was that the survival benefit suggested by the first trial was not there ⁴⁰. The lesson is the one this field keeps relearning: a secondary analysis is a hypothesis, and the trial that tests it can come back the other way.

Optimism did not end with ASCENT-2. A 2014 review in Nature Reviews Cancer wrote that preclinical and some clinical studies strongly suggested vitamin D deficiency increased cancer risk, while conceding that randomized trials did not yet exist ⁴. The trial came in 2019. In VITAL, 25,871 US adults took 2,000 IU, international units, of vitamin D3 a day or placebo for a median of 5.3 years: invasive cancer was no less common (hazard ratio 0.96, 95 percent confidence interval 0.88 to 1.06), and the lower rate of death from cancer in a secondary analysis (0.83, 0.67 to 1.02) did not reach significance ¹⁴⁵. In 2025 a monthly 50,000 IU dose of vitamin D3 did not slow progression in 123 men with early prostate cancer under active surveillance ¹⁴⁶. Both trials tested the parent vitamin, not the hormone; the fuller story belongs to the vitamin D page. The newest direction is the tumor's surroundings rather than the tumor ¹⁴⁷. In 2014 Ronald Evans and Michael Downes's group at the Salk Institute showed in mice that the analog calcipotriol quieted the fibrous stroma of pancreatic cancer, raised the chemotherapy drug gemcitabine inside tumors, and increased survival by 57 percent over chemotherapy alone ¹⁴⁷. The human trials have so far been small and safety-focused: paricalcitol added to pembrolizumab, an antibody that releases a brake on the immune system, as maintenance made no difference to progression or survival in a randomized phase 2 trial published in 2025; a 36-patient randomized run-in trial in 2026 found it could be given with chemotherapy, with moderate to life-threatening hypercalcemia, grades 2 to 4 on the standard toxicity scale, in 5 of 12 on the oral form and favorable changes in tumor biopsies; and a 2026 pilot enrolled only 3 patients ^52,148,149. The laboratory output continues, including a 2026 study in which calcitriol harmed one melanoma cell line and not another ¹⁵⁰.

The immune system, at its true strength

The laboratory evidence is strong and specific. The genes for two antimicrobial peptides, cathelicidin and beta-defensin 2, carry vitamin D response elements, and calcitriol switched them on in human keratinocytes and in two kinds of white blood cell, monocytes and neutrophils, giving secretions that killed Pseudomonas aeruginosa, a common hospital bacterium ¹³¹. Human macrophages that sense a microbe switch on CYP27B1 and the receptor, make calcitriol from the precursor and use it to kill Mycobacterium tuberculosis inside themselves, at least in culture ⁸⁶. In human T cells in culture, calcitriol cut production of the inflammatory signals interferon gamma and interleukins 17 and 21, interleukins being messenger proteins passed between immune cells, and, with interleukin 2, induced regulatory T cells that suppress other T cells ¹⁵¹. In mice, calcitriol completely prevented an experimental model of multiple sclerosis and halted it when started at the first symptoms ¹⁵². The receptor's binding sites in the genome cluster near genes linked to autoimmune disease ¹⁹.

The same machinery has a cost that the laboratory work explains. The macrophage enzyme that makes calcitriol to fight a microbe is the one that floods the blood with it in sarcoidosis and tuberculosis, and it is not under the kidney's feedback ^7,38. A system built to work locally does not obviously benefit from more hormone in the blood.

The trials of calcitriol itself are few and small, and none has shown a clinical benefit. In 67 critically ill adults with sepsis, a single 2 microgram intravenous dose did not raise plasma cathelicidin protein at 24 hours, the primary outcome, although cathelicidin and interleukin 10 messenger RNA in white cells rose; there was no clinical effect and no harm ¹⁵³. In 40 adults with newly diagnosed type 1 diabetes randomized to 0.25 microgram a day or placebo for nine months, the residual insulin production, measured as C-peptide, fell by about 40 percent in both groups over 18 months ¹⁵⁴. In 2025 a phase 2 trial in 150 critically ill adults at high risk of acute kidney injury compared oral calcitriol, its precursor calcifediol and placebo: neither drug changed the primary composite of death, dialysis and kidney injury within 7 days (calcitriol against placebo P = 0.58), although calcitriol switched on more immune and DNA-repair genes in circulating monocytes, and 1 of 50 patients on it became hypercalcemic; the National Institutes of Health funded it ¹⁵⁵. In a 50-patient open-label pilot in people hospitalized with COVID-19, 0.5 microgram a day improved oxygenation, a rise of 91.04 against 13.2 in the oxygen saturation ratio (P = .03), without a significant difference in length of stay ¹⁵⁶.

The tuberculosis trials used vitamin D3, the parent vitamin, not the hormone, and they show the gap between mechanism and medicine. Vitamin D was used to treat tuberculosis before antibiotics, and in 2011, 146 London adults on standard treatment were given four doses of 2.5 mg of vitamin D3 or placebo: time to sputum culture conversion was 36.0 against 43.5 days, a hazard ratio of 1.39 with a confidence interval from 0.90 to 2.16, not significant, with a faster response in one receptor genotype subgroup ¹⁵⁷. A secondary immunological analysis of 95 patients from a randomized trial of adjunctive vitamin D, by largely the same investigators, found faster resolution of inflammatory markers ¹⁵⁸. The observational signal persists, as in the 185 patients hospitalized in Istanbul in spring 2020 and reported in 2026, in whom low calcitriol was linked to severe disease, but low calcitriol in severe illness may be the illness talking ⁹⁷.

The honest summary is this. Calcitriol is a real immune signal, made locally by immune cells and acting on immune genes, and that is established in human cells and in animals ^86,131,152. Giving the hormone to sick people has so far produced changes in physiology and one small signal in oxygenation, not a proven clinical benefit ^{153,154,155,156}, and the trial of its precursor in tuberculosis missed its endpoint too ¹⁵⁷. The one large positive prevention trial used vitamin D3, not the hormone: in VITAL, 2,000 IU a day for a median of 5.3 years in 25,871 older US adults cut confirmed autoimmune disease from 155 cases to 123, a hazard ratio of 0.78 with a confidence interval from 0.61 to 0.99 ¹⁵⁹; two years after the pills stopped the effect was gone, 0.98 at 7 years, and counting the cases confirmed late moved the in-trial estimate to 0.85, from 0.70 to 1.04 ¹⁶⁰.

Magnesium, vitamin K2 and iron: the companion links at their strength

Magnesium has the most direct clinical link. In 23 patients whose low calcium was caused by magnesium deficiency, 16 had calcitriol below 30 pg/mL; after 5 to 13 days of intravenous magnesium, calcium returned to normal in the group as a whole, but calcitriol rose into the normal range in only 5, despite raised parathyroid hormone ⁴⁶. The authors concluded that magnesium depletion may impair vitamin D metabolism, and that a normal calcitriol was not needed for calcium to recover once magnesium was replaced ⁴⁶. It is an observational study; it shows a link and a slow recovery, not the enzyme step involved.

Vitamin K2 enters through one protein. Osteocalcin, a bone protein, carries three gamma-carboxyglutamic acid residues, the chemical modification that vitamin K-dependent enzymes make ¹⁶¹. Calcitriol switches on the osteocalcin gene: in rat bone cells it raised synthesis of the vitamin K-dependent protein sixfold at physiological concentrations, and a 21-base-pair response element in the human gene mediates that effect ^61,82. So calcitriol decides how much osteocalcin is made and vitamin K decides whether it is finished ^82,161. That is a mechanism in cells; it is not evidence that taking the two together does anything for bone in people, a question for the vitamin K2 and vitamin D pages.

Iron touches calcitriol through two different hormones. The first is hepcidin, the liver's iron-regulating hormone: calcitriol halved hepcidin messenger RNA in human liver cells and monocytes by acting on the hepcidin gene, and in a small uncontrolled pilot a single 100,000 IU, international unit, dose of vitamin D2 lowered circulating hepcidin by 34 percent within 24 hours ¹⁶². The second is FGF23. Iron deficiency was associated with high levels of FGF23 fragments, the inactive pieces left after the hormone is cut, but not of intact, active FGF23, in 55 women with heavy menstrual bleeding, and the intravenous iron ferric carboxymaltose, unlike iron dextran, transiently raised intact FGF23, dropping phosphate below 2.0 mg/dL in 10 women with lower calcitriol and higher parathyroid hormone ⁴⁵. Two randomized trials in 2020 found hypophosphatemia in 75.0 and 73.7 percent of patients after ferric carboxymaltose against 7.9 and 8.1 percent after iron isomaltoside, now called ferric derisomaltose, a difference the authors attributed to FGF23; one author worked for the maker of iron isomaltoside ¹⁶³. In kidney disease, lower calcitriol has been associated with poorer response to anemia drugs, an association only ¹²¹.

Klotho, the coreceptor FGF23 needs, is the last companion. Mice without klotho age early, mice without FGF23 have high calcitriol and phosphate, and klotho is what lets FGF23 reach its receptor ^14,59,72. Whether that shared biology matters for human aging is not established by the sources here.

The whole history, including the reversals

Read top to bottom, the history is a sequence of systems that each looked complete and each had a missing part: a vitamin that turned out to need activating, a kidney that turned out not to be the only factory, a feedback loop that turned out to have a bone hormone in it, and a drug that corrected its laboratory targets far more reliably than its clinical ones.

The 2025 to 2026 literature, verified

Hypoparathyroidism produced the most substantial new clinical data. Two-year results of the PaTHway trial, published in 2026, found 97 percent of the 76 participants still enrolled independent of active vitamin D, with mean urine calcium 158.8 mg a day and estimated kidney function up by 9.0 mL/min/1.73 m2 from baseline, in a post hoc analysis without a randomized comparator at that point ¹³⁰. A 2026 review argues that the drug restores the kidney's own calcitriol production ⁴³. Both papers were written largely by the manufacturer's employees, and they should be read as the strongest case for the drug rather than an independent appraisal ^43,130.

Calcitriol itself was tested in several randomized trials, most of them small. In 138 Korean adults with IgA nephropathy, a common inflammatory kidney disease, already on the maximal dose of the blood-pressure drugs that protect the kidney, 0.25 microgram a day for 12 months lowered the protein-to-creatinine ratio in the urine more than placebo, a mean difference of 187 mg/g (P = .04), though it did not change total daily protein excretion (P = .11), and the yearly fall in estimated kidney function was 0.32 against 3.64 mL/min/1.73 m2 (P = .02) ¹⁶⁴. In 72 Indian children with proteinuric kidney disease, adding calcitriol to enalapril did not reduce proteinuria significantly (P = 0.54) ¹⁶⁵. After kidney transplantation, 0.5 microgram a day for a year in 67 recipients did not protect bone density, microarchitecture or strength, and caused more hypercalcemia (P < .001) ¹⁶⁶. After total thyroidectomy, routine calcium with calcitriol for 15 days was no better than giving it only when parathyroid hormone was low at 4 hours, in 258 patients: symptomatic hypocalcemia occurred in 24 of them, 9.3 percent overall, odds ratio 0.68 (95 percent confidence interval 0.29 to 1.57), with less supplementation in the selective group ¹⁶⁸. In 78 adults with kidney disease not on dialysis already taking extended-release calcifediol, adding calcitriol, doxercalciferol or paricalcitol lowered parathyroid hormone by a further 35.4 percent but raised FGF23 by 155 percent, and estimated kidney function fell by 11.8 percent against 3.0 percent; the authors were largely employees of OPKO Health, which sells extended-release calcifediol ¹⁶⁷. And in 18 healthy adults, two 1.5 microgram doses of calcitriol increased amphetamine-induced dopamine release measured by positron emission tomography, a brain scan ¹⁶⁹.

The pancreatic cancer program moved from mice to people and has not yet shown benefit. A randomized phase 2 trial published in 2025 found that intravenous paricalcitol added nothing to pembrolizumab as maintenance therapy; the authors suspect its 5- to 7-hour half-life was too short ¹⁴⁸. A 36-patient randomized run-in published in Nature Cancer in 2026 found paricalcitol could be given safely with gemcitabine and nab-paclitaxel, two chemotherapy drugs, though 5 of 12 on the oral form developed hypercalcemia needing dose reduction, and on-treatment biopsies showed fewer activated fibroblasts and more cytotoxic T cells next to tumor cells ⁵². A companion pilot trial managed to enroll only three patients ¹⁴⁹. These are safety and mechanism studies; the efficacy question is still open ^52,148.

The off switch is being found in adults. A French national care protocol published in 2026 estimated infantile idiopathic hypercalcemia at 1 in 33,000 and called its natural history poorly understood ¹³⁸. Case reports from 2026 described a 58-year-old woman whose stones followed ordinary vitamin D supplementation, with a 25-hydroxyvitamin D to 24,25-dihydroxyvitamin D ratio above 80, and three adults treated with fluconazole ^50,139. A 2026 review of hypercalcemia in pregnancy placed CYP24A1 mutations among the leading causes of high calcium that is not driven by parathyroid hormone ⁹³.

Granulomatous hypercalcemia drew a large records study and a run of cases. In 117,395 US adults with sarcoidosis, parathyroid hormone was measured in fewer than a third of those with high calcium, and primary hyperparathyroidism was present biochemically in 3.0 percent and mostly unrecognized ⁹¹. Case reports added silicone granulomas with an inappropriately normal calcitriol, a liposarcoma making the hormone, and a holiday-triggered presentation of sarcoidosis ^87,88,89.

