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* Preliminary note on vitamin D testing: The standard way to assess your vitamin D status is to measure the blood (serum or plasma) concentration of 25-hydroxyvitamin D or 25OHD.  The latter chemical notation is conventionally written as 25(OH)D but I present it in this article as 25OHD.  I also use nanograms per milliliter, or ng/mL as the unit of measurement. European papers prefer to use nanomoles per liter, or nmol/L.  To convert from this to ng/mL, divide by 2.5; i.e., 50 nmol/L = 20 ng/mL. Multiply by 2.5 to convert from ng/mL to nmol/L.

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“Of the 30 leading causes of death in the United States in 2010, 19 have been linked to low vitamin D status, including various forms of cardiovascular disease, various cancers, diabetes mellitus, Alzheimer’s disease, and falls and fractures in the elderly. If the population of the United States were to increase their vitamin D status to 40 ng/mL, we could expect to see a potential reduction of as much as 336,000 deaths each year (out of 2.1 million deaths attributed to the diseases concerned).”

This provocative statement is excerpted from a 2015 review paper published in the Journal of the American College of Nutrition. The statement is not intended to be prescriptive. And yet, given the number of serious diseases listed and the death count potentially averted, anyone who takes his or her health seriously might be inclined to start popping vitamin D in order to meet the 40 ng/mL target.

The authors’ use of the phrase, “could expect to see a potential reduction", is a dead giveaway: the entire statement is pure conjecture. That’s because the connection between vitamin D and this plethora of health problems is based on association. And as all public health-savvy folks know, association or correlation does not mean causation. In many cases, correlation is simply coincidental, or it may be attributable to a common cause. Specific causal links can only be proven with controlled clinical trials. Until that happens, vitamin D status (as measured by the blood level of 25OHD) is really just a proxy for a healthy lifestyle that includes getting outdoors more often.

A case in point is the association between depression and vitamin D. Numerous studies point to vitamin D deficiency as a risk factor for depression, especially among the elderly. But of course blue skies alone can lift the spirit, and as I just said, clinical trials would be needed to determine if vitamin D can help curb late-life depression. An example of such evidence comes from a recent controlled clinical trial published in the 19 September 2018 issue of Clinical Nutrition.

The study enrolled 78 adults over age 60 with moderate to severe depression. Half the group was randomly assigned to a placebo, the other half to receive 50,000 IU of vitamin D3 once weekly for two months. Those receiving vitamin D3 doubled their blood 25OHD level, which rose to nearly 44 ng/mL. Compared to placebo, the vitamin D group’s depression score improved significantly based on the Geriatric Depression Scale.

This confirms the findings from a few other randomized trials. Overall, the clinical research shows that vitamin D supplementation (at least 800 I.U. daily) has a favorable impact on the management of depression, but only in studies that show a significant increase in 25OHD levels along with correction of the deficiency. It might lighten your mood to know that the size of this benefit is roughly comparable to that of most anti-depressant medications, according to an April 2014 systematic review and meta-analysis published in Nutrients.

What about links between vitamin D and the two biggest killer diseases, cancer and heart disease?  At this juncture, a great deal of clinical trial research is either under way or just being completed, and so we’re starting to get a clearer picture of the potential implications of taking vitamin D to raise 25OHD levels in the context of these diseases. Nonetheless, the necessary amassing of clinical research could take a decade or more before the medical community reaches a consensus.

One reason we need well-designed clinical trials for a disease like cancer is that even large observational studies of cancer patients can be misleading. That's because a cancer diagnosis may change plasma 25OHD levels due to the patients' getting less sun or less dietary vitamin D (eating less in general), or due to the effects of chemotherapy on vitamin D status. In these cases, the lower 25OHD levels may be a consequence of the cancer diagnosis, not vice versa. Well-designed intervention studies can avoid this pitfall, which is known as reverse causation.

At this time, we do have enough contextual knowledge from existing research to be able to make an educated guess regarding optimal vitamin D status for both specific and general health-related purposes.  At a bare minimum, it seems prudent to address vitamin D deficiency in older adults, along with attending to other known health-promoting lifestyle factors.

The central question I pose in this article is as follows. Given the best available evidence, what’s the ideal blood 25OHD level for promoting overall health as well as for addressing specific health outcomes, notably those related to cancer? In response, I highlight some key evidence and perspectives before offering tips for establishing optimal vitamin D status, with special considerations for individuals with cancer, those at risk, and those with a history of the disease.

Context Is Everything

Some three million years ago, our ancestors roamed the savannas of equatorial Africa and got all their vitamin D needs met by daily exposure to plentiful sunlight. In the savanna ecosystem, trees are widely spaced so that the canopy remains open, allowing an abundance of sunshine to bathe the plants and animals below. The human genome’s relationship with vitamin D was profoundly molded and informed by these sun-rich beginnings.

It’s safe to say that our modern-day relationship to the sunshine vitamin represents a serious departure from the Paleolithic program. Aside from the fact that most of us live far from the equator, we cover up with clothing and spend far less time outdoors. Though we may “catch some rays” during the summer, we tend to do so on a sporadic basis, often when sunlight is weakest. To help ward off skin cancer, we use sunscreen and avoid the mid-day sun. Such sun-shy lifestyle habits have contributed to vitamin D deficiency on a global scale.

I liken the public health context for vitamin D to the western world’s relationship to solar power. Solar energy technologies could ultimately supplant our reliance on oil, gas, and coal, thus helping to curb devastating climate change.  And yet, we seem terminally addicted to a fossil fuel-based economy. By analogy, many of us are blithely locked into a lifestyle that precludes adequate sun exposure and thus all but guarantees vitamin D deficiency for most of the year.

Where once we lived outdoors, many of us now spend the bulk of our days under some form of shelter from the elements. The current worldwide epidemic of vitamin D deficiency is mainly attributed to the transition from outdoor to indoor work. Shiftworkers, healthcare workers, and individuals working indoors (i.e., most readers) are especially prone to becoming vitamin D deficient.

Identity of a Star Supplement

Since 2000, there has been an explosion in scientific knowledge regarding the sunshine vitamin. Vitamin D is by far the most extensively researched of all nutrients, with well over 35,000 peer-reviewed papers published to date. And recent annual surveys by Consumer Labs indicate that vitamin D has emerged as the number one dietary supplement in the United States, unmatched in popularity for several years now.

We may think of vitamin D as a nutrient, but in its most biologically active form, vitamin D functions as a steroid hormone that binds to receptors throughout the body and affects the expression of nearly 3,000 genes. Variations in those receptors and pathways can powerfully impact how the D-hormone will influence health and wellness. The large number of genes involved suggests a role of vitamin D that extends far beyond the regulation of calcium and bone metabolism.

Although vitamin D does play an integral role in supporting musculoskeletal (bone, joint and muscle) health, it’s also a non-essential nutrient. That’s because dietary sources are not critical as long as one has adequate exposure to sunlight. Small yet significant amounts of the vitamin can be obtained from oily fish, egg yolks, liver, light-exposed mushrooms, and fortified dairy products and many milk substitutes.  

Supplementation is a different story altogether.  Many people meet their vitamin D needs with the help of multivitamins, cod liver oil, calcium supplements, and supplemental vitamin D, with per capsule doses ranging from 400 IU to 10,000 IU. With supplements, it’s possible to obtain doses of the vitamin that match the sun’s output on a summer day.

Solar Safeguards Against Vitamin D Excess

The efficiency of your body’s vitamin D production depends on the number of ultraviolet-B (UVB) photons that penetrate the skin, a process that can be curbed by excess body fat, clothing, sunscreen, and the skin pigment melanin (which turns the skin brown after tanning). Excess body fat also serves as a storage depot for the surplus vitamin D, retaining the vitamin for months at a time.

Skin pigmentation affects how much D is generated in a set amount of time. For most younger white people, a half-hour in a bathing suit under the summer sun can trigger the release of 50,000 IU of vitamin D into the circulation within 24 hours of exposure. This same amount of exposure yields 20,000–30,000 IU in tanned individuals and 8,000–10,000 IU in darker-skinned people. Those last levels I cited are at least 10 times higher than the current recommended daily allowance or RDA, for vitamin D.

