Safe Upper Limit of Vitamin D Identified for First Time

May 01, 2013

A new study examining more than a million individuals aged older than 45 years has, for the first time, verified an upper, safe limit for vitamin D in terms of mortality and cardiovascular events. The researchers also confirm the increased risk of death from suboptimal levels of the vitamin, corroborating the findings of many previous trials.

"In our large comprehensive database, we have determined the safe range of calcidiol blood levels and suggested a threshold for excess vitamin D, beyond which [our study participants] are at increased risk for…all-cause mortality and/or cardiovascular events. We defined a safe range of serum calcidiol of 20 to 36 ng/mL, and we found a U-shape association of the risk for [mortality or acute coronary syndrome] MACS and serum calcidiol," write Yosef Dror, PhD, from the Hebrew University of Jerusalem, Rehovot, Israel, and colleagues in their paper published online in the Journal of Clinical Endocrinology & Metabolism.

Dr. Dror told Medscape Medical News, "There is a crucial need to monitor serum calcidiol for the majority of the population."

"The amount of supplementation needs to be tailored specifically to individuals based on the range their vitamin-D blood level falls into," he and his colleagues assert. For example, in subjects with serum calcidiol levels of 20 ng/mL, supplementation of 30 µg (1200 IU) per day might suffice to attain serum calcidiol of 32 ng/mL, "while those whose blood level is 30 ng/mL may require only 5 µg (200 IU) per day, which would raise their serum calcidiol to a level of 32 ng/mL, which is still in the safe range."

The issue of whether to measure vitamin D and/or supplement it at the population level is a subject of intense interest and was debated most recently at the 2013 European Congress of Endocrinology.

Three Percent of Study Population Exceeded "Safe" Limit of Vitamin D

Dr. Dror and colleagues performed a large population-based historical prospective cohort study comprising more than 1,200,000 members of Clalit Health Services (CHS), an Israeli health maintenance organization, using electronic health records to identify CHS members who were tested for vitamin D between 2007 and 2011.

The risk of MACS was examined by vitamin-D levels, adjusted for a wide range of potential confounders.

During the 54-month study period, 422,822 CHS members were tested for calcidiol, of whom 12,280 died of any cause (905 with acute coronary syndrome) and 3933 were diagnosed with acute coronary syndrome.

Compared with those with levels of 20 to 36 ng/mL, the adjusted hazard ratios among those with levels of less than 10, 10 to 20, and greater than 36 ng/mL were 1.88, 1.25, and 1.13 (P < .05), respectively.

To Medscape Medical News, Dr. Dror noted that 3% of the studied population were at a significant risk because of high calcidiol levels (> 36 ng/L). The small size of this sample size limits the ability to perform any further analysis of this group, however, he and his colleagues note.

In contrast, "62% of our population was at significant risk for heart attack and death because of low serum calcidiol (<20 ng/mL)," he said, adding, "This…has been shown formerly by many studies."

Evidence "Not Convincing"

But in a letter published online in response to the paper by Dr. Dror et al, William B. Grant, MD, from the Sunlight, Nutrition and Health Research Center, San Francisco, California, and colleagues say this new work "is not convincing."

"Those with high serum 25(OH)D levels at the time of enrollment in the studies were most likely supplemented with vitamin D, possibly due to diagnosis of a vitamin-D-deficiency disease. Thus, their health could be undermined by years of vitamin-D deficiency, which vitamin-D supplementation late in life may not correct," they observe.

However, Dr. Dror and his team reply: "We started our study in mid-2007, due to the fact that prior to this date very few vitamin-D blood tests were taken in our [health maintenance organization]. We gathered the very first blood tests of each subject/patient during this study period, thus making it highly unlikely that these levels were influenced by supplementation.

"A substantial percentage of our patients had low or very low levels of this vitamin, and only a very small percentage exceeded the safe upper limit that we defined," they add. "Assuming that only those high-level cases were supplemented would therefore be quite improbable."

Reason for U-Shaped Curve Not Clear

"Our findings also corroborated the expected association between typical risk factors (and potential confounders), such as age, gender, ischemic heart disease history, hypertension, serum cholesterol, diabetes, smoking, and body mass index, and the risk of MACS," say the Israeli researchers. While each risk factor bears an independent risk by itself, "none of them obscured the U-shape correlation effect of serum calcidiol on MACS," they observe.

"The reason for a U-shape correlation between calcidiol blood concentration and all-cause mortality and cardiovascular morbidity that we found in our study is unclear," they add. "Vitamin D regulates the activity of more than 3000 different genes and there are at least 5 or more distinct forms of this vitamin in the circulation.

"The main activity of vitamin D is attributed to the absorption of calcium. This may explain our observation that high concentrations of this vitamin accelerate coronary calcification, an assumption that was also suggested by multiple other studies."

However, "it appears that calcitriol intervenes in more than 100 different biological functions, and at present, we do not have sound biological evidence regarding the mode of operation of vitamin D and in particular the deleterious effect of high concentrations," they conclude.

The authors have reported no relevant financial relationships. Dr. Grant receives funding from Bio-Tech Pharmacal and the Sunlight Research Forum and has received funding from the UV Foundation, the Vitamin D Council, and the Vitamin D Society.

J Clin Endocrinol Metab. Published online March 26, 2013. Abstract