Rebecca B Costello, Andrea Rosanoff, Qi Dai, Leila G Saldanha, Nancy A Potischman, Perspective: Characterization of Dietary Dietary supplements Containing Calcium and Magnesium and Their Respective Ratio—Is a Rising Ratio a Trigger for Concern?, Advances in Vitamin, Quantity 12, Subject 2, March 2021, Pages 291–297, https://doi.org/10.1093/advances/nmaa160
ABSTRACT
Introduction
Low magnesium intakes coupled with excessive calcium intakes and excessive calcium-to-magnesium (Ca:Mg) consumption ratios can enhance the danger for heart problems (CVD) and metabolic syndrome (1, 2), colorectal most cancers (3), prostate most cancers (4), survival following breast most cancers (5) and most cancers mortality (6) in addition to altered vitamin D standing (7, 8). Dietary magnesium intakes have declined worldwide with the processing of meals, particularly grains (9), whereas the ratio of Ca:Mg within the eating regimen seems to be steadily rising worldwide (10) as conventional diets give option to the trendy processed-food eating regimen. This pattern has been quantified in the US (Determine 1).
The two-to-1 calcium-to-magnesium dietary consumption ratio was first steered in 1989 by the French magnesium researcher Jean Durlach as a excessive stage to not be exceeded. He warned in opposition to extreme calcium relative to magnesium intakes—that’s, one’s calcium consumption from all sources together with meals, water, and dietary supplements mustn’t exceed one’s equally whole magnesium consumption by >2 components calcium to 1 half magnesium on a weight foundation (11). Analysis since 1989 suggests an optimum vary surrounding Durlach’s advice of two.00 and that both a excessive dietary Ca:Mg consumption ratio (>2.60) or a low ratio (<1.70) can modify the effects of calcium and magnesium on disease risk (12). Evidence for this range of dietary Ca:Mg intake ratio for optimal health is small but growing A number of studies, 1 from China (12) and 9 from the United States (3–5, 13–18), have a priori evaluated the dietary Ca:Mg ratio in relation to breast, prostate, gastric, and colorectal cancer; CVD; and all-cause mortality. Described here and in Table 1 are the case-control and cohort studies. The earliest study, a case-control study (14), demonstrated that a high intake of magnesium was significantly related to a reduced risk of colorectal adenoma, but only among those who consumed dietary Ca:Mg ratios ≤2.78, not those with ratios >2.78. Within the Prostate, Lung, Colorectal, and Ovarian (PLCO) most cancers screening trial (13), contributors consuming the next calcium consumption and Ca:Mg consumption ratios between 1.70 and a pair of.50 demonstrated decreased threat of recent cancers in contrast with controls with out energetic illness on entry into the research (13). Information from the North Carolina–Louisiana Prostate Most cancers Venture (4) revealed that each African-American and European-American males identified with prostate most cancers with a complete Ca:Mg consumption ratio >2.50 had elevated odds of getting high-aggressive prostate most cancers. Nonetheless, in girls identified with breast most cancers, contributors, notably postmenopausal girls with the very best Ca:Mg ratio (>2.59), had a considerably decrease threat of all-cause mortality than these with a Ca:Mg ratio <2.59 (5). Within the NIH-AARP Weight loss program and Well being Research (19), rising magnesium was related to a decreased threat of noncardiac gastric carcinoma unbiased of the Ca:Mg ratio; nonetheless, in these with a Ca:Mg consumption ratio <1.70 there was an elevated threat of esophageal adenocarcinoma (16). Using information from the NHANES 1999–2006, greater bodily exercise coupled with a dietary Ca:Mg ratio between 1.70 and a pair of.60 confirmed a decreased threat of loss of life because of most cancers (15). In 2 massive cohort research carried out in Chinese language populations, one in males and one in girls, with low Ca:Mg consumption ratios (median ratio = 1.70), the dietary Ca:Mg consumption ratio considerably modified mortality threat (12). Few research exist inspecting dietary Ca:Mg ratios <1.70 as well as >2.60, limiting the proof base for establishing an optimum Ca:Mg reference vary. Nonetheless, present proof means that discount in illness threat can happen with a dietary Ca:Mg ratio between 1.70 to 2.60, and that these advantages could also be depending on gender and the particular well being final result.
In US adults, the Ca:Mg consumption ratio from meals alone has been >3.00 since 2000 (20). There are a lot of dietary dietary supplements obtainable to this inhabitants that comprise each calcium and magnesium, however a survey of their Ca:Mg ratio is missing.
The targets of this paper are to quantify the nutrient values of calcium and magnesium and the Ca:Mg ratio in dietary complement merchandise and to narrate these findings to present literature on the well being results of various Ca:Mg ratios.
