Circulating Ionized Magnesium: Comparisons with Circulating Total Magnesium and the Response to Magnesium Supplementation in a Randomized Controlled Trial

Abstract

Ionized Mg (iMg) is considered the biologically active fraction of circulating total Mg (tMg). It is possible that iMg may be a more physiologically relevant marker than tMg. Using data from a double-blind pilot randomized controlled trial, we tested (1) whether oral Mg supplementation will increase iMg concentrations compared with placebo and (2) the relationship between iMg and tMg at baseline. Additionally, we evaluated the agreement between iMg measured in fresh whole blood versus stored samples. A total of fifty-nine participants were randomized 1:1 to oral Mg supplementation (400 mg/day, Mg Oxide) or placebo for 10 weeks. Fasting blood samples were obtained at baseline and follow-up. The analysis used linear regression and an intent-to-treat approach. Participants were generally healthy, the mean age was 62, and 73% were female. The baseline iMg and tMg were modestly and positively associated (r = 0.50). The ratio of baseline iMg to tMg was 64%. The mean supplement effect on iMg was 0.03 mmol/L (95% CI:0.01, 0.05) for Mg supplementation versus placebo. The supplement effect on iMg was not statistically significantly different according to baseline iMg status (above/below median). Compared to fresh blood, iMg was consistently higher in refrigerated and frozen samples by 0.14 and 0.20 mmol/L, respectively. In this relatively healthy adult population, Mg supplementation over 10 weeks resulted in increased iMg concentrations. Whether iMg is a more appropriate measure of Mg status than tMg, and the public health or clinical utility of measuring iMg remains to be determined.

Keywords: ionized magnesium; magnesium supplement; nutritional epidemiology; randomized controlled trial; total magnesium.

Figure 1

Scatterplot and linear fitted line between ionized and total magnesium at baseline, unadjusted, n = 49. Normalized ionized Mg (iMg) concentration, which is adjusted for blood pH.

Figure 2

Bland-Altman plot assessing the (a) change in ionized magnesium in response to magnesium supplementation over 10 weeks in the treatment arm, n = 22; (b) change in total magnesium in response to magnesium supplementation over 10 weeks in the treatment arm, n = 24; (c) change in ionized magnesium in response to magnesium supplementation over 10 weeks in the placebo arm, n = 27; (d) change in total magnesium in response to magnesium supplementation over 10 weeks in the placebo arm, n = 30. Normalized iMg concentration, which is adjusted for blood pH. Solid lines (black) are the mean difference ± 3 standard deviations; the long dash line (gray) is the fitted values; the short dash line (black) is the reference line for the mean difference of 0 mmol/L.

Figure 2

Bland-Altman plot assessing the (a) change in ionized magnesium in response to magnesium supplementation over 10 weeks in the treatment arm, n = 22; (b) change in total magnesium in response to magnesium supplementation over 10 weeks in the treatment arm, n = 24; (c) change in ionized magnesium in response to magnesium supplementation over 10 weeks in the placebo arm, n = 27; (d) change in total magnesium in response to magnesium supplementation over 10 weeks in the placebo arm, n = 30. Normalized iMg concentration, which is adjusted for blood pH. Solid lines (black) are the mean difference ± 3 standard deviations; the long dash line (gray) is the fitted values; the short dash line (black) is the reference line for the mean difference of 0 mmol/L.

Figure 3

Bland-Altman plot assessing the (a) association between ionized magnesium concentrations at baseline in fresh whole blood and in serum after refrigeration, n = 39; (b) the association between ionized magnesium concentrations at baseline in fresh whole blood and in serum following one freeze–thaw cycle, n = 39. Normalized iMg concentration, which is adjusted for blood pH. The median time in the fridge = 71 min. The median time frozen = 81 days. Solid lines (black) are the mean difference ± 3 standard deviations; the long dash line (gray) is the fitted values; the short dash line (black) is the reference line for the mean difference of 0 mmol/L.

Figure 3

Bland-Altman plot assessing the (a) association between ionized magnesium concentrations at baseline in fresh whole blood and in serum after refrigeration, n = 39; (b) the association between ionized magnesium concentrations at baseline in fresh whole blood and in serum following one freeze–thaw cycle, n = 39. Normalized iMg concentration, which is adjusted for blood pH. The median time in the fridge = 71 min. The median time frozen = 81 days. Solid lines (black) are the mean difference ± 3 standard deviations; the long dash line (gray) is the fitted values; the short dash line (black) is the reference line for the mean difference of 0 mmol/L.