Not surprisingly, given its built-in capacity to photosynthesize such large quantities of vitamin D, the human body very assiduously regulates how much of the vitamin is produced from sunlight in order to avoid toxicity. Various safeguards evolved to help keep our vitamin D levels in check.

The most basic safeguard is one I already mentioned: darker skin pigmentation, which slows the rate of vitamin D synthesis. Dark skin requires about five to six times more solar exposure than pale skin for an equivalent amount of vitamin D photosynthesis. But why would dark skin have evolved if it makes obtaining vitamin D more difficult?

It's helpful to recall that apes came before humans, so before we had dark skin, we had fur. As I discussed in my article, Benefits of Sunlight: A Bright Spot for Human Health, it is believed that early primates acquired their vitamin D requirements from frequent grooming and by ingesting oils rich in vitamin D compounds secreted by their skin onto their fur. The gradual loss of protective fur may have created evolutionary pressure to develop deeply pigmented skin, which would have curbed UV-induced destruction of micronutrients in the skin while shielding sweat glands from UV-induced injury.

To put it simply, early humans needed darker skin because they were inhabiting the sunniest part of the world. Then as now, the direct angle of equatorial sunlight delivered very strong UVB most of the year. Darker skin not only slowed the rate of vitamin D production but also afforded some degree of protection against skin cancer (such protection is even more critical for today's aging population). Back then, our problem was always one of UV excess, not deficiency. And so we adapted.

Other safeguards focus on different molecules generated by the sun’s UV rays. Whereas brief exposure to UVB radiation leads to ample vitamin D production, prolonged exposure leads to the formation of three biologically inactive forms of the vitamin—lumisterol, tachysterol, and 7-dehydrocholesterol.

An additional safeguard against toxicity is provided by the fact that any vitamin D3 surplus is itself degraded by the sun’s rays, producing yet another inactive substance called suprasterol. Thus the skin reaches an equilibrium whereby the extra vitamin D3 is degraded as fast as it’s generated in response to sunshine.

All of these safeguards against sun-induced vitamin D toxicity make biological sense in light of the tropical environment in which we evolved. Our protective design is reflected in the rarity of this problem in humans today. Indeed, toxic blood levels of 25OHD, typically 150 ng/mL or higher, seem to occur almost exclusively following large and frequent pharmacological doses of the vitamin (i.e., high-dose supplementation), not with sunlight per se.

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Assessing Vitamin D Status

The high prevalence of vitamin D deficiency worldwide has led to widespread testing in order to guide prescriptive decisions around supplemental vitamin D. Emphasis on testing and on tailored supplementation is especially strong among practitioners of complementary and integrative medicine (CIM). These practitioners prefer to combine nutrition, herbs and other natural medicines with conventional treatment strategies.

These days, most CIM physicians routinely request the 25OHD test for their patients, and many mainstream doctors have begun to follow suit. From 2000 to 2010, Medicare experienced an 83-fold increase in vitamin D blood tests, according to a 2017 New York Times report.  

There are different schools of thought as to how to best interpret your blood 25OHD level and thus assess vitamin D status. The National Academy of Medicine (formerly called the U.S. Institute of Medicine) defines vitamin D deficiency as a 25OHD level under 12 ng/mL. Once you drop below this level, you’re far more likely to show signs of the deficiency.

By contrast, the U.S. Endocrine Society defines deficiency as any 25OHD reading under 20 ng/mL, arguing that measurements in the 12-19 ng/mL range have been linked with significant bone loss in the elderly. Based on this minimum blood level, approximately 40% of the US population has a vitamin D deficiency.

The Endocrine Society also classifies the 20-29 ng/mL range as vitamin D insufficiency, since this range may predispose some individuals to various health problems. Survey data suggest that about 75% of the US population has either vitamin D insufficiency or deficiency throughout the year, making this the second most common nutritional deficit nationwide after magnesium deficiency.

This brings us to vitamin D sufficiency, as defined by a range of 30 to 100 ng/mL. This is the reference range now used by most laboratories that offer vitamin D testing, and many physicians refer to this range when advising their patients on supplementation. Applying this range, any reading below 30 ng/mL is thought to pose a potential health risk.

Of course, the Holy Grail of vitamin D research, and the primary focus of this article, is how to define optimal vitamin D status. Most experts agree that this is going to fall somewhere within the 30 to 100 range. But where exactly within that range, and what relevance does the target range have for people with cancer or other conditions? Is it even feasible to answer this question at this time?

Thresholds for Bone Health

One way to determine whether you’re getting the right amount of vitamin D is to define threshold levels for blood 25OHD that may be relevant to specific  diseases or health problems. Understanding these thresholds has major value for guiding supplementation strategies.

Much research has shown, for example, that supplementing with vitamin D to bolster bone density is more likely to be successful in individuals who have a frank deficiency (12 ng/mL or less) than in those who merely have vitamin D “insufficiency” (20-29 ng/mL).  

The osteoporosis-reversing effects of vitamin D may start with 25OHD levels as low as 10 ng/mL, or even lower. At such deficiency levels, most people will begin to see a steady reduction in the decline in bone density following high-dose vitamin D supplementation combined with calcium and vitamin K2.

Recent research suggests that supplemental vitamin D also may be critical for women at midlife with 25OHD levels less than 20 ng/mL. For perimenopausal women or other groups with higher risk of fractures and osteoporosis, maintaining a level above 20 could have important implications for long-term health.  

On the other hand, 32-35 ng/mL seems to be the upper part of the range needed to assure proper calcium homeostasis. Many studies point to this concentration when assessing the interrelations between vitamin D, calcium and bone health. Beyond the 32-35 ng/mL point, it seems unlikely that you'll derive any further boning-up benefit from vitamin D, and one study of community-dwelling older men found that both low (deficient) and high 25OHD levels may lead to more brittle bones and fractures.

Whereas the "low" 25OHD level in this study was defined as 14 ng/mL or less, the "high" cut-off was only 29 ng/mL! In other words, at or above that blood level—which the Endocrine Society ironically considers borderline "insufficient"—bone health actually showed a decline with more vitamin D added to the mix for these elderly men!  At this writing, at least three studies have found increased fracture rates among elderly people who received very high-dose vitamin D supplementation—for details, see this February 2013 paper published in an Endocrine Society journal.

Though the bone density improvements with vitamin D (together with calcium) are still quite small when compared to anti-osteoporosis drugs, supplementation with vitamin D3 can still play a key role in helping severely "D-ficient" elderly people. The effects might be further improved by the addition of vitamin K2 and other boning-up synergists. On the other hand, high "loading" doses of vitamin D2, or prolonged use of high-dose D3, may lead to more bone thinning and fractures.

Thresholds for Heart and Vascular Health

What about thresholds for cardiovascular health?  A meta-analysis of 19 prospective studies involving nearly 66,000 adults found that the risk of cardiovascular disease continued to increase in a linear fashion for decreasing 25OHD levels below 24 ng/mL. In other words, if you have a family history of heart disease, you may want to keep your blood level at or above the 24 mark.

Interestingly, the same meta-analysis found no further reduction in the risk of cardiovascular disease once 25OHD rose higher than 24 ng/mL (with a range of 16-30 ng/mL). A previous albeit cruder analysis by epidemiologist William Grant suggested that a plateau in vitamin D’s effects for cardiovascular disease risk might occur at about 43 ng/mL.

While it’s tempting to assume that substantially higher 25OHD levels may confer added protection against cardiovascular disease, there’s no evidence to support that view. Higher levels might even be harmful.  In a case-control study, South Indian men with 25OHD levels above 89 ng/mL were three times more likely to have suffered from ischemic heart disease than those with lower levels, as reported in the June 2001 European Journal of Epidemiology.

Thresholds for Fending Off Cancer

Excitement about vitamin D’s potential for cancer prevention and treatment is understandable. In laboratory studies, the vitamin has exhibited some salient cancer-fighting power—inducing cancer cell differentiation (reverting to normal cells) while inhibiting proliferation, angiogenesis, and metastasis. A lack of vitamin D could enable normal cells to transform more readily into malignant cells. In addition to having direct anti-cancer effects, vitamin D is linked to improvements in inflammation and insulin sensitivity, key factors in the genesis of various cancers.

