Vitamin D deficiency is widespread, and it leads to more than brittle bones. Deficiency of this key vitamin is associated with increased risk of heart disease, diabetes, depression and certain forms of cancer. Fortunately, this is easily reversible with short periods of sun exposure or vitamin D-rich nutraceutical products.

Vitamin D is widely recognized for its role in promoting calcium uptake and maintaining bone mineral density. But a growing body of evidence indicates that vitamin D can also reduce the risk of many types of cancer and inflammatory disorders. Attainment of optimal serum levels of vitamin D also reduces the incidence and severity of diabetes mellitus, insulin resistance, cancer, heart disease, and hypertension.

Recent clinical trials suggest that this versatile vitamin may also have a role in the treatment of polycystic ovary syndrome (PCOS), migraine headaches, depression, epilepsy, and musculoskeletal pain.

The reality is that vitamin D deficiency is nearly epidemic in the US, and has heretofore received insufficient attention from clinicians in all disciplines. Numerous studies have documented the remarkably high prevalence of vitamin D deficiency in medical patients (Kauppinen-Makelin R, et al. J Intern Med. 2001; 249(6): 559–563; Thomas MK, et al. N Engl J Med. 1998; 19; 338(12): 777–783). Given the clinical consequences of this deficiency, not to mention its reversibility, it is essential that health care practitioners make efforts to detect and treat it.

Overview of Vitamin D Metabolism

Vitamin D is produced from cholesterol in the skin via reactions induced by exposure to ultraviolet light or sunlight. Throughout human evolution, sun-induced endogenous production has been the most significant source of vitamin D; naturally-occurring food sources at best provide only small amounts of vitamin D.

Following its production in the skin or its oral ingestion, vitamin D is metabolized via two distinct pathways: 1) Endocrine pathways, which are relevant to calcium absorption and bone metabolism, and, 2) Autocrine pathways, relevant to the modulation of intracellular processes such as differentiation, proliferation, inflammation, and gene transcription.

In the endocrine pathway, vitamin D (cholecalciferol) is produced in the skin or consumed orally and then circulated to the liver for conversion to 25-hydroxyvitamin D (calcidiol) before its final conversion to 1,25-dihydroxyvitamin D (calcitriol) in the kidney. 1,25-dihydroxyvitamin D then circulates in the blood in an endocrine fashion to increase calcium and phosphorus absorption in the gut.

In its autocrine metabolism, 25-hydroxyvitamin D (calcidiol) is taken up directly by cells in various tissues such as the lymph nodes, colon, pancreas (islets), adrenal medulla, and brain (cerebellum and cerebral cortex) which then perform their own intracellular conversion to the more active 1,25-dihydroxyvitamin D (Zehnder D, et al. J Clin Endocrinol Metab. 2001; 86(2): 888–894). Nuclear or cytosolic vitamin D receptors are present in a wide range of tissues, including the islet cells of the pancreas, monocytes, transformed B-cells, activated T-cells, neurons, prostate cells, ovarian cells, pituitary cells, and aortic endothelial cells, thus indicating this vitamin’s wide range of influence (Zittermann A. Br J Nutr. 2003; 89(5): 552–572).

In accord with the different endocrine and autocrine pathways, vitamin D deficiency occurs in two distinct patterns: 1) acute deficiency diseases, such as rickets and hypocalcemia, and, 2) long-latency deficiency diseases, such as cancer and inflammatory disorders, which manifest only after years of subacute deficiency (Heaney RP. Am J Clin Nutr. 2003; 78(5): 912–919). As reviewed in the sections that follow, long-term vitamin D deficiency contributes to an increased risk of many serious health problems.

Sun or Supplement?

Full-body sun exposure at noon at equatorial latitudes can produce large amounts of vitamin D in a relatively short time. White-skinned people living in northern latitudes can obtain optimal levels of vitamin D of between 4,000–5,000 IU per day with 10-minute periods of mid-day sun exposure, wearing minimal clothing, each day. Longer or more frequent periods are needed during Fall and Winter seasons. Dark-skinned people need between 5 and 10 times longer to obtain the same levels. It is important to realize that cutaneous vitamin D production happens rapidly, tapers after about half an hour and cannot exceed more than 25,000 to 30,000 IU, which is reached within an hour. Further sun exposure will not produce more vitamin D.

Some vitamin D researchers believe public health efforts aimed at discouraging sun exposure in the interest of preventing skin cancers may ultimately be furthering the already widespread problem of vitamin D deficiency. While it is important to recognize that sunburn and UV-induced skin damage are major risk factors for melanoma and other skin cancers, it is equally important to realize that vitamin D deficiency contributes to the risk of several other types of cancer as well as other forms of illness (UK medical journalist, Oliver Gillie, recently wrote a very well researched treatise on this issue; it can be downloaded at www.healthresearchforum.org.uk).

