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More positive news for vitamin D....


Vitamin D dramatically cuts cancer risk: study

CTV.ca News Staff

Updated: Thu. Jun. 7 2007 10:54 PM ET

A landmark new study is raising the tantalizing spectre that a simple and cheap vitamin supplement may offer a highly effective way of preventing cancer.

The research, published in the online edition of the American Journal of Clinical Nutrition, finds that a combination of vitamin D3 and calcium has a substantially marked effect on reducing cancer incidence.

The four-year study out of Creighton University in Nebraska found that women who regularly took vitamin D3 had a 60 per cent reduction in cancer infections compared to a group taking placebos.

The study followed 1,179 healthy, women 55 years and older from rural eastern Nebraska between 2000 and 2005. Participants were randomly assigned to receive 1400-1500 mg of calcium alone, or supplemental calcium plus 1,100 IU vitamin D3, or placebo.

The researchers studied only vitamin D3, which comes from animal sources and seems to be more active than vitamin D2, which is derived from plant sources.

Among the 288 women taking placebo, 20 developed breast, colon, lung or another form of cancer. Among the 445 women taking just calcium, 17 developed cancer. But among the largest group -- the 446 women taking vitamin D daily -- just 13 developed cancer.

"What we found is that a vitamin D supplement decreased the cancer incidence in postmenopausal women by about 60 per cent," lead investigator Joan Lappe, an associate professor of both medicine and nursing at Creighton University, told CTV News.

On the premise that some of the women who did develop cancer may have entered the study with undiagnosed cancers, researchers then eliminated the first-year results and looked at the last three years of the study. When they did that, the results became even more dramatic with the calcium/vitamin D3 group showing a startling 77 per cent cancer-risk reduction.

"The findings are very exciting. They confirm what a number of vitamin D proponents have suspected for some time but that, until now, have not been substantiated through clinical trial," said Lappe.

"Vitamin D is a critical tool in fighting cancer as well as many other diseases."

While the study was open to all ethnic groups, all participants were Caucasian, she noted. Lappe said further studies are needed to determine whether the results apply to different ethnic groups, to men, and to women of all ages.

This is not the first time that researchers have noted the health benefits of vitamin D. In February, two studies found that the vitamin was linked to lower rates of breast cancer and colorectal cancer. The "sunshine vitamin," as it's sometimes called, has also been shown to kill some cancer cells in laboratory experiments.

"There's a lot of evidence out there that populations in first world countries are deficient in vitamin D and if you give them more, we can prevent cancers and other diseases that have been reported to be prevented with vitamin D," said Lappe.

Humans can absorb vitamin D when ultraviolet rays from the sun trigger vitamin D synthesis in our skin. But because of our short summers in Canada and our latitude, most Canadians don't get anywhere near enough of it all year long.

That's why Dr. Reinhold Vieth, who has conducted numerous studies of vitamin D at Toronto's Mount Sinai Hospital, believes every Canadian could benefit from taking a vitamin D supplement.

"The vitamin D story is what I call a 'no-lose' proposition. Take it. You can only win," he told CTV News.

Cancer Society recommends vitamin D supplementation

Because of the growing body of evidence about vitamin D, for the first time, the Canadian Cancer Society is recommending a specific amount of supplementation for Canadians to consider taking. The Society is now recommending that:

* Adults living in Canada should consider taking vitamin D supplementation of 1,000 international units (IU) a day during the fall and winter.
* Adults at higher risk of having lower vitamin D levels should consider taking vitamin D supplementation of 1,000 IU/day all year round. This includes people who are older; with dark skin; who don't go outside often, and who wear clothing that covers most of their skin.
* At this time, the Canadian Cancer Society does not have a recommendation for vitamin D supplementation for children.

"The evidence is still growing in this area, but we want to give guidance to Canadians about this emerging area of cancer prevention based on what we know now," said Heather Logan, director of Cancer Control Policy with the Canadian Cancer Society.

"We're recommending 1,000 IUs daily because the current evidence suggests this amount will help reduce cancer risk with the least potential for harm," said Logan.

"As we find out more we will update our recommendation."

Logan cautions Canadians about relying too much on getting vitamin D through exposure to sunlight.

"It's not a good idea to rely solely on the sun to obtain vitamin D," said Logan. "For some people, it's possible that just a few minutes of unprotected sun exposure every day could increase skin cancer risk."

The Cancer Society is not changing its SunSense guidelines, as skin cancer is the most frequently diagnosed cancer in Canada.

The Society recommends that people reduce their exposure to the sun, particularly between 11 a.m. and 4 p.m. when the sun's rays are the strongest. And use a sunscreen with a sun protection factor (SPF) 15 or higher and SPF 30 if you work outdoors or if you will be outside for most of the day.

