Alex Vasquez, D.C., N.D., Gilbert Manso, M.D., John Cannell, M.D.

 

Introduction and Overview

While we are all familiar with the importance of vitamin D in calcium absorption and bone metabolism, many doctors and patients are not aware of the recent research on vitamin D and the widening range of therapeutic applications available for cholecalciferol, which can be classified as both a vitamin and a pro-hormone.  Additionally, we also now realize that the Food and Nutrition Board’s previously defined Upper Limit (UL) for safe intake at 2,000 IU/day was set far too low and that the physiologic requirement for vitamin D may be as high as 5,000 IU/day, which is less than half of the >10,000 IU that can be produced endogenously with full-body sun exposure.1,2  With the discovery of vitamin D receptors in tissues other than the gut and bone—especially the brain, breast, prostate, and lymphocytes—and the recent research suggesting that higher vitamin D levels provide protection from diabetes mellitus, osteoporosis, osteoarthritis, hypertension, cardiovascular disease, metabolic syndrome, depression, several autoimmune diseases, and cancers of the breast, prostate, and colon, we can now utilize vitamin D for a wider range of preventive and therapeutic applications to maintain and improve our patients’ health.3  Based on the research reviewed in this article, the current authors believe that assessment of vitamin D status and treatment of vitamin D deficiency with oral vitamin D supplements should become a routine component of clinical practice and preventive medicine.  Vitamin D supplementation with physiologic doses of 2,000 to 5,000 IU per day for adults is clinically safe and physiologically reasonable since such doses are less than that obtained by full-body sun exposure.  Periodic assessment of serum 25-OH-vitamin D (25(OH)D) and serum calcium will help to ensure that vitamin D levels are safe and effective for health maintenance and disease prevention.  Clinical research supporting the use of vitamin D in the management of type 2 diabetes, osteoporosis, osteoarthritis, hypertension, cardiovascular disease, metabolic syndrome, multiple sclerosis, polycystic ovary syndrome, musculoskeletal pain, depression, epilepsy, and the prevention of cancer and type 1 diabetes is presented along with our proposal for the interpretation of serum 25(OH)D laboratory values.
 


Basic Physiology of Vitamin D

Vitamin D is obtained naturally from two sources: sunlight and dietary consumption.  Vitamin D3 (cholecalciferol) is the form of vitamin D produced in the skin and consumed in the diet. Vitamin D2 (ergocalciferol), which is produced by irradiating fungi, is much less efficient as a precursor to the biologically active 1,25-dihydroxyvitamin D (calcitriol).  Additionally, since ergocalciferol forms a number of metabolic by-products that are not naturally found in humans, it is potentially more toxic than cholecalciferol.4   Although ergocalciferol is occasionally used clinically and in research studies, cholecalciferol is the preferred form of supplementation and will be implied in this article when supplementation is discussed.

Vitamin D can be described as having two pathways for metabolism: one being “endocrine” and the other “autocrine,” (within the cell) and perhaps “paracrine” (around the cell).  This elucidation, recently reviewed by Heany5, is vitally important in expanding our previously limited conception of vitamin D from only a “bone nutrient with importance only for the prevention of rickets and osteomalacia” to an extraordinary molecule with far-reaching effects in a variety of cells and tissues.  Furthermore, Heany’s distinction of “short-latency deficiency diseases” such as rickets from “long-latency deficiency diseases” such as cancer provides a conceptual handle that helps us grasp an understanding of the differences between the acute manifestations of severe nutritional deficiencies and the delayed manifestations of chronic subclinical nutritional deficiencies.5

In its endocrine metabolism, vitamin D (cholecalciferol) is formed in the skin following exposure to sunlight and then travels in the blood to the liver where it is converted to 25-hydroxyvitamin D (calcidiol, 25(OH)D) by the enzyme vitamin D-25-hydroxylase.  25(OH)D then circulates to the kidney for its final transformation to 1,25-dihydroxyvitamin D (calcitriol) by 25-hydroxyvitamin D3-1alpha-hydroxylase (1-OHase).6  Calcitriol is the most biologically active form of the vitamin and increases intestinal calcium absorption, increases phosphorus absorption, promotes calcium deposition in bone, and promotes a reduction in parathyroid hormone (PTH).  While increased calcium absorption is obviously important for nutritional reasons, suppression of PTH by vitamin D is also clinically important since relatively lower levels of PTH appear to promote and protect health, and higher levels of PTH correlate with increased risk for myocardial infarction, stroke, and hypertension.7,8 Relatedly, Fugita9 described the “calcium paradox” wherein elevations of PTH cause an increase in intracellular calcium and may thereby promote the cascade of cellular dysfunction that can contribute to the development of diabetes mellitus, neurodegenerative diseases, malignancy, and degenerative joint disease.

