Vitamin D Supplementation Dosage: A Road Map through the Confusion
By David Kiefer, MD. Dr. Kiefer is Clinical Instructor, Family Medicine, University of Washington, Seattle; Clinical Assistant Professor of Medicine, University of Arizona, Tucson; Adjunct Faculty, Bastyr University, Seattle; he reports no financial relationship to this field of study.
Researchers and clinicians now recognize Vitamin D as being a nutrient extremely important for human health. It has connections to many different body systems, with support from clinical trials and basic science research. There is evidence of efficacy for its therapeutic use in several medical conditions, as well as of the dangers associated with vitamin D insufficiency or deficiency.
What is less clear are the exact doses necessary to maintain vitamin D "health" or repair inadequacies, and what the evidence is upon which these official and anecdotal recommendations are made. Communication with colleagues recently illustrated the range of doses being used; I have heard about 1,000-2,000 IU daily for maintenance, up to 5,000 IU daily or 50,000 IU weekly for repletion, or 100,000 IU daily for three days during acute respiratory illness.
This review will draw upon a variety of sources to address this issue and provide specific clinically relevant dosing suggestions, applicable to a variety of patient situations.
Forms
Before launching into a description of the medical research, it is important to get a handle on vitamin D terminology. A variety of vitamin D forms and dosing schedules have been used in clinical trials (see Table 1). Most commonly used in supplementation are ergocalciferol (vitamin D2), a yeast-based derivative, or cholecalciferol (vitamin D3); there are some data pointing out that vitamin D2 is approximately 30% less effective in improving serum vitamin D levels than vitamin D3.1-3 Some researchers have studied the use of "active" forms of vitamin D, or the two forms, 1-alpha-hydroxy-vitamin D3 and 1,25-dihydroxyvitamin D3, that have already been partially or fully metabolized, respectively. These "active" forms have been studied in clinical trials, finding no difference in fall prevention when compared to ergocalciferol or cholecalciferol, but an increased rate of side effects such as hypercalcemia.4
Of note, most dosing is in terms of International Units, or IU (1 IU is the equivalent of 25 ng of vitamin D).
General Dosing Guidelines
Recommendations for vitamin D supplementation are varied and dependent on many factors. The top of the vitamin D treatment algorithm is to decide whether administration is for the treatment of vitamin D deficiency or insufficiency, or simply to maintain adequate vitamin D levels. For the former, recommendations vary, mostly because there is still some controversy about target serum 25-hydroxyvitamin D levels. Other considerations are oral vs. intramuscular dosing (seemingly equivalent3), and intermittent vs. daily dosing (still unresolved,5 but considered equal daily vs. weekly vs. monthly6). Of note, supplementation with 1,000 IU daily is thought to increase serum 25(OH)D by 10 ng/mL.6
Dosing from Expert Panels and Governmental Groups
As a baseline, the Dietary Reference Intake from the Institute of Medicine ranges from 200 IU to 600 IU, depending on age; these 1999 recommendations are in the midst of being re-evaluated with a report due in September 2010.1,7 Most experts now feel that, especially in the absence of regular sun exposure or for people with darker skin, maintenance dosing should be 800-1000 IU;8 certain populations may require even higher dosages (see below).
Dosing Guidance from Clinical Trials
There have been dozens of clinical trials testing the effects of supplementation of vitamin D, often with calcium, on various medical conditions. Another group of studies have attempted to correlate serum 25-hydroxy-vitamin D levels with the absence or presence of clinical pathology; such research is relevant to vitamin D dosing insofar as the resulting changes in serum levels with particular dosages. A summary list of dosing employed and results from meta-analyses and review articles can be found in Table 1.