Measurement and basic science filled the rest. A 2025 study found immunoassay and mass spectrometry agree for calcitriol in adults but not in children, and a 2025 stewardship benchmark set 50 precursor tests per calcitriol test ^96,99. In mice, lysophosphatidic acid was found to need calcitriol to raise FGF23 ⁶⁰. Cell studies reported calcitriol raising tyrosine hydroxylase, the first enzyme of dopamine synthesis, in human neural cell lines, with Mark Haussler among the authors fifty-seven years after his first receptor paper, and a mixed result in melanoma cells ^65,150,170. Observational studies linked low calcitriol to severe COVID-19 and to poor response to anemia drugs in kidney disease, associations that cannot establish cause ^97,121.

What was believed, and is not

That vitamin D acts as itself. Kodicek's ten years of tracer work concluded so; DeLuca's better-labeled vitamin found the metabolites, and by 1971 the hormone had been identified by three laboratories ^1,2,3,22.

That only the kidney makes calcitriol. A man with no kidneys made enough to become hypercalcemic in 1981, and lung macrophages from sarcoidosis made it in culture in 1983 ^7,37.

That parathyroid hormone, calcium and phosphate control the hormone between them. FGF23 from bone turned out to be a direct brake, acting within hours and independent of parathyroid hormone, and in kidney disease it was the stronger statistical predictor of the fall in calcitriol, in cross-sectional data backed by animal experiments ^13,35.

That 24,25-dihydroxyvitamin D is a second bone hormone, and then that it is inert. It proved dispensable for building bone in mice ⁷⁴, but later mouse work found it needed for normal fracture repair ⁷⁵; the question is open again, and so far only in animals.

That common receptor gene variants predict bone density. The 1994 claim of up to 75 percent of the genetic effect did not hold in 26,242 people ^83,84.

That high-dose calcitriol would extend survival in prostate cancer. A secondary signal in ASCENT was followed by more deaths in ASCENT-2, which was stopped ^40,144.

That active vitamin D protects the hearts of people with kidney disease. PRIMO and OPERA found no change in heart structure, and J-DAVID found no reduction in cardiovascular events or deaths, despite the observational survival advantage reported in 2003 ^{41,51,113,117}.

That idiopathic infantile hypercalcemia is simply vitamin D overdose. Many affected infants carry broken CYP24A1 or SLC34A1 genes that make ordinary doses dangerous, or that keep the disease going after vitamin D is stopped ^29,30.

That calcitriol measures vitamin D status. It stays normal until the precursor is almost gone ⁴⁷.

That calcium plus active vitamin D is the end of the story in hypoparathyroidism and in FGF23-excess rickets. Parathyroid hormone replacement and an antibody against FGF23 each did better on their trial endpoints, in trials funded by their makers ^73,129.

That the newer analogs spare calcium. Against placebo they still raised the risk of hypercalcemia about fivefold, and none of them reduced death or any other outcome that matters to a patient ^51,108.

That vitamin D supplements prevent cancer. VITAL, in 25,871 US adults over a median of 5.3 years, found no fewer cancers ¹⁴⁵.

That everyone should have a 25-hydroxyvitamin D test. The 2024 Endocrine Society guideline found no trial evidence that screening helps and suggests against routine testing in every population it considered ⁵⁷.

That replacing parathyroid hormone is a new idea. The hormone fragment was compared head to head with calcitriol in 1996, and full-length recombinant hormone was tested against placebo in 2013 ^124,126.

What is strange about it

The receptor was found two years before the hormone it receives, as a protein in chick chromatin that held on to an unidentified metabolite ^1,65.

The position of the crucial hydroxyl was first given away by an atom that disappeared: Kodicek's double-labeled vitamin D lost its hydrogen label at carbon 1, which is how the Cambridge group knew carbon 1 had been changed ^2,22.

The enzyme that makes a kidney hormone was cloned in one laboratory from skin, because there was more of it there, and in another from mice whose kidneys could no longer feel the hormone, because it ran unchecked in them ^6,9.

The hormone calls up its own brake: calcitriol raises FGF23, and FGF23 lowers calcitriol ¹³.

One drug-metabolizing enzyme sits on both sides of the disease. A mutant CYP3A4 that destroys calcitriol too fast causes rickets, and rifampin, which induces normal CYP3A4, has been used to treat patients who cannot destroy calcitriol at all ^28,63.

Mice without the receptor can be given healthy bones by diet alone, but nothing stops them going bald ³³.

A man with sarcoidosis had four bouts of hypercalcemia in seven years, every one of them in summer, and in 2026 another came home from a sunny holiday with his diagnosis waiting ^48,89.

A psoriasis ointment, applied for four days with a chemotherapy cream, turned out to recruit the immune system against precancerous skin ¹³⁵.

What is still unknown

Whether calcitriol has a physiological receptor at the cell membrane. Rapid effects within minutes were reported in 1984, but the protein responsible has never been fully characterized ^2,78.

What most of the hundreds of target genes do in people. The maps of receptor binding come from cell lines, and enrichment near disease genes is an association between maps, not evidence of an effect on disease ^5,19.

Whether any vitamin D receptor agonist helps pancreatic cancer. The 2025 and 2026 trials established safety and tissue effects, not benefit ^52,148.

How common the off-switch disorders really are. A national estimate puts infantile disease at 1 in 33,000, while database predictions suggested deleterious CYP24A1 genotypes in 4 to 20 percent of people, figures that cannot both describe disease ^49,138.

Whether replacing parathyroid hormone protects the kidneys better than calcium and calcitriol over decades. The two-year improvement in kidney function is a post hoc finding without a randomized comparator ¹³⁰.

Whether low calcitriol in acute and chronic illness is ever a cause rather than a consequence. The associations with COVID-19 severity and anemia-drug response are observational ^97,121.

Whether calcitriol measurements can be harmonized across methods, especially in children ^32,99.

Where it connects

Sources

170 sources, numbered as they are cited. Every one was checked against PubMed or its publisher before it was cited here; the note under each says what it shows and what it does not.

1. 1
   Norman AW, Myrtle JF, Midgett RJ, Nowicki HG, Williams V, Popják G. 1,25-dihydroxycholecalciferol: identification of the proposed active form of vitamin D3 in the intestine.Science · 1971 · 173(3991):51-4doi:10.1126/science.173.3991.51 · PMID 4325863

   Norman's group at Riverside, July 1971: mass spectrometry gave the formula C27H44O3 for the major polar metabolite in chick intestine, made in the kidney and 4 to 13 times as active as vitamin D3 at stimulating calcium transport. Chick tissue; the potency figure is from the authors' earlier work.

2. 2
   Jones G. 100 YEARS OF VITAMIN D: Historical aspects of vitamin D.Endocr Connect · 2022 · 11(4):e210594doi:10.1530/EC-21-0594 · PMID 35245207

   Read in full. The source for Kodicek's ten-year conclusion that vitamin D acts unchanged and why it was wrong, each of the three groups' contributions, Semmler's first synthesis, Hoffmann-La Roche's commercial synthesis under Milan Uskokovic, the clinical name calcitriol, and the statement that a membrane receptor has never been fully characterized at the molecular level. The author declares no conflict of interest.

3. 3
   Holick MF, Schnoes HK, DeLuca HF. Identification of 1,25-dihydroxycholecalciferol, a form of vitamin D3 metabolically active in the intestine.Proc Natl Acad Sci U S A · 1971 · 68(4):803-4doi:10.1073/pnas.68.4.803 · PMID 4323790

   DeLuca's laboratory, April 1971: the 'peak V' metabolite isolated pure from chicken intestine and identified by mass spectrometry, ultraviolet spectroscopy and specific chemical reactions. Animal tissue only; it identifies the molecule, not its function in people.

4. 4
   Feldman D, Krishnan AV, Swami S, Giovannucci E, Feldman BJ. The role of vitamin D in reducing cancer risk and progression.Nat Rev Cancer · 2014 · 14(5):342-57doi:10.1038/nrc3691 · PMID 24705652

   A review at the high-water mark of optimism, calling vitamin D the precursor of the steroid hormone calcitriol and saying preclinical and some clinical studies strongly suggest deficiency increases cancer risk, while conceding that randomized trials did not yet exist.

5. 5
   Bikle DD. Vitamin D metabolism, mechanism of action, and clinical applications.Chem Biol · 2014 · 21(3):319-29doi:10.1016/j.chembiol.2013.12.016 · PMID 24529992

   A review of the pathway: CYP2R1, CYP27B1, CYP24A1, and a receptor with thousands of binding sites regulating hundreds of genes in a cell-specific way. Review.

6. 6
   Takeyama K, Kitanaka S, Sato T, Kobori M, Yanagisawa J, Kato S. 25-Hydroxyvitamin D3 1alpha-hydroxylase and vitamin D synthesis.Science · 1997 · 277(5333):1827-30doi:10.1126/science.277.5333.1827 · PMID 9295274

   The kidney enzyme, CYP27B1, cloned from mice lacking the vitamin D receptor, and its suppression by the hormone shown to require the liganded receptor. Mouse work; the negative feedback it describes is the basis of every later clinical observation on this page.

7. 7
   Adams JS, Sharma OP, Gacad MA, Singer FR. Metabolism of 25-hydroxyvitamin D3 by cultured pulmonary alveolar macrophages in sarcoidosis.J Clin Invest · 1983 · 72(5):1856-60doi:10.1172/JCI111147 · PMID 6688814

   Lung macrophages from five of seven people with sarcoidosis made a calcitriol-like metabolite in culture, most from the patient who was hypercalcemic. Identifies the source cell; in vitro and small.

8. 8
   Weisman Y, Harell A, Edelstein S, David M, Spirer Z, Golander A. 1 alpha, 25-Dihydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 in vitro synthesis by human decidua and placenta.Nature · 1979 · 281(5729):317-9doi:10.1038/281317a0 · PMID 551281

   Human decidua and placenta make calcitriol in vitro. No abstract in the record; cited for its title finding. It shows capacity, not how much of the pregnancy rise comes from the placenta.

9. 9
   Fu GK, Lin D, Zhang MY, Bikle DD, Shackleton CH, Miller WL, Portale AA. Cloning of human 25-hydroxyvitamin D-1 alpha-hydroxylase and mutations causing vitamin D-dependent rickets type 1.Mol Endocrinol · 1997 · 11(13):1961-70doi:10.1210/mend.11.13.0035 · PMID 9415400

   The human enzyme cloned from skin keratinocytes, where it is more abundant than in kidney, mapped to chromosome 12, and two null mutations found in a child with vitamin D-dependent rickets type 1. Establishes the molecular cause; one patient.

10. 10
    Garabedian M, Holick MF, Deluca HF, Boyle IT. Control of 25-hydroxycholecalciferol metabolism by parathyroid glands.Proc Natl Acad Sci U S A · 1972 · 69(7):1673-6doi:10.1073/pnas.69.7.1673 · PMID 4340153

    In rats on a low-calcium diet, removing the thyroid and parathyroid glands cut calcitriol production to negligible levels within 40 hours, and parathyroid extract restored it. The authors called parathyroid hormone a tropin for the hormone. Rat physiology.

11. 11
    Boyle IT, Gray RW, DeLuca HF. Regulation by calcium of in vivo synthesis of 1,25-dihydroxycholecalciferol and 21,25-dihydroxycholecalciferol.Proc Natl Acad Sci U S A · 1971 · 68(9):2131-4doi:10.1073/pnas.68.9.2131 · PMID 4332247

    In rats, the more calcium in the diet and blood, the less calcitriol was made, the first evidence that the hormone's production adapts calcium absorption to intake. Animal data.

12. 12
    Tanaka Y, Deluca HF. The control of 25-hydroxyvitamin D metabolism by inorganic phosphorus.Arch Biochem Biophys · 1973 · 154(2):566-74doi:10.1016/0003-9861(73)90010-6 · PMID 4691503

    The rat study establishing phosphorus as a regulator of the kidney's vitamin D metabolism. The record has no abstract; cited for the finding as its title states it.

13. 13
    Shimada T, Hasegawa H, Yamazaki Y, et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis.J Bone Miner Res · 2004 · 19(3):429-35doi:10.1359/JBMR.0301264 · PMID 15040831

    In rats and mice, one injection of FGF23 lowered calcitriol by 3 hours, before phosphate fell, by suppressing CYP27B1 and inducing CYP24A1 messenger RNA within 1 hour, independent of parathyroid hormone; calcitriol injection raised FGF23 within 4 hours. Kirin authors. Animal data.

14. 14
    Urakawa I, Yamazaki Y, Shimada T, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23.Nature · 2006 · 444(7120):770-4doi:10.1038/nature05315 · PMID 17086194

    Klotho binds FGF23 and converts the ordinary FGF receptor 1(IIIc) into a specific FGF23 receptor; an antibody against klotho made mice unresponsive to FGF23. Cell and mouse work; Kirin authors.

15. 15
    Esvelt RP, Schnoes HK, DeLuca HF. Isolation and characterization of 1 alpha-hydroxy-23-carboxytetranorvitamin D: a major metabolite of 1,25-dihydroxyvitamin D3.Biochemistry · 1979 · 18(18):3977-83doi:10.1021/bi00585a021 · PMID 486408

    In rats, the major side-chain-oxidized product of the hormone, an acid, isolated and named calcitroic acid. Shows the end product of inactivation; it does not show the enzyme, which was identified later.