In its autocrine metabolism, circulating 25(OH)D is taken up by a wide variety of cells that contain both 1-OHase as well as nuclear vitamin D receptors (VDR).  Therefore, these cells are able to make their own calcitriol rather than necessarily relying upon hematogenous supply.  Cells and tissues that are known to contain 1-OHase, and which therefore make their own calcitriol, include the breast, prostate, lung, skin, lymph nodes, colon, pancreas, adrenal medulla, and brain (cerebellum and cerebral cortex).3,10  Cells and tissues with nuclear, cytosolic, or membrane-bound VDR include islet cells of the pancreas, monocytes, transformed B-cells, activated T-cells, neurons, prostate cells, ovarian cells, pituitary cells, and aortic endothelial cells.11  Indeed, given the wide range of cells and tissues that metabolize vitamin D in an autocrine manner, we see that there is biological potential for vitamin D to influence function and pathophysiology in a wide range of processes and disease states.

Since many cells and tissues of the body have the ability to metabolize vitamin D, we should not be surprised that vitamin D plays a role in the function of these cells.  Calcitriol is known to modulate transcription of several genes, notably those affecting differentiation and proliferation such as c-myc, c-fos, and c-sis6; this may partially explain the inverse relationship between sun exposure and cancer mortality.12  Vitamin D appears to modulate neurotransmitter/neurologic function as shown by its antidepressant13 and anticonvulsant14 benefits.  Vitamin D is obviously immunoregulatory as manifested by its ability to reduce inflammation15, suppress and/or prevent certain autoimmune diseases16,17,18, reduce the risk for cancer12, and may even reduce the severity and frequency of infectious diseases, such as acute pneumonia in children.19

 

Clinical Applications and Therapeutic Benefits of Vitamin D

Support for a broad range of clinical applications for vitamin D supplementation comes from laboratory experiments, clinical trials, and epidemiologic surveys.  Despite the imperfections of current data, we can still see significant benefits from vitamin D supplementation in a variety of human diseases, as briefly reviewed below.

 

Cardiovascular Disease: Deaths from cardiovascular disease are more common in the winter, more common at higher latitudes and more common at lower altitudes, observations that are consistent with vitamin D insufficiency.20 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.21  Patients with congestive heart failure were recently found to have markedly lower levels of vitamin D. 

 

Hypertension: It has long been known that blood pressure is higher in the winter than the summer, increases at greater distances from the equator and is affected by skin pigmentation—all observations consistent with a role for vitamin D in regulating blood pressure.22  When patients with hypertension were treated with ultraviolet light three times a week for six weeks their vitamin D levels went up 162% and their blood pressure fell significantly.23  Even small amounts of oral cholecalciferol (800 IU) for eight weeks lowered both blood pressure and heart rate.24

 

Type 2 Diabetes: Hypovitaminosis D is associated with insulin resistance and beta-cell dysfunction in diabetics and healthy young adults.25   Healthy adults with serum 25 (OH)D levels above 40 ng/ml (100 nmol/L) had significantly lower 60 min, 90 min and 129 min postprandial glucose levels and significantly better insulin sensitivity.  The authors concluded that the 60% improvement in insulin sensitivity afforded by vitamin D appears to be “more potent than either troglitazone or metformin,” two medications commonly prescribed to treat type 2 diabetes.  In fact, supplementation with even small amounts of cholecalciferol (1,332 IU) for a short time (30 days) resulted in significant improvements in insulin secretion.26

 

Osteoarthritis: Many practitioners know that vitamin D helps prevent and treat osteoporosis, but fewer know that the progression of osteoarthritis, the most common arthritis, is lessened by adequate blood levels of vitamin D.  Framingham data showed osteoarthritis of the knee progressed more rapidly in those with 25(OH)D levels lower than 36 ng/ml (90 nmol/L).27  Another study found that osteoarthritis of the hip progressed more rapidly in those with 25(OH)D levels lower than 30 ng/ml (75 nmol/L).28

 

Multiple Sclerosis: Since the autoimmune/inflammatory disease multiple sclerosis (MS) is notably rare in sunny equatorial regions and becomes increasingly prevalent among people who live farther from the equator and/or who lack adequate sun exposure, it is not surprising to find that vitamin D deficiency is common among patients with MS.  In a clinical trial with 10 MS patients, Goldberg, Fleming, and Picard17 prescribed daily supplementation with approximately 1,000 mg calcium, 600 mg magnesium, and 5,000 IU vitamin D (from 20 g cod liver oil) for up to two years and found a reduction in the number of exacerbations and an absence of adverse effects.  This is one of very few studies in humans that employed sufficient daily doses of vitamin D (5,000 IU) and had sufficient duration (2 years).  More recently, Mahon et al29 gave 800 mg calcium and 1,000 IU vitamin D per day for six months to 39 patients with MS and noted a modest anti-inflammatory effect.