Strategies
The NIH’s Dietary Complement Label Database (DSLD) was used to establish dietary dietary supplements containing each calcium and magnesium. The DSLD consists of label-derived info from dietary complement merchandise marketed in the US. As of February 2020, there have been 61,054 labels categorized as On Market, of which 7370 had been recognized as containing calcium and magnesium. The Superior Search function was used to customise the search by components (i.e., calcium and magnesium ≥10.0 mg), complement type (i.e., pill, liquids, powders), supposed goal group (>4 y), and by product sort [i.e., containing only minerals or containing only vitamins and minerals (MVM)]. Within the DSLD, an MVM is outlined as containing solely nutritional vitamins and minerals (MVM) and no different components. Merchandise within the database containing a mix of nutritional vitamins, minerals, and botanicals are coded individually. Solely distinctive merchandise and labels that included the quantities of calcium and magnesium had been included within the last analyses (i.e., labels in a number of package deal sizes and flavors had been deleted). The Excel 2010 statistical package deal (Microsoft Company) was used to calculate Ca:Mg ratios and imply, median, variance, and vary of Ca:Mg values for every complement type. Frequency distributions had been additionally calculated and plotted for Ca:Mg ratio by complement type. The Ca:Mg ratio by complement type for the share of dietary supplements beneath, inside, and above the ratio vary of 1.70–2.60 was decided. One-factor ANOVA was used to check variations in Ca:Mg between merchandise with significance set at P < 0.05.
Outcomes
Roughly 12% of the labels within the DSLD had been from merchandise containing each magnesium and calcium. As a comparability, 463 labels within the DSLD had been calcium-only containing merchandise with quantities starting from 19 to 3000 mg/serving, and 26 labels had been from magnesium-only containing merchandise with quantities starting from 25 to 500 mg/serving. Of the 7 separate information searches carried out in DSLD, one for every complement type, carried out between 20 January 2020 and 10 February 2020, 4308 distinctive merchandise had been entered into information evaluation for evaluate after assembly the inclusion standards (Desk 2). One-factor ANOVA of ratio means demonstrated vital Ca:Mg variations between complement classes (F worth: 21.77; F crucial issue: 2.1) with a P worth <0.05. We found a mean ratio of 2.90 across all calcium- and magnesium-containing products, with differences by product form. Powder products displayed the largest ratio spread from a low of 0.30 to a high of 48.5 (Table 2). Figure 2 displays the frequency distribution of Ca:Mg ratio by product form. Soft gels were the only supplement form that did not include products with a Ca:Mg ratio >10.0. Powders as consumed confirmed a big variety of merchandise with a ratio of ≥20.0 and displayed the very best frequency (43%) of merchandise exceeding the focused ratio vary. Total, 31% of merchandise fell beneath, 40.5% fell inside, and 28.3% fell above the ratio vary of 1.70–2.60 (Determine 3).
As some antacids carry a dietary complement label, we searched the DSLD for merchandise with antacid within the product identify. Fourteen merchandise had been recognized, solely 5 contained magnesium together with calcium. The Ca:Mg ratios for these 5 merchandise had been all >2.6, and a few considerably so, as calcium is the principle ingredient in antacids.
Present standing of information
Understanding the physiology of calcium and magnesium helps to know the potential impression of the Ca:Mg ratio. Inside cells, the magnesium ion (Mg2+) is a physiological antagonist of the calcium ion (Ca2+) (21). Thus, the mobile Ca:Mg ratio is of main significance for Ca2+-dependent signaling occasions together with the uncoupling mitochondrial electron switch from ATP synthesis, activation, and overstimulation of enzymes together with proteases, protein kinases, and NO synthase and Ca2+ transporting proteins. It’s attainable that cytosolic calcium activation outcomes from a magnesium deficit. Even small modifications in Mg2+ concentrations inside the cell could trigger disturbed Ca2+ signaling or Ca2+ toxicity (1, 21). Small will increase in dietary calcium above regular necessities have been proven to exacerbate magnesium deficiency in rats fed a low-magnesium eating regimen (22).
One idea to elucidate how extra calcium may antagonize magnesium is that magnesium and calcium share a homeostatic regulating system that entails the calcium-sensing receptor. Additionally, magnesium and calcium could compete throughout absorption within the gastrointestinal tract (12).
In relation to ailments, corresponding to most cancers, magnesium performs a key function in cell development and mediates most cancers pathology by sustaining genomic stability; regulation of cell differentiation, proliferation, and apoptosis; and prevention of angiogenesis. Mobile DNA research have indicated that >30 genes are affected by up-and-down modifications in Mg2+ content material inside the cell (23).