16. 16
    Baker AR, McDonnell DP, Hughes M, et al. Cloning and expression of full-length cDNA encoding human vitamin D receptor.Proc Natl Acad Sci U S A · 1988 · 85(10):3294-8doi:10.1073/pnas.85.10.3294 · PMID 2835767

    The human receptor cloned: a 1,281-base-pair coding sequence, a member of the steroid-receptor gene family closest to the thyroid hormone receptor. The first author's affiliation was California Biotechnology Inc., a company.

17. 17
    Rochel N, Wurtz JM, Mitschler A, Klaholz B, Moras D. The crystal structure of the nuclear receptor for vitamin D bound to its natural ligand.Mol Cell · 2000 · 5(1):173-9doi:10.1016/s1097-2765(00)80413-x · PMID 10678179

    The 1.8-angstrom crystal structure of the receptor's ligand-binding domain holding calcitriol, built from a construct lacking a variable insertion that proved dispensable for binding and activation. Shows the pocket; it is one domain, not the whole receptor on DNA.

18. 18
    Orlov I, Rochel N, Moras D, Klaholz BP. Structure of the full human RXR/VDR nuclear receptor heterodimer complex with its DR3 target DNA.EMBO J · 2012 · 31(2):291-300doi:10.1038/emboj.2011.445 · PMID 22179700

    Cryo-electron microscopy of the whole liganded receptor paired with the retinoid X receptor on its DNA target, a complex of about 100 kilodaltons, in an open conformation where coregulators can bind.

19. 19
    Ramagopalan SV, Heger A, Berlanga AJ, et al. A ChIP-seq defined genome-wide map of vitamin D receptor binding: associations with disease and evolution.Genome Res · 2010 · 20(10):1352-60doi:10.1101/gr.107920.110 · PMID 20736230

    After calcitriol stimulation of human cells, 2,776 genomic sites occupied by the receptor and 229 genes whose expression changed, with binding sites enriched near genes linked to autoimmune disease and cancer in genome-wide studies. Cell lines; enrichment is association, not effect in people.

20. 20
    Higgins V, Truong D, White-Al Habeeb NMA, Fung AWS, Hoffman B, Adeli K. Pediatric reference intervals for 1,25-dihydroxyvitamin D using the DiaSorin LIAISON XL assay in the healthy CALIPER cohort.Clin Chem Lab Med · 2018 · 56(6):964-972doi:10.1515/cclm-2017-0767 · PMID 29389662

    Healthy Canadian children: 77 to 471 pmol/L under one year, 113 to 363 after, and 108 to 246 pmol/L from age 3, with no seasonal or sex effect; some infant values may reflect a cross-reacting substance. One immunoassay; intervals are method-specific.

21. 21
    Reichel H. Optimum mode of administration of vitamin D in renal failure. Insights from experimental data.Nephrol Dial Transplant · 1995 · 10 Suppl 4:33-6doi:10.1093/ndt/10.supp4.33 · PMID 7478149

    A summary of rat and clinical data: calcitriol's plasma half-life is only several hours while its effect on the parathyroid glands lasts days, the argument for pulse dosing. Largely experimental.

22. 22
    Lawson DE, Fraser DR, Kodicek E, Morris HR, Williams DH. Identification of 1,25-dihydroxycholecalciferol, a new kidney hormone controlling calcium metabolism.Nature · 1971 · 230(5291):228-30doi:10.1038/230228a0 · PMID 4323313

    Kodicek's group, dated 26 March 1971, the first of the three identifications to reach print and the first to call the molecule a kidney hormone in its title. No abstract in the record; the tracer method (a lost tritium atom marking carbon 1) is described in the historical review.

23. 23
    Hardin SR. Rocaltrol (calcitriol/Roche).Crit Care Nurse · 1985 · 5(3):66-7PMID 3847331

    A short drug profile naming Roche as the maker of Rocaltrol. No abstract or DOI; cited for the brand and manufacturer only.

24. 24
    The Medical Letter. Calcitriol.Med Lett Drugs Ther · 1979 · 21(12):50-1PMID 449839

    The independent drug bulletin's June 1979 review of the newly available drug, indexed under hypocalcemia, kidney disease and dialysis. No abstract or DOI in the record; cited for the date and indication.

25. 25
    Kitanaka S, Takeyama K, Murayama A, et al. Inactivating mutations in the 25-hydroxyvitamin D3 1alpha-hydroxylase gene in patients with pseudovitamin D-deficiency rickets.N Engl J Med · 1998 · 338(10):653-61doi:10.1056/NEJM199803053381004 · PMID 9486994

    Four unrelated patients with homozygous missense mutations at 12q13.3, every one abolishing enzyme activity; parents and a sibling were carriers. Confirms the single-enzyme cause of type 1 in a small series.

26. 26
    Cheng JB, Levine MA, Bell NH, Mangelsdorf DJ, Russell DW. Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase.Proc Natl Acad Sci U S A · 2004 · 101(20):7711-5doi:10.1073/pnas.0402490101 · PMID 15128933

    A child with low 25-hydroxyvitamin D and classic signs of deficiency was homozygous for a CYP2R1 mutation that abolished 25-hydroxylase activity: the genetic evidence that CYP2R1 is the liver enzyme, and the basis of rickets type 1B.

27. 27
    Hughes MR, Malloy PJ, Kieback DG, et al. Point mutations in the human vitamin D receptor gene associated with hypocalcemic rickets.Science · 1988 · 242(4886):1702-5doi:10.1126/science.2849209 · PMID 2849209

    In two families, single-letter mutations in the receptor's zinc fingers left hormone binding normal but crippled binding to DNA. The molecular cause of type II.

28. 28
    Roizen JD, Li D, O'Lear L, et al. CYP3A4 mutation causes vitamin D-dependent rickets type 3.J Clin Invest · 2018 · 128(5):1913-1918doi:10.1172/JCI98680 · PMID 29461981

    Two unrelated children with the same new mutation in the drug-metabolizing enzyme CYP3A4, which then destroyed calcitriol 10 times faster than normal CYP3A4 and twice as fast as CYP24A1. Two patients; enzyme kinetics in vitro.

29. 29
    Schlingmann KP, Kaufmann M, Weber S, et al. Mutations in CYP24A1 and idiopathic infantile hypercalcemia.N Engl J Med · 2011 · 365(5):410-21doi:10.1056/NEJMoa1103864 · PMID 21675912

    Recessive loss-of-function mutations in CYP24A1 in six children with familial idiopathic infantile hypercalcemia and in a second group of infants who became severely hypercalcemic after bolus vitamin D prophylaxis. The paper that explained the British epidemic of the 1950s as a gene-environment collision; genetics in small cohorts.

30. 30
    Schlingmann KP, Ruminska J, Kaufmann M, et al. Autosomal-Recessive Mutations in SLC34A1 Encoding Sodium-Phosphate Cotransporter 2A Cause Idiopathic Infantile Hypercalcemia.J Am Soc Nephrol · 2016 · 27(2):604-14doi:10.1681/ASN.2014101025 · PMID 26047794

    A second cause: loss of the kidney phosphate transporter NaPi-IIa in 4 index cases and 12 sporadic patients wastes phosphate, suppresses FGF23 and drives inappropriate calcitriol production; it persists without vitamin D and responds to phosphate. Genetics with mouse confirmation.

31. 31
    Lainis V, Katsouli O, Gazi S, Kassi E, Chronopoulos E, Tournis S. Hereditary disorders of vitamin-D metabolism and its receptor.Hormones (Athens) · 2025 · 24(2):335-346doi:10.1007/s42000-025-00630-w · PMID 39893280

    A review using the current names: rickets type 1A from CYP27B1 loss, type 1B from CYP2R1 loss, type 2 from receptor loss and type 3 from a CYP3A4 gain of function, with idiopathic infantile hypercalcemia from CYP24A1 loss. Review.

32. 32
    Sempos CT, Heijboer AC, Bikle DD, et al. Vitamin D assays and the definition of hypovitaminosis D: results from the First International Conference on Controversies in Vitamin D.Br J Clin Pharmacol · 2018 · 84(10):2194-2207doi:10.1111/bcp.13652 · PMID 29851137

    A 2017 conference: 25-hydroxyvitamin D remains the critical measurement of status, 50 to 125 nmol/L appears sufficient for bone, and other markers including calcitriol must be standardized before they can be used. Consensus.

33. 33
    Li YC, Amling M, Pirro AE, et al. Normalization of mineral ion homeostasis by dietary means prevents hyperparathyroidism, rickets, and osteomalacia, but not alopecia in vitamin D receptor-ablated mice.Endocrinology · 1998 · 139(10):4391-6doi:10.1210/endo.139.10.6262 · PMID 9751523

    A mineral rescue diet prevented hyperparathyroidism, rickets and osteomalacia in receptor-knockout mice but not hair loss: most of the hormone's skeletal work is done by getting calcium out of the gut. Mouse work.

34. 34
    Wasserman RH, Taylor AN. Vitamin D3-induced calcium-binding protein in chick intestinal mucosa.Science · 1966 · 152(3723):791-3doi:10.1126/science.152.3723.791 · PMID 17797460

    In rachitic chicks, vitamin D3 induced an intestinal calcium-binding protein whose concentration tracked calcium absorption. The first molecular footprint of the hormone, found five years before the hormone itself; animal work.

35. 35
    Gutierrez O, Isakova T, Rhee E, et al. Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease.J Am Soc Nephrol · 2005 · 16(7):2205-15doi:10.1681/ASN.2005010052 · PMID 15917335

    A cross-sectional study of 80 people with kidney disease: FGF23 rose early, and once it was accounted for, kidney function and phosphate no longer predicted calcitriol. An association in one sample, consistent with the animal mechanism.

36. 36
    Fraser D, Kooh SW, Kind HP, Holick MF, Tanaka Y, DeLuca HF. Pathogenesis of hereditary vitamin-D-dependent rickets. An inborn error of vitamin D metabolism involving defective conversion of 25-hydroxyvitamin D to 1 alpha,25-dihydroxyvitamin D.N Engl J Med · 1973 · 289(16):817-22doi:10.1056/NEJM197310182891601 · PMID 4357855

    The demonstration, two years after the hormone was found, that type 1 vitamin D-dependent rickets is a failure to make it. No abstract in the record; cited for its title finding.

37. 37
    Barbour GL, Coburn JW, Slatopolsky E, Norman AW, Horst RL. Hypercalcemia in an anephric patient with sarcoidosis: evidence for extrarenal generation of 1,25-dihydroxyvitamin D.N Engl J Med · 1981 · 305(8):440-3doi:10.1056/NEJM198108203050807 · PMID 6894783

    A man with no kidneys who still made enough calcitriol to become hypercalcemic. A single case; no abstract in the record; cited for the finding its title states, which ended the belief that only the kidney makes the hormone.

38. 38
    Tebben PJ, Singh RJ, Kumar R. Vitamin D-Mediated Hypercalcemia: Mechanisms, Diagnosis, and Treatment.Endocr Rev · 2016 · 37(5):521-547doi:10.1210/er.2016-1070 · PMID 27588937

    A review: hypercalcemia in up to 4 percent of the population; ectopic CYP27B1 in granulomas (sarcoidosis, tuberculosis) and lymphomas; CYP24A1 loss with high calcitriol, suppressed parathyroid hormone, stones and nephrocalcinosis, sometimes from a single mutated copy; and evidence of impaired 24-hydroxylation in first-time calcium stone formers. Review.

39. 39
    Khan AA, Bilezikian JP, Brandi ML, et al. Evaluation and Management of Hypoparathyroidism Summary Statement and Guidelines from the Second International Workshop.J Bone Miner Res · 2022 · 37(12):2568-2585doi:10.1002/jbmr.4691 · PMID 36054621

    50 experts using GRADE: conventional therapy with calcium and active vitamin D as first line, a weak recommendation on low-quality evidence, with parathyroid hormone when that fails; complications include nephrocalcinosis, stones and kidney failure. Guideline.

40. 40
    Scher HI, Jia X, Chi K, et al. Randomized, open-label phase III trial of docetaxel plus high-dose calcitriol versus docetaxel plus prednisone for patients with castration-resistant prostate cancer.J Clin Oncol · 2011 · 29(16):2191-8doi:10.1200/JCO.2010.32.8815 · PMID 21483004

    ASCENT-2: 953 men; halted at interim analysis for more deaths in the calcitriol arm, median survival 17.8 against 20.2 months (P = .002), adjusted hazard ratio 1.33. The two arms also differed in docetaxel schedule, so the harm cannot be pinned on DN-101 alone. Sponsor not stated in the indexed record.

41. 41
    J-DAVID Investigators; Shoji T, Inaba M, Fukagawa M, et al. Effect of Oral Alfacalcidol on Clinical Outcomes in Patients Without Secondary Hyperparathyroidism Receiving Maintenance Hemodialysis: The J-DAVID Randomized Clinical Trial.JAMA · 2018 · 320(22):2325-2334doi:10.1001/jama.2018.17749 · PMID 30535217

    976 Japanese dialysis patients without secondary hyperparathyroidism, alfacalcidol 0.5 microgram a day or none, median 4 years: cardiovascular events 21.1 versus 17.9 percent, hazard ratio 1.25 (0.94 to 1.67), and deaths 18.2 versus 16.8 percent. Open label with blinded endpoints; the trial that tested the observational survival claim and found nothing.

42. 42
    Isakova T, Wahl P, Vargas GS, et al. Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease.Kidney Int · 2011 · 79(12):1370-8doi:10.1038/ki.2011.47 · PMID 21389978

    In 3,879 adults with stage 2 to 4 kidney disease (the CRIC cohort), high FGF23 was more common than raised parathyroid hormone or phosphate at every level of kidney function. Cross-sectional; shows timing, not cause.

