High-Dose Vitamin D Supplementation: Title and subTitle BreakToo Much of a Good Thing?

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.