Nevertheless, the findings from observational studies and clinical trials have been inconsistent. In 2014, a Cochrane meta-analysis that included 18 randomized clinical trials comparing supplemental vitamin D versus no intervention in healthy people found no difference regarding cancer rates between the groups. Since that time, most clinical trials have failed to show any protective effect of vitamin D against cancer development, even at daily doses of 2000 IU per day. It’s possible that the reason for these failures has to do with not taking enough of the vitamin to attain the therapeutic threshold for 25OHD.

Several key thresholds for possibly curbing or repelling cancer have been identified. A study of 3301 men and women in Japan found a threshold effect for cancer prevention starting at about 16-18 ng/mL. The main insight gleaned from this study was that no additional advantage was provided once a 25OHD level of 32 ng/mL was reached, as published online in the 7 March 2018 issue of BMJ.  

Recall that 32 ng/mL is the threshold for calcium homeostasis or bone health. It’s interesting to note that the same 25OHD level that confers benefits for bone health could also be helpful for warding off cancer. Similar conclusions were previously reached by four other studies: the ESTHER study, EPIC study, Framingham Offspring Study, and the CHANCES consortium for total cancer incidence.

In other words, below the 32 ng/mL mark, there was a steadily increasing anticancer benefit associated with increasing 25OHD. But any patients taking vitamin D after reaching the 32 ng/mL point would not show a benefit. This threshold is of special interest given the results of two controlled clinical trials in Nebraska in which postmenopausal women were randomly assigned to receive either vitamin D (plus calcium) or the placebo.


In the first trial, the women had a relatively lower 25OHD level averaging 29 ng/mL at the start of the study (i.e., baseline). This study found a significant reduction in cancer risk with supplemental vitamin D, as reported by Dr. Joan Lappe and her Creighton University colleagues in 2007.

In Lappe’s second trial, published 10 years later, the average 25OHD level was 33 ng/mL at baseline in a similar population of postmenopausal women. There was no statistically significant drop in cancer risk despite the fact that the vitamin D dose (2000 IU) was nearly twice the dose provided in the first trial (1100 IU). These findings appeared in the 28 March 2017 Journal of the American Medical Association.

Taken together, the findings suggest that women with a higher 25OHD level (above 32 ng/mL) are less likely to benefit from vitamin D supplementation compared to women with a lower level. The findings also seem to further support the idea that this threshold could represent a ceiling for cancer protection. Of course, long-term clinical trials would be needed to test this hypothesis and to determine the optimal 25OHD level for preventing cancer.

Although prospective studies of breast cancer have not provided consistent evidence for demarcating 25OHD target levels, some studies have suggested that the relationship may depend on menopausal status. A dose-response meta-analysis found that postmenopausal women (but not premenopausal women) showed increased protection against breast cancer once the blood 25OHD level reached 27 ng/mL.  

In this same study, there was a 12% reduction in breast cancer risk for women with a blood level of 32 ng/mL. At 35 ng/mL, however, a ceiling was reached with no further reduction in breast cancer risk provided by vitamin D supplementation. Previous data suggested that the ceiling or upper part of that range may be closer to 40 ng/mL.

In short, meta-analyses of cohort studies suggest there is a threshold effect of vitamin D status in terms of lowering the risk of some cancers, cardiovascular disease, osteoporosis, and all-cause mortality. The threshold range for protective effects of 25OHD is 16-35 ng/mL, depending on the disease. For postmenopausal breast cancer, the target threshold may be between 32 and 35 ng/mL, based on the above-mentioned research.

Given that the 25OHD thresholds identified in these studies represent average levels, we can expect that some women will benefit from supplementation to attain higher 25OHD levels, possibly in the 40-60 range. Once again (and forgive the broken record here), controlled clinical trial data would be needed to further clarify and refine the target blood levels for postmenopausal breast cancer and other types of cancer, as well as possibly other health-related outcomes.

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Optimal Vitamin D Status: Did Evolution Set the Standard?

Though a blood 25OHD level of 20 ng/mL may be adequate for avoiding the bone-deforming malady known as rickets, it seems wholly inadequate for supporting balanced immunity and other aspects of optimal health. The 30 ng/mL level that defines the threshold for sufficiency appears to be able to support good health, and yet substantially higher levels can be achieved in a sun-rich environment. There's ample reason to believe that those higher concentrations of the D-hormone are what’s optimal for human health.  But how high should we go?

In the absence of rigorous clinical research, I contend that exposure to sunlight should set the standard for optimal vitamin D levels. The reasoning is Bio-Logic 101: Over millions of years of evolution, our human physiology has been fine-tuned by natural selection to benefit from a certain vitamin D level. That level is most likely what we experienced when our ancestors lived in equatorial Africa for hundreds of thousands of years.  

Even random exposures to the intense tropical sun on a daily basis would’ve given us all the D-hormone we needed to support bone health, muscle strength and immune system functioning. Deficiencies were either extremely rare or non-existent. All of that changed dramatically some 100,000 years ago when humans began migrating northward.  

To approximate the vitamin D status of ancestral humans, we can take our cue from studies of tribes living in East Africa, the presumed birth place of the first humans. Two Dutch scientists, Martine Luxwolda and Remko Kuipers, traveled to East Africa to identify the vitamin D levels that most likely informed the human genome from the outset.

The Dutch researchers focused on two tribes, the pastoral Maasai and hunter–gatherer Hadza, both living in equatorial East Africa. The Maasai keep cattle and spend most of the day outside working in the sun with no sunscreen. The Hadza are also outside most of the day, either hunting animals or searching for fruits and tubers.

Both tribes have daily sun exposures that probably best approximate those of our hominid ancestors. Both wear clothing that covers the upper body and upper legs, and they tend to seek shade in the middle part of the day. All of their sun exposures take place during routine daily activities, and certainly not by sunbathing!

Based on studies of these two tribal cultures, Luxwolda and Kuipers concluded that an average serum 25OHD level of 46 ng/mL was probably most compatible with that of our hominid ancestors before their migration northward some 100,000 years ago. (If you just checked the hyperlink, remember to divide 115 nmol/l by 2.5 to get 46 ng/mL!) This level is about twice the US average of 24 ng/mL.

It bears mentioning that studies of children and adults living in Gambia and South Africa have yielded somewhat lower 25OHD levels despite frequent and robust exposures to sunlight. These measurements fall in the range of 30–45 ng/mL. As you can see, the upper end of this range just touches the 46 ng/mL level highlighted by the Dutch researchers.

If we assume that these sun-driven 25OHD levels do indeed reflect our evolutionary programming, then perhaps a range of 32-46 ng/mL may provide the best available estimate for a healthy vitamin D range from the evolutionary perspective. This assumes that moderately high intensity exposures to equatorial sunlight should help us identify the target blood levels of 25OHD for people with darker skin.  

On the other hand, perhaps our relationship with the tropical sun was one of relative moderation and self-regulation. It’s logical to assume that, back in our Paleolithic past, we would have sought shade during the hottest part of the day (just as the African tribes do today), when vitamin D production was at its peak. So even though we were getting all that intense equatorial sun, we probably found ways to temper our exposure with shade and primitive garb.

Primitive forms of sunscreen could have been used as well, thus further reducing vitamin D synthesis in the skin. According to Weston Price’s observations of the Pacific Islanders, these people were coating the surface of their bodies with coconut oil, which had the effect of absorbing the UV rays, thus serving as a natural sunscreen.

The oily coating also enabled them to shed the rain that was often torrential albeit fairly brief. Additionally, the natives believed that the solar irradiation of coconut oil on the skin provided a special source of nourishment, though it’s unclear what exactly that was.

These are just speculations of course, but given the above-mentioned research on Africans receiving generous daily doses of sunlight, an overall general range (30–50 ng/mL) may best reflect the blood 25OHD levels of our hominid ancestors living in sunny equatorial Africa.  

The more focused target range of 32-46 ng/mL could reasonably be expanded to 32-55 ng/mL, though in truth we don’t have any solid data to assess the benefits of raising the blood level above 50 ng/mL.  

Implications of the Solar-Evolutionary Benchmark

Of course, whether this range of vitamin D status is truly ideal for modern humans remains a matter of debate. It’s possible that higher levels may be optimal, but that would need to be demonstrated in clinical trials.  For example, perhaps a target level of 45-60 ng/mL would be more appropriate for people with lighter skin, i.e., Caucasians. We just don’t have the clinical data to show whether this is actually the case.

