Vitamin d status during cancer treatment?

[Ted Hutchinson]

I am reposting the whole text of this newsletter online as it is an important subject and may not be available online for some time.
The Vitamin D Newsletter January, 2008
The January newsletter is coming early as I will be out of touch for awhile. If you remember, the last newsletter was on preventing cancer, not treating it. Below is a sampling of the tragic emails the last newsletter generated:
"Dr. Cannell, I was just diagnosed with breast cancer, how much vitamin D should I take?"
"My mother has colon cancer, how much vitamin D should she take?"
"I've had prostate cancer for four years, is there any reason to think vitamin D would help?"
"Dr. Cannell, my son has leukemia, should I give him vitamin D?"
It's one thing to talk about evidence vitamin D may prevent cancer but something quite different to discuss evidence vitamin D might help treat cancer. I used to think the answers to all the above questions were the same. Like anyone else, people with cancer should be screened for vitamin D deficiency and be treated if deficiency is present. Simple. However, it's not that simple. The real questions are, What are reasonable 25-hydroxy-vitamin D [25(OH)D] levels for someone with a life-threatening cancer? How much vitamin D do they need to take to obtain such levels? Is there any evidence, of any kind, that vitamin D will help treat cancer? The risk/benefit analysis of taking vitamin D is quite different if you are in perfect health than if your life, or your child's life, is on the line.
Remember, unlike cancer prevention, not one human randomized controlled trial exists showing vitamin D has a treatment effect on cancer. By treatment effect, I mean prolongs the lives of cancer patients. However, as I cited in my last newsletter, Dr. Philippe Autier of the International Agency for Research on Cancer, and Dr. Sara Gandini of the European Institute of Oncology, performed a meta-analysis of 14 randomized controlled trials showing even low doses of vitamin D extend life but they looked at all-cause mortality, not just cancer (Arch Intern Med. 2007;167(16):1730-1737). However, some epidemiological studies indirectly address the treatment issue and are quite remarkable. The first are a series of discoveries by Professor Johan Moan, Department of Physics at the University of Oslo, with Dr. Alina Porojnicu as the lead author on most of the papers.
Moan J, et al. Colon cancer: Prognosis for different latitudes, age groups and seasons in Norway. (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=18029190)
Lagunova Z, et al. Prostate cancer survival is dependent on season of diagnosis. (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17624920)
Porojnicu AC, et al. Changes in risk of death from breast cancer with season and latitude: sun (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17028983)exposure and breast cancer survival in Norway. Breast Cancer Res Treat. 2007 May;102(3):323-8.
Porojnicu A, et al. Season of diagnosis is a predictor of cancer survival. Sun-induced vitamin D may be involved: (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17229569) a possible role of sun-induced Vitamin D. J Steroid Biochem Mol Biol. 2007 Mar;103(3-5):675-8.
Porojnicu AC, et al. Season of diagnosis is a prognostic factor in Hodgkin's lymphoma: a possible role of sun-induced vitamin D. (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=16136030)
Porojnicu AC, et al. Seasonal and geographical variations in lung cancer prognosis in Norway. (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17207891) Does Vitamin D from the sun play a role? Lung Cancer. 2007 Mar;55(3):263-70.
What Professor Moan's group discovered, repeatedly, is quite simple, whether it be cancer of the breast, colon, prostate, lung, or a lymphoma. You live longer if your cancer is diagnosed in the summer. And it is not just Moan's group who has found this. A huge English study recently confirmed Moan's discovery.

