Assessing the potential adverse consequences of supplemental calcium on cardiovascular outcomes: should we change our approach to bone health?

OBJECTIVE: To assess cardiovascular risks associated with supplemental calcium use to assist clinicians with evidence-based recommendations for patients who have, or who are at risk for, osteoporosis or osteopenia. DATA SOURCES: Literature was accessed through December 2011 using MEDLINE, Cochrane Library, and International Pharmaceutical Abstracts using the terms calcium compounds and cardiovascular disease. In addition, reference citations from the publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION: All English-language articles were evaluated. Randomized controlled trials, observational studies, and meta-analyses were included. DATA SYNTHESIS: While supplemental calcium and vitamin D have been demonstrated to improve bone mineral density and decrease the risk of fractures, there have been recent reports that calcium supplements may increase the risk for cardiovascular events. Nine clinical trials and/or meta-analyses were reviewed; 3 documented increases in cardiovascular risk associated with calcium supplements, and 6 did not. No studies were designed to assess cardiovascular outcomes as primary end points. Balancing the evidence from these analyses with the results of randomized controlled trials assessing the effect of calcium on fracture prevention suggests that the benefits of calcium outweigh the cardiovascular risk. CONCLUSIONS: At this time, there is no cause to change routine practice surrounding supplemental calcium use in patients who have, or are at risk for, osteoporosis or osteopenia.

Transcriptional co-operativity between distant retinoic acid response elements in regulation of Cyp26A1 inducibility.

Cyp26A1 encodes an RA (retinoic acid)-catabolizing CYP (cytochrome P450) protein that plays a critical role in regulating RA distribution in vivo. Cyp26A1 expression is inducible by RA, and the locus has previously been shown to contain a RARE (RA response element), R1, within the minimal promoter [Loudig, Babichuk, White, Abu-Abed, Mueller and Petkovich (2000) Mol. Endocrinol. 14, 1483-1497]. In the present study, we report the identification of a second functional RARE (R2) located 2.0 kb upstream of the Cyp26A1 transcriptional start site. Constructs containing murine sequences encompassing both R1 and R2 showed that these elements work together to generate higher transcriptional activity upon treatment with RA than those containing R1 alone. Inclusion of R2 also dramatically enhanced the sensitivity of reporter constructs to RA, as even treatment with 10(-8) M RA resulted in a 5-fold induction of reporter activity. Mutational analysis identified R2 as the functional element responsible for the increased RA inducibility of promoter constructs. The element was shown to bind RARgamma (RA receptor gamma)/RXRalpha (retinoid X receptor alpha) heterodimers in vitro, and inclusion of nuclear receptors in transfections boosted the transcriptional response. A construct containing both R1 and R2 was used to generate a stable luciferase reporter cell line that can be used as a tool to identify factors regulating Cyp26A1 expression. The analysis of R1 and R2 has led to the proposal that the two elements work synergistically to provide a maximal response to RA and that R2 is an upstream enhancer.