Use of Vitamin D in Clinical Practice

Use of Vitamin D in Clinical Practice

This section is compiled by Frank M. Painter, D.C.
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FROM:   Alternative Medicine Review 2008 (Mar); 13 (1): 6–20 ~ FULL TEXT

John J. Cannell, MD and Bruce W. Hollis, PhD

The recent discovery--from a meta-analysis of 18 randomized controlled trials--that supplemental cholecalciferol (vitamin D) significantly reduces all-cause mortality emphasizes the medical, ethical, and legal implications of promptly diagnosing and adequately treating vitamin D deficiency. Not only are such deficiencies common, and probably the rule, vitamin D deficiency is implicated in most of the diseases of civilization. Vitamin D's final metabolic product is a potent, pleiotropic, repair and maintenance, seco-steroid hormone that targets more than 200 human genes in a wide variety of tissues, meaning it has as many mechanisms of action as genes it targets. One of the most important genes vitamin D up-regulates is for cathelicidin, a naturally occurring broad-spectrum antibiotic. Natural vitamin D levels, those found in humans living in a sun-rich environment, are between 40-70 ng per ml, levels obtained by few modern humans. Assessing serum 25-hydroxy-vitamin D (25(OH)D) is the only way to make the diagnosis and to assure treatment is adequate and safe. Three treatment modalities exist for vitamin D deficiency: sunlight, artificial ultraviolet B (UVB) radiation, and vitamin D3 supplementation. Treatment of vitamin D deficiency in otherwise healthy patients with 2,000-7,000 IU vitamin D per day should be sufficient to maintain year-round 25(OH)D levels between 40-70 ng per mL. In those with serious illnesses associated with vitamin D deficiency, such as cancer, heart disease, multiple sclerosis, diabetes, autism, and a host of other illnesses, doses should be sufficient to maintain year-round 25(OH)D levels between 55 -70 ng per mL. Vitamin D-deficient patients with serious illness should not only be supplemented more aggressively than the well, they should have more frequent monitoring of serum 25(OH)D and serum calcium. Vitamin D should always be adjuvant treatment in patients with serious illnesses and never replace standard treatment. Theoretically, pharmacological doses of vitamin D (2,000 IU per kg per day for three days) may produce enough of the naturally occurring antibiotic cathelicidin to cure common viral respiratory infections, such as influenza and the common cold, but such a theory awaits further science.

Incidence of Vitamin D Deficiency

Adult vitamin D deficiency is the rule rather than the exception in industrialized nations. [31-33] A high number of otherwise healthy children and adolescents are also vitamin D deficient. [34, 35] Rickets, a disease of the industrial revolution, is being diagnosed more frequently, 36 especially in breast-fed infants. [37] Alarmingly, given mounting animal data that gestational vitamin D deficiency causes subtle but irreversible brain damage in mammalian offspring, [38, 39] severe deficiencies are common in newborn infants and pregnant women, especially African-Americans. [40] A population-based study of 2,972 U.S. women of childbearing age found 42 percent of African-American women had 25(OH)D levels below 15 ng/mL, and 12 percent had levels below 10 ng/mL. [41] Furthermore, the definition of vitamin D deficiency changes almost yearly as research shows the low end of ideal 25(OH)D ranges are higher than were previously thought. The aforementioned prevalence studies used outdated reference values for low-end 25(OH) D ranges and therefore underestimate the incidence of vitamin D deficiency. Obviously, the higher the low end of the 25(OH)D cutoff point, the higher the percentage of the population defined as deficient. Only 10 percent of the subjects in any of the above studies had 25(OH) D levels > 40 ng/mL.

Treatment of Disease

By far the most common reason to treat with vitamin D is osteoporosis, but the dose needed remains controversial because the lowest effective dose (800 IU/ day) is known, but the ideal dose is not. [72] Currently, virtually all of the evidence that vitamin D is an effective adjuvant for the treatment of other serious medical conditions is anecdotal, implied by epidemiological studies, from open trials, or inferred from vitamin D’s mechanism of action. For example, there is an anecdotal report that pharmacological doses of vitamin D are effective in treating – not just preventing – viral respiratory infections. [73] Doses of 2,000 IU/kg body weight for three days (200,000 IU per day for three days for a 100-kg adult) may seem excessive to those unfamiliar with vitamin D’s pharmacology and toxicity. In fact, such doses are common in many parts of the world simply to prevent or treat vitamin D deficiency.

