Normal calcium levels and a genetic predisposition to increased levels of serum calcium does not provide protection against fractures and is not associated with increases in estimated bone mineral density (BMD), according to study results published in the British Medical Journal.

This international mendelian randomization study was designed to determine whether genetically increased levels of serum calcium were associated with increased BMD and reduced bone fractures, and to assess the potential benefits of calcium supplementation because of the cardiovascular risks that can result from increased serum calcium. Mendelian randomization was utilized to overcome confounding by using natural variations in genotype to strengthen causal inference with information that mimics a lifelong randomized controlled trial (RCT).

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A previous RCT showed that 500 mg calcium citrate in a fasting state increased total serum calcium by 1.26 mg/dL. Therefore, the analyses in this study represented a serum calcium change of 1 standard deviation (2.34 mg/dL) as the anticipated effect of calcium supplementation.

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For this study, data on genotype and estimated BMD were taken from the United Kingdom (UK) Biobank cohort; genotypic and fracture data were taken from 25 United States, UK, European, and Chinese cohorts; and genotypic and serum calcium data were taken from 17 European cohorts. Genetic determinants of serum calcium were identified by a genome-wide association meta-analysis of data on up to 61,079 individuals. The association of genetic predisposition to elevated levels of serum calcium with estimated BMD was assessed using the UK Biobank data on heel ultrasounds from 426,824 individuals with predominantly normal calcium levels. From these analyses, the researchers performed a genome-wide fracture association meta-analysis that included 76,549 cases and 470,164 in a control group.

A standard genetically derived increase in serum calcium (0.51 mg/dL) was not associated with a clinically relevant increase in estimated BMD (0.003 g/cm2; 95% CI, −0.059 to 0.066; P =.92); increase in serum calcium was also not associated with reduced odds of bone fracture in inverse variance weighted mendelian randomization analyses (odds ratio, 1.01; 95% CI, 0.89-1.15; P =.85). Sensitivity analyses did not reveal any evidence of pleiotropic effects.

Study investigators wrote, “Since genetically elevated serum calcium is strongly associated with increased risk [for] coronary artery disease, widespread calcium supplementation in the general population does not appear to have a favourable risk-benefit profile.”


Cerani A, Zhou S, Forgetta V, et al. Genetic predisposition to increased serum calcium, bone mineral density, and fracture risk in individuals with normal calcium levels: mendelian randomisation study [published online August 1, 2019]. BMJ. doi:10.1136/bmj.l4410