With a report from CTV medical specialist Avis Favaro and medical producer Elizabeth St. Philip

Study shines light on possible MS cause 15 June 2007

SLIP, slop, slapping to avoid skin cancer could be exposing people to increased risk of multiple sclerosis.

Researchers believe rising rates of MS could be linked to reduced levels of vitamin D, which is produced in the body by sunlight.

About 18,000 Australians are thought to have MS, where the body's killer T cells attack the protective myelin sheath around nerve fibres in the brain.

The disease usually strikes people aged in the 20s and 30s, progressively breaking down functions like mobility and eyesight or hitting in unpredictable bursts punctuated by temporary remissions.

MS Research Australia executive director Jeremy Wright said the number of MS cases was jumping by about six or seven per cent each year.

"We're seeing up to 1000 new cases every year, and that is now outpacing the rate of population growth," he said.

Mr Wright said it was unclear what was behind the rise, but there was growing evidence of a link to sunlight and vitamin D.

He said research showed the further people lived from the equator, the greater the rate of MS.

Mr Wright said Victoria's MS rate was four to five times higher than that of Queensland.

He said Victorians needed 10 to 15 minutes of sunlight exposure two to three days a week to give them adequate vitamin D levels.

"One theory is maybe we've gone a bit over the top with the slip, slop, slap campaign," Mr Wright said.

He said another favoured theory was that our increasingly hygienic environments meant our immune systems did not develop properly.

"Our children have less exposure to nasty things that might give them diseases and excite the immune system into action early in life," Mr Wright said.

"If you don't use your immune system early, it doesn't learn how to become strong against other diseases later."

Mr Wright said research promised major breakthroughs in MS.

He said new drugs that could dramatically reduce the number of attacks suffered by people with the relapse-remitting form of the disease were being tested and could be on the market within five years.

Other researchers, including at Melbourne and Monash universities, were making advances in the repair of damaged cells that made up the myelin sheath.

Source: News.com.au Copyright 2007 News Limited. (15/06/07)

It seems funny to read an article like this where there is a vitamin that is considered a possible cause of ms and yet people are risking their lives with drugs that could bring down a horse to stop their RRMS. If i was one of those people any talk of a goddam vitamin being the cause of such a complex disease would scare me.

I have had soooooo much exposure to the sun, unprotected, in the past and I STILL have MS. This theory never made sense to me. Quite the opposite, I thought I had fried my brain with so much sunbathing and tennis. Carole

bromley, I find this article incredulous not because of the vitamin D and MS association but rather from the apparent ignorance of the MS Research Australia executive director Jeremy Wright. Granted his comments might have been taken out of context or abbreviated but there are few issues that I'd like to point out.

The author made no allusion to previous research out of Australia (van der Mai et al 2001) which found a stronger association between MS prevalence and the inverse of ultra violet radiation than the relationship between skin cancer and UVR. This not a moot point as the thrust of the article was how the Aussie campaign to reduce skin cancer appears to be raising the incidence and prevalence of MS there.

The director is quoted to have said

research promised major breakthroughs in MS.

He said new drugs that could dramatically reduce the number of attacks suffered by people with the relapse-remitting form of the disease were being tested and could be on the market within five years.

WTF? On one hand he is commenting on how vitamin D is a probable reason for influencing MS and then goes on to say new drugs could be available in five years.

How about recommending people with MS take 4,000 IU/d beginning today, to induce immunomodulation now!

Unfortunately this mindset is pervasive in the conventional, drug based world which dictates the practices of the MS Societies yet I don't think this is in the best interests of the supposed client base of the MS Society.

carolew, your bio indicates you reside in Canada. Unless you have taken previously unheard amounts of vitamin D supplements in winter or vacationed regularly to a tropical clime in winter, I can safely assume you have been vitamin D deficient for substantial portions of your life while in Canada.

Your degree of disability or age of symptom onset though could be correlated to your pattern of sun exposure in summer in Canada. It is necessary to consider that the active hormonal form of vitamin D in your body takes a month or so to form after UVR exposure or from pill format ingestion and the hormone only says in your body for a month or so before it degrades. The graph in this paper demonstrates nicely the relationship between seasonal vitamin D levels and lesion activity.

robbie, I don't think vitamin D is considered a cause per se of MS but rather an intrinsic element to the disease process. However, I feel it is such a significant protective factor that MS can be considered a disease of latent vitamin D deficiency. Of course we at DIRECT-MS feel dietary proteins in predisposed individuals are the driving instigators of MS.

I also think that many cancers will eventually be thought of diseases of latent vitamin D deficiency too considering the significant influence it has in cellular differentiation. See this post in this forum for an article on vitamin D's substantial effect on cancer prevention.