For example, single injections of 600,000 IU (15 mg) vitamin D raised 25(OH)D levels from 2 ng/ mL to 22 ng/mL at two weeks and to 27 ng/mL at six weeks in 10 elderly subjects, with no evidence of toxicity. [74] Indeed, a single injection of 600,000 IU of vitamin D is not only safe; such doses were recently recommended in the autumn for the elderly, simply to prevent wintertime vitamin D deficiency. [75] Likewise, there was no evidence of toxicity in young men taking 50,000 IU of vitamin D per day for six weeks (although such a dose would become toxic if taken over a longer period). [76] In 32 severely vitamin D-deficient elderly patients, 50,000 IU/day for 10 days showed no evidence of toxicity and only raised 25(OH)D levels by an average of 5 ng/mL three months after administration. In no patient did levels increase more than 11 ng/mL at three months. [77] Treatment of colds and influenza with pharmacological doses of vitamin D may only be the tip of the infectious disease iceberg. As Aloia and Li-Ng have pointed out, [12] it is intriguing that vitamin D-sensitive antimicrobial peptides (AMP) inhibit the HIV virus and there is evidence that vitamin D plays a role in HIV. [78] Invasive pneumococcal disease, meningococcal disease, and group A streptococcal disease are more common when vitamin D levels are lowest (winter) [79-81] and all three bacteria are sensitive to AMP, [82-84] raising the possibility that pharmacological doses of vitamin D would be an effective adjuvant treatment. In fact, the dramatically increased production of AMPs by vitamin D and the broad spectrum of action of AMP make it reasonable to hypothesize that pharmacological doses of vitamin D are effective adjuvants in treating a large number of infections.

In a recent report, 12 patients in active phases of multiple sclerosis were treated with progressively increasing weekly doses of vitamin D3 (the equivalent of starting with 4,000 IU per day and increasing to 40,000 IU per day) and calcium. [85] Mean serum concentrations of 25(OH)D initially were 31 ng/mL and rose to a mean of 154 ng/mL at the end of 28 weeks, with no abnormalities in serum or urine calcium detected in the 12 subjects. The number of MS lesions per patient on brain scan decreased from an initial mean of 1.75 at the beginning to a mean of 0.83 (p=0.03) at the end of the study. However, doses of 40,000 IU per day may cause toxicity if given for longer periods; certainly, such doses flirt with toxicity. Doses of 10,000 IU per day may well have achieved the same result without the risk of toxicity. Both epidemiological evidence and vitamin D’s mechanism of action suggest it may have a treatment effect in early cancer. For example, a study of recurrencefree survival in early-stage, non-small-cell lung cancer patients found those with the highest vitamin D input had double the five-year recurrence-free survival and much better overall survival than those with the lowest. [86] This strongly implies a vitamin D treatment effect, i.e., untreated vitamin D deficiency in non-small-cell lung cancer patients is a risk factor for early death. Season of diagnosis has a survival effect on numerous cancers; i.e., cancer patients live longer if the diagnosis is made in the summer rather than the winter. [87, 88] Although no one has proven vitamin D causes this summer-season treatment effect, vitamin D’s anticancer mechanism of action is basic to all cancers. Thus, it is reasonable to hypothesize a general cancer treatment effect, at least in cancer’s early stages, when aberrant cells are more likely to retain both the vitamin D receptor and the enzyme needed to activate vitamin D. Practitioners who treat type-2 diabetic or hypertensive patients with physiological doses of vitamin D should be prepared for the possibility of either hypoglycemia or hypotension, especially after several months of treatment. Theoretically, such doses of vitamin D should eventually lower both blood sugar and blood pressure, although blood sugars may worsen for several weeks after initiation or increase of vitamin D. Should either hypoglycemia or hypotension occur, the diabetic and/or hypertensive medication should be lowered, not the vitamin D.

Although modern science knows little or nothing about the metabolic clearance of vitamin D in different disease states, it is reasonable to predict that vitamin D is cleared more rapidly in some disease states. For example, patients with diabetes, HIV, or cancer may rapidly use 25(OH)D as substrate to make large amounts of 1,25(OH)2D to fight their disease. Therefore, a patient with cancer may require significantly higher doses of vitamin D to maintain 25(OH)D levels of 55-70 ng/ mL than a healthy adult of similar weight and body fat. Practitioners should supplement such patients (assuming they are not hypercalcemic) to high natural levels, even if it means taking 10,000 IU or more per day. Frequent monitoring of 25(OH)D and calcium levels should guide dosing in patients with cancer and other serious illnesses, and such treatment should be adjunctive and never take the place of standard treatment. The authors believe that those who claim the lack of RCTs showing vitamin D’s effectiveness as adjuvant cancer treatment means it should never be so used miss an important point. For example, recent studies show a high incidence of vitamin D deficiency in patients undergoing treatment for cancer. [89] Even at the end of summer, 48 percent of cancer patients in Boston had levels less than 20 ng/mL. [89] In another study, 72 percent of 60 cancer patients had 25(OH)D levels less than 30 ng/mL, and virtually none had natural levels. [90] A 1998 study of inpatients at Massachusetts General Hospital found 57 percent had 25(OH)D levels less than 15 ng/mL. [91]

Thus, the question should not be, “Should cancer (or multiple sclerosis, septic, cardiac, HIV, or hepatitis B) patients be treated with vitamin D?” The better question is, “Should practitioners routinely screen and aggressively treat vitamin D deficiency in patients with serious or potentially fatal illnesses, or should such patients combat their disease vitamin D deficient?” As referenced above, the vast majority of such patients probably expire severely vitamin D deficient.

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