43. 43
    Levine MA, Ukena J, Sibley CT, Kjelgaard-Hansen M. The impact of parathyroid hormone replacement with palopegteriparatide on synthesis of 1,25-dihydroxy vitamin D in hypoparathyroidism.Expert Rev Clin Pharmacol · 2026 · 19(8):705-715doi:10.1080/17512433.2026.2718374 · PMID 42605157

    A review: hypoparathyroidism causes calcitriol deficiency, and over 3.5 years of PaTHway calcitriol stayed within normal limits as the drug restored the kidney's own production. Three of four authors work for Ascendis Pharma; a review by the manufacturer.

44. 44
    Shimada T, Mizutani S, Muto T, et al. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia.Proc Natl Acad Sci U S A · 2001 · 98(11):6500-5doi:10.1073/pnas.101545198 · PMID 11344269

    FGF23 cloned from a tumor causing osteomalacia; in mice, recombinant FGF23 lowered phosphate within 12 hours and continuous production reproduced the disease, including low calcitriol. The authors worked at Kirin Brewery's pharmaceutical laboratory, a commercial affiliation.

45. 45
    Wolf M, Koch TA, Bregman DB. Effects of iron deficiency anemia and its treatment on fibroblast growth factor 23 and phosphate homeostasis in women.J Bone Miner Res · 2013 · 28(8):1793-803doi:10.1002/jbmr.1923 · PMID 23505057

    55 women with heavy menstrual bleeding: iron deficiency raised FGF23 fragments but not intact hormone; ferric carboxymaltose, not iron dextran, transiently raised intact FGF23, dropping phosphate below 2.0 mg/dL in 10 women with lower calcitriol and higher parathyroid hormone. Randomized comparison of two iron products; the sponsor is not named in the abstract.

46. 46
    Rude RK, Adams JS, Ryzen E, et al. Low serum concentrations of 1,25-dihydroxyvitamin D in human magnesium deficiency.J Clin Endocrinol Metab · 1985 · 61(5):933-40doi:10.1210/jcem-61-5-933 · PMID 3840173

    23 hypocalcemic magnesium-deficient patients: 16 had calcitriol below 30 pg/mL, and after 5 to 13 days of intravenous magnesium only 5 rose into the normal range, although calcium normalized. Observational; it shows the association and a slow recovery, not the enzyme mechanism.

47. 47
    Need AG, O'Loughlin PD, Morris HA, Coates PS, Horowitz M, Nordin BE. Vitamin D metabolites and calcium absorption in severe vitamin D deficiency.J Bone Miner Res · 2008 · 23(11):1859-63doi:10.1359/jbmr.080607 · PMID 18597633

    Records of 3,661 patients, 319 with 25-hydroxyvitamin D at or below 40 nmol/L: calcitriol and calcium absorption fell only when 25-hydroxyvitamin D reached about 10 nmol/L, because parathyroid hormone held the hormone up until then. Cross-sectional, one center.

48. 48
    Papapoulos SE, Clemens TL, Fraher LJ, Lewin IG, Sandler LM, O'Riordan JL. 1, 25-dihydroxycholecalciferol in the pathogenesis of the hypercalcaemia of sarcoidosis.Lancet · 1979 · 1(8117):627-30doi:10.1016/s0140-6736(79)91076-6 · PMID 85869

    One man with sarcoidosis and four summer episodes of hypercalcemia in seven years: calcitriol 26 to 62 pg/mL when calcium was normal and up to 137 pg/mL when it was high. The first report linking the hypercalcemia to the hormone; a single patient.

49. 49
    Nesterova G, Malicdan MC, Yasuda K, et al. 1,25-(OH)2D-24 Hydroxylase (CYP24A1) Deficiency as a Cause of Nephrolithiasis.Clin J Am Soc Nephrol · 2013 · 8(4):649-57doi:10.2215/CJN.05360512 · PMID 23293122

    Two patients at the NIH with biallelic CYP24A1 loss: high calcitriol, normal 25-hydroxyvitamin D, low 24,25-dihydroxyvitamin D, high calcium, suppressed parathyroid hormone and kidney stones. Its estimate that 4 to 20 percent of people might carry predicted deleterious biallelic variants rests on database predictions, not on measured disease.

50. 50
    Martone J, Trost S. Vitamin D-induced hypercalcemia and nephrolithiasis in a 58-year-old woman with biochemical findings suggestive of 24-hydroxylase deficiency: a case report.AME Case Rep · 2026 · 10:182doi:10.21037/acr-2026-0045 · PMID 42871701

    One woman whose stones and hypercalcemia followed 2,000 IU a day of vitamin D, with a high calcitriol and a 25-hydroxyvitamin D to 24,25-dihydroxyvitamin D ratio the authors call diagnostic above 80; genetic testing was declined, so the diagnosis is biochemical.

51. 51
    Thadhani R, Appelbaum E, Pritchett Y, et al. Vitamin D therapy and cardiac structure and function in patients with chronic kidney disease: the PRIMO randomized controlled trial.JAMA · 2012 · 307(7):674-84doi:10.1001/jama.2012.120 · PMID 22337679

    227 patients with moderate kidney disease and thickened hearts, 11 countries, paricalcitol 2 micrograms a day or placebo for 48 weeks: parathyroid hormone normalized but left ventricular mass index did not change (0.34 versus -0.07 g/m2.7), and hypercalcemia was more frequent. A well-designed negative trial on an imaging endpoint. Sponsor not stated in the indexed record.

52. 52
    Perez KJ, Dias Costa A, Jordan A, et al. Gemcitabine and nab-paclitaxel with or without the VDR agonist paricalcitol for metastatic pancreatic cancer: a randomized, multiarm, run-in phase trial.Nat Cancer · 2026 · 7(6):928-943doi:10.1038/s43018-026-01165-8 · PMID 42185478

    36 patients randomized to chemotherapy with placebo, intravenous or oral paricalcitol: safe overall, but 5 (42 percent) on oral paricalcitol had grade 2 to 4 hypercalcemia; biopsies showed fewer activated fibroblasts and more T cells near tumor cells. A safety run-in with tissue endpoints, not an efficacy trial.

53. 53
    Koeffler HP, Hirji K, Itri L. 1,25-Dihydroxyvitamin D3: in vivo and in vitro effects on human preleukemic and leukemic cells.Cancer Treat Rep · 1985 · 69(12):1399-407PMID 2416438

    Patient leukemia cells differentiated at 1 micromolar but not at 1 nanomolar; 18 patients with myelodysplastic syndrome given 2 micrograms a day had no lasting benefit, 7 developed leukemia and 9 became hypercalcemic. The first clinical lesson: the doses that work in a dish cannot be reached in a person. The record gives no DOI.

54. 54
    Mitchell DM, Regan S, Cooley MR, et al. Long-term follow-up of patients with hypoparathyroidism.J Clin Endocrinol Metab · 2012 · 97(12):4507-14doi:10.1210/jc.2012-1808 · PMID 23043192

    120 Boston patients, 1988 to 2009, mostly on calcium and active vitamin D: 38 percent of those tested had a urine calcium above 300 mg a day, 31 percent of those imaged had kidney calcification, and stage 3 kidney disease was 2 to 17 times more common than expected. Chart review; it cannot separate disease from treatment.

55. 55
    Jones G, Prosser DE, Kaufmann M. 25-Hydroxyvitamin D-24-hydroxylase (CYP24A1): its important role in the degradation of vitamin D.Arch Biochem Biophys · 2012 · 523(1):9-18doi:10.1016/j.abb.2011.11.003 · PMID 22100522

    A review of CYP24A1: it 24-hydroxylates both 25-hydroxyvitamin D and calcitriol as the first step of their degradation, its first crystal structure, the human disease of its loss, and its induction by phosphate and FGF23 in kidney disease. Review; the authors' own work is prominent in it.

56. 56
    IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). Nomenclature of vitamin D. Recommendations 1981.Eur J Biochem · 1982 · 124(2):223-7PMID 7094913

    The formal naming rules for vitamin D compounds. The PubMed record has no abstract and no DOI; cited only for the existence and date of the recommendations.

57. 57
    Demay MB, Pittas AG, Bikle DD, et al. Vitamin D for the Prevention of Disease: An Endocrine Society Clinical Practice Guideline.J Clin Endocrinol Metab · 2024 · 109(8):1907-1947doi:10.1210/clinem/dgae290 · PMID 38828931

    The 2024 Endocrine Society guideline: no trial evidence was found to support screening and no clear evidence for an optimal target level, so the panel suggests against routine 25-hydroxyvitamin D testing in all the populations considered. Guideline.

58. 58
    Best CM, Sherwood R, Novotny JA, Zhang S, Pressman EK, O'Brien KO. Vitamin D kinetics in nonpregnant and pregnant women after a single oral dose of trideuterated vitamin D.J Steroid Biochem Mol Biol · 2022 · 216:106034doi:10.1016/j.jsbmb.2021.106034 · PMID 34843870

    A pilot stable-isotope study that opens by stating the plasma pool of calcitriol is increased throughout most of human pregnancy, and measured the 25-hydroxyvitamin D half-life at 18.8 days in pregnant and 13.6 in nonpregnant women, not significantly different. Small pilot.

59. 59
    Shimada T, Kakitani M, Yamazaki Y, et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism.J Clin Invest · 2004 · 113(4):561-8doi:10.1172/JCI19081 · PMID 14966565

    Mice without FGF23 had high phosphate and high calcitriol from enhanced CYP27B1 expression, with severe growth retardation and a short life. Proof that FGF23 is a physiological brake, in mice; Kirin authors.

60. 60
    Ay B, Cyr SM, Iwasaki Y, et al. Lysophosphatidic Acid Synergizes With 1,25-Dihydroxyvitamin D to Promote Fibroblast Growth Factor-23 Synthesis via MAPK Signaling and Induction of the IL12A Gene.FASEB J · 2026 · 40(1):e71435doi:10.1096/fj.202502235R · PMID 41511413

    In mouse bone explants, mice and an osteocyte cell line, lysophosphatidic acid needed calcitriol's action to raise FGF23. Laboratory and animal work that refines the loop by which the hormone calls up its own brake.

61. 61
    Kerner SA, Scott RA, Pike JW. Sequence elements in the human osteocalcin gene confer basal activation and inducible response to hormonal vitamin D3.Proc Natl Acad Sci U S A · 1989 · 86(12):4455-9doi:10.1073/pnas.86.12.4455 · PMID 2786632

    A 21-base-pair element in the human osteocalcin gene that makes it respond to calcitriol, one of the first vitamin D response elements defined. Cell culture.

62. 62
    Li YC, Pirro AE, Amling M, et al. Targeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia.Proc Natl Acad Sci U S A · 1997 · 94(18):9831-5doi:10.1073/pnas.94.18.9831 · PMID 9275211

    Mice without a working receptor were normal at birth, hypocalcemic by 21 days, rachitic by 35, and lost their hair from 4 weeks, a feature absent from dietary vitamin D deficiency. Mouse model.

63. 63
    Hawkes CP, Li D, Hakonarson H, Meyers KE, Thummel KE, Levine MA. CYP3A4 Induction by Rifampin: An Alternative Pathway for Vitamin D Inactivation in Patients With CYP24A1 Mutations.J Clin Endocrinol Metab · 2017 · 102(5):1440-1446doi:10.1210/jc.2016-4048 · PMID 28324001

    Two patients with CYP24A1 loss treated with rifampin, 10 mg/kg a day to a maximum of 600 mg, for up to 13 months, with normalization or improvement of calcium, urine calcium and calcitriol. A case series; no control group.

64. 64
    DeLuca HF. History of the discovery of vitamin D and its active metabolites.Bonekey Rep · 2014 · 3:479doi:10.1038/bonekey.2013.213 · PMID 24466410

    A first-hand history by the head of one of the three laboratories; read as abstract. Useful for the shape of the story, and partisan by position, which is why the priority account on this page leans on the independent review.

65. 65
    Haussler MR, Norman AW. Chromosomal receptor for a vitamin D metabolite.Proc Natl Acad Sci U S A · 1969 · 62(1):155-62doi:10.1073/pnas.62.1.155 · PMID 5253652

    A protein in chick intestinal chromatin that bound an active vitamin D metabolite with high affinity, purified 167-fold: the receptor, two years before its ligand was identified. Biochemistry in birds.

66. 66
    Fraser DR, Kodicek E. Unique biosynthesis by kidney of a biological active vitamin D metabolite.Nature · 1970 · 228(5273):764-6doi:10.1038/228764a0 · PMID 4319631

    The Cambridge report that the kidney makes an active vitamin D metabolite; the PubMed record carries no abstract and is indexed under nephrectomy, so it is cited for the finding and its date, with the experimental detail taken from the historical review read in full.

67. 67
    Holick MF, Schnoes HK, DeLuca HF, Suda T, Cousins RJ. Isolation and identification of 1,25-dihydroxycholecalciferol. A metabolite of vitamin D active in intestine.Biochemistry · 1971 · 10(14):2799-804doi:10.1021/bi00790a023 · PMID 4326883

    The full Wisconsin paper of July 1971. The record carries no abstract; it is cited for the fact and date of the full identification.

68. 68
    Kovacs CS. Maternal Mineral and Bone Metabolism During Pregnancy, Lactation, and Post-Weaning Recovery.Physiol Rev · 2016 · 96(2):449-547doi:10.1152/physrev.00027.2015 · PMID 26887676

    A review: a term fetus holds about 30 g of calcium, 80 percent laid down in the third trimester at 300 to 350 mg a day in the last six weeks, and the mother's intestinal calcium absorption doubles in pregnancy. Review.