Cheers
Nick

nick that is interesting. which dietary proteins are suspect?

jimmylegs wrote:nick that is interesting. which dietary proteins are suspect?

jl

The foods with the potential to precipitate autoimmunity in predisposed individuals are cow's milk, gluten, legumes, yeast and eggs. It's not such a stretch to conceive of food proteins being able to do this as celiac disease is a well defined autoimmune disease in which the body's immune system is unable to differentiate between a food antigen (gluten/gliadin) and self tissue(endomysium) so it attcks both.

This case of mimicry has been identified in MS in a few studies already. This study by Winer et al in 2001 that found striking similarities between IDDM and MS. In essence, the two diseases are, in a test tube, virtually identical. It’s only their final expression of what self tissue is attacked which differs.
It compliments the research by Guggenmos et al by showing mimicry between self tissue and dietary proteins. It strongly implicates dairy as a causal element in MS and very strongly implicates dairy as a causal element in type 1 diabetes.

This study by Winer et al in 2001 that found striking similarities between IDDM and MS. In essence, the two diseases are, in a test tube, virtually identical. It’s only their final expression of what self tissue is attacked which differs.

This relationship is important to recognise because children with neurological autoimmune diseases develop immune reactions to other targets in their bodies and in food early in their disease, according to research that was presented at the American Academy of Neurology 58th Annual Meeting in San Diego, Calif., April 1 - 8, 2006.

T cells are the body's regulators of the immune response. Increased T cell proliferation is a characteristic of autoimmune disease, in which the immune system attacks body tissues. However, it wasn't known whether this increased proliferation occurred early, or as a result of chronic autoimmunity, said lead researcher Brenda Banwell, MD, from the Department of Pediatric Neurology at the Hospital for Sick Children in Ontario, Canada.

The researchers studied 166 children: 63 with an autoimmune demyelinating syndrome (either multiple sclerosis or an isolated event of central nervous system autoimmunity), 43 with type I diabetes (also an autoimmune disease), 31 with a non-autoimmune neurological condition, and 30 healthy controls. They examined blood samples for T cell proliferation in response to exposure to a variety of antigens (targets), including myelin protein from nerve cells, proteins in the pancreas, and proteins in milk.

As expected, more children with central nervous system autoimmunity had T cell proliferation after exposure to myelin than control children (50 percent versus 10 percent). About a quarter of these children also showed a response to proinsulin, a T-cell target in type I diabetes. Over sixty percent also responded to a protein in milk. Ninety percent of the children with type I diabetes responded to pancreatic antigens as expected, but almost as many (79 percent) responded to myelin, and 90 percent responded to milk protein.

Even at the onset of their disease, children with autoimmune diseases harbor T cells that will react against proteins within their tissues, Banwell said. The responses seen against milk proteins raise the possibility that substances in food may be associated with autoimmunity.

Cheers
Nick

thanks for all that nick. so are you saying that some people need more vitamin d supplementation than others in order to help their immune system put the brakes on the self-tissue issues?

i like this kind of article, kind of takes the pressure off one supplement when you consider all the interrelationships and variables.

Med Hypotheses. 2001 Feb;56(2):163-70. Links
The multifaceted and widespread pathology of magnesium deficiency.Johnson S.
sjohnson@qwksilvr.com

Even though Mg is by far the least abundant serum electrolyte, it is extremely important for the metabolism of Ca, K, P, Zn, Cu, Fe, Na, Pb, Cd, HCl, acetylcholine, and nitric oxide (NO), for many enzymes, for the intracellular homeostasis and for activation of thiamine and therefore, for a very wide gamut of crucial body functions. Unfortunately, Mg absorption and elimination depend on a very large number of variables, at least one of which often goes awry, leading to a Mg deficiency that can present with many signs and symptoms. Mg absorption requires plenty of Mg in the diet, Se, parathyroid hormone (PTH) and vitamins B6 and D. Furthermore, it is hindered by excess fat. On the other hand, Mg levels are decreased by excess ethanol, salt, phosphoric acid (sodas) and coffee intake, by profuse sweating, by intense, prolonged stress, by excessive menstruation and vaginal flux, by diuretics and other drugs and by certain parasites (pinworms). The very small probability that all the variables affecting Mg levels will behave favorably, results in a high probability of a gradually intensifying Mg deficiency. It is highly regrettable that the deficiency of such an inexpensive, low-toxicity nutrient result in diseases that cause incalculable suffering and expense throughout the world. The range of pathologies associated with Mg deficiency is staggering: hypertension (cardiovascular disease, kidney and liver damage, etc.), peroxynitrite damage (migraine, multiple sclerosis, glaucoma, Alzheimer's disease, etc.), recurrent bacterial infection due to low levels of nitric oxide in the cavities (sinuses, vagina, middle ear, lungs, throat, etc.), fungal infections due to a depressed immune system, thiamine deactivation (low gastric acid, behavioral disorders, etc.), premenstrual syndrome, Ca deficiency (osteoporosis, hypertension, mood swings, etc.), tooth cavities, hearing loss, diabetes type II, cramps, muscle weakness, impotence (lack of NO), aggression (lack of NO), fibromas, K deficiency (arrhythmia, hypertension, some forms of cancer), Fe accumulation, etc. Finally, because there are so many variables involved in the Mg metabolism, evaluating the effect of Mg in many diseases has frustrated many researchers who have simply tried supplementation with Mg, without undertaking the task of ensuring its absorption and preventing excessive elimination, rendering the study of Mg deficiency much more difficult than for most other nutrients.

jimmylegs wrote:thanks for all that nick. so are you saying that some people need more vitamin d supplementation than others in order to help their immune system put the brakes on the self-tissue issues?

