Recommendations for consumption of a nutrient are a function of the Tolerable Upper Intake Level (UL) and the Recommended Dietary Allowances (RDA) or for some nutrients the Adequate Intake (AI). For vitamin D, the necessary evidentiary basis for a RDA (i.e., the mean requirement and an estimate of variance) could not be identified by the Institute of Medicine (IOM) in 1997 and, instead, an AI was identified[118
]. The AI is an estimated average intake by a group or groups of healthy people and may not reflect the intake needed to achieve a specific health outcome. In order to assess whether a higher vitamin D intake resulting in higher achieved 25(OH)D levels is desirable and safe, we performed a dose-response evaluation bringing together data on benefits and risks of higher doses and higher achieved 25(OH)D levels.
Based on endpoints with established causality from double-blind RCTs as well as epidemiologic data on cardiovascular health (incident hypertension, general mortality and cardiovascular mortality) and colorectal cancer prevention, our review suggests that the target range of 25(OH)D level for these benefits is not accompanied by increased risk of hypercalcemia. Notably, all endpoints evaluated for dose-response with higher 25(OH)D levels point to a similar target range of at least 75 nmol/l and better approximately 100 nmol/l.
Based on our benefit assessment, the current intake recommendations for vitamin D using the AI are insufficient to bring a majority of individuals up to at least 75 nmol/l 25(OH)D and close to 100 nmol/l. Revising recommendations towards a higher dose of vitamin D thus needs an assessment of risk with vitamin D supplementation doses that may bring most of the population into the target range of 75 to 110 nmol/l. This 25(OH)D range was reached in most trials with 1800 to 4000 IU vitamin D per day. Likely, individuals who start with lower 25(OH)D levels will need a supplementation dose at the higher end of this range[59
]. Most vulnerable to low vitamin D levels are elderly [120
], individuals living in northern latitudes with prolonged winters and thus low UVB exposure [122
], obese individuals[124
], and African Americans of all ages[36
In our current risk assessment, hypercalcemia was chosen as the critical effect
, the adverse effect occurring at the lowest intake. There were no increases in mean calcium levels with higher vitamin D intakes tested in controlled trials up to 100,000 IU per day. For single cases of hypercalcemia from RCTs, there were cases of mild hypercalcemia from 2 of 28 studies, which resolved on repeating fasting samples in one study[48
], and were more frequent in the placebo group in the second study[47
When we extend our assessment of risk to include case reports of hypercalcemia and associated 25(OH)D levels, hypercalcemia occurred in 22 of 24 cases beyond 240 nmol/l 25(OH)D. Of the two cases that occurred at serum levels below 240 nmol/l 25(OH)D, one case involved a 85 year old woman who reported consuming 400 IU/d vitamin D and had a 25(OH)D of 62 nmol/l[93
]. The other was described in a newly arrived adoptee with unknown vitamin D exposure[110
]. Notably, 21 of 24 cases of hypercalcemia occurred with 25(OH)D levels beyond 400 nmol/l.
The only RCT that documented an increased risk of nephrolithiasis was the Women's Health Initiative (WHI), which tested 400 IU vitamin D in combination with 1000 mg of calcium (hazard ratio,1.17; 95 percent confidence interval, 1.02 to 1.34)[24
]. Whether this was the only trial large enough to detect a small risk of nephrolithiasis with vitamin D supplementation or whether this was caused by the substantial calcium supplement intake taken in combination with the vitamin D and/or the additional calcium and vitamin D supplements taken by the majority of participants outside the study protocol in the WHI trial is unclear. However, the low dose vitamin D used in the WHI argues against a causal role of the increased risk of nephrolithiasis. Based on epidemiologic data, a higher vitamin D intake was not independently associated with nephrolithiasis in one large cohort[127
] consistent with findings from a recent study of 18 healthy postmenopausal women with vitamin D deficiency where vitamin D supplementation did not increase urinary calcium excretion [128
]. On the other hand, calcium supplementation was associated with a 20% increased risk of nephrolithiasis in the Nurses Health Study I[129
], although not in a cohort of younger women [129
]. Overall, the data are insufficient to identify nephrolithiasis as the critical effect
The issue of vascular calcification in persons on renal dialysis has also been addressed in detail in the 2007 risk assessment and are not addressed in this review[22
]. However, reports in the literature continue to be restricted to extremely high doses of vitamin D3 or administration of the active hormonal form, 1,25(OH)2D3 and/or related analogues, and most of these reports are in animals, not humans. There continues to be no credible evidence to support the notion that oral vitamin D doses up to and even exceeding 10,000 IU per day are associated with vascular calcification in humans, including dialysis patients, and there is no basis for identifying vascular calcification as the critical effect
There are several limitations to the evaluation of dose-response relationship through a trend-plot approach using mean serum calcium levels after treatment in trials that also report 25(OH)D levels. This approach may miss single cases of hypercalcemia. To address this problem we also assessed the report of hypercalcemia in all available controlled trials without evidence of an increased risk with higher achieved 25(OH)D levels up to 640 nmol/l or a daily dose of 100,000 IU vitamin D from controlled trials. Also, in theory, a direct comparison of the benefit and risk resulting from consumption of vitamin D would require a common metric. As an indicator of risk, we used increases in mean or individual case serum calcium level (a continuous variable, within the range permitted by physiological controls), while the benefit was assessed with the endpoints fall and fracture prevention, as well as endpoints of cardiovascular health and colorectal cancer prevention (categorical outcomes for individuals with population effects identified as relative risk). General limitations to this assessment of benefit and risk of vitamin D are that our findings may not be generalizable to particularly vulnerable subgroups of the population, such as patients of high age in critical care or those with hypersensitivity to vitamin D (e.g. sarcoidosis), as high-dose vitamin D trials are either ongoing or have not been performed in such populations. Also, we used the equivalent daily dose of vitamin D for intermittent dosing of weekly or monthly applications, which may over-estimate the per day dose to some degree[130
]. However, the benefit and risk assessment from RCTs is similar if achieved 25(OH)D levels are plotted instead of dose. Finally, we have selected observational data on the benefit of vitamin D, which largely, but may not fully represent the available literature.
