It is possible but not known if correction of vitamin D deficiency might counteract any potential detrimental vascular effect of calcium supplements [34, 35]. Finally, with the exception of the relatively small-sized trial from the same group [28], individual trials with calcium supplements did not show a significant increase in cardiovascular risk. In fact, a recent randomised placebo-controlled trial by Lewis et al., not included in the meta-analysis, did not find a higher risk of death or first-time

hospitalization from atherosclerotic vascular disease in patients on calcium supplements [36]. A subset analysis even suggested a cardioprotective effect of calcium Aurora Kinase inhibitor supplements in patients with pre-existing cardiovascular diseases. Nevertheless, the meta-analysis by Bolland et al. should be taken seriously, not as conclusive evidence but as a significant safety signal. Future LY2874455 chemical structure studies with calcium should be designed to include careful assessment of cardiovascular endpoints, preferably by learn more independent and blinded adjudication. Calcium and cancer risk There is also much controversy about the effect of calcium on the risk of cancer, with observational studies showing no effect, a protective effect or even an increased cancer risk [37]. Because the topic is diverse and the findings inconsistent, this section will

only briefly discuss the association between calcium exposure and colorectal cancer, breast cancer and prostate cancer, since these have received most attention in recent years [9]. Whilst several observational studies concluded that calcium intake does not affect the risk of colorectal cancer [38], a number

of cohort studies did find evidence for a protective effect of high total calcium intake (dietary intake plus supplements) [37, 39, 40]. In one of the main studies, a NIH-funded 7-year prospective Non-specific serine/threonine protein kinase trial in 293,907 men and 198,903 women aged 50 to 71 years, the risk reduction for colorectal cancer in the highest compared to the lowest quintile of total calcium intake was 0.79 (95% CI 0.70 to 0.89) in men and 0.72 (95% CI 0.61 to 0.86) in women [37]. Moreover, in a meta-analysis of randomised controlled trials in patients with previously removed colorectal adenomas and randomly assigned to calcium (1,200, 1,600 or 2,000 mg) or placebo, calcium supplements were significantly associated with a reduction in the risk of recurrent adenomas, considered as the precursors of colorectal cancer [41]. In line with these findings, the American College of Gastroenterology recommends daily dietary supplementation with 3 g calcium carbonate (1,200 mg calcium) in the prevention of recurrent colorectal adenomas [42]. Despite these data from observational studies and adenoma prevention trials, it is still uncertain if calcium supplements prevent colorectal cancer because large-scale long-term randomised controlled trials are not available.