Jim

I feel that every adult who has an autoimmune disease or suspects a predisposition yet is not dx'd should have an intenal concentration of 25 hydroxyvitamin D > 100nmol/L (ideally 125 nmol/L). If you don't have concerns about coping with or preventing an autoimmune disease that it not critical.

From what is known now this serum concentration is considered optimal because the data we have now implies that is what best modulates the immune system. This internal concentation is achieved from an intake of approximatel 4,000 IU/d (or the equivalent of ultraviolet radiation exposure)depending on the individual. It is estimated that adults use 4,000 IU/d in normal physiological fuctioning.

Because vitamin D3 deficiency is so stongly linked to cancer prevalence, I think everybody, regardless of autoimmune concerns, has the same daily intake of 4,000 IU/d (or the equivalent in UVR) until future research indicates taking more (or less) will yield better results. Maybe a person already with cancer would benefit from more but this has't, to my knowledge, yet been demonstrated.

Cheers
Nick

hi nick, when i first asked for a D3 test i had been supplementing for a few months, and for the last few weeks it had been at 4000 per day. so i never knew my real baseline number, but at that point i got tested and i was only at 72!

after that, i went for 150 nmol/L by taking 50,000 per day for ten days, divided into two 25,000 doses (i couldn't make it any smaller at that concentration, or i would have done 10,000 at a time). i got to 149 which was great. last year i stopped supplementing because i was working outside in australian late spring, and then i went a while without supplements even when i got back to canadian winter, so that i could get a clean baseline test, but i waited too long and my level was down to 80.

i'm back on 4000 a day because i'm not really getting out in the sun so far this summer, only a few hours so far. and i'm not perfect about taking my supps every day. but i need to have another test to see if i'm at least back up to 100 at a minimum.

i have this cal mag d3 pill that has 1000 units in it, plus an additional 3000 in little d3 pills. should i just be taking four of the big cal mag d3s you think, to get the right balance?

jimmylegs wrote:hi nick, when i first asked for a D3 test i had been supplementing for a few months, and for the last few weeks it had been at 4000 per day. so i never knew my real baseline number, but at that point i got tested and i was only at 72!

after that, i went for 150 nmol/L by taking 50,000 per day for ten days, divided into two 25,000 doses (i couldn't make it any smaller at that concentration, or i would have done 10,000 at a time). i got to 149 which was great. last year i stopped supplementing because i was working outside in australian late spring, and then i went a while without supplements even when i got back to canadian winter, so that i could get a clean baseline test, but i waited too long and my level was down to 80.

i'm back on 4000 a day because i'm not really getting out in the sun so far this summer, only a few hours so far. and i'm not perfect about taking my supps every day. but i need to have another test to see if i'm at least back up to 100 at a minimum.

i have this cal mag d3 pill that has 1000 units in it, plus an additional 3000 in little d3 pills. should i just be taking four of the big cal mag d3s you think, to get the right balance?

J

You haven't said what the CaMg amount is in the pill. Without knowing more I'd speculate that 4,000 IU/d of D3 and Calcium – 1000 to 1200 mg/d and Magnesium – 500 to 600 mg/d is desireable.

Nick

hi there, i've had the feeling that the ratio is right in the cal mag d3 pills, but i've been dumping in an extra 3000 d3, which i should probably stop doing i suppose, thanks

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At the right dose, vitamin D is important for bone development and may help protect against the development of several cancers, particularly colorectal cancer. However, large quantities designed to exploit the vitamin's anticancer properties can lead to a toxic overdose of calcium in the blood. Now, research done at Georgetown University's Lombardi Comprehensive Cancer Center indicates that it may be possible to separate the anticancer properties of vitamin D from its other functions.

"We found a mutation which caused rickets but not alopecia but which still allowed beta catenin to bind to the vitamin D receptor," he said. This suggested to the researchers that it may be possible to separate the anti-cancer role of vitamin D from its effects on bone and calcium.

I wonder if this "modified D" would also lead to benefits for MS? If you search on MS and beta catenin, it returns a lot of hits, but the material is way over my head.

The "toxic" possibility was also interesting.