 

Prevention of Type 1 Diabetes:  Type 1 diabetes is generally caused by autoimmune/inflammatory destruction of the pancreatic beta cells.  Vitamin D supplementation shows significant preventive and ameliorative benefits in animal models of type 1 diabetes.  In a study with more than 10,000 participants, Hypponen et al16 showed that supplementation in infants and children with 2,000 IU of vitamin D per day reduced the incidence of type 1 diabetes by approximately 80%.  Relatedly, several studies using cod liver oil as a rich source of vitamin D have also documented dramatic reductions in the incidence of type 1 diabetes.

 

Depression:  Seasonal affective disorder (SAD) is a particular subtype of depression characterized by the onset or exacerbation of melancholia during winter months when bright light, sun exposure, and serum 25(OH)D levels are reduced.  Recently, supplementation with 100,000 IU of vitamin D was found superior to light therapy in the treatment of SAD after one month.30  Similarly, in a study involving 44 subjects, supplementation with 400 or 800 IU per day was found to significantly improve mood within five days of supplementation.13

 

Epilepsy: Seizures can be the presenting manifestation of vitamin D deficiency.31 Hypovitaminosis D decreases the threshold for and increases the incidence of seizures, and several “anticonvulsant” drugs interfere with the formation of calcitriol in the kidney and further reduce calcitriol levels via induction of hepatic clearance.  Therefore, antiepileptic drugs may lead to iatrogenic seizures by causing iatrogenic hypovitaminosis D.32   Conversely, supplementation with 4,000 – 16,000 IU per day of vitamin D2 was shown to significantly reduce seizure frequency in a placebo controlled pilot study by Chirstansen, et al.14

 

Migraine headaches: Calcium clearly plays a role in the maintenance of vascular tone and coagulation, both of which are altered in patients with migraine.  Thys-Jacobs33 reported two cases showing a reduction in frequency, duration, and severity of menstrual migraine attacks following daily supplementation with 1,200 mg of calcium and 1,200 – 1,600 IU of vitamin D in women with vitamin D deficiency. 

 

Polycystic Ovary Syndrome: Polycystic ovary syndrome (PCOS) is a disease seen only in humans and is characterized by polycystic ovaries, amenorrhea, hirsuitism, and obesity.  In vivo studies have shown that calcium is essential for 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.34

 

Musculoskeletal Pain: Patients with non-traumatic, persistent musculoskeletal pain show an impressively high prevalence of overt vitamin D deficiency.  Plotnikoff and Quigley35 recently showed that 93% of their 150 patients with persistent, nonspecific musculoskeletal pain were overtly deficient in vitamin D.  Masood et al36 found a high prevalence of vitamin D deficiency in children with limb pain, and vitamin D supplementation ameliorated pain within three months of supplementation.  Faraj and Al Mutairi37 found vitamin D deficiency in 83% of their 299 patients, and supplementation with 5,000 – 10,000 IU of vitamin D per day lead to pain reduction in nearly 100% of patients after three months.

 

Critical Illness and Autoimmune/Inflammatory Conditions:  Deficiency of vitamin D is common among patients with inflammatory and autoimmune disorders.  In addition to the previously mentioned epidemic of vitamin D insufficiency in patients with MS, we also see evidence of vitamin D insufficiency in most patients with Grave’s disease38, ankylosing spondylitis39, systemic lupus erythematosus40, and rheumatoid arthritis.  Clinical trials with proper dosing and duration need to be performed in these patient groups.  A recent trial of vitamin D supplementation in patients with prolonged critical illness showed a significant and dose-dependent “anti-inflammatory effect” evidenced by reductions in IL-6 and CRP.41  However, the insufficient dose of only 400 IU per day (administered intravenously) for only ten days precluded more meaningful and beneficial results, and we present guidelines for future studies later in this paper.

 

Cancer Prevention and Treatment:  The prevalence of many human cancers is inversely proportional to exposure to ultraviolet light and serum vitamin D levels.  Vitamin D has anti-cancer effects mediated by anti-proliferative and proapoptotic mechanisms which are augmented by modulation of nuclear receptor function and enzyme action42, and limited research shows that synthetic vitamin D analogs may have a role in the treatment of human cancers.43   Grant12 has shown that inadequate exposure to sunlight, and hence hypovitaminosis D, is associated with an increased risk of cancer mortality for several malignancies, namely those of the breast, colon, ovary, prostate, bladder, esophagus, kidney, lung, pancreas, rectum, stomach, uterus, and non-Hodgkin lymphoma.  He proposes that adequate exposure to ultraviolet light and/or supplementation with vitamin D could save more than 23,000 American lives per year from a reduction in cancer mortality alone.   

The aforementioned clinical trials using vitamin D in a wide range of health conditions have helped expand our concept of vitamin D and to appreciate its manifold benefits.  Guidelines for the critique and design of clinical trials are proposed in this article to aid readers and researchers in evaluating and designing clinical studies for the evaluation of the therapeutic efficacy of vitamin D.

