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High-Dose Vitamin D Supplementation, Too Much of a Good Thing?
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JAMA. May 12 2010;303(18):1861-1862.
Bess Dawson-Hughes, MD, Sarah S. Harris, DSc, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University
from Jules: there is a very serious unaddressed question in HIV: does high dose vitamin D supplementation or any dose of vitamin D supplementation result in lasting benefits?? This research question has I think never been examined and is of obvious importance. We know vitamin D levels are low in HIV+, many researchers have recently said 'well, rates of low D levels are the same among HIV-negs as among HIV+' but this belies the problem. HIV+ individuals may suffer extremely low vit D levels for the same reasons as HIVneg individuals: not enough sun or poor diet, but also among HIV+ individuals they may suffer low vitamin D levels due to ARTs and HIV, and perhaps metabolism eats up D, and we now know HIV+ individuals suffer more osteopenia & osteoporosis at much earlier ages than in the general population & most recently data show this does in fact translate into greater fracture risk as reported at CROI and in a published study in JCEM by Grinspoon et al. So the mechanisms and the impact of low vit D levels are different in HIV+ individuals. BUT we do not know if supplementation has a lasting benefit. I can tell you the reason I raise this is because I tried two times high dose supplementation of 50,000 units for 6 weeks and several months later mu D levels were not very high and they appear to decline again over time, suggesting that low vit D levels & supplementation in HIV+ individuals is a serious concern, moreso than in HIV-neg individuals, and we NEED research to address this problem. I suspect something eats up vit D in HIV+ individuals, it might be metabolism, HIV or ARTs or all 3, but we need to examine this question with well-designed research.
"The findings raise the possibility that infrequent high doses of vitamin D are counterproductive. They also raise some question about the ultimate value of the common clinical practice of treating vitamin D-deficient patients with loading doses of vitamin D (typically 50 000 IU twice weekly for 6 to 8 weeks) at the outset of repletion. There is no evidence for adverse effects of more frequent, lower-dose regimens, so daily, weekly, or monthly dosing with vitamin D3 appears to be the best option for clinicians at this time.....The study by Sanders et al underscores the importance of simultaneously continuing to improve understanding of basic vitamin D physiology, particularly as it relates to the increased variety of supplement forms that have become available by prescription and over-the-counter. Specifically, the effect of dose size, route (intramuscular vs oral), and dosing interval on aspects of vitamin D metabolism including CYP24 activity and on local tissue-specific 1,25-dihydroxyvitamin D levels and actions should be investigated. It may also be necessary to reevaluate the risks and benefits of the current clinical practice of providing high loading doses of cholecalciferol to patients who are vitamin D deficient."
Many randomized controlled trials indicate that vitamin D will reduce falls and fractures. Therefore, the hypothesis in the study by Sanders et al1 in this issue of JAMA, that a single annual 500 000-IU oral dose of cholecalciferol (vitamin D3) would be effective in reducing falls and fractures in older women with 1 or more risk factors for falling was a reasonable one. However, not only was this regimen not effective in lowering risk, it also increased risk of falls and fractures, with the greatest increase occurring during the first 3 months after dosing. An increase in fractures but not falls was reported in another trial in which high-dose ergocalciferol was given intramuscularly each year to men and women 75 years or older.2
The biological plausibility of these findings remains speculative. One possibility is that the 500 000-IU dose may have triggered a short-term "protective" reaction in which CYP24 (25-hydroxyvitamin D-24-hydroxylase), the enzyme that catabolizes 1,25-dihydroxyvitamin D, was up-regulated, resulting in decreased blood and tissue levels of 1,25-dihydroxyvitamin D. This would be consistent with a previous study in which rats given high-dose vitamin D supplementation (75 000 IU/wk, sufficient to cause hypercalcemia) had a 46-fold increase in renal CYP24 that resulted in an almost 60% decrease in plasma 1,25-dihydroxyvitamin D.3 A similar reaction to patients in the study by Sanders et al1 may have resulted in a precipitous decrease in 1,25-dihydroxyvitamin D available to tissues with known or postulated vitamin D-receptor activity (eg, bone, muscle, brain) potentially increasing the risk of falls and fractures over a short period such as the first 3 months after dosing.
Alternatively, undocumented benefits of the intervention in this study may ironically have resulted in the untoward increase in falls and fractures. Vitamin D affects many organ systems and the level of vitamin D needed for optimal function in many tissues is not yet defined. For example, some evidence suggests that vitamin D may improve physical performance,4 reduce chronic pain,5 and improve mood6 in older adults. Such benefits may have led to increased mobility and opportunity for falls among the women who received the cholecalciferol supplement, although the proportion of falls occurring during active behavior was similar in the 2 groups. Another plausible explanation is that supplemental cholecalciferol may have decreased the rate of wintertime infections. For instance, in an observational study of Finnish soldiers, those with 25-hydroxyvitamin D levels higher than 16 ng/mL (>40 nmol/L) had fewer respiratory infections than those with lower levels.7 More recently, in a double-blind randomized controlled trial involving school girls, supplementation with 1200 IU/d of cholecalciferol during the wintertime significantly reduced influenza A infections.8 A decrease in wintertime respiratory infections in the vitamin D group could plausibly have occurred and resulted in reduced "down time," thereby increasing the opportunity for falls and fractures.
How should the findings from the study by Sanders et al1 be incorporated into clinical practice? First, these results do not alter the importance of correcting widespread vitamin D deficiency and insufficiency. Scientists and clinicians recommend maintaining a 25-hydroxyvitamin D level of at least 30 ng/mL (75 nmol/L),9 whereas others recommend different minimal values. The report by Sanders et al indicates that the specific vitamin D dosing regimen may be important. The findings raise the possibility that infrequent high doses of vitamin D are counterproductive. They also raise some question about the ultimate value of the common clinical practice of treating vitamin D-deficient patients with loading doses of vitamin D (typically 50 000 IU twice weekly for 6 to 8 weeks) at the outset of repletion. There is no evidence for adverse effects of more frequent, lower-dose regimens, so daily, weekly, or monthly dosing with vitamin D3 appears to be the best option for clinicians at this time.
The effect of vitamin D supplementation on the risk of multiple chronic conditions is currently an area of intensive and broad-reaching research efforts. The study by Sanders et al underscores the importance of simultaneously continuing to improve understanding of basic vitamin D physiology, particularly as it relates to the increased variety of supplement forms that have become available by prescription and over-the-counter. Specifically, the effect of dose size, route (intramuscular vs oral), and dosing interval on aspects of vitamin D metabolism including CYP24 activity and on local tissue-specific 1,25-dihydroxyvitamin D levels and actions should be investigated. It may also be necessary to reevaluate the risks and benefits of the current clinical practice of providing high loading doses of cholecalciferol to patients who are vitamin D deficient. In the meantime, it is important to reiterate that although vitamin D insufficiency is widespread, it can be safely corrected with a variety of existing supplement types and regimens and it should continue to be identified and treated in clinical practice.
AUTHOR INFORMATION
Corresponding Author: Bess Dawson-Hughes, MD, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington St, Boston, MA 02111 (bess.dawson-hughes@tufts.edu).
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