Kind of an interesting study of the relationship to Vita D levels and calcium/etc... absorption.

http://www.jacn.org/cgi/content/full/22/2/142

Calcium Absorption Varies within the Reference Range for Serum 25-Hydroxyvitamin D
Robert P. Heaney, MD, FACN, M. Susan Dowell, PhD, Cecilia A. Hale, PhD and Adrianne Bendich, PhD, FACN
Creighton University, Omaha, Nebraska (R.P.H., M.S.D.)
GlaxoSmithKline, Parsipanny, New Jersey (C.A.H., A.B.)

Address reprint requests to: Robert P. Heaney, M.D., Creighton University, 601 N. 30th St., Suite 4841, Omaha, NE 68131. Email: rheaney@creighton.edu


ABSTRACT

Background: Calcium absorption is generally considered to be impaired under conditions of vitamin D deficiency, but the vitamin D status that fully normalizes absorption is not known for humans.

Objective: To quantify calcium absorption at two levels of vitamin D repletion, using pharmacokinetic methods and commercially marketed calcium supplements.

Design: Two experiments performed in the spring of the year, one year apart. In the first, in which participants were pretreated with 25-hydroxyvitamin D (25OHD), mean serum 25OHD concentration was 86.5 nmol/L; and in the other, with no pretreatment, mean serum concentration was 50.2 nmol/L. Participants received 500 mg oral calcium loads as a part of a standard low calcium breakfast. A low calcium lunch was provided at mid-day. Blood was obtained fasting and at frequent intervals for 10 to 12 hours thereafter.

Methods: Relative calcium absorption at the two 25OHD concentrations was estimated from the area under the curve (AUC) for the load-induced increment in serum total calcium.

Results: AUC9 (± SEM), was 3.63 mg hr/dL ± 0.234 in participants pretreated with 25OHD and 2.20 ± 0.240 in those not pretreated (P < 0.001). In brief, absorption was 65% higher at serum 25OHD levels averaging 86.5 nmol/L than at levels averaging 50 nmol/L (both values within the nominal reference range for this analyte).

Conclusions: Despite the fact that the mean serum 25OHD level in the experiment without supplementation was within the current reference ranges, calcium absorptive performance at 50 nmol/L was significantly reduced relative to that at a mean 25OHD level of 86 nmol/L. Thus, individuals with serum 25-hydroxyvitamin D levels at the low end of the current reference ranges may not be getting the full benefit from their calcium intake. We conclude that the lower end of the current reference range is set too low.


Key words: vitamin D, calcium absorption, 25-hydroxyvitamin D, vitamin D status, parathyroid hormone, vitamin D requirement

INTRODUCTION

In 1997 the Food and Nutrition Board of the Institute of Medicine accepted serum 25-hydroxyvitamin D concentration (25OHD) as the functional indicator of vitamin D status [1], but data were insufficient at that time to characterize fully the physiological normal range for this indicator. Most reference laboratories cite lower limits varying from 37.5 to 50 nmol/L (15 to 20 ng/mL), but this lower limit is empirically based on measurements in ostensibly "normal" individuals. Since there is a growing consensus that vitamin D insufficiency is more common than previously thought, such empiric estimates may well be circular; furthermore, individuals who would benefit from higher vitamin D status may be inappropriately classified as "normal" if their serum 25OHD concentration falls within the reference range.

Studies that have evaluated serum parathyroid hormone (PTH) concentration as a function of 25OHD level have generally found that PTH is higher at low 25OHD levels than at higher 25OHD values. The curve flattens out above 25OHD values that range, in various reports, from 75 to 110 nmol/L [2–4]. The tendency for higher PTH levels below such inflection points is usually interpreted to indicate a physiological adaptation to reduced calcium entry into the body, and there are arguments on both sides of the question whether such physiological adaptation is conducive to or indicative of optimal health [5–6]. What is lacking in the data available to date is evidence of quantitative variation in function at 25OHD levels in the disputed zone between the lower end of the nominal reference range and the level where PTH becomes constant.

In an attempt to provide such data, we present in this paper the results of paired studies of calcium absorption in healthy postmenopausal women performed under different conditions of vitamin D repletion.

METHODS

Protocol
Two studies were conducted in Omaha, Nebraska at 41.3° N. latitude, approximately one year apart, in the spring of the year at the time of the seasonal nadir for serum 25OHD. Each was a randomized, cross-over study, designed to test the relative absorbabilities of two calcium supplement sources, ingested at single, 500 mg loads taken as part of a standard low calcium breakfast. Results from the first study, comparing the two calcium sources, have been published previously [7]. The protocol for the first study included pre-dosing with 25OHD (CalderolTM, Organon, West Orange, NJ), at a dose of 20 µg given on alternate days for an average of three weeks prior to the absorption measurements, a stratagem designed to bring all participants rapidly into a state of vitamin D sufficiency. By contrast, in the second study, there was no pretreatment with vitamin D or 25OHD. The test substances in both studies were commercially marketed preparations of Os-CalTM and CitracalTM in doses providing 500 mg of calcium (as calcium carbonate for Os-Cal) and 515 mg of calcium (as calcium citrate for Citracal). Both sources also provided 200 IU of vitamin D, which the participants received one time only, on the day of the test. Subjects were fed a low calcium lunch five hours after the test breakfast.