My preference for now is to trust the solar-evolutionary benchmark, with a target range of 32-50 ng/mL, and perhaps a more specific target of 45-50 ng/mL. If this target is indeed optimal, then high-dose supplementation with vitamin D may lead to chronically high 25OHD levels that are out of synch with our evolutionary heritage.  

One of the more reputable national studies of nutritional issues in the U.S. population was the Third National Health and Nutrition Examination Survey (NHANES III). That study determined that the threshold for 25OHD excess was 50 ng/mL. The lowest mortality was associated with the 40-49 ng/mL range—very much in line with the blood 25OHD levels recorded in the tribes of equatorial East Africa.  

Back in 2011, the U.S. Endocrine Society and National Academy of Medicine issued separate guidelines on vitamin D testing and treatment. The two reports differed mainly in terms of the upper threshold for which vitamin D is deemed “safe”. Whereas the National Academy of Medicine set the upper threshold at 50 ng/mL, the Endocrine Society’s guideline was exactly twice that level, at 100 ng/mL. What to make of such a whopping disparity? Perhaps the truth lies somewhere in between?

We know that long-term, high-dose supplementation with vitamin D can lead to blood levels above 150 ng/mL, the toxic threshold. The classic sign of vitamin D toxicity is abnormally high blood calcium levels, also known as hypercalcemia. This is accompanied by bone loss, calcification of blood vessels and the kidneys, as well as an array of symptoms, including fatigue, weakness, muscle pain, headaches, brain fog, confusion, depression, nausea, constipation, thirst, and frequent urination.

So what might be the consequences of raising your blood 25OHD levels above, say, 50-60 ng/mL yet still below the toxic threshold (150 ng/mL)? Is there any potential downside to maintaining blood levels that are substantially higher than what most people can attain with a robust yet tempered amount of sun exposure (taking skin cancer risk into consideration) and/or supplementation?  

There is increasing evidence that these higher yet non-toxic blood levels have the potential to cause harm to people either diagnosed with cancer or at risk of developing cancer. I’ve seen enough studies to warrant some degree of caution, even with regard to blood levels that some claim would be therapeutically beneficial. I’ll return to this concern shortly.

The Kidneys: Too Much Solar "Fire"?

Before going further, it's helpful to consider the vitamin D research on high-level exposures to sunlight.  In 1971, Haddad and Chyu reported that tropical lifeguards who sunbathed year-round had a 25OHD level averaging around 64 ng/mL. This level was about two and a half times higher than that of the “normal” population they sampled.

To date, the highest known 25OHD level achieved by sun exposures alone for a single individual was a farmer in Puerto Rico, who had a reading of 90 ng/mL. Claims can be found online for sun-induced 25OHD levels higher than 100 ng/mL for tropical farmers and lifeguards, but these claims are unsubstantiated (anyone can make claims).

But let’s assume the internet does post occasional anecdotal truths, and that tropical farmers and lifeguards can indeed achieve 25OHD levels ranging from 60 to 100 ng/mL. If such profuse sun exposures can yield such high blood levels, is this really a good thing?

When we consider the hunter-gatherer data from East Africa, it seems more likely that the higher levels found in tropical farmers and lifeguards could reflect excessive sun exposure in lighter skinned individuals (who can pump out more vitamin D in a shorter period of time).  

When you consider situations in which getting lots of sunshine is a daily reality, lifeguarding is probably among the professions that comes to mind. It turns out that lifeguards may be more prone to the excruciating problem known as kidney stones. Lifeguards in Israel are diagnosed with kidney stones at a rate 20 times higher than the general population. A likely explanation for this association is that high blood 25OHD levels tend to raise calcium levels in the blood and urine. Dumping more calcium into the urine increases one’s chances of producing the calcium-rich crystals that cause so much agony in these unfortunate individuals.

In Traditional Chinese Medicine, life-energy or "Chi" (pronounced Chee) undergoes various transformations, each of which is represented by a different element and corresponding organs. The kidneys (Water element) are closely related to the heart (Fire element). Any "disharmony" between the Fire and Water elements may indicate a pathological state in the kidneys and bladder. Perhaps too much sunshine contributes to "excess Fire", and kidney stones could very well be among the consequences of this energetic imbalance.

Given that kidney stones are a good indicator of excessive 25OHD levels, we should not assume that being out in the sun all day to spike vitamin D levels has uniformly favorable consequences. And aside from exacting a toll on the kidney’s delicate tissues, 25OHD levels exceeding 40 ng/mL may lead to calcium accumulations in the blood vessels (vascular calcification), which is strongly associated with death from cardiovascular disease.

On the other hand, exposure to the sun causes both skin cancer and vitamin D production, a solar Catch-22 if you will. In this vein, it’s fascinating to note that sun-induced 25OHD levels may help ward off basal cell carcinoma and possibly other forms of skin cancer. A clinical trial found that among women with a history of keratinocyte cancers, better vitamin D status increased protection against melanoma. In other studies, low levels of 25OHD were associated with more aggressive cutaneous malignant melanomas and a poorer prognosis.

These findings suggest the body’s photosynthesis of vitamin D may have evolved in part to protect against skin cancers. But of course there’s a limit, as too much sun exposure will cause skin cancer and override the protection that might be afforded by vitamin D synthesis in the skin. This suggests that we’re not designed for day-long intensive sun exposures.

The take-home lesson is that moderation applies to the sun as well. A health-conscious lifestyle with moderate recreational sun exposure (weekends, holidays) seems to lower the risk of hip fracture, type 2 diabetes, fatal heart attack, and early death. This seems to be the most prudent public health advice on how to reap the sun's benefits.

Intriguingly, as an aside, supplementing with vitamin D does not appear to provide the same degree of protection, and some research suggests that both low and high vitamin D intakes may even predispose to basal cell carcinoma, the most common form of skin cancer.  This brings us to the concept of a more balanced, intermediate range for 25OHD.

Finding the Middle Way

Evidence from some observational studies suggests the possibility of a U-shaped pattern of association between vitamin D levels and various diseases. Graphically, this means that both low (deficient) and high (excessive) 25OHD levels may be linked with a range of health problems, notably higher rates of falls, fractures, heart attacks, and various cancers.  

The risk of dying—especially from heart disease—has been shown to follow this U-shaped pattern. For example, a study led by Dr. Kenneth Christopher found that patients admitted to two hospitals in Boston had significantly higher 90-day mortality rates for 25OHD concentrations less than 30 and greater than 60 ng/mL (see Figure 2 in this paper).

A particularly impressive example comes from the previously mentioned NHANES III, a large study involving 13,331 adults and representing approximately 175 million people in the United States. The all-cause mortality rate was highest for those with 25OHD levels either below 30 or above 50 ng/mL.

This U-shaped pattern also shows up in various cancers. Most of the evidence for this pattern has focused on cancers of the breast, colon, prostate, esophagus, and pancreas. For example, in the Malmö Diet and Cancer Study, women with either low or high blood levels showed at least a doubling in their risk of dying from breast cancer. Low 25OHD levels were classified as 30 ng/mL or less, while high levels were 40 ng/mL or more, as reported in the September 2014 issue of Cancer Causes and Control.

A similar U-shaped pattern was seen in a community-based prospective study of elderly men living in Sweden, Finland and Norway. Death from cancer occurred twice as often among men with the lowest 10% and nearly three times as often among those with the highest 5% of 25OHD levels. In this study, the lowest cut-off point was 17 ng/mL or less, while the highest cut-off point was 40 ng/mL or more, as reported in the October 2010 American Journal of Clinical Nutrition.  

In the Nordic study just mentioned, the lowest risk of prostate cancer was in the relatively low and narrow range of 16-24 ng/mL. These findings are consistent with several other studies’ findings. Thus it appears that the optimal vitamin D intake and 25OHD levels for prostate cancer may be lower than for other cancers, such as colorectal cancer.

In a 2017 meta-analysis of studies on colorectal cancer, there was a dose-response protective relationship for 25OHD levels up to concentrations of about 55 ng/mL. Beyond that point, however, the likelihood of being diagnosed with colorectal cancer increased. The authors concluded that the protective effect of vitamin D seemed to be lost as the blood 25OHD level increased within and beyond the 50-60 ng/mL range.

