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Recommended upper limits for vitamin D, calcium associated with hypercalciuria

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September 13, 2018

The upper-limit intake for vitamin D recommended by the Endocrine Society, when coadministered with calcium intake at the upper recommended level, is associated with increased odds for hypercalciuria when compared against recommendations from the Institute of Medicine, according to findings from a randomized, double-blind controlled trial.

The 2011 Institute of Medicine (IOM) report recommends an upper limit of 4,000 IU per day for vitamin D and 2,000 mg per day for calcium for adults aged at least 51 years, whereas the Endocrine Society guideline on vitamin D, which followed the IOM report, recommends an upper limit of 10,000 IU vitamin D per day for those considered vitamin D deficient, based on the risk for hypercalcemia, John Aloia, MD, of the Bone Mineral Research Center at Winthrop University Hospital in Mineola, New York, and colleagues wrote in the study background.

“There has been prolific research activity concerning the health benefits of calcium and vitamin D in the last 2 decades and many meta-analyses about their benefits,” Aloia and colleagues wrote. “There have not been as many studies of the possible harms of excessive intakes of these nutrients. Rather, harms data have usually been collected from adverse events in trials with a beneficial outcome as their primary aim. Many older trials did not even collect adverse events. Since the primary outcomes were unrelated to the harms, data on variables, such as serum and urinary calcium, were often not collected or presented.”

Aloia and colleagues analyzed data from 132 healthy, white, postmenopausal women aged at least 50 years with a 25-hydroxyvitamin D level less than 32 ng/mL and no history of osteoporotic fracture, hypercalciuria or hypercalcemia, recruited from Winthrop University Hospital employees and direct mail (mean age, 62 years; mean BMI, 27.2 kg/m²). Researchers randomly assigned participants to 10,000 IU daily vitamin D plus 2,000 mg per day of calcium (600 mg daily calcium carbonate twice daily with meals) or 600 IU vitamin D daily plus 2,000 mg daily calcium. Researchers assessed markers of calcium homeostasis, including serum calcium, 24-hour urinary calcium, parathyroid hormone, vitamin D metabolites and bone turnover markers at baseline and every 3 months for 1 year. Participants were monitored routinely for hypercalcemia and hypercalciuria; those who developed either condition had their calcium supplement dose reduced to 600 mg daily.

Within the cohort, mean baseline serum vitamin D level was 28 ng/mL for both groups; no participants were considered vitamin D deficient according to the IOM guidelines.

Median baseline dietary calcium intake was 878 mg per day in the high vitamin D group and 900 mg per day in the 600 IU daily group, rising to a median total intake of 1,986 mg per day and 1,843 mg per day in the high- and lower-dose vitamin D groups, respectively. At 12 months, vitamin D levels rose by a mean of 33.7 ng/mL and 8.6 ng/mL in the high- and lower-dose groups, respectively.

Hypercalciuria was defined as a 24-hour urinary calcium excretion of more than 250 mg, the generally accepted value for white women, according to researchers. Hypercalcemia was defined as serum calcium level at least 10.2 mg per 100 mL (laboratory upper range).

Hypercalcemia and hypercalciuria occurred in both the high-dose and 600-IU vitamin D groups. In the high-dose vitamin D group, 34 participants had at least one instance of hypercalciuria, with 14 developing it once, 15 developing it two to three times and five people developing it four times during follow-up.

In the lower-dose (600 IU) vitamin D group, 19 participants had at least one instance of hypercalciuria, including 10 who developed it once, seven who developed it two to three times and two who developed it four times during follow-up.

Researchers found that participants assigned to the high-dose vitamin D group were 3.6 times more likely to develop hypercalciuria vs. those in the lower-dose group (OR = 3.6; 95% CI, 1.39-9.3). There were no between-group differences for development of hypercalcemia, according to the researchers. There were no between-group differences for adverse events.

“Until further large-scale studies are performed, the [upper limit] for vitamin D proposed by the IOM is to be preferred to that proposed by the Endocrine Society,” the researchers wrote. “The [upper limit] for calcium intake should also be re-examined. The increased risk of kidney stones due to the addition of vitamin D to calcium supplements should be evaluated in large population studies.” – by Regina Schaffer

Reference:

Holick MF, et al. J Clin Endocrinol Metab. 2011; doi:10.1210/jc.2011-0385.

Dietary reference intakes for calcium and vitamin D, Available at: http://www.nationalacademies.org/hmd/~/media/Files/Report%20Files/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D/Vitamin%20D%20and%20Calcium%202010%20Report%20Brief.pdf

Disclosures: The Winthrop Research Institute funded this study. The authors report no relevant financial disclosures.

itj+ Perspective

Author Name
Perspective

Aloia and colleagues’ examination of serum and urinary calcium levels in patients on low (600 IU daily) and high (10,000 IU daily) doses of vitamin D adds to our understanding of the possible adverse effects of vitamin D and calcium supplementation. However, the description of the 10,000 IU daily dose as being an Endocrine Society recommendation for vitamin D replacement is not correct.

Like that of the Institute of Medicine, the Endocrine Society’s recommendation for routine vitamin D intake is between 600 and 800 IU daily (recommendation 2.3). Both groups also suggested 4,000 IU daily as the upper limit replacement dose that should be given to adults without medical supervision (recommendation 2.6).

The Endocrine Society’s guideline recognized that some patients with vitamin D deficiency might require higher doses. For those patients, an upper limit of 10,000 IU daily was suggested in the setting of correcting vitamin D deficiency (recommendation 2.6).

In the Aloia study, the baseline vitamin D level for patients in the 10,000 IU daily treatment group was 27.5 ng/mL. The Endocrine Society’s definition of vitamin D deficiency is less than 20 ng/mL. Therefore, the treatment of those patients with 10,000 IU daily would not have been indicated according to Endocrine Society recommendations.

Aloia and colleagues correctly note that our guideline’s discussion of hypercalciuria as a possible complication of high-dose vitamin D therapy incorrectly references a paper that does not address that issue. I appreciate them bringing this oversight to our attention. It is also important to point out that both the Institute of Medicine’s and the Endocrine Society’s guidelines are now more than 7 years old. Much has changed since that time, including suggested levels for calcium intake and testing strategies for vitamin D deficiency. While guidelines are static documents, medicine is a constantly evolving field.

Aloia and colleagues have presented important data on the possible adverse effects of high-dose vitamin D and calcium replacement. However, their findings should not be interpreted as being at odds with existing guidelines regarding vitamin D use.

Robert Lash, MD

Chief Professional and Clinical Officer,
Endocrine Society

Disclosure: Lash reports no relevant financial disclosures.