In both studies the two marketed products tested were found to be bioequivalent, with nearly identical (and nonsignificantly different) indices of absorption. Hence, for purposes of this analysis, within-subject averages of calcemia for the two calcium sources in each study were taken as the best estimates of each participant’s absorptive performance under the then prevailing vitamin D status.

Participants
Participants were 34 postmenopausal women, 14 of whom took part in both studies. Average age at time of study was 56 ± 7 years in the first study and 64 ± 9 years in the second. Body mass index (kg/m2) was 29.2 ± 5.2 for the study with 25OHD supplementation and 28.8 ± 3.8 for the study without. Twelve of the 24 women in the first study were receiving estrogen replacement therapy, and 10 in the second study. Individuals with digestive disorders, antibiotic use within five days or unstable medical conditions of any sort were excluded. The study was approved by the Creighton University Institutional Review Board, and each subject gave written consent.

Absorption Measurement
Relative absorption was estimated from the area under the curve over intervals ranging from 9 to 12 hours after dosing (AUCt). Blood was drawn immediately prior to the test breakfast (time zero) and at frequent intervals thereafter out to 24 hours in the first study and to 12 hours in the second. AUC was calculated for 9, 10 and 12 hours by the trapezoidal method using the increment above each individual’s baseline serum calcium value, and the individual participant AUCt values were aggregated across each study. Comparative absorption was expressed as the ratio of the means of the two AUCt values. Since the timing of the blood samples was not identical for the two studies, AUCt was calculated for each using values confected at 9 or 10 hours (as the case may be) by linear interpolation between measurements on either side of the desired time point. As the values were close to baseline by nine hours, this assumption of linearity can have introduced at most only a trivial error. Because AUC9 has been shown elsewhere [8] to be better correlated with true absorption than AUC values at earlier or later times, the primary comparisons we report will be based on AUCt calculated over nine hours. Fractional absorption was calculated from the AUC9 values using the following formula [8]:





Analytical Methods
Serum calcium was measured by atomic absorption spectrophotometry (AAnalyst 100, Perkin-Elmer, Norwalk, CT). Serum 25OHD was measured once at baseline on each subject in each study (Nichols Institute Diagnostics, Catalog No. 40-2135, San Juan Capistrano, CA). Serum immunoreactive parathyroid hormone (iPTH) was measured as the intact molecule by IRMA (Nichols, San Juan Capistrano, CA).

Statistical Analyses
Data were analyzed in two ways. Since approximately half of the subjects in each group were not common to the two studies, the two sets of values were analyzed as independent samples, using ANOVA and testing for period and treatment effects. For the 14 women common to each study, a repeated measures ANOVA was performed, also testing for treatment and period effects. In both instances we used SAS (SAS Institute, Cary, North Carolina), as well as the various descriptive statistics provided by Excel (Microsoft, Redmond, WA).

RESULTS

Table 1 sets forth the numerical values for the principal findings in this study. Serum 25OHD at baseline was 36 nmol/L higher in the study in which participants had been pretreated with 25OHD. The fact of this difference is not surprising, since that was the intent of the pretreatment. The size of the difference is of greater interest. The mean within-individual difference in the 14 participants common to both studies was 34.3 nmol/L ± 3.7 (SEM), virtually the same as the difference between the two group means. The primary outcome was the incremental AUC9 for serum calcium, which was 65% higher in the 25OHD treated study (D+) than in the untreated study (D-). This difference was highly significant.




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Table 1. Serum Ca AUC and Related Variables*




Fig. 1 shows the calcemia time course for each calcium source in the two studies (with and without vitamin D repletion). The figure shows graphically not only that baseline vitamin D status significantly influenced calcium absorption but that the effect of D-status was equivalent for the two calcium salts.




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Fig. 1. Time course of the incremental calcemia following ingestion of 12.5 mmol Ca loads from two different sources and with and without pretreatment with 25OHD. The top two lines are the calcemia curves observed in participants pretreated with 25OHD, and the bottom two, those measured without vitamin D. Error bars are 1 SEM. ( & represent CitracalTM and & represent OscalTM.) (Copyright Robert P. Heaney, 2002. Used with permission.)