Some studies of pancreatic cancer also suggest a U-shaped pattern, though the data are highly variable. Among male smokers in Finland, higher 25OHD levels were linked with a tripling in the rate of pancreatic cancer. Notably, there was a dose-response relationship between increasing concentrations of 25OHD and the risk of developing pancreatic cancer. Similarly, the Vitamin D Pooling Project of Rarer Cancers found a doubling in pancreatic cancer risk for 25OHD levels above 40 ng/mL.

In summary, there is increasing evidence for an optimal blood level of vitamin D that is neither too high nor too low for averting cancer and other diseases and health problems.  Overall, it would seem that a range of 50 ng/mL or higher represents a potential cautionary zone for people who engage in long-term supplementation. The threshold for protection appears to be substantially lower for both prostate cancer and pancreatic cancer.

As an aside, the U-shaped pattern also holds true for other lipid-soluble nutrients, including vitamins A and E and beta-carotene. Lipid-soluble means these substances can be stored in fatty tissues. For example, high-dose supplementation with vitamin E may lead to increased rates of stroke, heart failure and total mortality.  On the other hand, deficiencies of this same antioxidant are linked with increased mortality rates as well. Similar concerns have been voiced for beta-carotene supplementation, with both high and low levels promoting cancer mortality (lung and stomach) in smokers and asbestos workers.

Can Too Much Vitamin D Promote Cancer?

How do we explain the U-shaped pattern with cancer, and in particular the risk associated with chronically elevated 25OHD levels?  A number of explanations have been offered for the possibility that high doses of vitamin D and maintaining higher blood levels on an ongoing basis may adversely affect the biology of a person with cancer.

First, as a matter of basic biological principle, the U-shaped relationship makes intuitive sense when we think of how hormones typically function and are regulated within the body. Levels that are either too low or too high are generally undesirable; a narrow range in between is considered ideal. Since vitamin D acts as a hormone, one would expect there to be an optimal range of blood 25OHD concentrations in which the pre-hormone form (25OHD) has a more balanced, biologically appropriate impact on our health and physiology. Excessive levels, on the other hand, could prove undesirable.

It now appears that there may be some valid cancer-related reasons for being concerned about the high 25OHD levels, or what I refer to as vitamin D excess. What follows is a quick summary of potential connections between vitamin D excess and the development and progression of cancer.

• Aging/growth factor production. Aging and cancer are closely related phenomena. Experimental studies have shown that excessive vitamin D can cause premature aging in laboratory animals, changes related in part to an effect of vitamin D on various growth-stimulating pathways that may fuel tumor growth and progression.
• CYP24. Many cancer cells produce an enzyme called CYP24, which stimulates tumor growth while also breaking down vitamin D. At the same time, vitamin D metabolites are known to stimulate the production of this protein within cancer cells.‍
• VDR. Most of the anticancer effects of vitamin D seem to be mediated by the vitamin D receptor (VDR).  Variants or polymorphisms in the VDR have been linked with a poor prognosis for different cancers, and high vitamin D levels may interact adversely with some polymorphisms.‍
• Bile acids. High vitamin D levels can suppress or inactivate the farnesoid X receptor that detoxifies cancer-causing bile acids. This in turn leads to an accumulation of those toxic bile acids in the colon, potentially contributing to colorectal cancer in the context of a Western Diet.
• Osteocalcin. Vitamin D induces osteocalcin, which is expressed in pancreatic cancer cells and increases their growth, proliferation, and invasion. Osteocalcin is also linked with the development of bone metastases.
• Th2 Immune Imbalance. Excessive vitamin D3 may promote an imbalanced immune response that’s accompanied by a worsening of allergic conditions. This shift may be explained by vitamin D's role in altering the Th1–Th2 balance in favor of pro-inflammatory Th2 cells. This Th2 imbalance leads to a reduction in anticancer immunity as well as increased inflammatory signals that support cancer’s growth and progression. In essence, when the immune system is skewed or polarized toward the Th2 response, cancer can grow unchecked.
  

Taken together, the above mechanisms could help explain some of the U-shaped associations between vitamin D status and cancer risk, and in particular why some studies have found a link between high concentrations of 25OHD and an increased cancer risk. In some cases, multiple mechanisms may be active at the same time.

Research Relevant to the High-Dose D Debate

I confess that it’s not easy finding good studies of high blood 25OHD levels and their effects on cancer-related outcomes, such as prognosis, mortality or survival. But there are many studies out there. For our present purposes, we will focus mainly on breast cancer and colorectal cancer, since we have systematic reviews for both. Let's start with some individual studies.

One study found a high pre-diagnostic intake of vitamin D supplements associated with a 47% higher death rate from breast cancer, as reported in the December 2014 issue of Maturitas. The fact that the 25OHD measure was taken before the diagnosis is not particularly important here, though ideally one would also want to have another test taken before and after treatment.

Another study showed that the median level of 25OHD was significantly higher in breast cancer patients with metastasis compared to those with earlier or non-metastatic stages of the disease, as reported in the June 2011 Asian Pacific Journal of Cancer Prevention. In truth, however, the data are too mixed in terms of negative prognostic factors like metastases, and it’s unclear as to why there’s so much inconsistency.

What about the results from meta-analyses considering the potential impact of higher levels of 25OHD versus lower levels?  At first glance, you might be led to believe that higher levels are good, while lower levels are bad. But that would be a serious oversimplification and misreading of the evidence to date.

Two recent meta-analyses, both published in 2018, show just how misleading a cursory “sound byte” approach can be when considering research on the impact of vitamin D status on cancer survival.  Both of these analyses concluded that the lowest levels of 25OHD had the highest mortality compared to the highest levels. When you look more closely, however, you realize that the “high” 25OHD measures were not very high at all.

The first meta-analysis involved six cohort studies and found a linear relationship between increasing 25OHD levels and reduced overall mortality after the breast cancer diagnosis.  At or above 9 ng/mL (the low threshold), the risk of dying decreased by about 14% for every 10 ng/mL increase in 25OHD. Thus, at 19 ng/mL, the mortality rate decreased by 14% and at 29 ng/mL, it decreased by 28%.  

Again, looking more closely, we see that the highest 25OHD levels in three of the six studies were 38, 49, and 75 ng/mL. These higher levels were only estimates and thus were deemed unreliable, as reported in the June 2018 issue of Integrative Cancer Therapies. Therefore, when viewed in terms of reliability, the “high” readings in these studies did not even exceed the mid thirties!

What about colorectal cancer?  Several impressive meta-analyses have shown improved survival with higher blood 25OHD levels. The most recent of these was a dose-response meta-analysis that included 11 studies of over 7,000 colorectal cancer patients. As expected, the researchers found an improvement in overall and cancer-specific survival with increasing blood 25OHD levels.  But what do we know about those higher 25OHD levels?

Overall, the lowest 25OHD cut-off category in these studies was between 2 and 30 ng/mL, while the highest 25OHD cut-offs ranged between 13 and 75 ng/mL. That upper part of the latter range sounds impressive until you realize the majority of studies only showed an improvement with 25OH levels above 10 to 20 ng/mL!  In other words, it doesn’t take much 25OHD to have an impact, and these studies were not especially designed to examine the potential impact of higher levels (say, in the 50-75 ng/mL range).

Speaking to that point, a randomized controlled trial of patients with metastatic colorectal cancer is underway in Canada. This study has randomly assigned  patients into a standard vitamin D dose of 2000 IU versus higher doses.  The goal is to allow cancer patients to raise their blood 25OHD levels up to 80 to 100 ng/mL during a 16-month period. It will be very interesting to see what impact, if any, these higher blood levels might have on survival and other outcomes.

In the absence of this more rigorous clinical trial data, it seems likely that moderately high levels of 25OHD may be helpful following a diagnosis of breast or colorectal cancer. But again, we don’t know what the anticancer benefits are, if any, for these somewhat elevated levels, let's say 55-70 ng/mL (a somewhat arbitrary choice for a range). We certainly lack research support for the 80-100 ng/mL range that many practitioners are aiming for as a therapeutic or remission maintenance target.

As noted earlier, numerous studies suggest cancer-countering effects of moderate levels of 25OHD—levels often referred to in these studies as “high” or “higher” simply because they’re being compared to deficiency levels. Again, simplistic conclusions can be misleading, perhaps perilously so. One needs to look carefully at the study’s “higher” 25OHD levels before saying whether they are truly “high” or in reality just moderate.  