69. 69
    Econs MJ, Drezner MK. Tumor-induced osteomalacia--unveiling a new hormone.N Engl J Med · 1994 · 330(23):1679-81doi:10.1056/NEJM199406093302310 · PMID 8177274

    An editorial arguing that tumors causing phosphate-wasting osteomalacia secrete an unidentified hormone. No abstract in the record; cited for the idea and its date, six years before the hormone was found.

70. 70
    ADHR Consortium. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23.Nat Genet · 2000 · 26(3):345-8doi:10.1038/81664 · PMID 11062477

    Positional cloning in families with autosomal dominant hypophosphatemic rickets found missense mutations in a new fibroblast growth factor, FGF23, the first mutations found in a human FGF gene. Genetics; it does not yet show what FGF23 does.

71. 71
    Gerber JS, Arroyo EMP, Pastor J, et al. Controlled dietary phosphate loading in healthy young men elevates plasma phosphate and FGF23 levels.Pflugers Arch · 2025 · 477(3):495-508doi:10.1007/s00424-024-03046-4 · PMID 39601886

    A randomized crossover study in 10 healthy young men: 5 days of extra dietary phosphate raised plasma phosphate and intact FGF23 and suppressed klotho, and higher intact FGF23 went with lower calcitriol, although calcitriol itself did not change significantly.

72. 72
    Kuro-o M, Matsumura Y, Aizawa H, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing.Nature · 1997 · 390(6655):45-51doi:10.1038/36285 · PMID 9363890

    The discovery of klotho in mice whose defect produced a syndrome resembling aging. It did not yet connect klotho to FGF23 or vitamin D.

73. 73
    Imel EA, Glorieux FH, Whyte MP, et al. Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial.Lancet · 2019 · 393(10189):2416-2427doi:10.1016/S0140-6736(19)30654-3 · PMID 31104833

    61 children with FGF23-excess rickets: switching from oral phosphate plus active vitamin D to burosumab, an antibody against FGF23, improved rickets more at week 40 (difference 1.1 points, 0.8 to 1.5). Open label; funded by Ultragenyx and Kyowa Kirin, the drug's makers.

74. 74
    St-Arnaud R, Arabian A, Travers R, et al. Deficient mineralization of intramembranous bone in vitamin D-24-hydroxylase-ablated mice is due to elevated 1,25-dihydroxyvitamin D and not to the absence of 24,25-dihydroxyvitamin D.Endocrinology · 2000 · 141(7):2658-66doi:10.1210/endo.141.7.7579 · PMID 10875271

    Mice without CYP24A1 could not clear calcitriol and mineralized some bone poorly; crossing them with receptor-knockout mice rescued the defect, showing that the excess hormone, not the missing 24,25-dihydroxyvitamin D, was to blame. Mouse work.

75. 75
    Martineau C, Naja RP, Husseini A, et al. Optimal bone fracture repair requires 24R,25-dihydroxyvitamin D3 and its effector molecule FAM57B2.J Clin Invest · 2018 · 128(8):3546-3557doi:10.1172/JCI98093 · PMID 30010626

    Mice unable to make 24,25-dihydroxyvitamin D healed fractures with smaller, less stiff callus; 24,25-dihydroxyvitamin D, and not calcitriol, corrected the defect, acting through a binding protein named FAM57B2. Mice only.

76. 76
    Kooij I, Mitrofanov K, Rehfeld A, et al. The 24,25(OH)2D-TLCD3B signaling complex and reproductive function in mice and men.J Steroid Biochem Mol Biol · 2026 · 264:107060doi:10.1016/j.jsbmb.2026.107060 · PMID 42365880

    The same 24,25-dihydroxyvitamin D-TLCD3B signal, TLCD3B being the new name of FAM57B2, proved dispensable for reproductive function in mice and had limited effects in human spermatozoa.

77. 77
    Brumbaugh PF, Haussler MR. 1 Alpha,25-dihydroxycholecalciferol receptors in intestine. I. Association of 1 alpha,25-dihydroxycholecalciferol with intestinal mucosa chromatin.J Biol Chem · 1974 · 249(4):1251-7PMID 4360685

    The follow-up showing the identified hormone itself bound to intestinal chromatin. No abstract or DOI in the record; cited for its title finding and date.

78. 78
    Nemere I, Yoshimoto Y, Norman AW. Calcium transport in perfused duodena from normal chicks: enhancement within fourteen minutes of exposure to 1,25-dihydroxyvitamin D3.Endocrinology · 1984 · 115(4):1476-83doi:10.1210/endo-115-4-1476 · PMID 6548181

    In perfused chick duodenum, 130 picomolar calcitriol raised calcium transport within 14 minutes, too fast for gene transcription, through what the authors called unknown mechanisms. The founding evidence for a rapid, non-genomic action; animal tissue.

79. 79
    Norman AW. From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health.Am J Clin Nutr · 2008 · 88(2):491S-499Sdoi:10.1093/ajcn/88.2.491S · PMID 18689389

    A review by one of the 1971 discoverers counting at least 36 cell types with the receptor and paracrine hormone production in at least 10 extrarenal organs, and arguing for higher intakes; the receptor counts are descriptive and the intake argument preceded the large negative trials.

80. 80
    Yoshizawa T, Handa Y, Uematsu Y, et al. Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning.Nat Genet · 1997 · 16(4):391-6doi:10.1038/ng0897-391 · PMID 9241280

    A second receptor-knockout mouse: normal until weaning, then hair loss, hypocalcemia, infertility and severely impaired bone formation, with most dying within 15 weeks. Mouse model.

81. 81
    Balsan S, Garabédian M, Larchet M, et al. Long-term nocturnal calcium infusions can cure rickets and promote normal mineralization in hereditary resistance to 1,25-dihydroxyvitamin D.J Clin Invest · 1986 · 77(5):1661-7doi:10.1172/JCI112483 · PMID 3009551

    A child with hereditary resistance to the hormone and calcitriol about 100 times normal, unresponsive to every vitamin D drug: 7 months of nocturnal calcium infusions corrected the biochemistry and healed the rickets, and bone biopsies showed normal mineralization, although her bone cells still did not respond to calcitriol. One patient.

82. 82
    Price PA, Baukol SA. 1,25-Dihydroxyvitamin D3 increases synthesis of the vitamin K-dependent bone protein by osteosarcoma cells.J Biol Chem · 1980 · 255(24):11660-3PMID 6969260

    In rat osteosarcoma cells, physiological calcitriol (half-maximal at 0.04 ng/mL) raised synthesis of the vitamin K-dependent bone protein sixfold; the first bone protein shown to be specifically induced by the hormone. Cell culture; the record gives no DOI.

83. 83
    Morrison NA, Qi JC, Tokita A, et al. Prediction of bone density from vitamin D receptor alleles.Nature · 1994 · 367(6460):284-7doi:10.1038/367284a0 · PMID 8161378

    The claim that common receptor gene variants accounted for up to 75 percent of the genetic effect on bone density in healthy people. Later large studies did not confirm it; cited here as the belief that was reversed.

84. 84
    Uitterlinden AG, Ralston SH, Brandi ML, et al. The association between common vitamin D receptor gene variations and osteoporosis: a participant-level meta-analysis.Ann Intern Med · 2006 · 145(4):255-64doi:10.7326/0003-4819-145-4-200608150-00005 · PMID 16908916

    26,242 participants in nine European cohorts: FokI, BsmI, ApaI and TaqI receptor variants were not associated with bone density (differences under 0.011 g/cm2) or fracture (odds ratios 0.98 to 1.02); the Cdx2 variant had a 9 percent lower vertebral fracture risk of borderline significance.

85. 85
    Dawson-Hughes B, Huggins GS, Nelson J, Vickery E, Powers SN, Pittas AG. Vitamin D Receptor Polymorphisms and the Effect of Vitamin D Supplementation on Diabetes Risk Among Adults With Prediabetes.JAMA Netw Open · 2026 · 9(4):e267332doi:10.1001/jamanetworkopen.2026.7332 · PMID 42024385

    A genetic analysis of 2,098 participants in the D2d trial: 4,000 IU of vitamin D3 a day lowered diabetes risk by 19 percent in carriers of the ApaI C allele (hazard ratio 0.81, 0.66 to 0.99) and not at all in AA carriers (1.02). A subgroup analysis made after the fact.

86. 86
    Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response.Science · 2006 · 311(5768):1770-3doi:10.1126/science.1123933 · PMID 16497887

    In human macrophages, Toll-like receptor activation switched on the vitamin D receptor and CYP27B1, inducing cathelicidin and killing intracellular Mycobacterium tuberculosis; sera low in 25-hydroxyvitamin D supported the response poorly. In vitro; the population comparison is an association.

87. 87
    Ali MB, Ciner A. Dedifferentiated liposarcoma and 1,25 dihydroxyvitamin D-induced paraneoplastic hypercalcaemia.BMJ Case Rep · 2026 · 19(4)doi:10.1136/bcr-2025-269928 · PMID 41980790

    A retroperitoneal liposarcoma making calcitriol; the authors count only three earlier published sarcoma cases of this mechanism. One case.

88. 88
    Alfaour A, Ganeshpure S, Kunduvalappil Thachankandy MN, Batool F. Granuloma-Related Hypercalcemia Secondary to Silicone-Induced Granulomatous Lymphadenopathy: A Case Report.Cureus · 2026 · 18(4):e106585doi:10.7759/cureus.106585 · PMID 42109939

    A 77-year-old woman with recurrent hypercalcemia from silicone granulomas, suppressed parathyroid hormone and a calcitriol the authors describe as inappropriately normal. One case; it shows that a normal value does not exclude the mechanism.

89. 89
    Ferrie S, Malhotra P, Amal Calist A. Hypercalcaemia After a Sunny Holiday.Cureus · 2026 · 18(5):e108642doi:10.7759/cureus.108642 · PMID 42281697

    A man who became severely hypercalcemic after a holiday in Portugal, with parathyroid hormone in the normal range and sarcoid granulomas on biopsy; the authors attribute it to granuloma calcitriol amplified by sunlight. One case.

90. 90
    Adams JS, Diz MM, Sharma OP. Effective reduction in the serum 1,25-dihydroxyvitamin D and calcium concentration in sarcoidosis-associated hypercalcemia with short-course chloroquine therapy.Ann Intern Med · 1989 · 111(5):437-8doi:10.7326/0003-4819-111-5-437 · PMID 2764407

    A case report of chloroquine lowering calcitriol and calcium in sarcoidosis. No abstract in the record; cited for its title finding.

91. 91
    Ghaleb A, Abdelmaksoud A, Bashumeel Y, et al. Prevalence and Outcomes of Primary Hyperparathyroidism in Sarcoidosis Patients: A Large-Scale Retrospective Cohort Study.J Clin Endocrinol Metab · 2026 · online ahead of printdoi:10.1210/clinem/dgag302 · PMID 42508809

    Electronic records of 117,395 US adults with sarcoidosis: 31.3 percent had high calcium, only 30.5 percent of those had parathyroid hormone measured, and 3.0 percent met biochemical criteria for primary hyperparathyroidism, three quarters uncoded. Observational; the mortality comparisons are associations open to confounding.

92. 92
    Kovacs CS. Vitamin D in pregnancy and lactation: maternal, fetal, and neonatal outcomes from human and animal studies.Am J Clin Nutr · 2008 · 88(2):520S-528Sdoi:10.1093/ajcn/88.2.520S · PMID 18689394

    A review concluding that maternal and fetal adaptations supply calcium relatively independently of vitamin D status, and that the deficient newborn, not the mother, is the one at risk. Review of human and animal data.

93. 93
    Martin M, Heim C, Mueller M, Mohaupt M. Gestational hypercalcemia: a narrative review of literature.Front Med (Lausanne) · 2026 · 13:1909975doi:10.3389/fmed.2026.1909975 · PMID 42707509

    A narrative review: more than 90 percent of hypercalcemia in pregnancy is primary hyperparathyroidism; granulomatous disease and CYP24A1 mutations are the main PTH-independent causes, and in sarcoidosis during pregnancy the kidney's increased calcitriol production adds to the granulomas'. Review.

94. 94
    Bishop CW, Ashfaq A, Choe J, Strugnell SA, Johnson LL, Norris KC, Sprague SM. Extended-Release Calcifediol Normalized 1,25-Dihydroxyvitamin D and Prevented Progression of Secondary Hyperparathyroidism in Hemodialysis Patients in a Pilot Randomized Clinical Trial.Am J Nephrol · 2025 · 57(1):109-119doi:10.1159/000546615 · PMID 40466630

    A pilot randomized trial in 44 hemodialysis patients: raising the precursor with extended-release calcifediol lifted calcitriol from 9.4 to 50.7 pg/mL, above the lower limit of normal in 93 percent, which the authors read as production outside the kidney. Most authors were employees of OPKO Health, which sells the drug.

95. 95
    Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab · 2011 · 96(7):1911-30doi:10.1210/jc.2011-0385 · PMID 21646368

    The 2011 guideline naming serum 25-hydroxyvitamin D by a reliable assay as the initial diagnostic test in people at risk of deficiency; the task force reports no corporate funding.