The risk of cancer from sun exposure may be linked to the fact that many whites living in northern climates have a “feast or famine” relationship with the sun. For months, they live most of their lives indoors in a state of chronic vitamin D deficiency, a cancer-promoting state. Then, on vacation, they expose themselves to prolonged and massive doses of solar UV radiation.

Dietary supplements provide an alternative to sun-exposure as a way of increasing vitamin D. Cod liver oil, used historically for the treatment and prevention of rickets, is one of the richest food sources of vitamin D. However, the amount of vitamin D present in cod liver oil and other foods is clearly inadequate given the amounts naturally produced in the skin following full-body sun exposure.

Recent evidence suggests that the physiologic requirement for vitamin D in adults may be as high as 5,000 IU per day (Heaney R, et al. Am J Clin Nutr. 2003; 77: 204–210). To attain our suggested 4,000 IU per day for adults, patients would have to consume an unreasonable 30 capsules per day of cod liver oil, or more than a one-quarter to one-half cup, depending on brand and concentration. It is clear that food sources cannot adequately meet physiological needs of vitamin D, and that in the absence of regular full-body sun exposure, vitamin D supplementation is necessary.

Vitamin D Deficiency and Cancer Risk

Epidemiologically, cancer risk and vitamin D deficiency go hand-in-hand. The risk of cancer in humans increases in direct proportion to the reduction in sun exposure and vitamin D levels, a fact that has been repeatedly verified since its first publication more than 60 years ago (Apperly FL. Cancer Res. 1941; 1: 191–195). It is widely recognized that African-American males have both the lowest serum 25-hydroxy-vitamin D concentrations and the highest prostate cancer incidence of any population group in the United States (Heaney RP. Am J Clin Nutr. 2003; 78(5): 912–919). Women with low intakes of dietary vitamin D and low sun exposure have a higher incidence of breast cancer compared to women with higher levels of vitamin D from sun exposure, food, and vitamin D supplements (John EM, et al. Cancer Epidemiol Biomarkers Prev. 1999; 8(5): 399–406).

William B. Grant, PhD, director of the Sunlight, Nutrition and Health Research Center (SUNARC) in San Francisco, has published numerous epidemiologic analyses showing the connection between vitamin D deficiency and increased cancer risk. Based on an exhaustive review of available data, he has estimated that at least 23,000 and perhaps as many as 47,000 cancer deaths might be prevented in the US each year, if we employed simple interventions such as vitamin D supplementation to safely raise vitamin D levels (Grant WB. Cancer. 2002; 94: 1867–1875).

The mechanisms by which vitamin D can reduce cancer incidence and mortality are complex and manifold. First, vitamin D plays an important role in maintaining effective immunity, a fact recently evidenced by its apparent ability to reduce the incidence and severity of respiratory infections (Wayse V, et al. Eur J Clin Nutr. 2004; 58: 563–567). Second, vitamin D affects transcription of several genes that influence cellular differentiation and proliferation, such as c-myc, c-fos, and c-sis (Holick MF. Clin Lab Med. 2000; 20: 569–590). Third, cancer is increasingly viewed as an inflammatory disease, and vitamin D has powerful anti-inflammatory benefits in humans (Timms PM, et al. QJM. 2002; 95: 787–796). Recent controlled in vitro and in vivo studies have shown an anticancer benefit provided by vitamin D (Banerjee P, Chatterjee M. Mol Cell Biochem. 2003; 253: 247–254). Further clinical research in this field is clearly warranted.

Cardiovascular Disease Prevention

Epidemiological data indicate that deaths from cardiovascular disease are more common in the winter, more common at higher latitudes, and more common at lower altitudes, observations that are most consistently explained by lower vitamin D status (Scragg R. Int J Epidemiol. 1981; 10(4): 337–341). The risk of heart attack is twice as high for those with 25-(OH)-D levels less than 34 ng/ml (85 nmol/L) than for those with vitamin D status above this level (Scragg R, et al. Int J Epidemiol. 1990; 19(3): 559–563).

Suboptimal vitamin D levels increase the risk for and severity of hypertension; augmentation of vitamin D levels with sunlight or oral supplementation has been shown to safely and consistently reduce blood pressure in hypertensive patients (Pfeifer M, et al. J Clin Endocrinol Metab. 2001; 86: 1633–1637).