Given the potential for the adverse effects I discussed in the preceding section, an approach based on the precautionary principle may be best. This risk-minimizing perspective means avoiding very elevated 25OHD levels, at least on an ongoing or chronic basis. The possibility that those higher levels could be harmful after the cancer diagnosis should hold sway over any wishful thinking from a “more is better” perspective.

What Some in the Medical Profession Are Saying

Everyone has their biases and opinions, me included. My pet peeve about vitamin D is that it's more often treated as a nutrient than as a hormone, and thus we've tended to assume that more is probably better. Over the years, I’ve heard many nutrition-literate doctors say we need to supplement with an amount of D3 that enables us to reach the 60-100 ng/mL range. And yet again, as far as I know, there’s no evidence that striving to achieve these higher 25OHD levels is going to reap major dividends (with the exception of muscle pain relief in some cases).  

Against this backdrop, clinical judgment has come to rule the day. Clinical judgment is developed mainly through a doctor’s experience, practice, knowledge and ongoing critical analysis.  Ideally, that analysis would be based on repeated observations with hundreds of patients over time. The physician would then compare these patients to another group of patients who did not receive any vitamin D. This kind of practice is obviously beyond the scope and capacity of any single physician or medical office.

A high-profile example of how clinical judgment plays out comes from osteopathic physician Joseph Mercola, who runs a popular alternative medicine website. In a 2017 article, Mercola states the following: “If you've followed the progression of vitamin D science, you will be aware of the fact that recommended vitamin D levels—and the dosages typically needed to achieve those levels if you're not getting regular sun exposure—have dramatically risen over the years.”

It’s a curious statement, because it implies that the higher blood levels are scientifically validated and grounded in solid research. And yet, Mercola insists that any 25OHD level below 50 should be regarded as a deficiency, while the “optimal” range is 50 to 70 ng/mL. Moreover, he contends that the range needed to treat cancer and heart disease is 70 to 100 ng/mL.

This same line of thinking was echoed at several integrative medicine conferences I attended in recent years. Speakers said repeatedly that 50 ng/mL should be the minimally acceptable 25OHD level for optimal vitamin D status, and that much higher levels are needed to realize a therapeutic impact of the vitamin. Again, however, there’s really no science to back up these assertions.

The only reliable way to determine the optimal 25OHD level would be to conduct a randomized controlled trial with varying supplemental doses of vitamin D in relation to specific blood levels of 25OHD. Different levels of supplementation and 25OHD would then be assessed in relation to health outcomes such as fracture rate, insulin resistance, blood sugar control, cancer, and cardiovascular disease. Large numbers of participants will be needed with low 25OHD levels at the start of the study.  It could be a very long time, at least a decade or more, before enough of this kind of evidence is available.

On the other hand, as I showed previously in this article, there is increasing scientific support for raising the 25OHD level to 32-45 ng/mL. This range is not only linked with better cancer control, but also may lead to optimal bone health (bone mineral density) by maximally increasing calcium absorption while also maximally suppressing parathyroid hormone (which leaches calcium from the bone when 25OHD levels are too low).  The lower part of this range seems especially effective for bolstering bone health.

Moreover, in recent randomized trials, vitamin D supplementation was shown to reduce insulin resistance in healthy, obese and diabetic individuals. The most powerful effects were seen in those who raised their 25OHD level to 30-32 ng/mL or higher. Unfortunately, these studies were not designed to identify the upper part of the 25OHD range whereby the insulin-sensitizing benefits might start to diminish, or whereby heart disease risk might increase due to calcification of the blood vessels.
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Metabolic Insights: Another Angle on the Optimal Range

To understand the body’s vitamin D needs, it’s helpful to have a basic idea of how the vitamin is metabolized. Vitamin D undergoes two key hydroxylations (enzyme-mediated chemical reactions) before it becomes the active hormone. The first conversion occurs in the liver and yields 25OHD (calcidiol), which is the form measured by the standard vitamin D test. The circulating 25OHD then undergoes a second conversion in the kidneys or in target tissues to produce the hormonally active form, calcitriol.

We now know that vitamin D saturates its liver activation enzymes (hydroxylases) when 25OHD levels reach 35 ng/mL. This also appears to be the point at which vitamin D (as 25OHD) accumulates within the body, both in serum and probably in body fat. Such accumulation could indicate that the body has reached a certain threshold in meeting its needs. Body fat itself serves as a kind of buffer against vitamin D excess, at least for a while.

My concern here focuses on two groups of breast cancer patients: lean postmenopausal women and overweight (or obese) premenopausal women. Even more specifically, my concern lies with cases of latent or undiagnosed breast cancer. Keep in mind that cancer can grow in the body for a decade or more before it can be detected.

First consider the lean women who are supplementing with vitamin D. Leaner bodies are less able to store the surplus 25OHD. It seems likely that if these women keep their blood levels much higher than 35 ng/mL (see second paragraph, above, on liver activation enzymes) on a frequent basis, they may be more prone to the aforementioned problems associated with vitamin D excess. Though we don’t yet have the research to test this hypothesis, we do have a supplementation study with suggestive results.

Among postmenopausal women who had never received hormone therapy, vitamin D supplementation was associated with a 51% increase in breast cancer risk in women with a lean body composition, as assessed by a BMI under 25, but not in women with higher BMI. This risk was even higher (62%) in the leanest women, those with a BMI under 22. This may suggest a potential adverse interaction between vitamin D and low estrogen levels.  Unfortunately, no 25OHD measures were reported.

On the flipside, overweight women could also be at risk once their adipose tissue stores of vitamin D become saturated, as reflected by high blood levels. In the Nurses’ Health Study II, higher 25OHD levels in overweight (high BMI) women were linked with an increased breast cancer risk, as reported in the 11 May 2011 issue of Breast Cancer Research. The relationship was not seen in women with a normal BMI.

As an aside, Drs. Michael Holick and Bruce Hollis, both respected vitamin D researchers, propose that we should base optimal vitamin D needs on three criteria: (1) vitamin D status of African tribes exposed to year-round sunlight at the equator;  (2) the point at which parathyroid hormone concentrations are lowest, thus when vitamin D ceases to be a limiting factor in calcium absorption; and (3) the blood 25OHD level that a breastfeeding mother needs to support her infant’s health.  

Intriguingly, all three of these criteria converge on a blood 25OHD level of 48 ng/mL. This level, combined with the enzyme saturation level mentioned above (35 ng/mL) and the previously discussed anticancer thresholds and measurements of the East African tribes living at the equator, suggest that a reasonable target range for optimal vitamin D status may be between 32 and 55 ng/mL. For now it would seem that maintaining a level above that range may be a roll of the dice.

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The Sunny Side of Vitamin D

Optimizing your vitamin D levels can be an important step toward supporting your long-range health.  Probably the healthiest way to do this is by exposing large amounts of skin to sunlight or a safe tanning bed.  If either of these is not an option, then orally supplementing with vitamin D3 is the best way to go (see next section).

How does the body generate vitamin D? Upon absorbing the sun’s UVB rays, cholesterol molecules in the skin can churn out a surfeit of pre-vitamin D, which then undergoes conversions in the liver and kidneys before becoming the hormonally active form of vitamin D, which is called calcitriol or 1,25-dihydroxyvitamin D3.

Our bodies generate more vitamin D when we’re outside with skin exposed in the middle of a summer day, generally between the hours of 10 AM and 3 PM. Depending on various factors, your body can produce adequate amounts of vitamin D with relatively moderate sun exposure to the face, arms and legs.  

During the warmer months of the year, you can get enough D by averaging 5–30 minutes of sun exposure twice weekly, or approximately 25% of the time needed for your body to develop a mild sunburn. The older you are, the weaker the sunlight and darker your skin, the more time you will need to be out in the sun.

Generally speaking, people with black and brown skin need two to three times more time in the sun than white people in order to achieve a similar level of vitamin D synthesis.  Thankfully, the extra skin pigment (melanin) increases the degree of protection

Your location on the planet does play a role in how much vitamin D can be generated from sun exposure, but this role is not as critical as once thought. Many experts have asserted that sunlight may be inadequate for vitamin D synthesis during the winter at latitudes above 37 degrees (i.e., for us East Coast folk, that’s from Richmond, VA, and on northward).  