Lim HS, et al. Cancer survival is dependent on season of diagnosis and sunlight exposure. (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=16671100)

[Ted Hutchinson]

What do these studies mean? Something about summer has a treatment effect on cancer. Whatever it is, you live longer if you are diagnosed in the summer but die sooner if you are diagnosed in the winter. What could it be about summer? Exercise? Fresh air? Melatonin? Sunlight? Pretty girls? Remember, these patients already had cancer. Whatever it is about summer, it is not a preventative effect that Professor Moan discovered, it is a treatment effect. Something about summer prolongs the life of cancer patients.
Dr. Ying Zhou, a research fellow, working with Professor David Christiani at the Harvard School of Public Health, went one step further. The stuffy Harvard researchers assumed summer worked its magic, not by pretty girls, but by summer sunlight making vitamin D. So they looked at total vitamin D input, from both sun and diet, to see if high vitamin D input improved the survival of cancer patients. Yes, indeed, remarkably. They found that early stage lung cancer patients with the highest vitamin D input (from summer season and high intake from diet) lived almost three times longer than patients with the lowest input (winter season and low intake from diet). Three times longer is a huge treatment effect, a treatment effect that most conventional cancer treatment methods would die for.
Zhou W, Vitamin D is associated with improved survival in early-stage non-small cell lung cancer patients. (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=16214909)
And that's not all, Marianne Berwick and her colleagues, at the New Mexico Cancer Institute, found malignant melanoma patients with evidence of continued sun exposure had a 60% mortality reduction compared to patients who did not. That implies a robust treatment effect from sunlight.

Berwick M, et al. Sun exposure and mortality from melanoma. (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=15687362)

I will not list the thousands of animal studies that indicate vitamin D has a treatment effect on cancer as almost all of them studied activated vitamin D or its analogs, drugs that bypass normal regulatory mechanisms, cannot get autocrine quantities of the hormone into the cell, and that often cause hypercalcemia. However, Michael Holick's group found that simple vitamin D deficiency made cancers grow faster in mice. That is, vitamin D has a cancer treatment effect in vitamin D deficient mice. Professor Gary Schwartz, at Wake Forest, recently reviewed the reasons to think that vitamin D may have a treatment effect in cancer.
Tangpricha V, et al. Vitamin D deficiency enhances the growth of MC-26 colon cancer xenografts in Balb/c mice (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=16177194).
Schwartz GG, Skinner HG. Vitamin D status and cancer: new insights (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17143048).
Finally, one human interventional study exists. In 2005, in an open trial, Professor Reinhold Vieth and his colleagues found just 2,000 IU of vitamin D per day had a positive effect on PSA levels in men with prostate cancer.
Woo TC, et al. Pilot study: potential role of vitamin D (Cholecalciferol) in patients with PSA relapse after definitive therapy. (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=15749627)
So we come back to the crucial question. If you have cancer, how much vitamin D should you take, or, more precisely, what 25(OH)D level should you maintain? We don't know. You can correctly say that definitive studies have not been done and, incorrectly, conclude physicians treating cancer patients should do nothing. I say incorrectly because standards of medical practice have always demanded that doctors make reasonable decisions based on what is currently known, doing a risk/benefit analysis along the way to decide what is best for their patients based on what is known today. If a patient has a potentially fatal cancer, the doctor cannot dismiss a relatively benign potential treatment modality just because definitive studies have not been done, and passively watch his patient die. Standards of care require doctors consider what is known now, using information currently available, perform a risk/benefit analysis, and then act in the best interest of their patient.
Luckily, such doctors recently obtained some guidance. In the first study of its kind, Professor Bruce Hollis of the Medical University of South Carolina gave all of us something to think about. He asked and answered a simple question: How much vitamin D do you have to take to normalize the metabolism of vitamin D?
Remember, unlike other steroid hormones, vitamin D has very unusual metabolism in most modern humans, called first-order, mass action, kinetics. All this means is that the more vitamin D you take, the higher the 25(OH)D level in your blood, and the higher the 25(OH)D level in your blood, the higher the levels of activated vitamin D in your tissues. No other steroid hormone in the body behaves like this. Think about it, would you like your estrogen level to be dependent on how much cholesterol you ate? Or your cortisol level? (I'd ask the same about testosterone levels but I know men well enough not to ask.) No, the body must tightly regulate powerful steroid hormones through substrate inhibition, that is, if an enzyme turns A into B, when the body has enough B, B inhibits the enzyme and so limits its own production.
Not so with vitamin D, at least at modern human vitamin D levels. Professor Reinhold Vieth was the first to write about this and Vieth's Chapter 61 in Feldman, Pike, and Glorieux's wonderful textbook, Vitamin D (Elsevier, 2005, second edition), (http://www.amazon.com/Vitamin-D-David-Feldman/dp/0122526899/ref=sr_1_9?ie=UTF8&s=books&qid=1196793504&sr=1-9")is a great reason to buy the textbook or have your library do so. [ I'm glad to see Amazon is out of stock of the new ones (someone must be reading about vitamin D) but you can still buy used editions.)
Why would the kinetics of vitamin D be different from all other steroids? Maybe they are not, Hollis reasoned, like Vieth before him. Maybe vitamin D levels are so low in modern humans that its metabolic system is on full blast all the time in an attempt to give the body all the vitamin D metabolites it craves. So Hollis asked, Is vitamin D's metabolism different in populations in the upper end of 25(OH)D levels (a population of sun-exposed people and a group of women prescribed 7,000 IU per day)? Note, the Hollis study is free on Medline, you can download the entire paper on the right hand of the PubMed page below.
Hollis BW, et al. Circulating vitamin D3 and 25-hydroxyvitamin D in humans: An important tool to define adequate nutritional vitamin D status. (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17218096)

