Friday 17 September 2021

Covid-19 & Vitamin D: Success of Calcitriol in New York study

New York: the successful RCT of Calcitriol, activated Vitamin D

To understand the basis of this important paper (details below), it is necessary to have some understanding of Vitamin D metabolism and activation. A recap:

Vitamin D (cholecalciferol) is produced only by the action of UV from the sun on the oil 7-dehydrocholesterol (7-DHC), which is synthesised in our skin and that of many other mammals. It is also synthesised in plankton in the sea, the food of fish. Vitamin D is thus produced directly in our skin (about 80%) or it is taken in our food (about 20%), mainly oily fish.

Whether produced in our skin or consumed in our food, Vitamin D is taken in the blood-stream to the liver. It is there stored while it is slowly converted into its part-activated form 25(OH)D, otherwise known as Calcifediol. If Vitamin D is taken by mouth by someone deficient, it takes up to two weeks before it achieves blood levels that are appropriate for optimal defensive immunity (greater than 30ng/ml, 75nmol/L). This is too slow for correction of vitamin D deficiency at the time of critical Covid-19 infection, and giving Vitamin D itself to the critically ill has been predictably without benefit.

It would always be sensible to correct Vitamin D deficiency in advance of possible infection so as to optimise defensive immunity. It is much more urgent to optimise defensive immunity in someone already very ill with Covid-19, whether vaccinated or not. An imaginative approach was pioneered in Spain, in Córdoba and Barcelona, by treating patients admitted to hospital on account of serious Covid-19 with the activated form Calcifediol. The results have shown spectacular benefit. 

For reasons explained previously, these results have been ignored and the papers have been rubbished by individuals who should have know better. The UK National Institute for Health and Care Effectiveness (NICE) advised that doctors should not use Calcifediol. This would inevitable have contributed to the 133,000 Covid-19 deaths in the UK, and many more thousands in other countries.

A huge amount of Calcifediol is produced each year, mainly in China, but a problem has been that the great majority is destined for cattle. We accept without question the common occurence vitamin D deficiency in human beings, even at times of crisis, but it is not acceptable in cattle. Calcifediol is readily available across the counters of pharmacies in Spain and Italy, but not in other countries. Approval for human use in Covid-19 would have been a simple process but it did not happen.

Calcifediol circulates in the blood as a reservoir, ready for instant use when required. Natural vitamin D has one -OH group. The part-activation to Calcifediol requires a second -OH groups, hence -diol. When Calcifediol is required, is is taken up into target cells (including cells of immunity) and a third -OH group is added, and thereby it is converted into the fully-active form Calcitriol. When Calcitriol, 1,25(OH)D, has been used, and it can only be used once, it is inactivated by the addition of another -OH group to form 24,25(OH)D.

Most Calcitriol is created and used within cells, but there is a biological need for a tiny amount of Calcirtriol to circulate in the blood. This is created in cells of the kidneys and its purpose is calcium homeostasis, to maintain a steady blood level of ionised calcium. Clinical problems arise in advanced kidney disease, when there are insufficient specialised kidney cells to produce adequate Calcitriol, and this has been recognised for more than forty years. Calcitriol as a pharmaceutical product is now readily available for human use, and there is considerable experience of its use.

Because vitamin D is activated too slowly for use in those very ill with Covid-19, and because the proven Calcifediol is not available for human use in most countries (Spain, Italy and I think now Australia excepted), it has been suggested that the readily-available and immediately-active Calcitriol be of clinical value. 

It has now been tested as a pharmaceutical agent in severe Covid-19 infection and the result is available.

The RCT of Calcitriol

Bone  2021 Sep 8;116175. doi: 10.1016/j.bone.2021.116175. Online ahead of print.

Elamir YM et al.

Mount Sinai Beth Israel, Mount Sinai Morningside, Mount Sinai West Hospitals, New York.

The clinical trial has been undertaken in New York and it was published on-line September 8th 2021 as a pre-print.

It is a study of 50 patients admitted to three hospitals on account of Covid-19 pneumonia. 25 of the 50 were randomly allocated (electronically) to receive Calcitriol in a dose of 0.5 micrograms daily for 14 days, or until discharge from hospital if earlier.

Please note that 0.5 microgram is a very tiny amount and it must not be confused with milligrams, and so it is better to avoid abbreviations. 0.5 microgram is 500 nanograms.