A number of inhabitants research report imply magnesium and calcium intakes, normally with a worth for SD and infrequently a spread. Only a few, if any, calculate Ca:Mg consumption ratios for every topic. Thus, we’ve got some medians however only a few means or variance measures of this vital consumption ratio.
Impression on the Ca:Mg ratio by supplementation
In the US, dietary complement use is widespread, with over half of adults reporting use and older adults reporting the very best use (6, 24, 25). Pooled information from 6 cycles of NHANES (1999–2000 to 2009–2010) in 30,899 adults aged ≥20 y offered info on dietary complement use (6). Of the 24,763 dietary complement customers, 33.3% used magnesium dietary supplements, consuming a imply dose of 146 mg/d. Blumberg and colleagues (26) offered an NHANES evaluation for survey years 2009–2012 in adults displaying a ten–19% lower within the prevalence of magnesium inadequacy (beneath the Estimated Common Requirement) with complement use, besides in adults >71 y of age, who retained a excessive prevalence of inadequacy of 55.2%.
Inspecting outcomes from the NHANES surveys of the Ca:Mg ratio of dietary complement customers, it’s almost definitely that dietary supplements would have a tendency to boost the Ca:Mg consumption ratio within the inhabitants of complement shoppers as proven in Determine 1. This was additionally seen in our search of the DSLD: 12% of dietary supplements within the market comprise each calcium and magnesium, with ranges of calcium as much as 3000 mg/serving. In Determine 1, the ratio calculated from complement use versus from meals from What We Eat in America clearly exhibits a generalized Ca:Mg ratio greater for these utilizing dietary supplements.
Within the North Carolina–Louisiana Prostate Most cancers Venture, the Ca:Mg ratio in complement customers was greater than in non–complement customers (common Ca:Mg of two.55 in contrast with 2.36, respectively) (Desk 1) (4), nonetheless inside the steered optimum vary however indicating that calcium supplementation (and/or a eating regimen of complete milk) was contributing to altering the ratios in a much less favorable path, as seen within the NHANES information introduced earlier.
Final, in a randomized managed trial (RCT), Dai and colleagues (3) discovered that the baseline dietary Ca:Mg ratio modified the impact of calcium supplementation on adenoma recurrence. Amongst topics with a baseline ratio above the median (>2.6), calcium supplementation (1200 mg/d) had no impact on the danger of ≥1 recurrent adenomas. In distinction, amongst these with a baseline ratio lower than or equal to the median (i.e., 2.6), 1200 mg/d calcium therapy was related to decreased threat. Very not too long ago, in the identical RCT, lowering the Ca:Mg ratio from 3.8 to ∼2.3 utilizing magnesium dietary supplements considerably improved cognitive perform amongst these aged >65 y, and led to vital demethylation within the APOE gene, a gene discovered to be an vital genetic consider Alzheimer illness.
Desk 3 summarizes the research on this evaluate by Ca:Mg reference interval. As proven, the vast majority of research present constructive or improved outcomes when the Ca:Mg consumption ratio falls inside the vary of 1.70–2.60. Each RCTs reviewed fell inside this interval ratio. It’s fascinating to notice that, inside the NIH-AARP potential cohort research, a Ca:Mg ratio <1.7 increased the risk of esophageal adenocarcinoma (16), whereas in noncardiac gastric carcinoma Ca:Mg intake ratio intervals showed no effect on risk (19), suggesting that cancer pathologies may act differently under different dietary conditions. Gender differences in total mortality were evident in the Shanghai Men's and Women's Health Study (12), with reduced risk of total mortality in men with a ratio >1.70, however in girls an elevated threat was seen with a ratio ≤1.70.
Not solely has enhancing the Ca:Mg ratio decreased the danger of a number of power ailments it has additionally improved the standing of serum vitamin D. Each in vitro and in vivo research point out that magnesium deficiency impacts enzymes that synthesize and metabolize 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] (27). In a precision-based randomized trial (7) in contributors in danger for the event of adenomas or hyperplastic polyps, the investigators discovered that lowering Ca:Mg ratios by supplementing contributors with magnesium glycinate to a ratio of ∼2.30 from 3.8 optimized vitamin D concentrations (i.e., elevated vitamin D concentrations when baseline vitamin D concentrations had been low, however decreased vitamin D concentrations when baseline vitamin D concentrations had been excessive). In one other research (8), 2 mo of magnesium supplementation (500 mg/d) in wholesome postmenopausal girls, lots of whom had been deemed to be vitamin D and magnesium poor on entry into research, confirmed that serum vitamin D [25(OH)D] concentrations elevated from a baseline of 23.6 ± 5.70 ng/mL to 27.8 ± 7.56 ng/mL. Though there was a rise in vitamin D concentrations, it was not statistically vital on this small pattern. Within the intervention group, the Ca:Mg consumption ratio on entry into the research was 3.98 and on completion of research was 1.14. The authors concluded {that a} excessive consumption of both dietary or supplemented magnesium may reduce the danger of vitamin D deficiency. This research exhibits how moderating the Ca:Mg consumption ratio with supplementation can have an effect on vitamin D standing.
