Assessment of bioavailability of Mg from Mg citrate and Mg oxide by measuring urinary excretion in Mg-saturated subjects
Tanja Werner1, Martin Kolisek1,2, Ju¨ rgen Vormann1, Ivana Pilchova2, Marian Grendar3, Eva Struharnanska4, Michal Cibulka2,5
1NuOmix Research k.s. Applied Nutriomic Research, Martin Slovakia; 2Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Biomedical Center Martin, Division of Neurosciences, Martin Slovakia;3Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Biomedical Center Martin, Department of Biostatistics, Martin Slovakia;4Comenius University in Bratislava, Faculty of Natural Sciences, Department of Molecular Biology, Bratislava Slovakia; 5Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Institute of Medical Biochemistry, Martin Slovakia
Correspondence: Tanja Werner, NuOmix Research k.s., Applied Nutriomic Research, Palisady 33, 81106 Bratislava, Slovakia; Michal Cibulka, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Institute of Medical Biochemistry, Mala Hora 4D, 03601 Martin, Slovakia
<werner@nuomix-research.com> <cibulka12@uniba.sk>
Abstract. Background: Low magnesium (Mg) levels are linked to many diseases. Studies suggest that organic salts of Mg are more readily bioavailable than its oxide or inorganic salts used for supplements production. Unfortunate- ly, the plethora of variables in the previous study designs complicates the making of any clear and reliable conclusions.Methods: 14 healthy males were supplemented for five days with 400 mg Mg to saturate Mg pools before intake of the test products. Bioavailability of 400 mg Mg from Mg citrate (MgC) and Mg oxide (MgO) after single-dose administration was assessed by measuring renal Mg excretion in 24-h urine and blood plasma [Mg] at time points 0, 2, 4, 8, and 24 h.Results: Single-dose MgC supplementation led to a significant (P< 0.05) increase in 24 h urinary Mg excretion, but this was not significant following MgO. Plasma [Mg] was also significantly higher for MgC than for MgO at 4 h (P< 0.05) and 8 h (P< 0.05). Compared with baseline levels, MgC supplemen- tation showed a significant increase in plasma [Mg] at all time points, in contrast to MgO.Conclusions: MgC shows higher bioavailability compared with MgO. Furthermore, urinary Mg excretion should be determined as the primary endpoint of Mg bioavailability studies
Key words: magnesium, bioavailability, oral magnesium supplementation, urinary magnesium excretion, plasma magnesium concentration
Introduction
Magnesium cation (Mg2+) is involved in a plethora of essential enzymatic reactions in the body. Key cellular physiological processes, including protein
synthesis, the synthesis of nucleic acids, carbohy- drate metabolism, respiration, and energy pro- duction, are dependent on Mg2+. At the systemic level, Mg2+is involved in blood glucose control and the regulation of blood pressure [1-3].
doi:10.1684/mrh.2019.0457
63
To cite this article: Werner T, Kolisek M, Vormann J, Pilchova I, Grendar M, Struharnanska E, Cibulka M.Magnes Res2019; 32
Over the past few decades, especially in industrialized countries, dietary magnesium (Mg) intake has decreased mainly because of processed food intake and overall changed food preferences and ways of food preparation. In the US, nearly one-fourth of the population has a dietary Mg intake lower than 50% of that recommended. Data from UK and Germany indicate similar tendencies [4]. Therefore, a significantly large proportion of the population is at increased risk of developing Mg deficiency.
Inadequate Mg intake contributes to the onset and progression of several complex disease conditions such as cardiovascular disease,dia- betes mellitus type 2, neurodegenerative and neuropsychiatric disorders, and migraine [5-7].
The beneficial effects of Mg supplementation in these but also in other disease conditions are extensively documented [3, 4].
Oral Mg supplementation is well documented and widely accepted to be effective in the treatment of Mg deficiency. A broad variety of Mg preparations as either medicinal or dietary supplements are currently available on the market. However, these supplements differ in their galenic preparation including their dosage, their application form, and/or the chemical form in which Mg is provided. Mg can be delivered in an inorganic form,e.g., Mg oxide (MgO, oxide) or Mg carbonate (salt), or in an organic form,e.g., Mg citrate (MgC), Mg aspartate, Mg lactate, or Mg threonate (all organic salts). Various studies on the bioavailability of Mg have suggested that, in order to improve the Mg status of the individual, organic Mg salts are more effective than inorganic Mg compounds [8]. However, because of differences in methodological proce- dures and overall study design, the results from these studies are difficult to compare.