 


Diagnosing Vitamin D Inadequacy with Measurement of Serum 25-OH-Vitamin D

Periodic monitoring of serum calcium and serum 25-OH-vitamin D [25(OH)D] levels can guide dosage modifications to ensure that treatment is both safe and effective.  Current laboratory reference ranges for 25(OH)D simply report average levels for the population, most of whom are deficient.  They do not report ideal levels so they will mislead the practitioner unless he or she is aware of current research.  The low end of the reference range is set too low due to previous misinterpretations of the research resulting in an overestimation of vitamin D toxicity and an underappreciation of the benefits and safety of higher vitamin D levels.44,45 Therefore, new reference ranges need to be determined based on the current research, and we present our proposals here and in Figure 1: 

           Vitamin D Deficiency: less than 20 ng/mL (50 nmol/L).  Serum 25(OH)D levels below 20 ng/mL (50 nmol/L) are clearly indicative of vitamin D deficiency.  However, several authorities note that this level appears to be too low; Heaney5 and Holick44 both state that 25(OH)D levels should always be greater than 30 ng/mL (75 nmol/L).  

           Vitamin D Insufficiency: less than 40 ng/mL (100 nmol/L).  According to Zittermannn11, hypovitaminosis D, wherein tissue levels are depleted and PTH is slightly elevated, correlates with serum levels of 30 - 40 ng/mL (75 - 100 nmol/L).  Independently, Dawson-Hughes et al46 showed that serum levels of PTH begin to elevate when 25(OH)D levels fall below 45 ng/mL (110 nmol/L) in elderly men and women, and these findings were supported by Kinyamu et al47 who found that optimal PTH status deteriorates when 25(OH)D levels fall below 49 ng/mL (122 nmol/L) in elderly women.  Therefore, in order to maintain physiologic suppression of PTH, serum levels of 25(OH)D need to be greater than 40 ng/mL (100 nmol/L). 

            Optimal Vitamin D Status: 40 – 65 ng/mL (100 - 160 nmol/L).  Based on our review of the literature, we propose that the optimal—“sufficient and safe”—range for 25(OH)D correlates with serum levels of 40 - 70 ng/mL (100 - 175 nmol/L).  This proposed optimal range is compatible with other published recommendations: Zittermann11 states that serum levels of 40 - 80 ng/mL (100 - 200 nmol/L) are “adequate”, and Mahon et al29 recently advocated an optimal range of 40 - 100 ng/mL (100 - 250 nmol/L) for patients with multiple sclerosis.  The lower end of our proposed range is consistent with suggestions by Mercola49,50 who advocates an optimal range of 45 - 50 ng/mL (115 - 128 nmol/L) and by Holick44 who states that levels should be 30 - 50 ng/mL (75 - 125 nmol/L).  The upper end of our proposed optimal range is modified from the previously mentioned ranges offered by Zittermann11 (up to 80 ng/mL [200 nmol/L]) and Mahon et al29 (up to 100 ng/mL (250 nmol/L)).  According to the authoritative monograph by Vieth1, there is no consistent, credible evidence of vitamin D toxicity associated with levels below 80 - 88 ng/mL (200 - 220 nmol/L).  Vieth1 states, “Although not strictly within the ‘normal’ range for a clothed, sun-avoiding population, serum 25(OH)D concentrations £ 220 nmol/L [88 ng/mL] are consistent with certain environments, are not unusual in the absence of vitamin D supplements, and should be regarded as being within the physiologic range for humans.”  Similarly, in his very thorough review of the literature, Zittermann11 concludes that serum 25(OH)D concentrations up to 100 ng/mL (250 nmol/L) are subtoxic.  Additional support for the safety of this upper limit comes from documentation that sun exposure alone can raise levels of 25(OH)D to more than 80 ng/mL (200 nmol/L)1 and that oral supplementation with 10,000 IU per day in healthy men resulted in serum levels greater than 80 ng/mL (200 nmol/L) with no evidence of toxicity.3  Until more data becomes available, we have chosen 65 ng/mL (160 nmol/L) rather than 80 ng/mL (200 nmol/L) as the upper end of the optimal range to provide a safety zone between the optimal level and the level which may possibly be associated with toxicity, and to allow for other factors which may promote hypercalcemia, as discussed below.  Long-term prospective interventional studies with large groups and clinical trials involving patients with vitamin D-associated illnesses such as multiple sclerosis will be needed in order to accurately define the optimal range—the serum level of vitamin D that affords protection from illness but which does not cause iatrogenic complications.  In reviewing much of the current literature, we found no evidence of adverse effects associated with a 25(OH)D level of 65 ng/mL (160 nmol/L), and we found that this level is considered normal by some medical laboratories6 and that it can be approximated and safely exceeded with frequent full-body exposure to ultraviolet light1 or oral administration of physiologic doses of 5,000 - 10,000 IU cholecalciferol per day for twenty weeks.2  Prospective studies and interventional clinical trials comparing different serum levels of 25(OH)D with clinical outcomes are necessary to elucidate the exact optimal range in various clinical conditions.  There are no acute or subacute risks associated with the 25(OH)D levels suggested here.  Conversely, there is clear evidence of long-term danger associated with vitamin D levels that are insufficient.  

