Recent Clinical Trials of Vitamin D3 Supplementation and Serum Calcium Levels in Humans: Implications for Vitamin D-based Chemoprevention

Clinical trials of vitamin D supplementation published from 2000 to 2009 are reviewed, with an emphasis on changes in serum calcium levels. In these trials, vitamin D supplementation often resulted in modest increases in serum calcium levels, but rarely caused hypercalcemia. Although hypercalcemia is considered to be the only toxicity of vitamin D, many prospective studies have demonstrated associations between high normocalcemia (serum calcium levels that are high but fall within the normal reference range) and premature mortality, predominantly from cardiovascular disease. These findings suggest that high normocalcemia may represent a more sensitive index of the long-term toxicity associated with vitamin D supplementation than hypercalcemia. Therefore, efforts to chemoprevent diseases with vitamin D must consider the potential health risks associated with high normocalcemia.