But a far more relevant factor now appears to be clothing, or how much we cover up to keep warm in the higher latitudes. People living in more tropical or semi-tropical areas tend to wear less clothing when they go outdoors, hence the tendency to have higher vitamin D levels. But even folks living in the sunny tropics will become vitamin D deficient if they cover up all the time.

Practical Pointers and Rules for the Road

When blood 25OHD levels drop below 30, most doctors and dietitians will prescribe vitamin D2 at a dose of 50,000 IU per week for eight weeks. After this phase, many people elect to supplement on their own with vitamin D3, the more efficacious form, using doses ranging from 400 to 10,000 IU.  In some cases the dosage choice is made based on the interpretation of test results; in other cases, it’s either an educated guess or a stab in the dark.

In this section, I hope to provide some clarity as to a course of action for enhancing and maintaining your vitamin D status.

First off, in temperate regions of the planet, supplementation with vitamin D3 is most important in wintertime, a period when it’s impossible to produce vitamin D through sun exposure in many northern areas. I generally don’t advise people to take D3 during the summer unless they’re not getting out in the sun for days at a time.

Vitamin D can bolster bone health as long as other boning-up factors are present. Recent research suggests the best way to counteract bone and muscle loss after menopause entails a combined strategy of dietary protein, vitamin D and calcium, all in the context of a carefully designed exercise training program.

DHEA, a steroid hormone sold as a dietary supplement, might further improve outcomes for bone and muscle health as we age. There is some evidence that vitamin D can help improve bone density when combined with supplemental calcium and DHEA. DHEA mainly seems to benefit older or elderly individuals with low serum DHEA-sulfate levels, preferably done in tandem with weight-bearing exercise. (Note:  DHEA should only be taken at night, never earlier in the day.)

There is good evidence that high-dose vitamin D will exert toxic effects when vitamins K2 and A are in short supply. Therefore, you should always take vitamin D3 together with vitamin K2, and at the same time consume a plant-based diet that contains lots of carrots, squashes, and dark leafy greens such as kale, collards, and swiss chard. Such a carotenoid-rich diet would generally provide ample amounts of vitamin A.  It is also possible to get a supplement that contains the three vitamins all in one.

One additional caveat about taking vitamin D3 relates to the fact that it’s fat-soluble. To improve the vitamin’s assimilation, take it with some healthy fats, such as nuts, avocado, or olive oil. Taking the supplement at the beginning of a meal is ideal, but if you forget to do so, you can always take it during the meal or even afterward.

Should you be getting your 25OHD level checked, and if so, how often? A baseline vitamin D test can confirm suspicions of either gross deficiency or vitamin D excess (60 ng/mL or higher), which is not uncommon.  

But does everyone need to get tested? Not necessarily. If you’ve had a bone density test and know that your bones are in great shape, and if you've taken steps to maintain good vitamin D status (e.g., getting out in the sun and taking vitamin D3 fairly often), I don’t think testing is necessary. But of course there are many potential mitigating factors to consider.

Your health care practitioner may have specific reasons for wanting your vitamin D status checked. Testing can take place once or twice a year. The best time for testing is in the early spring. Remember that your 25OHD levels are likely to be lower in winter and early spring, higher in summer and early fall, assuming you get outdoors enough.

In my view, however, this blood test is being overused and often in an unprincipled manner.  Part of the problem is that many people are aiming for excessively high blood 25OHD levels. Again, I contend that the “solar benchmark” target range should be 32-55 ng/mL, not 60-100 ng/mL, as many people are currently aiming for.

In my opinion, most healthy individuals do not need to get retested unless the following are true: (a) they haven’t exposed their bodies, unprotected, to the mid-day sun for 15 to 30 minutes during the summer, (b) they never take supplements containing vitamin D; and (c) they rarely consume fatty fish, egg yolks, or D-fortified foods.  

Failing to meet these criteria, getting retested once a year, in late winter or early spring (March-April), should be adequate. On the other hand, if you have obvious bone health issues such as osteopenia or osteoporosis, or if you’re at high risk of developing these diseases, then testing on an annual or biannual basis is a must. People with a diagnosis or history of cancer should also get retested once a year.

In general moderate supplementation is best because you can readily “overshoot” ideal levels of vitamin D or unknowingly exceed your adipose (body fat) storage capacity. Blood levels may not necessarily reflect the body’s total vitamin D stores or status, especially in obese or overweight individuals.

For most individuals, the “solar benchmark” target range (32-55 ng/mL) can be achieved with a moderate course of vitamin D3 supplementation: 1,000-2,000 IU per day for a few months before taking a break.  According to the U.S. Endocrine Society, 1,500-2,000 IU is the minimum daily dose needed to raise your 25OHD above 30 ng/mL.  

Now, to raise the 25OHD level from, say, the typical US average of 25 ng/mL to a target level of 50 ng/mL, the typical adult, weighing around 170 pounds, needs to take about 4000 IU.  A heavier adult (over 200 pounds) might use 5000 IU instead.

Assuming you’re willing to get tested once or twice a year, you might consider the following basic suggestions, which may apply to the majority of U.S. adults:

• Insufficiency (20-29 ng/mL) may warrant 4,000-5,000 IU’s daily to reach and maintain the 45-50 ng/mL target.
• Gross deficiency (under 12 ng/mL) may warrant 8,000-10,000 IU daily until reaching the target range (up to 3 months)
• If you decide to forgo testing, 2,000 IU daily is a reasonable strategy for most healthy people who get outdoors often.  
• Safest long-term dose without testing is 1,000 IU, or between 800 and 1,200 IU.
• If you’re resistant to taking supplements, then 8,000-10,000 IU a few times a week may be effective.

The second to last suggestion may be most important from the standpoint of safety. Without testing, it’s best not to exceed 1,200 IU daily over the long term, especially if you regularly get out in the sun and also consume fortified foods and beverages (of which there are an increasing number). The consequences could include altered immune system functioning and dangerous accumulations of calcium in the soft tissues of your heart and kidneys.  

If you’re seriously lax about taking supplements, you could take 40,000 to 50,000 IU once a week (like on a Sunday, since that day’s name is a good reminder) until you reach the target range. Keep in mind, though, that this once-a-week strategy is not as effective as daily supplementation with vitamin D3.

Once your blood 25OHD reaches 50 ng/mL, I would encourage you to stop taking vitamin D.  If you’re overweight, you can generally coast on these higher levels for two to three months.  With a lean body, however, you can coast only for a few weeks at most before returning to regular supplementation. Ideally you would get retested at this time.

Toxicity is possible—albeit exceedingly rare—if taking more than 10,000 IU per day for three months or longer. But as I’ve tried to emphasize in this article, it’s not just toxicity that we need to watch out for. Chronically high 25OHD levels (above 55-60 ng/mL) could have a number of adverse effects that translate into worsening outcomes for individuals with cancer, or those at risk.

One last point is that diet and lifestyle habits will further reinforce your vitamin D status. Eating whole fish, shellfish, organ meats, and eggs would provide additional support, though these vitamin D sources pale in comparison (pun intended) to what the sun can provide. Regular doses of mid-day sunlight and periodic supplementation with vitamin D3 will obviate the need for repeated vitamin D testing and will help curb anxiety about potential toxicity or untoward effects.

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And Finally, In Closing...

Many people throughout the United States are currently taking vitamin D, often with the goal of achieving 25OHD levels that may be abnormally high from an evolutionary and evidence-informed perspective. Still many others are taking it without any testing at all. Only in the past two decades have so many humans begun ingesting such high doses of vitamin D, setting the stage for a massive, uncontrolled public health experiment. Though most people may not be hurt by chronically high yet non-toxic blood levels, there is the potential for harm to certain segments of the population.

Individuals with cancer or with a history of cancer could be among those at risk. For these brave individuals, the belief that vitamin D confers cancer-fighting benefits regardless of one’s blood level often leads to using high doses for extended periods of time. Both the Endocrine Society and Vitamin D Council have set the upper tolerable limit at 10,000 IU, and thus many cancer patients are adopting this higher dose in the hope of becoming and staying cancer-free.

