Abstract and Introduction
Objective. This study aims to prospectively assess the incidence of hypercalciuria and hypercalcemia with different doses of vitamin D and with a calcium intake of approximately 1,200 mg/day.
Methods. This was a 1-year randomized placebo-controlled study of vitamin D (400-4,800 IU/d) in 163 white women aged 57 to 90 years. Calcium citrate tablets (200 mg) were added to the diet to achieve a total calcium intake of approximately 1,200 mg/day in all groups. All women had vitamin D insufficiency at baseline, with serum 25-hydroxyvitaminD levels lower than 20 ng/mL (50 nmol/L). Serum and 24-hour urine calcium were collected every 3 months on supplementation, any test result above the upper reference range represented an episode of hypercalcemia or hypercalciuria. Mixed-effects models and multivariate logistic regression were used in the analysis.
Results. Hypercalcemia (>10.2 mg/dL [2.55 mmol/L]) occurred in 8.8% of white women. Hypercalciuria (>300 mg/d [7.5 mmol]) occurred in 30.6% of white women. Episodes of hypercalciuria were transient in half of the group and recurrent in the other half. No relationship between hypercalcemia or hypercalciuria and vitamin D dose was found, and hypercalciuria was equally common in the placebo group.
Conclusions. Hypercalciuria and hypercalcemia commonly occur with vitamin D and calcium supplements. Whether hypercalciuria and hypercalcemia are caused by calcium, vitamin D, or both is unclear. These findings may have relevance to the reported increase in kidney stones in the Women's Health Initiative trial. Because calcium 1,200 mg and vitamin D 800 IU/day are widely recommended in postmenopausal women, systematic evaluation of the safety of supplements is warranted in clinical management and in future studies.
Calcium and vitamin D supplements are widely recommended for the prevention of osteoporosis in post menopausal women. The recommended dietary allowance for vitamin D3 and calcium in older people is 600 to 800 IU/day and 1,200 mg/day, respectively.
There have been many trials of the effects of vitamin D and calcium on bone; however, no systematic study of potential adverse events, such as hypercalcemia, hypercalciuria, and kidney stones, has been performed.
The exact dose of vitamin D associated with toxic symptoms in humans is not known, but 56 women who developed vitamin D intoxication and hypercalcemia from drinking fortified milk had serum 25-hydroxyvitamin D (25(OH)D) levels that varied from 56 to 696 ng/mL (140-1,740 mmol/L), and some women (22%) were discharged with renal impairment and metastatic calcification. The tolerable upper level is 4,000 IU/day. Recently, a reverse J-shaped curve demonstrated a 42% increase in mortality in 247,574 men and women with serum 25(OH)D levels higher than 55 ng/mL (137 nmol/L) compared with 20 ng/mL (50 nmol/L).
Studies of toxicity after high calcium intake are rare. The recommended dietary allowance for calcium in older adults aged 50 to 70 years is 1,000 to 1,200 mg/day, and the recommended upper limit is 2,000 mg/day. Recent clinical cases of hypercalcemia have been attributed to increased calcium intake, usually calcium carbonate. In such cases, the total calcium intake could be as small as 1,000 to 2,000 mg/day.[4,5] Hypercalcemia and renal failure have been reported with as little as 1,700 mg/day. Another possible adverse event reported recently was a 31% increase in cardiovascular events in a metaanalysis of osteoporosis trials that used calcium supplements; however, it is not known if such can be attributed to hypercalcemia and hypercalciuria.
The Women's Health Initiative (WHI) trial is the only large, long-term, prospective controlled study of calcium and vitamin D supplementation; at 7 years, it reported a 17% increase in the risk of nephrolithiasis compared with placebo in this study of 36,282 women.
There has never been an evidence-based evaluation of the safety of calcium and vitamin D supplements despite their widespread use. In this article, we report on the incidence of hypercalciuria and hypercalcemia measured prospectively as a secondary outcome in a clinical trial of vitamin D and calcium supplementation in older postmenopausal women.
Menopause. 2014;21(11):1173-1180. © 2014 The North American Menopause Society