           Vitamin D Excess: Serum Levels Greater than 80 ng/mL (200 nmol/L) with Accompanying Hypercalcemia.  Serum levels of 25(OH)D can exceed 80 ng/mL (200 nmol/L) with ultraviolet light exposure in the absence of oral vitamin D supplementation1,6 and with oral supplementation with 10,000 IU per day as previously mentioned2—in neither scenario is toxicity consistently observed. 25(OH)D greater than 80 ng/mL (200 nmol/L) are not indicative of toxicity unless accompanied by clinical manifestations and hypercalcemia.  Vieth1 notes that hypercalcemia due to hypervitaminosis D is always associated with serum 25(OH)D concentrations greater than 88 ng/mL (220 nmol/L), and Holick6 stated, “Vitamin D intoxication does not occur until the circulating levels of 25(OH)D are over 125 ng/mL [312 nmol/L].”  Assessment for hypervitaminosis D is performed by measurement of serum 25(OH)D and serum calcium.

 

Monitoring for Vitamin D Toxicity with 25(OH)D and Serum Calcium

Hypercalcemia can occur with vitamin D supplementation by either directly causing direct toxicity (rare) or by being associated with a vitamin D hypersensitivity syndrome (more common).  If serum calcium becomes abnormally high, then vitamin D supplementation must be discontinued until the cause of the hypercalcemia is identified; however, direct vitamin D toxicity will rarely be the sole cause of the hypercalcemia.  

The most important indicator of direct vitamin D toxicity is elevated serum calcium associated with a 25(OH)D level greater than 90 ng/ml (225 nmol/L).  Elevated 1,25(OH)D levels are commonly—though not always—seen with vitamin D toxicity.  Severe vitamin D intoxication is rare and usually seen only with industrial accidents, such as overdosing the fortification of milk, or with long-term administration of more than 40,000 IU of vitamin D per day.  Severe hypercalcemia may require urinary acidification and corticosteroids to expedite the reduction in serum calcium.51

Induction of vitamin D toxicity generally requires 1 - 4 months of 40,000 IU per day in infants.51  In adults, toxicity generally requires several months of supplementation of at least 100,000 IU per day.  Hypercalcemia appears to be the mechanism of vitamin D toxicity (rather than a direct toxic effect of the vitamin), and 25-OH-vitamin D levels may be normal in patients who are vitamin D toxic and hypercalcemic, particularly with vitamin D hypersensitivity syndrome.  It has therefore been suggested that serum calcium be measured on a weekly and then monthly basis in patients receiving high-dose vitamin D.  Manifestations attributable to hypervitaminosis D and hypercalcemia include anorexia, nausea, and vomiting followed by weakness, nervousness, pruritus, polyuria, polydipsia, renal impairment, and soft-tissue calcifications.

As a cause of hypercalcemia, vitamin D hypersensitivity syndromes are more common than vitamin D toxicity, and they generally arise when aberrant tissue uncontrollably produces the most active form of vitamin D (calcitriol).  Primary hyperparathyroidism, granulomatous disease (such as sarcoidosis, Crohn’s disease, and tuberculosis) and various forms of cancer may cause the syndrome.  25(OH)D levels are normal or even low in vitamin D hypersensitivity while serum calcium and 1,25 (OH)D levels are elevated. Additional causes include adrenal insufficiency, hyperthyroidism, hypothyroidism, and adverse drug effects, particularly with thiazide diuretics.  Whatever the cause, patients with persistent hypercalcemia should discontinue vitamin D supplementation and receive a thorough diagnostic evaluation to determine the cause of the problem.

Past and Future Vitamin D Studies: Critique and Design

Nearly all published clinical trials have suffered from flawed design, including inadequate dosing, inadequate duration, wrong type of vitamin D being used, failure to test serum vitamin D levels, and/or failure to ensure that serum vitamin D levels entered into the optimal range.  The following guidelines are provided for clinicians and researchers using vitamin D in clinical practice and therapeutic trials.

1.       Dosages of vitamin D must reflect natural supply and physiologic requirements and should therefore be in the range of 4,000 – 10,000 IU per day:

The physiologic requirement for vitamin D appears to be approximately 4,000 IU per day in adults.2  Exposure to ultraviolet light (e.g., sunshine) can produce the equivalent of 10,000 IU of vitamin D3.1  Therefore, intervention trials with supplemental vitamin D should use between 4,000 IU per day, which is presumably sufficient to meet physiologic demands, up to 10,000 IU, which is the physiologic dose attained naturally via full-body sun exposure.  Based on these physiologic criteria, we see that the majority of intervention studies in adults have used inadequate, subphysiologic doses of vitamin D.  Therefore, many studies that failed to identify therapeutic benefits from vitamin D supplementation were flawed due to insufficient therapeutic intervention—the dose of vitamin D was too low.