If you look at the two graphs, Figures 1 and 2 of Hollis' paper, you find vitamin D's kinetics can be normalized, made just like all other steroid hormones in the body, but you have to get enough sunshine or take enough vitamin D to get your 25(OH)D level above 50 ng/ml, and 60 ng/ml would be better. Then your body starts to store cholecalciferol in the body without much further increase in 25(OH)D levels. The reaction becomes saturable. This is a remarkable discovery and it implies levels of 30 and 40 ng/ml are usually not sufficient. It also implies actual vitamin D levels (cholecalciferol levels), not just 25(OH)D levels, may be useful in diagnosing and treating deficiency. Note, that not all of the sun-exposed individuals or women prescribed 7,000 IU/day achieved such levels. That's because the sun-exposed individuals were tested after an Hawaiian winter and because prescribing and taking are two different things.

[Ted Hutchinson]

So my answer to "How much should I take if I have cancer?" is "Take enough to get your 25(OH)D level above 60 ng/ml, summer and winter." In doing so, you will have normalized the kinetics of vitamin D and stored the parent compound, cholecalciferol, in your tissues. In the absence of sunshine, you need to take about 1,000 IU/day per 30 pounds of body weight to do this. A 150 pound cancer patient may need to take 5,000 IU per day, a 210 pound cancer patient about 7,000 IU per day, all this in the absence of sunlight. And this may not be enough; cancer patients may use it up faster (increased metabolic clearance) and children may do the same due to their young and vital enzymes. Or you may need less, because you get more sun than you think, more from your diet, or because you are taking a modern medicine that interferes with the metabolism of vitamin D. An even easier way to do it is go to a sun tanning booth every day and obtain and keep a dark, full-body, tan. Then you don't have to worry about blood levels but I'd get one anyway, just to be sure it was above 60 ng/ml.
Given what Hollis discovered, given the well-known potent anti-cancer properties of activated vitamin D, given epidemiological evidence that summer extends the life of cancer patients, given a meta-analysis of randomized controlled trials showed that vitamin D prolongs life, given animal data that simple vitamin D has a treatment effect on cancer, and given a patient with a life-threatening cancer, what would a reasonable physician do? Simply let their patient die while muttering something about the lack of randomized controlled trials?
No, they would simply check a 25(OH)D level every month and advise cancer patients to take enough vitamin D or frequent sun tanning parlors enough to keep their level above 60 ng/ml. Toxicity does not start until levels reach 150 ng/ml but if you take more than 2,000 IU per day have your doctor order a blood calcium every month or two along with the 25(OH)D. Both you and he will feel better and because if you have cancer, you are probably taking lots of other drugs and little is known about how modern drugs interact with vitamin D metabolism. By getting your level above 60 ng/ml, all you are doing is getting your level to where most lifeguards' levels are at the end of summer, to levels our ancestors had when they lived in the sun, to levels regular users of sun-tan parlors levels achieve, and most importantly, to levels where vitamin D's pharmacokinetics are normalized.
In the end, if you have cancer and your physician won't do a risk/benefit analysis, do it yourself. The risk side of that equation is easy. Both Quest Diagnostics and Lab-Corp, the two largest reference labs in the USA, report the upper limit of 25(OH)D normal is 100 ng/ml and toxic is above 150 ng/ml, so 60 ng/ml is well below both. The reason levels up to 100 ng/ml are published normals is because there is no credible evidence in the literature that levels of 100 ng/ml do any harm and because sun worshipers often have such levels. (If you don't believe me, go to the beach in the summer for one month, sunbath every day for 30 minutes on each side in your bathing suit, and go home and have a 25(OH)D level.) By getting your level above 60 ng/ml, all you are doing is getting your levels into the mid to upper range of laboratory reference normals. Little or no risk.
What are the potential benefits? It probably depends on a number of things. Did your cancer cells retain the enzyme that activates vitamin D? Many do. Did your cancer cells retain the vitamin D receptor? Many do. If your cancer cells get more substrate [25(OH)D], will that substrate induce the cancer cells to make more vitamin D receptors or more of the activating enzyme? Some cancer cells do both. In practical terms, vitamin D is theoretically more likely to help your cancer the earlier you start taking it. However, no one knows. Certainly there is no reason, other than bad medicine, for cancer patients to die vitamin D deficient. Unfortunately, most do.