Delving into the particulars in two often-quoted meta-analyses lends some interesting insight to this topic. Recent Cochrane reviews on pain9 and fractures10 have addressed the effects of vitamin D supplementation. For chronic pain, the primary outcome reviewed, only one of four clinical trials found an effect of vitamin D supplementation; that trial used 1-2 mg of alfacalcidol daily over 16 weeks in rheumatoid arthritis. One of the other trials had another positive effect: 100,000 IU daily of calciferol over 12 months for rheumatoid arthritis led to decreased anti-inflammatory medicine use compared to the placebo group. Two other trials, 35 mg per day (25 days of the month) of 25-hydroxyvitamin D over 9 months for polymyalgia rheumatica, and 50,000 IU D2 weekly over 3 months for diffuse musculoskeletal pain, showed no difference in subjective pain reports and visual analogue scale, respectively. For fractures, the Cochrane review of 45 trials (total participants 84,585) examined the use of several forms of vitamin D, with and without calcium, to prevent fractures in older people. The meta-analysis was able to comment on dosing, form, and connection with decreased fractures (see Table 2 for details).
Other meta-analyses have examined the connection of vitamin D to other medical conditions; these are summarized in Table 2.4,5,9-12
Dosing from Experts and Review Articles
One excellent review outlines in detail a variety of approaches to maintenance dosing and correction of vitamin D insufficiency/deficiency, with nuances relevant to specific populations.1 For example, 50,000 IU vitamin D2 every 2-4 weeks, or 800-1,000 IU D3 daily (except if pregnant or lactating, then use 1,000-2,000 IU D3 daily) are adequate maintenance doses, whereas 50,000 IU vitamin D2 every week for 8 weeks, then every 2-4 weeks, is one approach that can be used to correct deficiency.1 Effective alternative maintenance dosages are 3,000 IU D2 daily or 100,000 IU D3 every 3 months.1
Dosing for Specific Populations
Children who are breastfeeding, especially if the mother is vitamin D-deficient, need vitamin D supplementation of 400 IU D3 daily up to age 1 year, and 400-1,000 IU daily from years 1-18.1,13 Patients with kidney disease need annual monitoring of vitamin D status with dosing regimens that may include active vitamin D forms (both oral and IV), especially for stages 4 and 5 kidney failure.1 For people suffering from malabsorption syndromes, 50,000 IU D2 is used orally daily to weekly, or adequate sun exposure; tanning beds have also been explored for use in this context;1,6 it is possible that people who are obese also need higher vitamin D dosing.1,6
One specific group may be more susceptible to overtreatment with supplemental vitamin D. People with granulomatous disorders and some lymphomas may be more likely to develop hypercalcemia and hyperphosphatemia when serum 25(OH)D levels rise above 30 ng/mL; supplementation with 400 IU D3 daily may be adequate to maintain vitamin D status and avoid adverse effects in this population.1
Vitamin D Dosing in the Context of Recommendations for Sun Exposure
The issue of sun exposure is relevant not only for people with problems absorbing or converting vitamin D; the medical literature contains many references to the relevance of sufficient sun exposure, for all ages, to vitamin D status and various disease states, of course balanced by concerns from the dermatological camp about increased risk of skin cancer. Approximately 10,000-25,000 IU of vitamin D can be generated by 10-15 minutes of direct whole-body sun exposure, depending on sun intensity (latitude, time of year) and skin pigmentation (people with darker skin may need 5-10 times longer sun exposure to generate the same vitamin D).1,13 One expert recommends "sensible sun exposure" as an important adjuvant to vitamin D supplementation; such exposure, from either sunlight or ultraviolet radiation (tanning beds), would involve 5-30 minutes to arms and legs twice weekly between the hours of 10 am and 3 pm while wearing sunscreen on the face.1 A recent attempt to quantify the vitamin D production from sun exposure at different times of the day, at different latitudes, and in people with different amounts of skin pigmentation, found too much variation in vitamin D produced to accurately predict whether an individual would meet official recommendations of daily vitamin D needs, leading the authors to favor vitamin D supplementation.14 It is, of course, important to avoid excessive sun exposure, especially that which would lead to a sunburn, due to the well-known concerns about skin cancer. Of note, most experts recommend against direct sun exposure for children under the age of 6 months; for this demographic, vitamin D supplementation by itself is the best option.