The determination of the bioavailability of Mg salts is complicated. Most pharmacological pre- parations have no natural equivalents in the body, and their uptake into various compart- ments can be readily determined by starting at zero concentration. In contrast, Mg is always present and, moreover, its homeostasis regulates the complex homeostatic network within the organism. An increased blood Mg concentration is also effectively reduced by renal excretion [9].
Therefore, the measurement of plasma/serum Mg concentration after oral supplementation alone is insufficient to determine the rate and amount of Mg absorption. The kidneys play a
central role in the regulation of systemic Mg homeostasis by adjusting urinary Mg excretion.
Approximately 80% of serum Mg is filtered in the glomerulus, and 95–99% of the filtered Mg is reabsorbed along the nephron [9, 10]. Therefore, in human studies, the assessment of Mg bioavailability should be based on measure- ments of urinary Mg excretion, as any surplus Mg absorbed by the intestines is finally excreted into the urine. However, a prerequisite of this method is that Mg pools are saturated, and that no Mg is retained in the body to fill up deficient compartments.
In Mg-replete subjects, Mg excretion into the urine starts approximately 1-2 hours after ab- sorption. In non-Mg-deficient subjects, 24-h urine collections can be used to determine Mg absorption accurately after oral Mg supplemen- tation [11, 12].
The aim of this study was to assess the Mg bioavailability of 400 mg Mg from MgC and MgO after single-dose administration by measuring urinary excretion in Mg-saturated subjects under controlled conditions. In addition, a time course of plasma Mg concentration was deter- mined.
Methods
This single-center, randomized, open, single- dose, cross-over study of healthy male volunteers was performed to compare the bioavailability of 400 mg Mg from MgC and MgO. The bioavail- ability of Mg was determined by measuring the quantity of Mg excreted via the kidneys during a 24-h interval after Mg administration and the Mg plasma concentration before and at time points two, four, eight, and 24 hours after a single-dose administration. Because of the cross- over design, individuals served as their own control for the measured parameters.
The study was approved by the Ethical Committee at Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava (JFM CU; record numbers: EK1959/2017 and EK 2/2019).
Volunteers
Fourteen healthy male volunteers of Caucasian origin were recruited among graduate students and employees of JFM CU. The age of the
probands ranged from 23 to 56 years with a mean age of 33.148.91 years; their height ranged from 175 cm to 195 cm with a mean height of 184.36 cm6.82 cm; and their weight ranged from 76 kg to 115 kg with a mean weight of 84.21 kg10.69 kg. BMIs (body mass indexes) of probands were between 20 and 35 with a mean BMI of 24.953.75. Only male subjects were eligible because the female hormone estrogen affects Mg distribution and therefore Mg excre- tion [13].
Exclusion criteria included illnesses (e.g., diabetes) or the use of medication influencing renal function (e.g., diuretics), conditions influ- encing the absorption of test products (e.g., Crohn´s disease, ulcerative colitis), or any gas- trointestinal complaints. All subjects gave writ- ten informed consent prior to the study.
Mg preloading/Mg status equalization efficiency evaluation
To find an optimal length of the Mg status equalization period the efficiency of Mg equali- zation in 14 probands was monitored by the determination of plasma Mg concentrations [Mg]pat 0, 5, and 28 days of daily supplementa- tion with Magnesium Diasporal1 400 EXTRA (Protina Pharm. GmbH, Germany; the compo- sition is provided in table 1). Based on the outcome of the test, the 5-day Mg status equalization period was found to be optimal.
Study design
From day -7 to day -3, volunteers received daily Magnesium Diasporal1400 EXTRA containing 400 mg elemental Mg as MgC per dose to
equalize the Mg status among the subjects (figure 1). During days -2 and -1 and during sampling days 0, 1, 7, and 8, all subjects received a controlled diet strictly avoiding Mg-rich foods and any beverages including chocolate, dried fruits and nuts, mineral supplements, and Mg- rich mineral waters. All subjects collected their urine over 24 hours from the morning of day -1 (second morning urine) to the morning of day 0 (first morning urine). This sample was used as a baseline sample for all the calculations.