96. 96
    Liao HC, Saitman A, Dickerson J. Developing Benchmarking Metrics for Appropriate Ordering of Vitamin D, Thyroid Testing, and Iron Workups.J Appl Lab Med · 2025 · 10(1):184-191doi:10.1093/jalm/jfae126 · PMID 39749447

    Nine laboratories set a benchmark of 50 orders of 25-hydroxyvitamin D for every one of calcitriol, a higher ratio meaning calcitriol is being ordered on purpose. A stewardship metric, not an outcome study; one author worked at LabCorp.

97. 97
    Canbolat Unlu E, Karabela SN, Yesilbag Z, et al. Low 1,25-dihydroxyvitamin D levels are associated with severe COVID-19: an observational study in hospitalized patients.Front Nutr · 2026 · 13:1836021doi:10.3389/fnut.2026.1836021 · PMID 42325512

    185 hospitalized adults in Istanbul in 2020: low calcitriol was independently associated with severe disease but not with death. Observational; it cannot tell whether low calcitriol is a cause or a consequence of severe illness.

98. 98
    Brooks MH, Bell NH, Love L, et al. Vitamin-D-dependent rickets type II. Resistance of target organs to 1,25-dihydroxyvitamin D.N Engl J Med · 1978 · 298(18):996-9doi:10.1056/NEJM197805042981804 · PMID 205789

    A 22-year-old woman with rickets, hypocalcemia and a calcitriol of 137 pg/mL, markedly high: the hormone was present but not working. The paper that named type II; a single patient whose resistance was partial.

99. 99
    Tang JCY, Dunn R, Dutton JJ, et al. Measurement of 1,25-dihydroxyvitamin D in serum by LC-MS/MS compared to immunoassay reveals inconsistent agreement in paediatric samples.Clin Chem Lab Med · 2025 · 63(5):962-971doi:10.1515/cclm-2024-1032 · PMID 39648164

    In 80 young adults an immunoassay and mass spectrometry agreed closely (r = 0.9331); in 422 children they did not (r = 0.6536, mean bias -9.8 pmol/L). Shows the assay problem; it does not say which method is right in children.

100. 100
     Ketteler M, Block GA, Evenepoel P, et al. Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder: Synopsis of the Kidney Disease: Improving Global Outcomes 2017 Clinical Practice Guideline Update.Ann Intern Med · 2018 · 168(6):422-430doi:10.7326/M17-2640 · PMID 29459980

     The synopsis: 15 revised recommendations, treatment based on trends rather than single values, and caution to avoid hypercalcemia when treating secondary hyperparathyroidism. Guideline; the public review included industry.

101. 101
     Maxwell DR, Benjamin DM, Donahay SL, Allen MK, Hamburger RJ, Luft FC. Calcitriol in dialysis patients.Clin Pharmacol Ther · 1978 · 23(5):515-9doi:10.1002/cpt1978235515 · PMID 205382

     A randomized blinded comparison with vitamin D3 in 22 hemodialysis patients: a mean 0.579 microgram of calcitriol a day raised calcium from 8.7 to 10.25 mg/dL and lowered alkaline phosphatase, and hypercalcemia up to 13.2 mg/dL in 2 of 13 patients reversed promptly when the dose was cut.

102. 102
     Christiansen C, Rødbro P, Christensen MS, Hartnack B, Transbøl I. Deterioration of renal function during treatment of chronic renal failure with 1,25-dihydroxycholecalciferol.Lancet · 1978 · 2(8092 Pt 1):700-3doi:10.1016/s0140-6736(78)92702-2 · PMID 80633

     A controlled trial in 18 people with chronic renal failure not yet on dialysis: creatinine clearance fell faster during calcitriol treatment than before it in every patient on the drug, and 7 of 8 became hypercalcemic. The authors called deteriorating kidney function a major limitation of the drug before dialysis.

103. 103
     Slatopolsky E, Weerts C, Thielan J, Horst R, Harter H, Martin KJ. Marked suppression of secondary hyperparathyroidism by intravenous administration of 1,25-dihydroxy-cholecalciferol in uremic patients.J Clin Invest · 1984 · 74(6):2136-43doi:10.1172/JCI111639 · PMID 6549016

     In dialysis patients, oral calcitriol at doses keeping calcium at the upper limit of normal did not lower parathyroid hormone, while intravenous calcitriol suppressed it by 70.1 percent in all 20, partly without any change in calcium. Uncontrolled physiological study.

104. 104
     Binderup L, Bramm E. Effects of a novel vitamin D analogue MC903 on cell proliferation and differentiation in vitro and on calcium metabolism in vivo.Biochem Pharmacol · 1988 · 37(5):889-95doi:10.1016/0006-2952(88)90177-3 · PMID 2830885

     Calcipotriol matched calcitriol on human cells in culture but was at least 100 times less active on calcium in rats. The authors worked at Leo Pharmaceutical Products, the developer; laboratory and animal data.

105. 105
     Martin KJ, González EA, Gellens M, Hamm LL, Abboud H, Lindberg J. 19-Nor-1-alpha-25-dihydroxyvitamin D2 (Paricalcitol) safely and effectively reduces the levels of intact parathyroid hormone in patients on hemodialysis.J Am Soc Nephrol · 1998 · 9(8):1427-32doi:10.1681/ASN.V981427 · PMID 9697664

     Three placebo-controlled trials, 78 dialysis patients: at least a 30 percent fall in parathyroid hormone in 68 percent on intravenous paricalcitol against 8 percent on placebo, without hypercalcemia before the target was reached. Twelve weeks; a laboratory endpoint. Sponsor not stated in the indexed record.

106. 106
     Frazão JM, Elangovan L, Maung HM, et al. Intermittent doxercalciferol (1alpha-hydroxyvitamin D(2)) therapy for secondary hyperparathyroidism.Am J Kidney Dis · 2000 · 36(3):550-61doi:10.1053/ajkd.2000.16193 · PMID 10977787

     138 dialysis patients, 99 completing: oral doxercalciferol lowered parathyroid hormone by 55 percent at 16 weeks; in the blinded phase 3.26 percent of calcium values exceeded 11.2 mg/dL against 0.46 percent on placebo. A laboratory endpoint. Sponsor not stated in the indexed record.

107. 107
     Franchi M, Gunnarsson J, Gonzales-Parra E, Ferreira A, Ström O, Corrao G. Paricalcitol and Extended-Release Calcifediol for Treatment of Secondary Hyperparathyroidism in Non-Dialysis Chronic Kidney Disease: Results From a Network Meta-Analysis.J Clin Endocrinol Metab · 2023 · 108(11):e1424-e1432doi:10.1210/clinem/dgad289 · PMID 37235771

     Nine trials, 1,426 patients, no head-to-head comparison: similar parathyroid hormone lowering, with paricalcitol raising calcium by about 0.2 mg/dL more than extended-release calcifediol. Indirect comparison; two authors were at a research consultancy.

108. 108
     Palmer SC, McGregor DO, Macaskill P, Craig JC, Elder GJ, Strippoli GFM. Meta-analysis: vitamin D compounds in chronic kidney disease.Ann Intern Med · 2007 · 147(12):840-53doi:10.7326/0003-4819-147-12-200712180-00004 · PMID 18087055

     76 trials, 3,667 participants: vitamin D compounds did not reduce death, bone pain, vascular calcification or parathyroidectomy; the newer analogs, against placebo, still raised the risk of hypercalcemia (relative risk 5.15, 95 percent confidence interval 1.06 to 24.97); only 5 trials compared newer with older compounds directly. Meta-analysis.

109. 109
     Tilyard MW, Spears GF, Thomson J, Dovey S. Treatment of postmenopausal osteoporosis with calcitriol or calcium.N Engl J Med · 1992 · 326(6):357-62doi:10.1056/NEJM199202063260601 · PMID 1729617

     622 New Zealand women with vertebral fractures, calcitriol 0.25 microgram twice a day or calcium 1 g, single-blind, 3 years: new vertebral fractures 9.9 versus 31.5 per 100 patient-years in year 3, but only in women with five or fewer fractures at entry. Compared with calcium, not placebo.

110. 110
     Ott SM, Chesnut CH. Calcitriol treatment is not effective in postmenopausal osteoporosis.Ann Intern Med · 1989 · 110(4):267-74doi:10.7326/0003-4819-110-4-267 · PMID 2913914

     86 women, double-blind against placebo, 2 years, mean 0.43 microgram a day: no difference in bone mass, and new fractures in 26 percent on calcitriol against 16 percent on placebo (difference not significant); calcium in blood and urine rose. Small and negative.

111. 111
     Matsumoto T, Ito M, Hayashi Y, et al. A new active vitamin D3 analog, eldecalcitol, prevents the risk of osteoporotic fractures--a randomized, active comparator, double-blind study.Bone · 2011 · 49(4):605-12doi:10.1016/j.bone.2011.07.011 · PMID 21784190

     1,054 Japanese patients, eldecalcitol 0.75 microgram against alfacalcidol 1.0 microgram for 3 years: vertebral fractures 13.4 versus 17.5 percent, hazard ratio 0.74 (90 percent interval 0.56 to 0.97). Sponsor not stated in the indexed record. Active comparator only; rises in serum and urine calcium were more common on eldecalcitol.

112. 112
     Oussaada SM, Akkermans I, Chohan S, et al. The effect of active vitamin D supplementation on body weight and composition: A meta-analysis of individual participant data.Clin Nutr · 2024 · 43(11):99-105doi:10.1016/j.clnu.2024.08.031 · PMID 39357088

     Individual data from 411 participants in placebo-controlled calcitriol trials (206 on calcitriol): no effect on weight, body mass index, waist, fat or lean mass. None of the trials was designed for weight.

113. 113
     Wang AY, Fang F, Chan J, et al. Effect of paricalcitol on left ventricular mass and function in CKD--the OPERA trial.J Am Soc Nephrol · 2014 · 25(1):175-86doi:10.1681/ASN.2013010103 · PMID 24052631

     60 patients with stage 3 to 5 kidney disease and thickened hearts, paricalcitol 1 microgram a day or placebo for 52 weeks: no change in left ventricular mass or function; parathyroid hormone and alkaline phosphatase fell, and cardiovascular hospitalizations, a secondary endpoint, were fewer. Small. Sponsor not stated in the indexed record.

114. 114
     Kissmeyer AM, Binderup L. Calcipotriol (MC 903): pharmacokinetics in rats and biological activities of metabolites. A comparative study with 1,25(OH)2D3.Biochem Pharmacol · 1991 · 41(11):1601-6doi:10.1016/0006-2952(91)90160-7 · PMID 2043150

     In rats, calcipotriol was cleared more than 100 times faster than calcitriol and broken into metabolites more than 100 times weaker, explaining its 100- to 200-fold weaker effect on calcium. Leo authors; rat data.

115. 115
     Kragballe K, Gjertsen BT, De Hoop D, et al. Double-blind, right/left comparison of calcipotriol and betamethasone valerate in treatment of psoriasis vulgaris.Lancet · 1991 · 337(8735):193-6doi:10.1016/0140-6736(91)92157-w · PMID 1670840

     345 patients treating one side of the body with calcipotriol and the other with a corticosteroid for 6 weeks: severity scores fell 68.8 versus 61.4 percent, with no change in serum calcium. Short; the sponsor is not named in the abstract.

116. 116
     Dalhoff K, Dancey J, Astrup L, et al. A phase II study of the vitamin D analogue Seocalcitol in patients with inoperable hepatocellular carcinoma.Br J Cancer · 2003 · 89(2):252-7doi:10.1038/sj.bjc.6601104 · PMID 12865912

     56 patients, uncontrolled: of 33 evaluable, 2 complete responses, 12 stable and 19 progressing, with hypercalcemia the main toxicity. The authors asked for controlled trials.

117. 117
     Teng M, Wolf M, Lowrie E, Ofsthun N, Lazarus JM, Thadhani R. Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy.N Engl J Med · 2003 · 349(5):446-56doi:10.1056/NEJMoa022536 · PMID 12890843

     A historical cohort of 67,399 dialysis patients: mortality 0.180 per person-year on paricalcitol against 0.223 on calcitriol, 16 percent lower after adjustment. The authors called a randomized trial critical; the first author was at Fresenius Medical Care, a dialysis company. Observational, open to confounding by indication.

118. 118
     Isakova T, Nickolas TL, Denburg M, et al. KDOQI US Commentary on the 2017 KDIGO Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD).Am J Kidney Dis · 2017 · 70(6):737-751doi:10.1053/j.ajkd.2017.07.019 · PMID 28941764

     The US work group agreed with most of the update but raised concerns about the advice on hypocalcemia and hypercalcemia and on treating abnormal parathyroid hormone. Commentary.

119. 119
     Yeung WG, Palmer SC, Strippoli GFM, et al. Vitamin D Therapy in Adults With CKD: A Systematic Review and Meta-analysis.Am J Kidney Dis · 2023 · 82(5):543-558doi:10.1053/j.ajkd.2023.04.003 · PMID 37356648

     128 randomized trials in 11,270 adults with stage 3 to 5 kidney disease: vitamin D compounds, plain and active together, probably had no effect on death (relative risk 1.04, 95 percent confidence interval 0.84 to 1.24), had uncertain effects on fracture and cardiovascular death, and lowered parathyroid hormone while raising calcium. Meta-analysis.

120. 120
     Ketteler M, Block GA, Evenepoel P, et al. Executive summary of the 2017 KDIGO Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Guideline Update: what's changed and why it matters.Kidney Int · 2017 · 92(1):26-36doi:10.1016/j.kint.2017.04.006 · PMID 28646995

     The executive summary of the selective 2017 update of the 2009 guideline, including revised advice on treating parathyroid hormone abnormalities; read as abstract, which does not quote individual recommendations.