2.       Vitamin D supplementation must be continued for at least 6-10 months: Since serum 25(OH)D levels do not plateau until after 3 months of supplementation, and we would expect clinical and biochemical changes to become optimally apparent some time after the attainment of peak serum levels, any intervention study of less than 6-10 months is of insufficient duration to determine either maximal benefit or that vitamin D supplementation is ineffective for the condition being investigated.

3.       Supplementation should be performed with D3 rather than D2:  Although cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2) are metabolized similarly, D3 is the human nutrient and is 70% more efficient in raising serum 25[OH]D levels.11  The type of vitamin D must always be clearly stated in published research reports.

4.        Effectiveness of supplementation must include evaluation of serum vitamin D levels:  Oral supplementation is a means by which to raise vitamin D levels; supplementation is not therapeutic in itself unless it raises serum 25(OH)D levels.  To assess both efficacy and compliance, serum 25(OH)D levels must be monitored in clinical trials involving vitamin D supplementation.  Assessment of serum levels is important also to assess the relative dose-effectiveness of different preparations of vitamin D; e.g., some evidence suggests that micro-emulsification facilitates absorption of fat-soluble nutrients.49,52,53 Measurement of 1,25-dihydroxyvitamin (calcitriol) is potentially misleading and is not recommended for the evaluation of vitamin D status.

5.       Serum vitamin D levels must enter the optimal range: The majority of clinical intervention studies using vitamin D have failed to use supplementation of sufficient dosage and duration to attain optimal serum levels of vitamin D.  Our proposed optimal range for 25(OH)D is 40 - 65 ng/mL (100 - 160 nmol/L) and is presented in Figure 1. 
 

The above-mentioned criteria will aid future researchers in designing interventional studies that can accurately evaluate the relationship between vitamin D and human illness.  Clinicians, who are not conducting research but rather are interested in attaining clinical improvement in their patients, should follow these guidelines as well when using vitamin D supplementation in patients, while remembering to monitor for toxicity with the triad of clinical assessments, serum 25(OH)D, and serum calcium.  Clinicians and researchers need to remember, however, that optimal clinical effectiveness often depends on synergism of diet, lifestyle, exercise, emotional health, and other factors.  Single intervention studies are a reasonable research tool only for evaluating cause-and-effect relationships based on the presumption of a simplistic, linear model that is generally inconsistent with the complexity and multiplicity of synergistic and interconnected factors that determine health and disease.  Thus, single intervention studies with vitamin D supplementation will be useful from an intellectual standpoint insofar as they will help us to further define the role of vitamin D in human physiology and pathophysiology.  However, optimal clinical results with individual patients are more easily attained with the use of multicomponent treatment plans that address many facets of the patient’s health.48

Interventional Strategies to Treat Vitamin D Deficiency by Increasing Serum Vitamin D Levels

Human physiology adapted to and was shaped by a natural environment with ample exposure to sunlight.5  Full-body exposure to ultraviolet light on clear days in equatorial latitudes can easily provide the equivalent of 4,000 – 10,000 IU of vitamin D1 or approximately 20,000 IU of vitamin D2.8  Slightly longer durations of full-body sun exposure of approximately thirty minutes (3x the minimal erythemal dose) will produce 50,000 IU of vitamin D in lightly pigmented persons, while 5x longer durations are required for more darkly pigmented people to attain the same vitamin D production.54  The dose of vitamin D required to obtain adequate blood levels depends on latitude, sun-exposure, skin type and dietary sources.   Therefore, vitamin D supplementation above the current Food and Nutrition Board’s 2,000 IU Upper Limit (UL) for adults and 1,000 IU for infants and children should always be guided by calcium and 25(OH)D levels.  1,25(OH)D (calcitriol) has no place in routine monitoring for vitamin D supplementation, as it will mislead the practitioner. 

Vitamin D Supplementation in Adults:  When 28 men and women were administered 4,000 IU per day for up to five months, in the absence of UVB from the sun, serum 25(OH)D levels reached approximately 40 ng/mL (100 nmol/L), and no toxicity was observed.4 When 67 men were administered 5,000 and 10,000 IU of cholecalciferol per day for twenty weeks, again in the absence of UVB from the sun, serum levels of 25(OH)D increased to approximately 60 ng/mL (150 nmol/L) and 90 ng/mL (225 nmol/L), respectively, and no toxicity was observed.2  Vitamin D administration above 2,000 IU/day in adults should be periodically monitored with serum calcium and 25(OH)D levels to ensure safety and the attainment of optimal 25(OH)D levels.
 