As a marker for systemic inflammation, elevated levels of C-reactive protein are now generally recognized as a major risk factor for cardiovascular disease, and a recent study by Timms and colleagues at Queen Mary’s School of Medicine and Dentistry, London, showed that vitamin D supplementation reduced CRP levels by 23% (Timms PM, et al. QJM. 2002; 95: 787–796). Thus, with its benefits in the reduction of hypertension and inflammation, vitamin D supplementation carries the potential to reduce the incidence of cardiovascular morbidity and mortality.

Insulin Resistance and Diabetes

Vitamin D deficiency is strongly associated with type 2 diabetes (Scragg R, et al. Diabetes Res Clin Pract. 1995; 27: 181–188) as well as insulin resistance (Baynes KC, et al. Diabetologia. 1997; 40: 344–347). Vitamin D is required for the biosynthesis of insulin in B cells, and it also facilitates the conversion of proinsulin to insulin (Bourlon, et al. J Endocrinol. 1999; 162: 101–109).

Data from a recent study of normal adults indicate that higher serum 25-(OH)-D levels are directly associated with better glucose tolerance and increased insulin sensitivity. The authors suggested that improving vitamin D status might improve insulin sensitivity by 60%, suggesting that vitamin D treatment “is more potent than either troglitazone or metformin treatment” (Chiu KC, et al. Am J Clin Nutr. 2004; 79: 820–825).

Gedik and Akalin showed that daily administration of 2,000 IU of oral vitamin D3 for six months improved insulin sensitivity in vitamin D deficient subjects (Diabetologia. 1986; 29: 142–145). Relatedly, Borissova and colleagues demonstrated improved insulin secretion and peripheral insulin sensitivity in type 2 diabetics after only one month of supplementation with 1,332 IU cholecalciferol per day (Int J Clin Pract. 2003; 57: 258–261). They documented a 21% improvement in insulin sensitivity within only one month of vitamin D supplementation, an outcome superior to that obtained with metformin, which improves peripheral glucose utilization by only 13% (Inzucchi SE, et al. N Engl J Med. 1998; 26; 338: 867–872). In a retrospective study with more than 10,000 participants, administration of 2,000 IU per day to infants in the first year of life was shown to reduce subsequent incidence of immune-mediated type-1 diabetes by 80% (Hypponen E, et al. Lancet. 2001; 358: 1500–1503).

A Broad Range of Benefits

Vitamin D has been tested in a wide range of clinical conditions. Following are brief summaries of some of the most compelling data.

• Depression: Vitamin D administration at 400–800 IU per day was shown to improve mood within 5 days of treatment in a controlled clinical trial of patients with wintertime depression (Lansdowne AT, Provost SC. Psychopharmacology (Berl). 1998; 135: 319–323).
• Epilepsy: Vitamin D deficiency can cause seizures. Many medications used to treat epilepsy commonly cause vitamin D deficiency by interfering with vitamin D formation and/or increasing excretion, and this can result in iatrogenic epilepsy (Ali FE, et al. Ann Pharmacother. 2004; 38: 1002–1005). Administration of vitamin D shows an anticonvulsant benefit (Christiansen C, et al. Br Med J. 1974; 2: 258–259).
• Polycystic Ovary Syndrome: Vitamin D modulates calcium metabolism, which in turn, plays an important role in many body processes, including oocyte activation and maturation. Vitamin D deficiency was highly prevalent among 13 women with PCOS, and supplementation with 1,500 mg of calcium per day and 50,000 IU of vitamin D2 on a weekly basis normalized menstruation and/or fertility in nine of nine women with PCOS-related menstrual irregularities within three months of treatment (Thys-Jacobs S, et al. Steroids. 1999; 64: 430–435).
• Osteoarthritis and Musculoskeletal Pain: Osteoarthritis develops more frequently and progresses more rapidly in patients who are deficient in vitamin D. Inversely, the deficiency is very common in patients with musculoskeletal pain (Plotnikoff GA, Quigley JM. Mayo Clin Proc. 2003; 78: 1463–1470). Treatment of patients with back pain and hypovitaminosis D with 5,000–10,000 IU per day of vitamin D alleviated pain in almost 100% of patients (Al Faraj S, Al Mutairi K. Spine. 2003; 28: 177–179). The mechanism by which vitamin D deficiency causes pain has been detailed by Holick, who holds that vitamin D deficiency leads to the production of an unmineralized collagen matrix that hydrates, swells, and then puts pressure on the sensory-innervated periosteum, resulting in dull, achy pain that does not respond to conventional treatments (Mayo Clin Proc. 2003; 78: 1457–1459). Vitamin D deficiency appears to result in increased calcium deposition in cartilage, thus facilitating the development of degenerative joint disease (Fujita T, J Bone Miner Metab. 2000; 18(4): 234–236).
• Inflammatory and Autoimmune Diseases: Vitamin D deficiency is common in patients with various autoimmune diseases such as Grave’s disease, lupus, rheumatoid arthritis, and ankylosing spondylitis. Preliminary evidence shows that vitamin D supplementation has a beneficial clinical and anti-inflammatory effect in patients with multiple sclerosis (Goldberg P, et al. Med Hypotheses. 1986; 21: 193–200; Mahon BD, et al. J Neuroimmunol. 2003; 134: 128–132).