The success of randomisation is given in the text of the paper, comparing baseline characteristics in the two groups. Randomisation was not absolutely perfect, and for example the average age of the control group was 64 years compared to 69 in the Calcitriol group. On the other hand 19 of the control group were over the age of 65 compared to 14 in the Calcitriol group.  There are no differences between the treatments and control groups that would be expected to have a significant influence on the outcome of the trial should there be major outcome differences, and that was the case.

The outcome measures are as follows:

Increase of oxygen concentration in the blood:

The unit of measurement is ratio of peripheral arterial oxygen saturation to the inspired fraction of oxygen (SpO2/FIO2), the greater the better.

Control group      31.2                  Calcitriol group    94.0

Discharged with no need for supplementary oxygen:

Control group      21 / 25               Calcitriol group    24 / 25

Length of stay (mean of 25 patients):

Control group      9.24 days           Calcitriol group    5.5 days

Transfer to ICU:

Control group      8 / 25                 Calcitriol group   5 / 25 

Need for invasive ventilation:

Control group      2 / 8                  Calcitriol group   0 / 5


Control group      3 / 25                 Calcitriol group    0 / 25

Readmission within 30 days:

Control group      4                        Calcitriol group    2

There were no ill-effects from Calcitriol and no examples of elevation of blood levels of calcium (hypercalcaemia) in the two groups. 


In all measures of outcome, there was a clear advantage among the patients randomised to Calcitriol. 

The most important are:

Out of 8 control patients requiring transfer to ICU, there was a reduction by 3 in the Calcitriol group. This is a 37.5% reduction and it would be great importance in reducing the pressures on ICUs.

3 control patients died, but no patients treated with Calcitriol died. 3 out of 25 deaths were eliminated, which is 12% death rate becoming zero.

Do not consider this clinical trial in isolation

This Calcitriol trial must not be considered on its own, and no clinical trial must be considered in isolation. The Criteria of Sir Austin Bradford Hill must always be in our minds, the several dimensions of proof. Is there evidence of vitamin D deficiency leading to critical or fatal Covid-19? Yes. Have there been previous studies of association and temporality? Yes. Is there consistency in the studies? Yes. Is there evidence from basic science that Vitamin D and its activated forms Calcifediol and Calcitriol would help in defensive immunity? Yes. Is it plausible that Calcitriol would be of benefit in someone critically ill with Covid-19? Yes. Are there other clinical experiments that indicate benefit from Vitamin D in its activated forms? Yes. Add this evidence to the New York clinical trial and we can see justification for using Calcitriol in the treatment of people admitted to hospital on account of serious Covid-19.

The important "significance" is clinical significance, and this involves the totality of supporting evidence as outlined. The study taken in isolation might be put aside as lacking statistical significance as indicated by high p-values, a statistical concept that is a huge oversimplification and is a short-cut taken by people who do not bother to read the results of the study in detail. A high p-value means that the result might be a chance finding, but this chance is diminished by taking into account the totality of information, as we learn from Sir Austin Bradford Hill. 

In respect of clinical significance, if we are dealing with a pandemic causing 136,000 UK deaths, if the proposed treatment is safe (the most over-riding issue), and if there is very strong supporting information, is a possibility of a chance result a reason not to give the treatment? Further surveillance will give greater information without waiting for more people to die. This is acceptance of clinical significance.

If deaths go down from 3/25 in the control group to 0/25 in the Calcitriol group, is the pragmatism of clinical medicine to use the Calcitriol overridden by the statistical purism that the difference might be a chance finding, and that the result is meaningless? The decision to use must include other evidence concerning Vitamin D and Calcifediol.

Remember that vaccines were authorised despite no evidence of an effect on hospital admissions or deaths, and without completed safety studies. Emergency Use Aurthorisation is also a pragmatic response to s serious pandemic.

What next?

There is clearly an international directive that any benefits of Vitamin D (or its active metabolites) must be denied, so as to enable Emergency Use Authorisation (EUA) for the unlicensed vaccines.

What can be done by official bodies to silence this study of Calcitriol? Some criticism will be found.

Can Calcitriol come into clinical use for patients with Covid-19 pneumonia? Yes, quite easily. It is in the power of any clinical doctor to prescribe Calcitriol in the protocol used in this trial. Will such doctors be over-ruled by hospital managers? If so what would be the logic? It would be a major interference with legitimate clinical responsibility.