The study consisted of two phases. Phase I comprised days 0 and 1, whereas phase II comprised days 7 and 8. On days 0 and 7, fasting blood samples were collected from all subjects.
Subsequently, on day 0, seven subjects received a MgC formulation (Magnesium Diasporal1400 EXTRA), and seven subjects received the MgO formulation (Magnesium Diasporal1 400 EX- TRA Kapseln, Protina Pharm. GmbH, Germany;
Table 1. Composition of Mg preparations.
Magnesium Diasporal1400 EXTRA oral solutiona
Magnesium Diasporal1400 EXTRA Capsulesa
Magnesium citrate Magnesium oxide Orange fruit powder Gelatine
Citric acid Talc (anticaking agent) Potassium bicarbonate Titanium dioxide (color) Orange flavor
Sucralose Riboflavin (color) Beetroot red
aEffective dose of elemental magnesium 400 mg per dose.
Time [day]
Recruitment (N = 14)
Saturation phase 400 mg elemental Mg
Ctrl N = 7 N = 7
N = 7 8 7 6 5 4 3 2 1 0 -1 -2 -3 -4 -5 -6 -7
N = 7 Wash out phase
Sampling (24 h urine) Sampling (Mg citrate) Sampling (Mg oxide)
Figure 1. Outline of the study design. Ctrl: control baseline urine sample.
the composition is provided intable 1). On day 7, this was reversed thereby giving the cross-over design of the experiments: the second set of seven subjects received MgC, and the first set of seven subjects received MgO. Peripheral blood samples were collected in lithium-heparinized vacutainer tubes at 2, 4, 8, and 24 hours after the intake of either MgC or MgO. Blood samples were immediately centrifuged at 425gat 48C for 20 minutes. Blood plasma was subsequently transferred into sterile Eppendorf tubes and stored at -458C until analysis. The 24-h urine samples were collected by all volunteers during all the phases (control days -1 to 0, sampling days 0 to 1 and days 7 to 8). Urine samples were stabilized with 6N HCl. Urine Mg concentration ([Mg]u) and [Mg]p were determined by the methylthymol blue spectrophotometry assay by using a Flex Magnesium Reagent Cartridge in the Dimension1 Clinical Chemistry System (Siemens Health Care Diagnostics, Germany).
Statistics
The statistical analysis was performed with Student´s t-test to investigate group differences for [Mg]u and [Mg]p (table 2, figure 4). The repeated measures ANOVA test (R [14] version 3.5.2, using the nlme [15] library) was performed to evaluate differences between [Mg]p of pro- bands at time points 0, 5, and 28 days of the Mg status equalization period (figures 2 and 3). The multcomp [16] library was used for post-hoc pairwise testing with the Benjamini Hochberg correction of theP-value (P). For all statistical tests, p 0.05 was considered statistically significant. Data are presented as means (M) standard deviations (SD).
Results
Mg preloading/Mg status equalization The equalization of Mg status among study participants is a crucial step for gaining compa-
Table 2. Time course of plasma Mg concentration after single-dose administration of Mg citrate (MgC) and Mg oxide (MgO) with statistical significant differences when compared with baseline values (time point 0 h).
Time MgC MgO
Mg [mmol/L] P-value Mg [mmol/L] P-value
0 h 0.860.06 - 0.890.04 -
2 h 0.900.05 0.013091* 0.890.04 0.297572
4 h 0.920.06 0.000173*** 0.880.05 0.689661
8 h 0.940.06 0.000013*** 0.900.04 0.327753
24 h 0.890.07 0.012784* 0.860.05 0.072905
The data are presented as MSD. *P-value < 0.05; ***P-value < 0.001 0.9
***
***
**
0.8
0.7
0 5
Time (days) [Mg]plasma (mmol/L)
28
Figure 2. Plasma Mg concentration of pro- bands (n= 14) before and after 5 and 28 days of Mg preloading/equalization phase. During this phase, probands were supplemented with a daily single-dose of 400 mg Mg as Mg citrate. Pre- sented supplementation scheme led to signifi- cant increase (P< 0.001) of [Mg]p ([Mg]p (time zero)= 0.780.05 mmol/L versus [Mg]p (time five days)= 0.850.06 mmol/L) after five days, and also after 28 days (P< 0.001; [Mg]p (time ze- ro)= 0.780.05 mmol/L versus [Mg]p (time 28 days)= 0.830.06 mmol/L) of supplementation when compared to day zero. Significant [Mg]p
decrease between time points day five and day 28 was observed (P< 0.01; [Mg]p (time five days)= 0.85 0.06 mmol/Lversus [Mg]p (time 28 days)= 0.83 0.06 mmol/L). The data are presented as M SD. **P< 0.01, ***P< 0.01.