Fig. 2 presents the full time course of the mean serum calcium increments for the two salts combined over the 10 to 12 hour periods following the test calcium loads. Not only was the AUCt different, but at most of the time points from 3 to 10 hours, the serum calcium increment was significantly greater in the D+ study than in the untreated. Additionally, as Table 1 shows, even the baseline serum calcium values, while all within the reference normal range (8.8 to 10.2 mg/dL), were significantly higher in the D+ participants (by 0.33 mg/dL; P < 0.002). While basal serum PTH was higher in the D- group, the difference was not statistically significant, largely because, unlike calcium, which is tightly regulated, PTH values exhibited broad dispersion with a coefficient of variation more than 10x greater. Similarly, the AUC for PTH showed less of a drop in the study without supplemental vitamin D, but the difference was not statistically significant. Finally, there was no difference in AUC9 in either study between those receiving estrogen replacement therapy and those not so treated (data not shown).




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Fig. 2. Time course of the mean increment in serum total calcium in two studies, in one of which vitamin D status was elevated ("D+"), and in the other, it was not ("D-"). Error bars are 1 SEM. (Copyright Robert P. Heaney, 2002. Used with permission.)




Even within each of the two treatment groups there was a broad range of 25OHD values; in fact, 25OHD values were continuously distributed across both groups. Hence we pooled the two studies and regressed AUC9 on 25OHD concentration (Fig. 3). As expected there was a significant positive association (P < 0.05). The coefficient of correlation improved substantially if the regression were confined to 25OHD values below 90 nmol/L (above which level the correlation was effectively zero).




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Fig. 3. Correlation of AUC9 with serum 25OHD concentration in 48 measurements of calcium absorption in 34 postmenopausal women. The lines represent the least squares regression line through the data and its 95% confidence limits. (Copyright Robert P. Heaney, 2002. Used with permission.)




Subjects in the second study, without supplemental 25OHD, were significantly older than those in the first study. Because of this age difference and the possibility that some or all of the absorptive difference was due to age rather than to vitamin D status, we separately evaluated the within-individual differences in AUC9 in the 14 participants common to both studies. In these women, the mean difference in AUC9 was 1.132 mg hr/dL ± 0.339 (SEM; P < 0.01), a value 45% greater than without supplemental 25OHD and, in absolute magnitude, nearly as large as the intergroup difference. Using the formula for conversion of AUC9 to true fractional absorption values (Eq. 1), mean calcium absorption under vitamin D repletion was 35.3% of load (± 11.8) and, without supplemental vitamin D, 22.5% of load (± 12.0).
DISCUSSION

Many nutrients exhibit what has been termed "threshold behavior," that is, the values for the physiological response change directly with intake up to some threshold value, above which the response does not change with further increases in intake. Calcium, iron and ascorbic acid are well recognized examples. Vitamin D is usually considered to exhibit similar behavior, and the limited evidence available is consistent with that interpretation. Threshold behavior in this instance would mean that, in a state of vitamin D sufficiency, variations in vitamin D intake within the physiological range would not alter calcium absorption efficiency, while absorption would vary with intake at subthreshold values for vitamin D status.

As noted earlier, the Food and Nutrition Board in its 1997 recommendations [1] was not able to specify the serum 25OHD value at which vitamin D status reaches the response threshold. Mortensen and Charles [9] had shown an improvement in absorption in healthy Danish subjects given short-term pretreatment with vitamin D, but unfortunately their study provides no data on serum 25OHD concentrations. Scotti et al. [11] more recently have shown very similar results in Italian male subjects, in this case with accompanying serum 25OHD values. Specifically, the index of calcium absorption used was higher at a serum 25OHD level of 67.5 nmol/L than at 55.5 nmol/L. Unfortunately both studies used, as their measure of calcium absorption, the induced rise in urine calcium excretion, which, while convenient, is a very insensitive indicator.

In this study, using classical pharmacokinetic methods, we found that healthy, postmenopausal women with serum 25OHD levels averaging 86.5 nmol/L had calcium absorptive efficiencies from 45% to 65% greater than those with mean 25OHD levels of 50.1 nmol/L. Aside from a general congruence with the findings of Scotti et al. [11], this is the first such evidence of which we are aware. Presumably it is precisely this reduced calcium absorption at 25OHD levels below 80 nmol/L which is the stimulus to the higher PTH secretion reported by others [2–4] at 25OHD values below 80 nmol/L.

We have recently shown that a drop in serum 25OHD from 122 to 74 nmol/L did not produce a significant difference in calcium absorption [10], in contrast to the findings in this study where a drop from 86.5 to 50.1 nmol/L produced a large drop in absorption. In the context of the threshold model, that means that a serum 25OHD of 50 nmol/L is on the ascending limb of the response curve, while 86 nmol/L is close to or above the threshold. Consistent with placement of the threshold near 80–90 nmol/L is not only the PTH behavior alluded to above [2–4], but our finding in this study that the correlation between 25OHD and AUC9 was tightest for 25OHD values below 90 nmol/L, and effectively non-existent above that level.