Vitamin D Supplementation in Pregnant Women:  In 1966, two case reports and a brief review of the literature showed no adverse effects of 100,000 IU per day of vitamin D in hypoparathyroid pregnant women.55  In 1971, a study of 15 hypoparathyroid pregnant women was reported wherein the women received more than 100,000 IU per day of vitamin D with no adverse effects to the mother or child, leading the authors to conclude that there was “no risk from vitamin D in pregnancy.”56  Doses of vitamin D for pregnant women were extensively reviewed by Hollis and Wagner54 immediately prior to the completion of this article, and the authors concluded that doses of 100,000 IU per day were safe for pregnant women.  The authors write, “Thus, there is no evidence in humans that even a 100,000 IU/d dose of vitamin D for extended periods during pregnancy results in any harmful effects.”  Data from several placebo-controlled clinical trials with pregnant women show that vitamin D supplementation results in superior health status for the mother and infant.  The current daily reference intake (DRI) for vitamin D of 200 - 400 IU per day is therefore “grossly inadequate”, and administration of less than 1,000 IU vitamin D per day to pregnant women is scientifically unjustifiable and ethically questionable.   Hollis and Wagner45 conclude that up to 4,000 IU per day is necessary for pregnant women, and this conclusion is consistent with previously cited research on physiologic requirements and endogenous vitamin D production in the range of 4,000 – 10,000 IU per day.  In order to ensure safety and efficacy, vitamin D administration above 2,000 IU/day in pregnant and lactating women should be monitored with serum calcium and 25(OH)D levels.

Vitamin D Supplementation in Infants and Children: In Finland from the mid-1950’s until 1964, the recommended daily intake of vitamin D for infants was 4,000 – 5,000 IU, a dose that was considered safe and was associated with significant protection from type 1 diabetes.54  More recently, in a study involving more than 10,000 infants and children, daily administration of 2,000 IU per day was safe and effective for reducing the incidence of type 1 diabetes by 80%.16  Thus, for infants and children, doses of 1,000 IU per day are certainly safe, and higher doses should be monitored by serum calcium and 25(OH)D levels. 

Options for Raising Vitamin D Blood Levels:  We have two realistic options for increasing vitamin D levels in the body: supplementation and sunlight (e.g., ultraviolet radiation).  Sunlight is commonly unavailable on rainy or cloudy days, during the winter months, and in particular geographic locations.  Furthermore, since many people work indoors where sunshine is inaccessible, or they are partially or fully clothed when outside, reliance on sunshine to provide optimal levels of vitamin D is generally destined to provide unsatisfactory and inconsistent biochemical and clinical results.  The use of UVB tanning beds can increase vitamin D levels; but this option is more expensive and time-consuming than oral supplementation.  Additionally, excess ultraviolet radiation exposure expedites skin aging and encourages the development of skin cancer.  Given the impracticalities and disadvantages associated with relying on sun exposure to provide optimal levels of vitamin D year-round, oral vitamin D supplementation is the best option for ensuring that biochemical needs are consistently met.  

Vitamin D is either absent or present in non-therapeutic amounts in dietary sources.  One of the only major dietary sources of vitamin D is cod-liver oil, but the amount required to obtain a target dose of 4,000 IU per day would require patients to consume at least three tablespoons of cod-liver oil, or the amount contained in 18 capsules.39 Clearly this would be unpalatable and prohibitively expensive for most patients, and it would result in very low compliance.  Additionally, such a high dose of cod-liver oil may produce adverse effects with long-term use, particularly with regard to excess vitamin A, and perhaps with an increased tendency for bleeding and reduced biological activity of gamma-linolenic acid.48, 57

Discussion and Conclusions

Vitamin D is not a drug, nor should it be restricted to prescription availability.  Vitamin D is not a new or unproven “treatment.”  Vitamin D is an endogenous, naturally occurring, photochemically-produced pre-steroidal molecule with essential functions in systemic homeostasis and physiology, including modulation of calcium metabolism, cell proliferation, cardiovascular dynamics, immune/inflammatory balance, neurologic function, and genetic expression.  Insufficient endogenous production due to lack of sufficient sun exposure necessitates oral supplementation to meet physiologic needs.  Failure to meet physiologic needs is synonymous with insufficiency/deficiency and results in subtle yet widespread disturbances in cellular function which may promote the manifestation of subacute long-latency deficiency diseases such as osteoporosis, cardiovascular disease, hypertension, cancer, depression, epilepsy, type 1 diabetes, insulin resistance, autoimmune disease, migraine, polycystic ovary syndrome, and musculoskeletal pain.  In case reports, clinical trials, animal studies, and/or epidemiologic surveys, the provision of vitamin D via sunlight or supplementation has been shown to safely help prevent or improve all of the aforementioned conditions. 