rability of the data acquired in our study.Figure 2depicts changes of [Mg]pof 14 probands at time 0, 5, and 28 days after a daily single-dose Mg administration (effective dose 400 mg in the form of MgC). The supplementation regime led to a significant increase (P< 0.001) of [Mg]p
(figures 2 and 3; [Mg]p (time zero)= 0.78 0.05 mmol/Lversus[Mg]p (time five days)=0.85 0.06 mmol/L). Further supplementation (for a total of 28 days) resulted in a significant (P< 0.001) increase of [Mg]p (figures 2 and 3;
[Mg]p (time zero)= 0.780.05 mmol/L versus [Mg]p (time 28 days)=0.830.06 mmol/L); however, [Mg]p after 28 days of Mg preloading/
supplementation was significantly lower (P< 0.01) than [Mg]p measured after 5 days of Mg supplementation (figures 2 and 3;
[Mg]p (time five days)= 0.850.06 mmol/Lversus [Mg]p (time 28 days)= 0.830.06 mmol/L). This pattern was apparent in 79% (11/14) of all the cases in the study (figure 3). In three cases (21%), [Mg]p either increased continuously over the
monitoring period (2 cases) or, after an initial [Mg]p drop measured on the day 5, [Mg]p
recovered but remained below the [Mg]p
measured at time 0 (one case; figure 3). We therefore assumed that, overall, the 5-day Mg status equalizations by supplementing pro- bands with Mg in effective dose of 400 mg in the form of MgC were sufficient and, in our setting, also optimal.
Magnesium excretion in 24-h urine
After the saturation phase with daily 400 mg Mg as MgC for 5 days, the mean 24-h urinary Mg excretion was 5.331.57 mmol. The total urine volume varied between 1170 mL and 2980 mL with a mean of 2176 mL558 mL.
Single-dose MgC supplementation led to a significant (P< 0.05) increase in 24-h urinary Mg excretion (6.602.66 mmol) compared with the control (5.331.57 mmol; figure 4). In
0.9
0.8
0.7
0 5 28
Time (days) [Mg]plasma (mmol/L)
Figure 3. Plasma Mg concentration ([Mg]p) of probands (n= 14) before and after 5 and 28 days of magnesium preloading/equalization phase. Each curve depicts the change of [Mg]p in a particular proband. In 11 (black triangles–black lines) out of 14 probands, the [Mg]p increased after 5 days of Mg supplementation and, in comparison with day 5, lowered after an additional 23 days of Mg supplementation. However, the [Mg]pafter 28 days of Mg supplementation was on average still higher than at time 0. In three (red balls– red lines) cases, the changes of [Mg]p over 28 days of Mg supplementation followed a differ- ent pattern.
10 *
8
6
4
2
0
Control Total Mg excretion in 24 h urine [mmol]
Mg citrate Mg oxide
Figure 4. Total Mg excretion in 24-h urine in mmol without supplementation (control) and after single-dose administration of 400 mg Mg as Mg citrate and Mg oxide. Significant increase (P< 0.05) was observed in total Mg excretion in case of single-dose administration of Mg citrate when compared to control (6.602.66 mmol versus (5.331.57 mmol). Differences were not significant between control and Mg oxide group and Mg citrate and Mg oxide group respectively. The data are presented as M SD. *P< 0.05.
contrast, no significant increase occurred after single-dose MgO supplementation compared with the control (6.022.19 mmolversus 5.33 1.57 mmol; P= 0.10; figure 4). No statistical difference was observed between the MgC and MgO groups (P= 0.36;figure 4).
Magnesium concentration in plasma The time course of total Mg concentration was also determined in blood plasma. Table 2 summarizes the course of plasma Mg concen- tration before and at 2, 4, 8, and 24 hours after the single-dose administration of 400 mg Mg as MgC and MgO.