Tangpricha V, et al. Prevalence of vitamin D deficiency in patients attending an outpatient cancer care clinic in Boston (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=15310552).
Plant AS, Tisman G. Frequency of combined deficiencies of vitamin D and holotranscobalamin in cancer patients (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17474859).
It is very important that readers understand I am not suggesting vitamin D cures cancer or that it replace standard cancer treatment. Oncologists perform miracles every day. Do what they say. The only exception is vitamin D. If your oncologist tells you not to take vitamin D, ask him three questions. 1) How do you convert ng/mls to nmol/Ls? How many IU in a nonogram? 3) How do you spell "cholecalciferol?" If he doesn't know how to measure it, weigh it, or spell it, chances are he doesn't know much about it.
All of the epidemiological and animal studies in the literature suggest cancer patients will prolong their lives if they take vitamin D. I can't find any studies that indicate otherwise. However, none of the suggestive studies are randomized controlled interventional trials; they are all epidemiological or animal studies, or, in the case of Vieth's, an open human study. However, if you have cancer, or your child does, do you want to wait the decades it will take for the American Cancer Society to fund randomized controlled trials using the proper dose of vitamin D? Chances are you, or your child, will not be around to see the results.
John Cannell, MD The Vitamin D Council (http://www.cholecalciferol-council.com)

[Ted Hutchinson]

Joint pain ebbs with vitamin D (http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17218096) is interesting as it shows a Doctor who is prepared to investigate Vitamin D status in his cancer patients and correct the Vitamin D deficiency situation.

He finds joint pain is reduced with adequate vitamin D and fatigue is less of a problem.

Interesting to note 75% of his breast cancer patients were vitamin D deficient. He works in Kansas. The problem is worse further north.
Mercola's Sunlight Special. (http://www.mercola.com/downloads/bonus/sunlight-special)

[bluebirdy]

Ted - I'm a long-time member of Braintalk (spiney) but didn't know there was a Prostate Cancer area!! My best friend's hubby has been dx'd. Wish there was more activity here ... I bet folks have no idea it exists ... bluebirdy

[Ted Hutchinson]

It may be worth suggesting your friend listen's to David Feldman's talk here (http://med.stanford.edu/medcast/2008/vitamind.html) Towards the end of the talk he details the different ways Vitamin D may help stop prostate cancer cells.