Reaching Optimal Vitamin D Status

	Figure 1. Proposed normal and optimal ranges for serum 25-(OH)-D based on current research. From Vasquez, Integrative Orthopedics, 2004, with permission.

We recently proposed that optimal vitamin D status be defined by serum levels of 25-(OH)-vitamin D in the range of 40 to 65 ng/mL (100–160 nmol/L). This proposal is based on our clinical experience and our extensive review of the literature, particularly the recent publications by Vieth (Am J Clin Nutr. 1999; 69: 842–856), Zitterman (Br J Nutr. 2003; 89: 552–572), Holick (Am J Clin Nutr. 2004; 79: 362–371), and Heaney et al. (Am J Clin Nutr. 2004; 79: 362–371). Our proposal is graphically illustrated in Figure 1 to help clinicians interpret results of serum testing and apply this information clinically.

It is now well established in vitamin D research that previous recommendations for vitamin D intake in the range of 400–800 IU were based on erroneous interpretations of data that failed to appreciate the importance of attaining optimal serum levels of 25-(OH)-D. Indeed, recommendations for the 400 IU daily dose were arbitrarily and unscientifically based upon this being the amount of vitamin D in a teaspoon of cod-liver oil, a sufficient dose to prevent rickets in children (Vieth R. Am J Clin Nutr. 1999; 69: 842–856). The doses that we recommend for patients should be commensurate with endogenous production of vitamin D following sun exposure (Vieth R. Am J Clin Nutr. 1999; 69: 842–856). Dosing should also be commensurate with physiologic utilization, which was recently shown to be approximately 4,000 IU per day for adult men (Heaney, et al. Am J Clin Nutr. 2003; 77: 204–210).

Safe and effective implementation of vitamin D therapy necessitates three components: 1) identifying patients who are vitamin D deficient or who have vitamin D-responsive conditions; 2) administering vitamin D via oral supplementation in the range of 1,000 IU per day for infants, 2,000 IU per day for children, and 4,000 IU per day for adults; and 3) periodically monitoring 25-(OH)-D levels and serum calcium to ensure efficacy and safety, respectively.

There are many available forms of vitamin D supplements. Bear in mind that as with coenzyme Q10, vitamin D is a fat-soluble nutrient and that absorption can be greatly improved by emulsification. A micro-emulsified form of vitamin D, called Bio-D-Mulsion is available from Biotics Research Corporation. The product provides patients with vitamin D in liquid form. Two concentrations are available: Bio-D-Mulsion, giving 400 IU per drop, and the more concentrated Bio-D-Mulsion Forte, giving 2,000 IU per drop.

Regardless of the particular product used, we contend that oral supplementation with vitamin D in amounts of 1,000 IU per day for infants, 2,000 IU per day for children, and 4,000 IU per day for adults is a safe and reasonable way to meet physiologic requirements, to promote optimal health, and to reduce the risk of several serious diseases. Safety and effectiveness of supplementation are assured by periodic monitoring of serum 25-(OH)-D and serum calcium. A clinical guide to the implementation of vitamin D therapy is available at http://www.bioticsresearch.com/Products/Bio-D-Mulsion.htm.

Additional information and references are available in a recent textbook on integrative orthopedics, Integrative Orthopedics: The Art of Creating Wellness While Effectively Managing Acute and Chronic Musculoskeletal Disorders, by Alex Vasquez, DC, ND (www.OptimalHealthResearch.com).

About the Authors

Alex Vasquez, DC, ND, is a licensed naturopathic physician in Washington and Oregon, and licensed chiropractor in Texas, where he maintains a private practice and is a researcher and lecturer at Biotics Research Corporation (BioticsResearch.com).

John Cannell, MD, is a medical doctor practicing in Atascadero, California and is president of the Vitamin D Council (Cholecalciferol-Council.com), a non-profit, tax-exempt organization working to promote awareness of the manifold adverse effects of vitamin D deficiency.