Baseline values before supplementation were 0.860.06 mmol/L in the MgC group and 0.89 0.04 mmol/L in the MgO group without significant difference (P= 0.11). MgC supple- mentation showed a significantly higher in- crease in plasma Mg concentration at 4 h (MgC 0.920.06 mmol/L versus MgO 0.88 0.05 mmol/L; P< 0.05) and 8 h (MgC 0.94 0.06 mmol/LversusMgO 0.900.04 mmol/L;
P< 0.05) when compared with values for MgO.
Compared with baseline values, MgC supple- mentation led to a significant increase in plasma Mg concentration at all time points (table 2, left) reaching the highest value of 0.94 0.06 mmol/L after 8 h. Even after 24 h, a significant increase could still be seen for single-dose MgC supplementation. No signifi- cant difference at any time point could be found for MgO supplementation when compared with baseline (table 2, right).
Discussion
The aim of this study was to compare the bioavailability of organic MgC and inorganic MgO after single-dose administration in healthy male volunteers.
When measuring Mg availability, input and output have to be compared after a saturation phase of Mg pools. On control and measuring days, volunteers received a single-dose of 400 mg elemental Mg as MgC or MgO compared with a standardized low Mg diet.
MgC supplementation led to a statistically significant increase in urinary Mg excretion (+
1.27 mmol) compared with baseline in contrast to MgO (+ 0.69 mmol). In addition, [Mg]psigni-
ficantly increased after MgC supplementation at all measured time points when compared with baseline. No significant increase was observed at any time point after MgO administration. Thus, in a comparison of the two treatments, MgC led to a significant higher increase after 4 and 8 h of supplementation.
These results confirmed a previous investi- gation in which a single-dose administration of 300 mg Mg as MgC led to a significantly higher renal Mg excretion and serum Mg concentra- tion compared with that of MgO [17]. A general problem exists in determining the bioavailabil- ity of a Mg supplement. As the determination of the absolute amount of Mg absorbed from the intestines is not possible, an overflow model is usually used that determines the urinary excretion of Mg as a measure of the absorbed Mg by the intestines. A prerequisite for this method is that all absorbed Mg is excreted within a certain time period. Hence, test subjects take Mg supplements for a few days prior to the phase of determination of bioavail- ability followed by a short period (1-2 days) of washout before the test is performed. The “fill up” period is needed to replenish possible pre- existing deficits. As a consequence, studies of Mg bioavailability are generally not made in a population in which Mg supplementation is clinically required. Of course, Mg supplements are indicated in subjects with a compromised Mg status requiring the filling up of previously depleted Mg stores. As is well known, under conditions of Mg deficits, Mg absorption in the intestines but, more importantly, Mg reabsorp- tion from primary urine in the kidney are upregulated. Under a normalized Mg status, Mg absorption and reabsorption are reduced compared with a deficiency state. Therefore, the individual Mg status decides the relative bioavailability of supplemented Mg. Currently no reliable method exists to determine the exact Mg status of a person. Extracellular Mg represents only 1% of total Mg, and of the rest, about half is stored in the bones that release Mg to the plasma during Mg deficiency. In Mg deficiency, some of the supplemented Mg will be used for refilling previously lost Mg from the bone. As a consequence, this Mg is absorbed and, hence, will not be excreted into the urine.
Therefore, the determination of Mg bioavail- ability by measuring urinary Mg excretion under these conditions will lead to artificial
low values. The interindividual variability of expression and activity of Mg transporters further complicates bioavailability studies.
These factors can only be minimized by a cross-over design in which every study partici- pant is its own control. Generally, all existing evidence supports the notion that organic Mg salts are better absorbed then inorganic Mg salts, and in particular, MgC has been shown to be readily absorbed. One placebo-controlled study compared MgC with MgO and Mg amino acid chelate [18]. Coincidentally, the study subjects had a low Mg status (low plasma Mg), and therefore, this study closely resembled the clinical situation for which Mg supplements are usually used. Only MgC was able to achieve significantly increased [Mg]p. Our results, albeit from a completely different study design, underline the superiori- ty of MgC for achieving the fast uptake of Mg.