A limitation of this study is that the data were obtained solely in postmenopausal women. Additional work needs to be done in men and in women at other ages. A further limitation is the pharmacokinetic method itself. While more sensitive and specific than urine calcium-based methods, the pharmacokinetic approach presents formidable analytic challenges. The degree of peak calcemia produced by a single 500 mg load, especially in the face of lower vitamin D status, is, as Figs 1 and 2 show, on the order of only 5% above basal values. Of necessity, some individuals will have below average peak elevations, and earlier and later values will be lower still. The error in quantifying the calcemic rise in individual subjects is, therefore, unavoidably large. While sample size can help overcome this limitation, it is of little help in evaluating associations, in which individual values must be employed. Thus, while we found a significant positive correlation between AUC9 and serum 25OHD concentration, the dispersion of the data around the regression line was large, mainly, we believe, because of the unavoidably poor precision of the individual AUC estimates for the load-induced calcemia.

Since calcium absorption is critical to the ability to maintain calcium balance, it follows that reduced absorptive performance at 25OHD levels between 50 and 80 nmol/L must be considered suboptimal, and, accordingly, 25OHD values in that range ought to be considered subnormal. While the precise location of the threshold remains uncertain, the evidence presented here points to a value closer to 80 or 90 nmol/L, consistent with the studies of PTH concentration [2–4]. In any event, it seems more certain now that the lower boundaries of the reference ranges (i.e., 37.5 to 50 nmol/L) are incorrect, i.e., such levels of serum 25 hydroxyvitamin D are associated with suboptimal calcium absorption, thereby exacerbating the negative effects of the low calcium intakes that are today found across most population segments.

Note Added to Proof
A very recent publication corroborates our conclusion about the inadequacy of 25OHD values in the lower half of the reference range. Trivedi et al. [12], in a population-based, randomized controlled trial of 2,686 individuals, aged 65 to 85, showed that treatment with vitamin D3 in a dose sufficient to raise serum 25OHD from 53 to 74 nmol/L, decreased fracture risk at hip, forearm, or spine by 33% (P = 0.02). This effect occurred over almost exactly the 25OHD range for which we here report a substantial difference in calcium absorption efficiency.


FOOTNOTES

Work supported in part by contracts with GlaxoSmithKline.

Received November 1, 2002. Accepted January 27, 2003.

REFERENCES


Food and Nutrition Board, Institute of Medicine:"Dietary Reference Intakes for Calcium, Magnesium, Phosphorus, Vitamin D, and Fluoride." Washington, DC: National Academy Press,1997 .
Chapuy M-C, Preziosi P, Maamer M, Arnaud S, Galan P, Hercberg S, Meunier PJ: Prevalence of vitamin D insufficiency in an adult normal population.Osteoporos Int7 :439 –443,1997 .[Medline]
Thomas MK, Lloyd-Jones DM, Thadhani RI, Shaw AC, Deraska DJ, Kitch BT, Vamvakas EC, Dick IM, Prince RL, Finkelstein JS: Hypovitaminosis D in medical inpatients.N Engl J Med338 :777 –783,1998 .[Abstract/Free Full Text]
Dawson-Hughes B, Harris SS, Dallal GE: Plasma calcidiol, season, and serum parathyroid hormone concentrations in healthy elderly men and women.Am J Clin Nutr65 :67 –71,1997 .[Abstract]
Burckhardt P: Calcium and vitamin D in osteoporosis: supplementation or treatment?Calcif Tissue Int70 :74 –77,2002 .[Medline]
Heaney RP: The importance of calcium intake for lifelong skeletal health.Calcif Tissue Int70 :70 –73,2002 .[Medline]
Heaney RP, Dowell MS, Bierman J, Hale CA, Bendich A: Absorbability and cost effectiveness in calcium supplementation.J Am Coll Nutr20 :239 –246,2001 .[Abstract/Free Full Text]
Heaney RP: Measuring calcium absorption by pharmacokinetic methods [Abstract].J Am Coll Nutr2 :478 ,2002 .
Mortensen L, Charles P: Bioavailability of calcium supplements and the effect of vitamin D: comparisons between milk, calcium carbonate, and calcium carbonate plus vitamin D.Am J Clin Nutr63 :354 –357,1996 .[Abstract]
Barger-Lux MJ, Heaney RP: Effects of above average summer sun exposure on serum 25-hydroxyvitamin D and calcium absorption fraction.J Clin Endocrinol Metab87 :4952 –4956,2002 .[Abstract/Free Full Text]
Scotti A, Bianchini C, Gianalfredo A, Marzo A: Absorption of calcium administered alone or in fixed combination with vitamin D to healthy volunteers.Arzneim-Forsch/Drug Res51 :493 –500,2001 .
Trivedi DP, Doll R, Khaw KT: Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial.BMJ326 :469 –474,2003 .[Abstract/Free Full Text]