It makes me so sad that people who are diagnosed with Prostate Cancer towards the end of Winter have the highest mortality. Vitamin d status is something that can be corrected in a matter of weeks for very little cost. Bio-Tech D3-5 - (http://www.bio-tech-pharm.com/products/d35.html) I just don't understand why people aren't encouraged to raise their status as soon as the even the possibility of cancer is considered.
If it doesn't turn out to be cancer you've not wasted much money as we know those with higher vitamin d status have less heart disease and fewer colds so it's not even as if the cost of the D3 is wasted.

If it turns out raising 25(OH)D status doesn't increase either length or quality of life (which I doubt) no harms been done. There isn't any evidence that raising vitamin d status to the NATURAL level we would obtain if we lived as we evolved to live is in any way harmful.

[bluebirdy]

Thanks Ted ... I'm listening to it. bluebirdy

[Ted Hutchinson]

http://i4.ytimg.com/vi/KOUR9JSmY3w/default.jpgConnection with Vitamin D and Cancer (http://www.youtube.com/watch?v=KOUR9JSmY3w&feature=related)
this 45 minute presentation sets out the way vitamin d may help cancer treatment. It's fairly detailed so I suggest you download it as you may need to watch it more than once.

In the same series is
http://i2.ytimg.com/vi/1PsyaYNX1dw/default.jpgVitamin D and Cancer Prevention (http://www.youtube.com/watch?v=1PsyaYNX1dw&feature=related) also well worth watching.

Both colon and prostate cancers are sun sensitive so the same basic information about vitamin d applies to both which is why I have posted the same in both forums.

[hrajanld]

Green tea, tomato, papaya, soy bean these are the best vitamin for male sexual health. For more information about prostate cancer and its treatment can visit at http://www.levitrabliss.com/

[Ted Hutchinson]

http://i4.ytimg.com/vi/3GM0CnO6-ds/default.jpgHow Vitamin D Reduces Incidence of Cancer: DINOMIT Model (http://www.youtube.com/watch?v=3GM0CnO6-ds&feature=channel)In a new study, researchers at the UCSD School of Medicine and Moores Cancer Center used a complex computer prediction model to determine that intake of vitamin D3 and calcium would prevent 58,000 new cases of breast cancer and 49,000 new cases of colorectal cancer annually in the US and Canada.
The researchers model also predicted that 75% of deaths from these cancers could be prevented with adequate intake of vitamin D3 and calcium.
Join Dr. Cedric Garland, lead researcher on the study, as he discuss the implications of these findings and the proposed actions.

Grassrootshealth D Action (http://www.grassrootshealth.net/d-action) provide 25(OH)D testing at cost for those participating in the trial. This is probably the cheapest way of monitoring your status to ensure you stay around the 50~60ng/ml range associated with least cancer incidence.

Please also share this information with your friends and on other forums. The facts about Vitamin D for Cancer Prevention and Survival (http://www.springerlink.com/content/bl1788224m55311n/) should not be a closely guarded secret and effective strength D3 (http://www.iherb.com/Now-Foods-Vitamin-D-3-Highest-Potency-5-000-IU-120-Softgels/10421?at=0) is cheap enough particularly if you also share your rewards codes like WAB666 to enable your friends to benefit from the $5 discount.

[Ted Hutchinson]

How to Optimize Vitamin D Supplementation to Prevent Cancer, Based on Cellular Adaptation and Hydroxylase Enzymology (http://www.ncbi.nlm.nih.gov/pubmed/19667164) Vieth R.

The question of what makes an 'optimal' vitamin D intake is usually equivalent to, 'what serum 25-hydroxyvitamin D [25(OH)D] do we need to stay above to minimize risk of disease?'.

This is a simplistic question that ignores the evidence that fluctuating concentrations of 25(OH)D may in themselves be a problem, even if concentrations do exceed a minimum desirable level.

Vitamin D metabolism poses unique problems for the regulation of 1,25-dihydroxyvitamin D [1,25(OH)2D] concentrations in the tissues outside the kidney that possess 25(OH)D-1-hydroxylase [CYP27B1] and the catabolic enzyme, 1,25(OH)2D-24 hydroxylase [CYP24].