121. 121
     Kim JY, Lee DW, Lee SB, Kim IY. Association of Serum 1,25-Dihydroxyvitamin D Levels with Erythropoietin Resistance Index-Based Relative Erythropoiesis-Stimulating Agent Hyporesponsiveness in Pre-Dialysis Chronic Kidney Disease.Int J Mol Sci · 2026 · 27(18)doi:10.3390/ijms27188044 · PMID 42794474

     363 Korean patients with anemia of kidney disease: lower calcitriol was independently associated with poorer response to erythropoiesis-stimulating drugs. Retrospective association.

122. 122
     Brandi ML, Bilezikian JP, Shoback D, et al. Management of Hypoparathyroidism: Summary Statement and Guidelines.J Clin Endocrinol Metab · 2016 · 101(6):2273-83doi:10.1210/jc.2015-3907 · PMID 26943719

     The First International Conference guidelines, Florence 2015. Read as abstract, which describes the process rather than individual recommendations, so it is cited here only for the first conference and the year its guidelines appeared.

123. 123
     Ali DS, Perrier ND, Khan AA. Hypoparathyroidism Post Thyroidectomy: Prevention, Evaluation, Management, and Application of Recent Guidelines.Thyroid · 2026 · 36(6):582-596doi:10.1177/10507256261454145 · PMID 42170800

     A narrative review from members of the same circle as the 2022 guideline: calcium with active vitamin D remains the mainstay of treatment, with parathyroid hormone replacement for patients who do not respond. Review.

124. 124
     Winer KK, Yanovski JA, Cutler GB. Synthetic human parathyroid hormone 1-34 vs calcitriol and calcium in the treatment of hypoparathyroidism.JAMA · 1996 · 276(8):631-6PMID 8773636

     A randomized crossover trial in 10 patients at the National Institutes of Health: once-daily PTH 1-34 kept serum calcium in the normal range with lower urine calcium than calcitriol with calcium. No DOI in the record.

125. 125
     Winer KK, Ko CW, Reynolds JC, et al. Long-term treatment of hypoparathyroidism: a randomized controlled study comparing parathyroid hormone-(1-34) versus calcitriol and calcium.J Clin Endocrinol Metab · 2003 · 88(9):4214-20doi:10.1210/jc.2002-021736 · PMID 12970289

     A 3-year randomized open-label trial in 27 adults: urine calcium stayed within the normal range on twice-daily parathyroid hormone 1-34 and above normal on calcitriol, with no difference in bone mineral density.

126. 126
     Mannstadt M, Clarke BL, Vokes T, et al. Efficacy and safety of recombinant human parathyroid hormone (1-84) in hypoparathyroidism (REPLACE): a double-blind, placebo-controlled, randomised, phase 3 study.Lancet Diabetes Endocrinol · 2013 · 1(4):275-83doi:10.1016/S2213-8587(13)70106-2 · PMID 24622413

     REPLACE: 48 of 90 patients (53 percent) on rhPTH(1-84) halved their calcium and active vitamin D while keeping serum calcium, against 1 of 44 (2 percent) on placebo. Two authors, Garceau and Lagast, worked for the developer, NPS Pharmaceuticals.

127. 127
     Khan S, Khan AA. Chronic Hypoparathyroidism-Current and Emerging Therapies.Endocr Pract · 2025 · 31(11):1478-1487doi:10.1016/j.eprac.2025.07.011 · PMID 40680836

     A review: the limits of conventional therapy, rhPTH(1-84) production being halted because of manufacturing problems, and palopegteriparatide now approved by the US Food and Drug Administration and the European Medicines Agency. Review.

128. 128
     Al Musaimi O, AlShaer D, de la Torre BG, Albericio F. 2024 FDA TIDES (Peptides and Oligonucleotides) Harvest.Pharmaceuticals (Basel) · 2025 · 18(3):291doi:10.3390/ph18030291 · PMID 40143070

     A review of the peptide and oligonucleotide drugs approved by the US Food and Drug Administration in 2024, palopegteriparatide among them. Review.

129. 129
     Khan AA, Rubin MR, Schwarz P, et al. Efficacy and Safety of Parathyroid Hormone Replacement With TransCon PTH in Hypoparathyroidism: 26-Week Results From the Phase 3 PaTHway Trial.J Bone Miner Res · 2023 · 38(1):14-25doi:10.1002/jbmr.4726 · PMID 36271471

     84 adults randomized 3 to 1: 79 percent on palopegteriparatide against 5 percent on placebo met normal calcium off active vitamin D, and 93 percent became independent of conventional therapy. Several authors were employees of Ascendis Pharma, the developer.

130. 130
     Rejnmark L, Gosmanova EO, Khan AA, et al. Sustained improvement in renal function with palopegteriparatide in adults with chronic hypoparathyroidism: 2-year results from the phase 3 PaTHway-trial.J Bone Miner Res · 2026 · 41(9):922-933doi:10.1093/jbmr/zjag085 · PMID 42166177

     At 104 weeks, 97 percent of those remaining were off active vitamin D, estimated filtration rose by 9.0 mL/min/1.73 m2 and urine calcium averaged 158.8 mg a day. A post hoc analysis of an open-label extension; several authors are Ascendis employees.

131. 131
     Wang TT, Nestel FP, Bourdeau V, et al. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression.J Immunol · 2004 · 173(5):2909-12doi:10.4049/jimmunol.173.5.2909 · PMID 15322146

     Vitamin D response elements in the cathelicidin and beta-defensin 2 genes; calcitriol induced them in human keratinocytes, monocytes and neutrophils, with activity against Pseudomonas aeruginosa. Cell culture.

132. 132
     Morimoto S, Yoshikawa K, Kozuka T, et al. An open study of vitamin D3 treatment in psoriasis vulgaris.Br J Dermatol · 1986 · 115(4):421-9doi:10.1111/j.1365-2133.1986.tb06236.x · PMID 3022784

     40 Japanese patients, open design: improvement in 13 of 17 on oral alfacalcidol, 1 of 4 on oral calcitriol and 16 of 19 on topical calcitriol, with no side effects. Uncontrolled.

133. 133
     Lebwohl M, Menter A, Weiss J, et al. Calcitriol 3 microg/g ointment in the management of mild to moderate plaque type psoriasis: results from 2 placebo-controlled, multicenter, randomized double-blind, clinical studies.J Drugs Dermatol · 2007 · 6(4):428-35PMID 17668541

     Two vehicle-controlled randomized double-blind trials, 839 patients with mild to moderate plaque psoriasis: calcitriol ointment 3 micrograms per gram twice daily beat its vehicle from week 2 onward, with no effect on calcium. No DOI in the record.

134. 134
     Kędra K, Reich A. Clinical Utility of Various Formulations of Calcipotriene and Betamethasone Dipropionate for the Treatment of Plaque Psoriasis in Patients Aged 12 Years or Older.Drug Des Devel Ther · 2024 · 18:5827-5839doi:10.2147/DDDT.S240867 · PMID 39670279

     A review: the most commonly used topical treatment for psoriasis combines calcipotriene with the potent corticosteroid betamethasone dipropionate, in several formulations approved by the US Food and Drug Administration. Review.

135. 135
     Cunningham TJ, Tabacchi M, Eliane JP, et al. Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy.J Clin Invest · 2017 · 127(1):106-116doi:10.1172/JCI89820 · PMID 27869649

     131 people with actinic keratoses, 4 days of calcipotriol plus 5-fluorouracil against petroleum jelly plus 5-fluorouracil: lesion counts fell 87.8 versus 26.3 percent, with a CD4 T cell infiltrate; in mice the effect needed TSLP. Investigator-initiated; a precancer endpoint.

136. 136
     Molin A, Wiedemann A, Demers N, et al. Vitamin D-Dependent Rickets Type 1B (25-Hydroxylase Deficiency): A Rare Condition or a Misdiagnosed Condition?J Bone Miner Res · 2017 · 32(9):1893-1899doi:10.1002/jbmr.3181 · PMID 28548312

     Seven patients from two unrelated families with homozygous loss-of-function mutations in CYP2R1: the pattern is a very low 25-hydroxyvitamin D with a normal or high calcitriol, which is easily mistaken for ordinary vitamin D deficiency, and the patients improved on 25-hydroxyvitamin D itself.

137. 137
     Mehak NU, Aftab S, Qureshi AA, Saeed A, Cheema HA. Vitamin D dependent rickets type 2A: a case series of two siblings with novel mutation in vitamin D receptor gene responded to high dose oral calcium and calcitriol.J Pediatr Endocrinol Metab · 2025 · 38(7):761-766doi:10.1515/jpem-2024-0611 · PMID 40219799

     Two brothers with the receptor form, named type 2A here, and a novel receptor mutation, managed with high doses of oral calcium together with calcitriol. A case series of two.

138. 138
     Amouroux C, Porquet-Bordes V, Adler E, et al. French national diagnosis and care protocol (PNDS) for infantile idiopathic hypercalcemia (IIH).Orphanet J Rare Dis · 2026 · 21(1)doi:10.1186/s13023-026-04483-3 · PMID 42469912

     A national expert consensus: prevalence estimated at 1 in 33,000, two genes (CYP24A1 and SLC34A1), disease driven by calcitriol-mediated calcium absorption, and a natural history the authors call poorly understood. Consensus, not trial evidence.

139. 139
     Vucenovic Basic N, Beck B, Balasko A, Vukovic Brinar I, Fistrek Prlic M. Case Report: Infantile hypercalcemia type 1 due to CYP24A1 pathogenic variants-three adult patients with nephrolithiasis and nephrocalcinosis successfully treated with fluconazole.Front Med (Lausanne) · 2026 · 13:1925619doi:10.3389/fmed.2026.1925619 · PMID 42745829

     Three adults with CYP24A1 disease, two first seen for kidney stones, treated with the antifungal fluconazole. A case series that supports, but cannot establish, the drug's role.

140. 140
     Abe E, Miyaura C, Sakagami H, et al. Differentiation of mouse myeloid leukemia cells induced by 1 alpha,25-dihydroxyvitamin D3.Proc Natl Acad Sci U S A · 1981 · 78(8):4990-4doi:10.1073/pnas.78.8.4990 · PMID 6946446

     Calcitriol turned mouse myeloid leukemia cells into macrophage-like cells at concentrations from 0.12 nanomolar, as strongly at 12 nanomolar as dexamethasone at 1 micromolar. In vitro; the start of the cancer story.

141. 141
     Colston K, Colston MJ, Feldman D. 1,25-dihydroxyvitamin D3 and malignant melanoma: the presence of receptors and inhibition of cell growth in culture.Endocrinology · 1981 · 108(3):1083-6doi:10.1210/endo-108-3-1083 · PMID 6257495

     High-affinity receptors in melanoma, and slower growth of human melanoma cells exposed to calcitriol, which the authors called the first demonstration of a hormone action on tumor cells. In vitro.

142. 142
     Zhang Y, Shi Y, Bai W. Cooperative Suppression of Ovarian Cancer Growth by 1,25-Dihydroxyvitamin D and Sodium Selenite Mediated Through SEPP1 Induction.Cancer Med · 2026 · 15(8):e72212doi:10.1002/cam4.72212 · PMID 42630036

     Cells and mice; its opening states the field's central problem plainly: the concentrations that suppress ovarian cancer cells in culture are not readily achievable in the body, and higher doses cause hypercalcemia.

143. 143
     Beer TM, Eilers KM, Garzotto M, Egorin MJ, Lowe BA, Henner WD. Weekly high-dose calcitriol and docetaxel in metastatic androgen-independent prostate cancer.J Clin Oncol · 2003 · 21(1):123-8doi:10.1200/jco.2003.05.117 · PMID 12506180

     37 men given 0.5 microgram/kg of Rocaltrol before weekly docetaxel: PSA fell by half in 30 (81 percent) and median survival was 19.5 months. Uncontrolled phase 2; the comparison with docetaxel alone was against other studies.

144. 144
     Beer TM, Ryan CW, Venner PM, et al. 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.J Clin Oncol · 2007 · 25(6):669-74doi:10.1200/JCO.2006.06.8197 · PMID 17308271

     ASCENT: 250 men, weekly docetaxel with 45 micrograms of DN-101 (a high-dose calcitriol formulation) or placebo: PSA response 58 versus 49 percent (P = .16), the primary endpoint missed; an adjusted hazard ratio for death of 0.67 on a secondary analysis the authors said needed confirmation. Sponsor not stated in the indexed record.

145. 145
     Manson JE, Cook NR, Lee IM, et al. Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease.N Engl J Med · 2019 · 380(1):33-44doi:10.1056/NEJMoa1809944 · PMID 30415629

     VITAL: 25,871 US adults on 2,000 IU of vitamin D3 a day or placebo for a median of 5.3 years; invasive cancer hazard ratio 0.96 (0.88 to 1.06), cancer death 0.83 (0.67 to 1.02). Tests the parent vitamin, not calcitriol; funded by the National Institutes of Health and others.

146. 146
     Nair-Shalliker V, Smith DP, Gebski V, et al. High-dose vitamin D supplementation and prostate cancer progression: a phase II randomised trial in localised prostate cancer cases with intermediate risk of progression (ProsD).Br J Cancer · 2025 · 134(5):735-745doi:10.1038/s41416-025-03278-w · PMID 41423505

     123 men with low to intermediate-risk prostate cancer on active surveillance given 50,000 IU of vitamin D3 monthly or placebo: no difference in active therapy-free survival (P = 0.44) or progression-free survival. Tests the parent vitamin, not calcitriol.