Vitamin D deficiency is epidemic in the developed world, particularly among people of color, the old, the sun-deprived and medical patients58,59 and is notably common in patients with chronic musculoskeletal pain35-37 and disorders such as rheumatoid arthritis18, multiple sclerosis29, Grave’s disease38, heart disease, hypertension, diabetes, cancer, ankylosing spondylitis39, and systemic lupus erythematosus.40  As a medically valid diagnosis (ICD-9 code 268.x) with a high prevalence and clinically significant morbidity, vitamin D deficiency deserves equal attention and status with other diagnoses encountered in clinical practice.  Given the depth and breadth of the peer-reviewed research documenting the frequency and consequences of this problem, failure to diagnose vitamin D deficiency and failure to correct hypovitaminosis D by providing vitamin D supplementation is indefensible and is below the level of good healthcare.  Failure to act prudently based on the research now available in favor of vitamin D supplementation appears likely to dwarf the previous failure to act on the research supporting the use of folic acid to prevent cardiovascular disease and neural tube defects—a blunder that appears to have resulted in hundreds of thousands of unnecessary cardiovascular deaths60 and which has contributed to incalculable human suffering related to otherwise preventable neural tube defects, cervical dysplasia, cancer, osteoporosis, and mental depression.  Currently, Grant12 estimates that at least 23,000 and perhaps as many as 47,000 cancer deaths61 might be prevented each year in America if we employed simple interventions (i.e., sunshine or supplementation) to raise vitamin D levels.  Of course, additional lives may be saved and suffering reduced by alleviating the morbidity and mortality associated with hypertension, autoimmune disease, depression, epilepsy, migraine, diabetes, polycystic ovary syndrome, musculoskeletal pain, osteoporosis, and cardiovascular disease.  Until proven otherwise, the balance of the research clearly indicates that 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 is safe and reasonable 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. 

About the Authors:

Dr. Alex Vasquez is a licensed naturopathic physician in Washington and Oregon, and licensed chiropractor in Texas, where he maintains a private practice (DrAlexVasquez.com) and is a member of the research team at Biotics Research Corporation (BioticsResearch.com).  As former Adjunct Professor of Orthopedics and Rheumatology for the Naturopathic Medicine Program at Bastyr University, he is the author of more than 20 published articles and a recently published textbook for healthcare providers, “Integrative Orthopedics: The Art of Creating Wellness While Managing Acute and Chronic Musculoskeletal Disorders” available from OptimalHealthResearch.com.

Dr. Gilbert Manso is a medical doctor practicing integrative medicine in Houston, Texas (DrManso.com).  In practice for more than 35 years, he is Board Certified in Family Practice and is Associate Professor of Family Medicine at University of Texas Medical School in Houston.  

Dr. John Cannell is a medical physician 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.
 

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1)      In clinical trials, augmentation of vitamin D levels with ultraviolet light exposure or oral supplementation has been shown to benefit which of the following conditions:

a)      Osteoporosis; Hypertension
b)      Depression; Multiple sclerosis
c)      Back pain; Insulin resistance
d)      All of the above

2)      In the absence of vitamin D supplementation, ultraviolet light exposure (i.e., sunshine) can produce 25(OH)D levels that exceed current laboratory reference ranges:

a)      True
b)      False

3)      Which of the following can cause hypercalcemia?

a)      Sarcoidosis and Crohn’s disease
b)      Adrenal insufficiency and hypothyroidsm
c)      Coadministration of vitamin D and thiazide diuretics
d)      All of the above

4)      According to the current research literature reviewed in this article, which of the following may be considered long-latency deficiency diseases associated with insufficiency of vitamin D?

a)      Metabolic syndrome
b)      Autoimmune disease such as multiple sclerosis and type 1 diabetes
c)      Depression
d)      All of the above

5)      If a patient has hypovitaminosis D and a vitamin D-responsive condition such as depression, hypertension, insulin resistance, or multiple sclerosis, which of the following is appropriate first-line treatment?

a)      Drugs only
b)      Vitamin D only
c)      Correction of the vitamin D deficiency, and co-administration of medications if necessary
d)      Use of synthetic vitamin D analogs

6)      Since vitamin D is highly effective for the prevention and alleviation of several health problems, it should be regulated as a prescription drug and prohibited from public access:

a)      True
b)      False

7)      Given the prevalence and consequences of vitamin D deficiency, failure to test for and treat vitamin D insufficiency is ethical:

a)      True
b)      False

8)      Since vitamin D has a wide margin of safety, patients should be administered vitamin D routinely and receive which of the following types of follow-up:

a)      Periodic measurement of serum 1,25-dihydroxyvitamin D (calcitriol) and urinary creatinine
b)      Periodic measurement of serum 25-hydroxyvitamin D (calcidiol) and serum calcium
c)      Clinical assessments only
d)      Liver function tests and electrocardiography