The IOM established a UL for vitamin D based on hypercalcemia as the critical effect
and two studies have been cited as a matter of concern by the IOM, (1) the trial by Honkanen et al. included in our risk assessment and (2) the trial by Narang et al. not included in our risk assessment as 25(OH)D levels were not available. Notably, in the trial by Honkanen et al. the hypercalcemia observed is not relevant to the risk assessment of vitamin D because it occurred in the institutionalized control
group with a mean serum 25(OH)D concentration of 10.4 nmol/l[45
]. Both groups of hospitalized and community-dwelling older adults showed no increase in serum calcium levels with 1800 IU vitamin D per day. The trial of Narang et al. [68
] that IOM relied upon to identify a no observed adverse effect level of 2400 IU vitamin D per day and establish a UL of 2,000 IU per day is now considered unreliable because several other more recent clinical trials included in our risk analysis have failed to confirm the occurrence of hypercalcemia at intakes of up to more than ten-fold those used in that study[118
]. Consequently, the 2007 risk assessment concluded that the UL could be safely adjusted upward to 10,000 IU [22
]. Nonetheless, in general the causal relationship between excessive vitamin D intake and hypercalcemia is well established [22
]but the dose that will result in this critical effect
is higher than any used in the RCTs and prospective cohort studies that have been reported. Thus, the flat-line relationship of serum calcium to the other parameters in does not contradict the identification of hypercalcemia as the critical effect for excess vitamin D; it indicates only that the effect must occur at higher 25(OH)D concentrations and with higher oral intakes of vitamin D.
As calcium absorption is improved with higher serum 25(OH)D levels[131
], future studies may need to evaluate whether current calcium intake recommendations with higher doses of vitamin D beyond 2000 IU per day are safe or require downward adjustment [131
]. If dietary calcium is a threshold nutrient, as suggested by Dr. Heaney[119
], then that threshold for optimal calcium absorption may be at a lower calcium intake when vitamin D status is adequate.
Regarding relevant endpoints, a downward adjustment of calcium intake recommendations is supported by the recent meta-analysis on non-vertebral fracture prevention where fracture prevention at a vitamin D dose greater than 480 IU per day was independent of additional calcium supplementation. Also two recent epidemiologic studies suggested that both PTH suppression[132
] and hip bone density[133
] may only depend on a higher calcium intake if serum 25-hydroxyvitamin D levels are very low.
In this analysis we examined benefits (reductions in fractures and falls) and risks (hypercalcemia) as a function of vitamin D intake and serum concentrations of 25(OH)D in randomized trials. We also used non randomized evidence to evaluate the levels of 25(OH)D at which benefits (reductions in colorectal cancer and cardiovascular disease) and risks (hypercalcemia and nephrolithiasis) are observed. We found no pattern of evidence to suggest that risks are elevated within the ranges of serum 25(OH)D or oral vitamin intake related to increased benefits ( 75–110 nmol/l). Instead, the reliable evidence that excess vitamin D can cause hypercalcemia in generally healthy adults comes from daily intakes of vitamin D greater than 100,000 IU or serum 25(OH)D exceeding 240 nmol/L, which are far higher than those necessary to achieve the benefits. The evidence from randomized trials suggests that the dose of vitamin D supplement needed to bring the large majority of persons to the range of optimal serum 25(OH)D, may be in the range of 1800 to 4000 IU/day. Further work is needed, taking into account subject and environment factors, to better define the doses that will achieve the optimal blood levels in the large majority of the population.