These enzymes behave according to first-order reaction kinetics. When 25(OH)D declines, the ratio of 1-hydroxylase/24-hydroxylase must increase to maintain tissue 1,25(OH)2D at its set-point level. The mechanisms that regulate this paracrine metabolism are poorly understood.

I propose that delay in cellular adaptation, or lag time, in response to fluctuating 25(OH)D concentrations can explain why higher 25(OH)D in regions at high latitude or with low environmental ultraviolet light can be associated with the greater risks reported for prostate and pancreatic cancers.

At temperate latitudes, higher summertime 25(OH)D levels are followed by sharper declines in 25(OH)D, causing inappropriately low 1-hydroxylase and high 24-hydroxylase, resulting in tissue 1,25(OH)2D below its ideal set-point.

This hypothesis can answer concerns raised by the World Health Organization's International Agency for Research on Cancer about vitamin D and cancer risk.

It also explains why higher 25(OH)D concentrations are not good if they fluctuate, and that desirable 25(OH)D concentrations are ones that are both high and stable.

These are the Dilemmas that challenge the vitamin D hypothesis when it comes to cancer of the pancreas and prostate. that Vieth's Hypothesis deals with.

1 How can the vitamin D hypothesis explain the U-shaped risk curve for prostate cancer when the data suggest that the average 25(OH)D concentrations in countries with relatively high rates of prostate cancer are apparently the optimal concentrations for preventing prostate cancer ?

2 What plausible mechanism, other than vitamin D, could account for the association between greater lifetime sun exposure and diminished risk of prostate cancer ?

3 How can latitude and environmental ultraviolet light be associated with increased risk of prostate cancer , and pancreatic cancer, yet not be a significant contributor to the lower average 25(OH)D concentrations theorized to be the key component of the mechanism that relates latitude to cancer risk ?

4 Why is summer season of diagnosis, or a higher serum 25(OH)D associated with better prognosis of prostate cancer?

5 If vitamin D is adverse for prostate cancer, then why is the rate of rise in prostate-specific antigen (PSA) slower in summer than in other seasons and why would vitamin D supplementation slow the rate of rise in PSA ?

6 Why, in regions of the United States where environmental UVB is low, is there a positive association between pancreatic cancer versus serum 25(OH)D, while at the same time, in regions where UVB is high (presumably providing even higher serum 25(OH)D levels), is there no relationship with 25(OH)D?

7 If 25(OH)D is antiproliferative in cell cultures of prostate cells in vitro, and pancreatic cells , then why would it contribute to the development of cancer in vivo?

The simple message is that until we have evidence that Vieth is wrong it is safer to assume that he is right. The safest action is therefore to avoid sudden rises or drops in 25(OH)D levels firstly by taking an effective amount of vitamin d to raise status equivalent to levels at end of summer associated with optimum prognosis. 60ng/mL 150nmol/l. and by maintaining that level firstly by checking 25(OH)D regularly and by adjusting the intake gradually upwards over late fall to prevent the winter decline and decreasing levels gradually late spring to account for the extra input from sunlight.

Anyone with a winter sun holiday in the tropics would be well advised to similarly increase D3 intake in the few weeks departure for the Winter sun holiday, not use supplements while also sunning on beach, but to resume D3 supplements before the flight home and continue at a slightly higher level but gradually tapering down to the usual maintenance dose level that keeps 25(OH)D steadily around 60ng/mL 150nmol/l.

The aim of this strategy is to raise levels SLOWLY rather than a rapid rise to allow the enzyme actions to readjust set point naturally, and to lower levels also gradually after the holiday so they come down equally slowly allowing time for the fine tuning of the enzyme balance to be achieved with least risk of making the oncogene CYP24 available. Not only do we want to spread the rise and fall over a longer period, we also need to reduce the amplitude of the peaks and troughs, so we neither go too high or drop too low.