Those with active disease may continue to supplement at this level until the cancer shows signs of abating. The motivation to do this is understandable—everyone wants a survival advantage—but could there be a serious downside that has slipped beneath the medical radar?  By maintaining the 60-100 range, could some individuals be missing out on the benefits of moderate 25OHD levels (see earlier section, “Thresholds for Fending Off Cancer”) while enabling the disease to advance?

Though the research I’ve presented in this article is not bulletproof and to some extent cherry-picked (systematic reviews notwithstanding), there are grounds for concern. Certainly the common practice of prolonged high-dose vitamin D supplementation merits scrutiny.  The assumption that more is better simply may not hold true when it comes to taking vitamin D in the context of cancer control and therapy. (This is especially true when using vitamin D to counteract the bone loss that accompanies many conventional treatments; it may also hold true when using the vitamin synergistically with certain chemotherapies, though that's thankfully more of a short-term situation in most cases.)

Again, we know what levels of vitamin D constitute outright toxicity.  What we don’t know is what levels are excessive and might lead to immune imbalances (see earlier discussion on Th2 polarization) that inadvertently fuel the growth and progression of cancer. It’s what we don’t know that can harm us in the end. It’s what we don’t know that should give way to a more precautionary approach to the hormone replacement therapy we call vitamin D supplementation.

Once we begin looking at the health implications of achieving 25OHD levels above 45-55 ng/ml, we enter the realm of conjecture. Evidence to support strategies to achieve these higher levels is just too scant to draw even the most preliminary conclusions. Higher levels could be better but could also be worse, even potentially promoting disease down the road.

To be on the safe side, let’s hold fast to the middle way, the way of balance and moderation. Since the key determinant for guiding vitamin D supplementation decisions is the serum 25OHD level, I favor the “solar benchmark”  of 45-50 ng/mL as the optimal target range, within the wider target range of 32-55 ng/mL, at least until we have sufficient clinical trial data that says otherwise. If you have cancer, your best option may be to attain this range by getting outdoors on a regular basis and/or taking vitamins D3 and K2 as needed.

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If you have questions or would like to schedule an integrative cancer coaching session, please reach out.

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© 2019 Mark Nathaniel Mead, MSc.

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Key References

Autier P, Mullie P, Macacu A, Dragomir M, Boniol M, Coppens K, Pizot C, Boniol M. Effect of vitamin D supplementation on non-skeletal disorders: a systematic review of meta-analyses and randomised trials. Lancet Diabetes Endocrinol. 2017 Dec;5(12):986-1004.

Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Wetterslev J, Simonetti RG, Bjelakovic M, Gluud C.  Vitamin D supplementation for prevention of mortality in adults. Cochrane Database Syst Rev. 2014 Jan 10;(1):CD007470. doi: 10.1002/14651858.CD007470.pub3.

Bolland MJ, Grey A, Avenell A.  Effects of vitamin D supplementation on musculoskeletal health: a systematic review, meta-analysis, and trial sequential analysis. Lancet Diabetes Endocrinol. 2018 Nov;6(11):847-858

Cantorna MT, Mahon BD.. D-hormone and the immune system. J Rheumatol Suppl 2005; 76:11-20

Chiba A, Raman R, Thomas A, Lamy PJ, Viala M, Pouderoux S, Mott SL, Schroeder MC, Thezenas S, Jacot W. Serum Vitamin D Levels Affect Pathologic Complete Response in Patients Undergoing Neoadjuvant Systemic Therapy for Operable Breast Cancer. Clin Breast Cancer. 2018 Apr;18(2):144-149

Cranney A, Horsley T, O'Donnell S, Weiler H, Puil L, Ooi D, Atkinson S, Ward L, Moher D, Hanley D, Fang M, Yazdi F, Garritty C, Sampson M, Barrowman N, Tsertsvadze A, Mamaladze V.  Effectiveness and safety of vitamin D in relation to bone health. Evid Rep Technol Assess (Full Rep). 2007 Aug;(158):1-235.

Eslami O, Shidfar F, Akbari-Fakhrabadi M.  Vitamin D and Cardiorespiratory Fitness in the General Population: A Systematic Review. Int J Vitam Nutr Res. 2018 Nov 30:1-12. [Epub ahead of print]

Gallagher JC.  Vitamin D and falls - the dosage conundrum.  Nat Rev Endocrinol. 2016 Nov;12(11):680-684.

Goulão B, Stewart F, Ford JA, MacLennan G, Avenell A.  Cancer and vitamin D supplementation: a systematic review and meta-analysis. Am J Clin Nutr. 2018 Apr 1;107(4):652-663.

Grant WB, Karras SN, Bischoff-Ferrari HA, Annweiler C, Boucher BJ, Juzeniene A, Garland CF, Holick MF. Do studies reporting 'U'-shaped serum 25-hydroxyvitamin D-health outcome relationships reflect adverse effects?  Dermatoendocrinol. 2016 May 16;8(1):e1187349.

Haddock L., Corcino J., Vazquez M.D. 25 OHD serum level in the normal Puerto Rican population and in subject with tropical sprue and parathyroid disease. Puerto Rico Health Sci. J. 1982;1:85–91

Heaney RP, Armas LA, Shary JR, Bell NH, Binkley N, Hollis BW. 25-Hydroxylation of vitamin D3: relation to circulating vitamin D3 under various input conditions.  Am J Clin Nutr. 2008 Jun;87(6):1738-42.

Holm M, Olsen A, Kroman N, Tjønneland A. Lifestyle influences on the association between pre-diagnostic hormone replacement therapy and breast cancer prognosis-Results from The Danish 'Diet, Cancer and Health' prospective cohort. Maturitas. 2014 Dec;79(4):442-8.

Kidd P.  Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease.  Altern Med Rev. 2003 Aug;8(3):223-46.

Luxwolda MF, Kuipers RS, Kema IP, Dijck-Brouwer DA, Muskiet FA. Traditionally living populations in East Africa have a mean serum 25-hydroxyvitamin D concentration of 115 nmol/l. Br J Nutr. 2012 Nov 14;108(9):1557-61.

Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, Gibson H, Gordon D, Copeland T, D'Agostino D, Friedenberg G, Ridge C, Bubes V, Giovannucci EL, Willett WC, Buring JE; VITAL Research Group. Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease. N Engl J Med. 2019 Jan 3;380(1):33-44.

Matheu V, Bäck O, Mondoc E, Issazadeh-Navikas S.   Dual effects of vitamin D-induced alteration of TH1/TH2 cytokine expression: enhancing IgE production and decreasing airway eosinophilia in murine allergic airway disease. J Allergy Clin Immunol. 2003 Sep;112(3):585-92.

Mellenthin L, Wallaschofski H, Grotevendt A, Völzke H, Nauck M, Hannemann A. Association between serum vitamin D concentrations and inflammatory markers in the general adult population. Metabolism. 2014 Aug;63(8):1056-62.

Mondul AM, Weinstein SJ, Layne TM, Albanes D.  Vitamin D and Cancer Risk and Mortality: State of the Science, Gaps, and Challenges. Epidemiol Rev. 2017; 39(1):28-48

Prieto-Alhambra D, Servitja S, Javaid MK, Garrigós L, Arden NK, Cooper C, Albanell J, Tusquets I, Diez-Perez A, Nogues X.  Vitamin D threshold to prevent aromatase inhibitor-related bone loss: the B-ABLE prospective cohort study. Breast Cancer Res Treat. 2012 Jun;133(3):1159-67.

Scragg R.  Emerging Evidence of Thresholds for Beneficial Effects from Vitamin D Supplementation.  Nutrients. 2018 May 3;10(5). pii: E561. doi: 10.3390/nu10050561

Scragg R, Khaw KT, Toop L, Sluyter J, Lawes CMM, Waayer D, Giovannucci E, Camargo CA Jr. Monthly High-Dose Vitamin D Supplementation and Cancer Risk: A Post Hoc Analysis of the Vitamin D Assessment Randomized Clinical Trial. JAMA Oncol. 2018 Nov 1;4(11):e182178.

Shurin MR, Lu L, Kalinski P, Stewart-Akers AM, Lotze MT. Th1/Th2 balance in cancer, transplantation and pregnancy. Springer Semin Immunopathol. 1999;21(3):339-59

Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JP. Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ. 2014 Apr 1;348:g2035. doi:  10.1136/bmj.g2035.

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