As described, an adequate saturation phase is needed to examine differences in renal Mg excretion, especially after single-dose adminis- tration. The differences in study outcomes regarding the bioavailability of Mg salts in previous studies might be attributable to the different Mg status of the test subjects.
Nevertheless, several former studies with different study designs have confirmed the superior bioavailability of MgC over MgO [18- 20].
Mg bioavailability depends on the type of Mg compound and its water solubility. MgC is water soluble in contrast to nonsoluble MgO and also shows, in an acidic environment, a better solubility than MgO [19]. With regard to solubility, the administration method or phar- maceutical form may also play a role. For example, Siener and coworkers demonstrated significantly better bioavailability of Mg from MgO if supplemented in the form of effervescent tablets instead of capsules; simply explained by the composition of the effervescent tablets (apart from MgO, sodium carbonate, sodium bicarbon- ate, and citric acid) and the reactions between auxiliary substances when dissolved in water resulting in CO2 production and acidic pH (secured by excess of citric acid), thus making Mg from MgO readily ionized and water soluble [21]. Even though, Seineret al. concluded that their results indicate better bioavailability of Mg from the effervescent tablets than from the
capsules [21], they did not compare bioavailabil- ity of Mg from MgO in effervescent form with bioavailability of Mg from any organic salt in their study (e.g., MgC). Thus, further studies comparing Mg bioavailability from effervescent MgO preparations and from MgC and/or other organic salts of Mg should be conducted to reach any conclusive data.
Overall, some studies have reported the bioavailability of various Mg preparations [22- 24], but comparative studies on the bioavailabil- ity of Mg from the different pharmaceutical formulations are lacking. In our study, MgC was given as granules for oral solution, and so Mg was dissolved and therefore in its ionized form when ingested. MgO was administered in the form of capsules because of its nonsolubility in water. As provided by the manufacturer, the capsules dissolve in an acidic environment, as found in the stomach, within 5-10 minutes, with up to 95% of Mg being released after this period.
Thus, Mg from the capsules will be dissolved and in an ionized form during the normal stomach passage time of 20 - 180 minutes [25, 26]. Both application forms were taken after overnight fasting to promote the most rapid uptake possible.
Conclusions
Future studies investigating the bioavailability of Mg salts should report urinary Mg excretion as the primary endpoint of the study after the saturation of Mg pools, because the mea- surement of the plasma/serum Mg concentration alone is insufficient to determine the rate of Mg2+ absorption and the amount of absorbed Mg2+. This should contribute to a harmonized assessment and interpretation of data from independent Mg supplementation/bioavailabili- ty studies.
Even though former studies have differed in study design, their results consistently show that organic Mg salts have a higher solubility and therefore better bioavailability than MgO.
At last, we would like to emphasize that this study was conducted with the small group of volunteers and under controlled conditions designed with the aim of creating an optimal situation to examine Mg bioavailability from MgC or MgOin vivo. Despite the low number of probands (which is comparable to other studies
of similar kind [21]), the data from this study confirm that MgC is an appropriate preparation for fast therapeutic treatment and supplement- ing purposes.
Acknowledgments
We extend our thanks to Mr. Martin Mara´k (Institute of Medical Biochemistry, Jessenius Faculty of Medicine in Martin) for competent technical support and to Dr. Theresa Jones for language editing. This study was funded by Protina Pharmazeutische GmbH. We declare that the sponsoring party did not interfere with the final study design, data acquisition, data analysis, data interpretation, or the manuscript writing.
Contributions
TW designed the study; MK, JV, IP, and MC contributed to study design; MC collected samples; TW, MK, JV, IP, ES, and MC were involved in sample postprocessing and data acquisition; TW, MK, JV, MG, and MC under- took data analysis; TW, MK, and MC wrote the manuscript; JV, MG, and IP contributed to manuscript writing.
References
1. Rude RK. Magnesium. In : Coates PM, Blackman MR, Cragg GM, Levine M, Moss J, White JD, (eds).
Encyclopedia of dietary supplements. United States: CRC Press;p. 10.
2. Rude RK, Magnesium. In : Ross CA, Cousins BHC, Tucker RJ, Ziegler KLT, (eds).Modern nutrition in health and disease. 11th ed, Netherlands: Wolters Kluwer Health Adis (ESP);159-75.
3. de Baaij JH, Hoenderop JG, Bindels RJ. Magne- sium in man: implications for health and disease.