147. 147
     Sherman MH, Yu RT, Engle DD, et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy.Cell · 2014 · 159(1):80-93doi:10.1016/j.cell.2014.08.007 · PMID 25259922

     In mice, the analog calcipotriol quieted the fibrous stroma of pancreatic cancer, raised gemcitabine inside tumors and increased survival by 57 percent over chemotherapy alone. Mouse work that launched the human trials.

148. 148
     Chung V, Alistar A, Becerra C, et al. Pembrolizumab ± paricalcitol in metastatic pancreatic cancer postmaximal cytoreduction.Oncologist · 2025 · 30(1)doi:10.1093/oncolo/oyae323 · PMID 39846984

     A randomized, double-blind phase 2 trial of maintenance pembrolizumab with intravenous paricalcitol or placebo: no difference in 6-month progression-free survival, overall survival or side effects; the authors blame paricalcitol's 5- to 7-hour half-life.

149. 149
     Gupta M, Choi H, Karasic T, et al. Co-Clinical Evaluation of Synthetic Vitamin D and Chemotherapy in Pancreatic Cancer by Integrated Imaging and Molecular Analyses.Cancer Res Commun · 2026 · 6(8):1983-1992doi:10.1158/2767-9764.CRC-26-0443 · PMID 42574460

     A pilot trial that enrolled only 3 patients but showed weekly paricalcitol infusions with three-drug chemotherapy were feasible, run alongside 140 mice. Feasibility only.

150. 150
     da Silva GB, Narzetti RA, Dallagnol P, et al. Calcitriol, the active form of vitamin D, induces cell death and purinergic signaling modulation in cutaneous melanoma cells.Med Oncol · 2026 · 43(10)doi:10.1007/s12032-026-03412-5 · PMID 42742798

     Two human melanoma cell lines at 1 to 50 nanomolar for 24 hours: effects in one line and not in the other. In vitro; the authors' conclusion that calcitriol is a promising adjuvant goes beyond these data.

151. 151
     Jeffery LE, Burke F, Mura M, et al. 1,25-Dihydroxyvitamin D3 and IL-2 combine to inhibit T cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3.J Immunol · 2009 · 183(9):5458-67doi:10.4049/jimmunol.0803217 · PMID 19843932

     In human T cells in culture, calcitriol cut interferon gamma, IL-17 and IL-21 and, with IL-2, induced regulatory T cells. Cell culture.

152. 152
     Cantorna MT, Hayes CE, DeLuca HF. 1,25-Dihydroxyvitamin D3 reversibly blocks the progression of relapsing encephalomyelitis, a model of multiple sclerosis.Proc Natl Acad Sci U S A · 1996 · 93(15):7861-4doi:10.1073/pnas.93.15.7861 · PMID 8755567

     In mice, calcitriol completely prevented experimental autoimmune encephalomyelitis and halted it when given at first symptoms; stopping it let the disease resume. Animal model.

153. 153
     Leaf DE, Raed A, Donnino MW, Ginde AA, Waikar SS. Randomized controlled trial of calcitriol in severe sepsis.Am J Respir Crit Care Med · 2014 · 190(5):533-41doi:10.1164/rccm.201405-0988OC · PMID 25029202

     67 critically ill adults with sepsis given one 2 microgram intravenous dose of calcitriol or placebo: plasma cathelicidin protein at 24 hours did not differ (the primary outcome), though leukocyte cathelicidin and IL-10 messenger RNA rose; no clinical effect and no harm. A small physiological trial.

154. 154
     Walter M, Kaupper T, Adler K, Foersch J, Bonifacio E, Ziegler AG. No effect of the 1alpha,25-dihydroxyvitamin D3 on beta-cell residual function and insulin requirement in adults with new-onset type 1 diabetes.Diabetes Care · 2010 · 33(7):1443-8doi:10.2337/dc09-2297 · PMID 20357369

     40 adults with new type 1 diabetes randomized to 0.25 microgram of calcitriol or placebo daily for 9 months: no difference in C-peptide, about 40 percent lost in both arms over 18 months. Small, but randomized and negative.

155. 155
     Leaf DE, Shenoy T, Zinchuk K, et al. Randomized trial of activated vitamin D for acute kidney injury prevention in critically ill patients.JCI Insight · 2025 · 10(20):e193523doi:10.1172/jci.insight.193523 · PMID 40924491

     A phase 2 trial in 150 critically ill adults at high risk of acute kidney injury: oral calcitriol (50 patients) and calcifediol (51) did not change the composite of death, dialysis and kidney injury within 7 days (calcitriol against placebo P = 0.58); calcitriol switched on more immune and DNA-repair genes in circulating monocytes; 1 patient on calcitriol became hypercalcemic. Funded by the National Institutes of Health.

156. 156
     Elamir YM, Amir H, Lim S, et al. A randomized pilot study using calcitriol in hospitalized COVID-19 patients.Bone · 2021 · 154:116175doi:10.1016/j.bone.2021.116175 · PMID 34508882

     An open-label randomized pilot in 50 adults hospitalized with COVID-19: the oxygen saturation ratio rose by 91.04 on 0.5 microgram of calcitriol a day against 13.2 without it (P = .03), with no significant difference in length of stay. Small and open-label.

157. 157
     Martineau AR, Timms PM, Bothamley GH, et al. High-dose vitamin D(3) during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial.Lancet · 2011 · 377(9761):242-50doi:10.1016/S0140-6736(10)61889-2 · PMID 21215445

     146 London adults with tuberculosis given four 2.5 mg doses of vitamin D3 or placebo: time to sputum culture conversion 36.0 versus 43.5 days, hazard ratio 1.39 (0.90 to 2.16), not significant; a subgroup by receptor genotype responded. Tests vitamin D3, the parent vitamin, not calcitriol; funded by the British Lung Foundation.

158. 158
     Coussens AK, Wilkinson RJ, Hanifa Y, et al. Vitamin D accelerates resolution of inflammatory responses during tuberculosis treatment.Proc Natl Acad Sci U S A · 2012 · 109(38):15449-54doi:10.1073/pnas.1200072109 · PMID 22949664

     A per-protocol immunological analysis of 95 patients from that trial: faster resolution of inflammatory markers on vitamin D. Secondary analysis of a trial whose primary outcome was negative.

159. 159
     Hahn J, Cook NR, Alexander EK, et al. Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial.BMJ · 2022 · 376:e066452doi:10.1136/bmj-2021-066452 · PMID 35082139

     An endpoint of VITAL: confirmed autoimmune disease in 123 participants on vitamin D3 against 155 on placebo, hazard ratio 0.78 (0.61 to 0.99). Tests the parent vitamin, not calcitriol.

160. 160
     Costenbader KH, Cook NR, Lee IM, et al. Vitamin D and Marine n-3 Fatty Acids for Autoimmune Disease Prevention: Outcomes Two Years After Completion of a Double-Blind, Placebo-Controlled Trial.Arthritis Rheumatol · 2024 · 76(6):973-983doi:10.1002/art.42811 · PMID 38272846

     Two years after VITAL ended the vitamin D effect had dissipated (hazard ratio 0.98, 0.83 to 1.17, at 7 years), and counting cases confirmed late moved the in-trial estimate to 0.85 (0.70 to 1.04).

161. 161
     Price PA, Otsuka AA, Poser JW, Kristaponis J, Raman N. Characterization of a gamma-carboxyglutamic acid-containing protein from bone.Proc Natl Acad Sci U S A · 1976 · 73(5):1447-51doi:10.1073/pnas.73.5.1447 · PMID 1064018

     The bone protein later called osteocalcin, carrying three gamma-carboxyglutamic acid residues, the modification vitamin K makes. Protein chemistry; it says nothing about vitamin D.

162. 162
     Bacchetta J, Zaritsky JJ, Sea JL, et al. Suppression of iron-regulatory hepcidin by vitamin D.J Am Soc Nephrol · 2014 · 25(3):564-72doi:10.1681/ASN.2013040355 · PMID 24204002

     In liver cells and monocytes, calcitriol halved hepcidin messenger RNA by binding the receptor at the hepcidin gene; in a pilot of healthy volunteers, 100,000 IU of vitamin D2 raised 25-hydroxyvitamin D from 27 to 44 ng/mL and cut circulating hepcidin by 34 percent within 24 hours. Cell work plus an uncontrolled pilot.

163. 163
     Wolf M, Rubin J, Achebe M, et al. Effects of Iron Isomaltoside vs Ferric Carboxymaltose on Hypophosphatemia in Iron-Deficiency Anemia: Two Randomized Clinical Trials.JAMA · 2020 · 323(5):432-443doi:10.1001/jama.2019.22450 · PMID 32016310

     Two trials, 245 patients: hypophosphatemia in 7.9 and 8.1 percent after iron isomaltoside against 75.0 and 73.7 percent after ferric carboxymaltose, which the authors describe as FGF23-mediated. One author worked for Pharmacosmos, maker of iron isomaltoside.

164. 164
     Joo YS, Chang TI, Kim DK, Han SH, Kang SW, Yoo TH. Additive renoprotective effects of oral calcitriol on patients with IgA nephropathy receiving RAS blockers.Nephrol Dial Transplant · 2026 · 41(3):566-574doi:10.1093/ndt/gfaf187 · PMID 41178795

     138 Korean adults with IgA nephropathy on maximal renin-angiotensin blockade: 0.25 microgram of calcitriol a day for 12 months lowered the urine protein-to-creatinine ratio by a further 187 mg/g (P = .04) but not daily protein excretion (P = .11); the annual fall in estimated filtration was -0.32 against -3.64 mL/min/1.73 m2 (P = .02).

165. 165
     Meena J, Thergaonkar RW, Sinha A, Lakshmy R, Bagga A, Hari P. Efficacy and safety of calcitriol therapy for reduction of proteinuria in children with chronic kidney disease: an open-label randomized controlled trial.Int Urol Nephrol · 2025 · 57(12):4271-4278doi:10.1007/s11255-025-04623-x · PMID 40583089

     72 Indian children with proteinuric kidney disease: adding calcitriol 0.25 microgram twice weekly to enalapril did not reduce proteinuria significantly (P = 0.54). Open-label.

166. 166
     Khairallah P, Cortez NE, McMahon DJ, et al. Calcitriol supplementation after kidney transplantation: results of a double-blinded, randomized, placebo-controlled trial.J Bone Miner Res · 2025 · 40(5):603-616doi:10.1093/jbmr/zjaf044 · PMID 40089990

     67 kidney transplant recipients on corticosteroid-sparing immunosuppression: 0.5 microgram of calcitriol a day for 12 months did not improve bone density, microarchitecture or strength, and hypercalcemia was more frequent than on placebo (P < .001).

167. 167
     Ashfaq A, Choe J, Strugnell SA, et al. Adjunctive Active Vitamin D Decreases Kidney Function during Treatment of Secondary Hyperparathyroidism with Extended-Release Calcifediol in Non-Dialysis Chronic Kidney Disease in a Randomized Trial.Am J Nephrol · 2025 · 56(4):490-499doi:10.1159/000544086 · PMID 39987904

     78 adults with non-dialysis kidney disease already on extended-release calcifediol: adding calcitriol, doxercalciferol or paricalcitol lowered parathyroid hormone by a further 35.4 percent but raised calcium and phosphate, raised FGF23 by 155 percent, and increased the fall in estimated filtration to 11.8 percent against 3.0 percent. Most authors were employees of OPKO Health, which sells extended-release calcifediol.

168. 168
     Garcia-Lozano C, Betancourt C, Sanchez JG, et al. Routine vs Selective Calcium Supplementation After Total Thyroidectomy: A Randomized Clinical Trial.JAMA Otolaryngol Head Neck Surg · 2026 · 152(4):392-399doi:10.1001/jamaoto.2025.5514 · PMID 41712216

     258 patients after total thyroidectomy, randomized to routine calcium with calcitriol for 15 days or to supplementation only when parathyroid hormone was below 15 pg/mL at 4 hours: symptomatic hypocalcemia in 24 of 258 overall (9.3 percent), odds ratio 0.68 (0.29 to 1.57), with less supplementation in the selective group. The per-group percentages in the abstract do not match the group sizes, so only the overall figure and the odds ratio are cited here.

169. 169
     Worhunsky PD, Mignosa MM, Gallezot JD, et al. Vitamin D's Capacity to Increase Amphetamine-Induced Dopamine Release in Healthy Humans: A Clinical Translational [11C]-PHNO Positron Emission Tomography Study.Biol Psychiatry · 2025 · 97(6):651-658doi:10.1016/j.biopsych.2024.09.028 · PMID 39395473

     18 healthy vitamin D-sufficient adults in a randomized within-subject study: two 1.5 microgram doses of calcitriol increased amphetamine-induced dopamine release measured by positron emission tomography.

170. 170
     Sausedo MA, Mallick S, Sabir ZL, et al. 1,25-Dihydroxyvitamin D Induces a NURR1-Tyrosine Hydroxylase Transcriptional Axis Modulated by Rexinoid/RXR Signaling in Parkinson's Disease-Relevant Human Neural Cell Models.Cells · 2026 · 15(13)doi:10.3390/cells15131210 · PMID 42439684

     In human neuroblastoma and glioblastoma cell lines, 10 nanomolar calcitriol raised messenger RNA of NURR1 and of tyrosine hydroxylase, the first enzyme of dopamine synthesis. Cell lines; Mark Haussler, co-discoverer of the receptor in 1969, is an author.