Adverse Effects
Gastrointestinal effects and renal calculi continue to be mentioned as statistically more likely in vitamin D treatment groups than placebo groups.10 The statistically significant increase in renal calculi from hypercalcemia appears to be more of a concern in groups treated with alfacalcidol and 1,25-dihydroxyvitamin D.9,10 The ceiling above which dosing becomes unsafe is still being debated in the medical literature. Some researchers argue that the much-mentioned safety level of 2,000 IU daily does not apply to vitamin D2, due to its decreased potency.3 Hypercalcemia and hyperphosphatemia have been demonstrated in people taking 50,000 IU daily, though 10,000 IU D3 daily (for 5 months) in adults appears to be safe.1
Annual bolus dosing may not be safe in some populations. One study in 2,258 women older than age 70 randomized to a single oral dose of 500,000 IU D3 annually in autumn or winter vs. placebo found that the treatment group had an increased risk of both falls and fractures.15
Summary
A few summary points can be culled from this overview of vitamin D dosing:
Current DRIs are too low for general vitamin D maintenance dosing; 800-1,000 IU D3 is better for avoiding vitamin D deficiency and maintaining adequate levels.
Some bolus dosing regimens may provide a more cost-effective, convenient approach to vitamin D repletion and maintenance, though single annual treatments may not be safe for all populations.
For supplementation, vitamin D2 and D3 are more desirable in their efficacy and lack of side effects as compared to 1-alpha-hydroxy- and 1,25-dihydroxyvitamin D.
A few trials, requiring further substantiation, seem to indicate that:
- Oral and intramuscular dosing are probably similar in their ability to raise serum 25(OH)D.
- Vitamin D3 is more potent than vitamin D2 in its ability to raise serum 25(OH)D.
Including calcium with vitamin D regimens is necessary for the prevention of fractures.
References
1. Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266-281.
2. Armas LA, et al. Vitamin D2 is much less effective than vitamin D3 in humans. J Clin Endocrinol Metab 2004;89:5387-5391.
3. Romagnoli E, et al. Short and long-term variations in serum calciotropic hormones after a single very large dose of ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3) in the elderly. J Clin Endocrinol Metab 2008;93:3015-3020
4. Bischoff-Ferrari HA, et al. Fall prevention with supplemental and active forms of vitamin D. BMJ 2009;339:b3692.
5. DIPART (Vitamin D Individual Patient Analysis of Randomized Trials) Group. Patient level pooled analysis of 68 500 patients from seven major vitamin D fracture trials in US and Europe. BMJ 2010;340:b5463.
6. Pilz S, et al. Vitamin D status and arterial hypertension. Nat Rev Cardiol 2009;6:621-630.
7. Institute of Medicine of the National Academies. Dietary Reference Intakes for Vitamin D and Calcium. Available at: www.iom.edu/Activities/Nutrition/DRIVitDCalcium.aspx. Accessed May 28, 2010.
8. Vieth R. Vitamin D supplementation, 25-hydroxy-vitamin D concentrations, and safety. Am J Clin Nutr 1999;69:842-856.
9. Straube S, et al. Vitamin D for the treatment of chronic painful conditions in adults. Cochrane Database Syst Rev 2010;(1):CD007771.
10. Avenell A, et al. Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis. Cochrane Database Syst Rev 2009;(2):CD000227.
11. Wang L, et al. Systematic review: Vitamin D and calcium supplementation in prevention of cardiovascular events. Ann Intern Med 2010;152:315-323.
12. Withman MD, et al. Effect of vitamin D on blood pressure. J Hypertens 2009;27:1948-1954.
13. Casey CF, et al. Vitamin D supplementation in infants, children, and adolescents. Am Fam Physician 2010;81:745-748.
14. Terushkin V, et al. Estimated equivalency of vitamin D production from natural sun exposure versus oral vitamin D supplementation across seasons at two US latitudes. J Am Acad Dermatol 2010;62:929.e1-e9.
15. Sanders KM, et al. Annual high-dose oral vitamin D and falls and fractures in older women. JAMA 2010;303:1815-1822.
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