Physiol Rev2015; 95(1):1-46.
4. Vormann J. Magnesium and kidney health–More on the ‘forgotten electrolyte’.Am J Nephrol2016;
44(5):379-80.
5. Rao YVD. Serum magnesium levels in type 2 diabetes.Int J Res Med Sci2016; 4 : 991-4.
6. Koseoglu E, Talaslioglu A, Gonul AS, Kula M.
The effects of magnesium prophylaxis in migraine without aura. Magnes Res 2008; 21 (2):101-8.
7. Rosique-Esteban N, Guasch-Ferre M, Hernandez- Alonso P, Salas-Salvado J. Dietary magnesium and cardiovascular disease: a review with emphasis in epidemiological studies. Nutrients 2018; 10 (2):168.
8. Rylander R. Bioavailability of magnesium salts–A review.J Pharm Nutr Sci2014; 4(1):57-9.
9. Wolf MT. Inherited and acquired disorders of magnesium homeostasis.Curr Opin Pediatr2017;
29(2):187-98.
10. Nielsen FH. Guidance for the determination of status indicators and dietary requirements for magnesium.Magnes Res2016; 29(4):154-60.
11. Schuchardt JP, Hahn A. Intestinal absorption and factors influencing bioavailability of magnesium –An update. Curr Nutr Food Sci 2017; 13(4):
260-78.
12. Joosten MM, Gansevoort RT, Bakker SJ. Assessing magnesium by 24-h urinary excretion.Am J Clin Nutr2015; 101(1):240-1.
13. Seelig MS. Interrelationship of magnesium and estrogen in cardiovascular and bone disorders, eclampsia, migraine and premenstrual syndrome.
J Am Coll Nutr1993; 12(4):442-58.
14. R Core Team.R: a language and environment for statistical computing. Vienna, Austria: R Founda- tion for Statistical Computing. https://www.R- project.org/.
15. Pinheiro J, Bates D, DebRoy S, Sarkar D, R Core Team. nlme: linear and nonlinear mixed effects models. R package version 3.1-137. 2018. https://
CRAN.R-project.org/package=nlme.
16. Hothorn T, Bretz F, Westfall P. Simultaneous inference in general parametric models. Biom J 2008; 50(3):346-63.
17. Kappeler D, Heimbeck I, Herpich C,et al. Higher bioavailability of magnesium citrate as compared to magnesium oxide shown by evaluation of urinary excretion and serum levels after single- dose administration in a randomized cross-over study.BMC Nutr2017; 3(1):7.
18. Walker AF, Marakis G, Christie S, Byng M. Mg citrate found more bioavailable than other Mg preparations in a randomised, double-blind study.
Magnes Res2003; 16(3):183-91.
19. Lindberg JS, Zobitz MM, Poindexter JR, Pak CY.
Magnesium bioavailability from magnesium cit- rate and magnesium oxide.J Am Coll Nutr1990; 9 (1):48-55.
20. Nestler A, Vormann J, Kolisek M. Mg supplemen- tation acutely affects intracellular Mg2+ in human leukocytes.FASEB J2012; 26(278).
21. Siener R, Jahnen A, Hesse A. Bioavailability of magnesium from different pharmaceutical formu- lations.Urol Res2010; 39(2):123-7.
22. Jahnen ASO, Hesse A. The availability of magne- sium from various preparations. In : Durlach JLB, ed. Magnesium—a relevant ion. London: John Libbey Co Ltd.;377-82.
23. Firoz M, Graber M. Bioavailability of US commer- cial magnesium preparations.Magnes Res2001; 14 (4):257-62.
24. Muhlbauer B, Schwenk M, Coram WM, et al.
Magnesium-L-aspartate-HCl and magnesium-
oxide: bioavailability in healthy volunteers.Eur J Clin Pharmacol1991; 40(4):437-8.
25. Minami H, McCallum RW. The physiology and pathophysiology of gastric emptying in humans. Gastroenterology 1984; 86(6): 1592- 610.
26. Henin E, Bergstrand M, Weitschies W, Karlsson MO. Meta-analysis of magnetic marker monitoring data to characterize the movement of single unit dosage forms though the gastrointestinal tract under fed and fasting conditions.Pharm Res2016;
33(3):751-62.