Calcitriol is licensed for clinical use, but this obviously does not yet extend to serious Covid-19 infection. However off-label prescribing is acceptable. As stated by the UK General Medical Council (GMC):

"The physician must be satisfied that there is sufficient evidence or experience of using the medicine to demonstrate safety ad efficacy. Prescribing may be necessary when no suitably licensed medicine is available to meet the patient's need (or when prescribing is part of approved research)."

The respect paid to Hill's Criteria is obviously of great importance.

The New York RCT stated at the end, rather modestly, that further larger scale trials should follow. To state this is not the reponsibility of the researchers. Benefit has clearly been demonstrated and to this we must add the powerful scientific basis, and the results of positive trials of Calcifediol. 

It is perhaps logical that a second trial might be undertaken, but there are ethical constraints as we are dealing with life and death.

If a further clinical trial of Calcitriol were to take place, it must be with informed consent of the subjects. Would such informed subjects agree to be controls and deny themselves treatment demonstarted to eliminate a 12% death rate and other disadvantages?

Would any informed person refuse treatment with Calcitriol if admitted to hospital with Covid-19 pneumonia?

It will be interesting to watch the sequence of events to silence this RCT and prevent the use of Calcitriol.

What about Calcifediol

The use of Calcifediol is more physiological, optimising circulating blood levels and provide a source of the precursor of Calcitriol to be produced within the immune cells. Normally we would not expect Calcitriol from the circulation to become active within immune cells where so much of it can be produced.

In practical terms it would seem to be the best plan for clinical doctors to prescribe Calcitriol 0.5 micrograms daily for 14 days in the treatment of patients with Covid-19 pneumonia, until our national leaders approve of Calcifediol to be used in appropriate dose (already worked out) in the treatment of human beings, in addition to cattle.

The pandemic continues. Covid-19 deaths continue. WHO states "population controls and vaccines", but we clearly need something in addition. The New York study provides the immediate answer.


  1. David - it seems cynical beyond belief that an effective pharmacological approach both for the prevention and treatment of life threatening Covid is suppressed in order to prioritise the use and efficacy of vaccines. I wonder if David Davis has been knobbled, because he was on the right track towards the end of last year.

    1. Just what I have been thinking. He even dared to mention ivermectin in one utterance to the PM in the House, but has been very quiet of late.

  2. David,

    "For reasons explained previously, these results have been ignored"

    Spain (as opposed to the Andalucia region whose doctors had advocated general vitamin D administration to the elderly several months ago) now appears to have accepted that Vitamin D works and has recently published the results of the nationwide expert working party on vitamin D, and recommends that patients be treated to archive 30 - 50 ng/ml level in their blood

    1. Good for Spain, knowing that vitamin D deficiency is common. It is only "mad dogs and Englishmen who go out in the midday sun". Spanish people take a siesta and go out in the evenings.

  3. Though not available over the counter Calcifediol drops are prescribed here in France under the brand name Dédrogyl.

  4. Excellent. Thank you. I take 1000 IU Vit D per day and my levels at last test were above the top limit. It's also possible to buy Vit D together with Calcium. Would that be better than just D alone instead of relying on enough Ca from food. I assume the ratio in each tablet is sufficient for optimum levels of both.

    1. Vitamin D is essential, but calcium is generally not important, Calcium is unpleasant and diminishes the amount of vitamin D taken. Dietary calcium deficiency does not happen in Europe and North America. In fact it occurs effectively only in famine conditions. Vitamin D 1,000 units daily is a small dose for an adult. 3,000 would be better.

    2. Individual 25(OH)D-Level, Sun exposure, BMI, Skin, Magnesium-Intake etc. define your need for Vitamin D-Supplementation.
      Better check your 25(OH)D-Concentration and aim for at least 40ng/mL and stay under 100 ng/mL. 3,000 IU/d are good for most people as David said, but individual requirements may be greater to achieve >40 ng/mL.

  5. Thank you David for sharing this study. It's a small study but the results are worth noting, in particular the change in the peripheral arterial oxygen saturation. The weakness is the power of the study because of the small numbers the other comparisons are statistically not significant. That's why it does require a larger study. It still won't change the mind set of NICE or SACN. What a missed opportunity !!!!

    1. Small study is inevitable but very important. It is essential to aavoid viewing this study on its own. It must b eintegrated into the knowedge of bascia science of vitamin D and immunity, plus the calcifediol studies. Clinical significance is far more important than statistical significance, as long as safety is assured. 133,000 UK Covid-19 deaths and still no treatment given to people ah test positive for Covid-19. Calcitriol 0.5 micrograms daily for 14 days would be cheap, effective, and safe.