An actual estimate of cumulative publicity because of complement use and the composition of the complement coupled with present meals patterns stays poorly outlined. Magnesium dietary supplements within the market at present comprise elemental magnesium as an inorganic or natural salt. Inorganic salts (e.g., magnesium oxide) comprise excessive ranges of elemental magnesium however could exhibit restricted bioavailability on account of their poor solubility. Then again, natural sources of magnesium are extremely soluble however present a lesser quantity of elemental magnesium (e.g., magnesium citrate) (28). Of curiosity is the rise in magnesium complement gross sales by 10.2% in 2018 and is on observe to go calcium because the top-selling ingredient in mineral dietary supplements, a pattern that might probably reasonable favorably the Ca:Mg ratio within the inhabitants (29).
This evaluate of dietary dietary supplements within the market confirmed that many merchandise had a Ca:Mg ratio above an optimum vary. It isn’t but recognized how continuous complement use or how the collection of inorganic versus natural types of elemental magnesium could impression a person’s total eating regimen. A limitation of this evaluate is that the data on the quantities of magnesium and calcium within the merchandise was derived from values printed on the label and weren’t analytically verified. As well as, the dietary dietary supplements containing each calcium and magnesium within the DSLD are a consultant pattern of the dietary supplements at present obtainable to the American public however not exhaustive. Because the dietary complement market is dynamic and ever altering, some off-market merchandise could have been captured within the information searches whereas new merchandise not but registered within the DSLD could have been missed. As well as, information on present whole dietary intakes, together with dietary supplements, are wanted to estimate standing within the populations and affiliation with threat of illness.
Conclusions – “calcium magnesium ratio”
This evaluate is the primary to calculate and study the Ca:Mg ratio in dietary complement merchandise by product type within the US market. All types of dietary dietary supplements contained merchandise with a Ca:Mg ratio inside the optimum vary of 1.70–2.60, however in various proportions, and over one-fourth of all merchandise confirmed Ca:Mg ratios above this optimum vary. Dietary supplements as powders, sometimes marketed to the bodily energetic inhabitants group and individuals who have issue swallowing massive drugs, confirmed a imply ratio of three.70, and MVMs confirmed a imply ratio of three.52. All complement formulations warrant shut scrutiny by shoppers when contemplating long-term consumption along side their typical dietary sample. Since Ca:Mg ratios from US diets are excessive, with out together with complement consumption, a complement with a decrease dietary Ca:Mg ratio may assist to cut back the imbalance of those vitamins however would must be primarily based on a person’s total common eating regimen. Within the case of people with excessive calcium intakes for prevention of osteoporosis, magnesium supplementation may additionally be warranted to ascertain a extra favorable Ca:Mg ratio of their total eating regimen. Extra analysis could present larger perception into whether or not the Ca:Mg ratio is a biomarker of curiosity for moderating power illness and which inhabitants teams could derive profit from moderating that ratio. Presently no conclusive suggestions might be put forth, however a steered optimum ratio vary is between 1.70 and a pair of.60.
ACKNOWLEDGEMENTS
We thank Joyce Merkel for her editorial help with the manuscript. The authors’ tasks had been as follows—RBC: compiled and analyzed the info, drafted the manuscript, and had duty for the ultimate content material; AR, LGS, QD, and NAP: revised and edited the manuscript and contributed to the content material; and all authors: learn and authorized the ultimate manuscript.
Notes
Supported by the workplace of dietary dietary supplements, nih.
Writer disclosures: RBC is a senior analysis fellow with the CMER Middle for Magnesium Schooling and Analysis. LGS holds inventory in meals and drug firms. AR serves because the director of CMER Middle for Magnesium Schooling and Analysis and holds a patent on a magnesium cream product, QD Vanderbilt College Medical Middle submitted a patent software (pending) for methylation biomarkers for measuring magnesium standing. The opposite authors report no conflicts of curiosity.
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Abbreviations used: Ca:Mg, calcium-to-magnesium (ratio); CVD, heart problems; DSLD, Dietary Complement Label Database; MVM, multivitamin-mineral; RCT, randomized managed trial; 25(OH)D, 25-hydroxyvitamin D.