  6. More great evidence stacking up in favour of Vitamin D. I'm on 2000-4000iu per day and never felt better.

  7. Calcitriol is given in micrograms right? Then what is equivalent micrograms to IU with calcitriol ?

    1. It is not really possible or useful to equate calcitriol and vitamin D as they are metabolically different. The dose of calcitriol used, effectively and safely, is 0.5 micrograms, a very tiny amount, and for a maximum of 14 days. Vitamin D is for long-term use, 3,000 units daily. Calcitriol is for only 14 days maximum for treatment of Covid.

    2. Ok, thanks for time and reply Dr Grimes!

  8. Thanks David. So for repletion of someone with Vitamin D deficiency and severe Covid infection, there are three main options, each with different attendant problems, and these need to be understood.

    The problem with taking The Sunshine Vitamin D3 (cholecalciferol) itself by mouth is that it is relatively non-polar, and so fat-soluble, and first absorbed with chylomicrons, traveling first in the lymphatics and draining into the bloodstream via the thoracic duct. And of course in those with defective fat absorption, liver dysfunction or no gall bladder it is therefore poorly absorbed. Once in the bloodstream it is also readily sequestered in adipose tissue before the liver can convert it to the more polar reservoir form, calcifediol (25OHD3).

    Calcifediol is the circulating reservoir form, for which we have evolved a high affinity binding protein, DBP, in plasma. Where rapid action is needed, oral calcifediol therefore has substantial advantages over cholecalciferol, one of which is that it is more polar and is absorbed readily from the mouth or upper GI tract. It is also drawn into the blood by virtue of its affinity for DBP. So for rapid loading in an individual with D-deficiency it wins hands down.

    Calcitriol (1,25OHD3), on the other hand, normally circulates in the blood only as a short-acting hormone, produced by 1-alpha hydroxylase in the renal tubules, acting on the reservoir 25-hydroxylated form, driven by PTH from the calcium-controlling parathyroid glands. It has a short half-life in blood, and is also attended by a high risk of hypercalcaemia, especially in the presence of a high calcium intake. It is a very roundabout way to give vitamin D to the immune system, cells of which normally make their own 1,25(OH)D for local use on their own VDR, an action also accompanied by induction of the enzyme 24-hydroxylase, which immediately destroys 1,25OHD after use. This seemingly wasteful process keeps immunocyte use of 25OHD3 below the ‘endocrine radar’.

    To support the immune system we need Calcifediol at a decent concentration (40 - 60 ng/ml, 100 - 150 nmol/l) in the blood from which both endocrine and immune systems can draw to make their own 1,25(OH)D to activate their own VDR/RXR heterodimer, and their own specific Vitamin D response elements. So for emergency use the reservoir form must be much safer, and easier to use, as found in Cordoba and Andalucia, and now confirmed by use in recent studies in Safdarjung Hospital, New Delhi, where of 49 ICU patients with Covid-19 were given 80,000 Units over 3 days, sent by me from Italy in May of this year. Nine of them were already in extremis and on ventilators, and all 9 of these died. The remaining 40, who were on nasal oxygen all recovered fully (Prof J.Kishore, personal communication).

    1. So you recommend taking calcifediol instead of cholecalciferol?
      More than 18month i am taking cholecalciferol by mouth like fat drops 2000-3000IU daily, and my cholesterol in blood it is bit high now. Should I worry?

    2. When you are well take vitamin D, cholecalciferol.
      When you are ill with Covid-19, take Calcifediol if it is available.
      If not take calcitriol, which is readily available.

      Continue with vitamin D/cholecalciferol.
      Have no concerns about cholesterol. There tends to be a reciprocal relationship between vitamin D / cholecalciferol and cholesterol.

  9. Hi David,

    I’m 64 and obese living in North America. Two years ago I started taking 3 2000 IU tablets a day. The pills started bothering my stomach so I switched to 1 50,000 IU pill a week. Everyone told me I was crazy and going to overdose on “D” so I had a blood test two weeks ago. My Vitamin D,25-OH Total was 52 with a recommended range between 30-100 ng/mL I’m not bulletproof but with continued weight loss I’ll be in the normal weight group by year-end. I know many people who have had the vaccine and now have the COVID-19 virus, they did nothing to increase their vitamin D levels.

    1. It sounds as though your present dose of vitamin D is just fine.
      An annual blood level check would be useful.
      You will not overdose on 50,000 units once a week.