International Journal of Endocrinology
Volume 2018 (2018), Article ID 9041694, 17 pages
https://doi.org/10.1155/2018/9041694

Review Article

Magnesium and Human Health: Perspectives and Research Directions

Abdullah M. Al Alawi,1,2 Sandawana William Majoni,1,3,4 and Henrik Falhammar1,3,5,6

¹Division of Medicine, Royal Darwin Hospital, Darwin, NT, Australia
²Department of Medicine, Sultan Qaboos University Hospital, Muscat, Oman
³Menzies School of Health Research, Darwin, NT, Australia
⁴Northern Territory Medical Program, Flinders University School of Medicine, Darwin, NT, Australia
⁵Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden
⁶Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

Correspondence should be addressed to Abdullah M. Al Alawi; dr.abdullahalalawi@gmail.com

Received 12 October 2017; Revised 22 February 2018; Accepted 5 March 2018; Published 16 April 2018

Academic Editor: Michael Horowitz

Copyright © 2018 Abdullah M. Al Alawi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Magnesium is the fourth most abundant cation in the body. It has several functions in the human body including its role as a cofactor for more than 300 enzymatic reactions. Several studies have shown that hypomagnesemia is a common electrolyte derangement in clinical setting especially in patients admitted to intensive care unit where it has been found to be associated with increase mortality and hospital stay. Hypomagnesemia can be caused by a wide range of inherited and acquired diseases. It can also be a side effect of several medications. Many studies have reported that reduced levels of magnesium are associated with a wide range of chronic diseases. Magnesium can play important therapeutic and preventive role in several conditions such as diabetes, osteoporosis, bronchial asthma, preeclampsia, migraine, and cardiovascular diseases. This review is aimed at comprehensively collating the current available published evidence and clinical correlates of magnesium disorders.

1. Introduction

Magnesium (Mg²⁺) has several functions in the human body. It acts as a cofactor for more than 300 enzymes, regulating a number of fundamental functions such as muscle contraction, neuromuscular conduction, glycemic control, myocardial contraction, and blood pressure [1, 2]. Moreover, magnesium also plays a vital role in energy production, active transmembrane transport for other ions, synthesis of nuclear materials, and bone development [2]. Furthermore, magnesium deficiency has been associated with a wide range of diseases. Additionally, many studies have demonstrated beneficial effects of magnesium supplementation. In this review, the magnesium cycle in the human body, magnesium deficiency and its causes, diseases associated with low magnesium, hypermagnesemia, and the role of magnesium in therapy and prevention will be discussed.

1.1. Magnesium and Nutrition

According to the United States Food and Nutrition Board, recommended daily allowance for magnesium is 420 mg for adult males and 320 mg for adult females, respectively [3]. Approximately 10% of the daily magnesium requirement is derived from water. Green vegetables, nuts, seeds, and unprocessed cereals are rich sources of magnesium. Also, some magnesium is available in fruits, fish, meat, and milk products [2].

The majority of the population in the Western countries consume less than the recommended amount of magnesium, contributed by the consumption of processed foods, demineralized water, and agricultural practices using soil deficient in magnesium for growing food [3–5].

2. Magnesium Absorption and Excretion

Magnesium homeostasis is regulated by the intestines, the bones, and the kidneys [4]. The majority of magnesium is absorbed by a passive paracellular mechanism in the ileum and distal parts of the jejunum, while a smaller amount is actively transported in the large intestine [2, 6]. Around 24–76% of ingested magnesium is absorbed in the gut and the remaining is eliminated in the feces. The proportion of absorbed magnesium from the gut depends on the amount of ingested magnesium [3] and the status of magnesium in the body [2, 4].

The magnesium homeostasis is primarily regulated by the kidneys [4]. The glomeruli filter around 2400 mg of magnesium per day. About 95% of excreted magnesium is reabsorbed, mainly by the thick ascending limb of the loop of Henle (65%) and to a lesser extent in the distal tubules (30%) [4, 7]. Only around 100 mg of magnesium is excreted in the urine each day, and the kidneys can regulate the amount excreted, depending on the serum level of magnesium [4]. Figure 1 illustrates the magnesium balance in the human body.

Figure 1: Magnesium balance in the human body.

3. Role of Hormones in Magnesium Homeostasis

Vitamin D, parathyroid hormone (PTH), and estrogen are hormones that play an important role in magnesium homeostasis (Table 1) [2, 8]. The relationship between PTH and magnesium is complex and similar to calcium; high serum magnesium levels suppress the secretion of PTH via activation of calcium-sensing receptor (CaSR) present on the chief cells of the parathyroid glands. In contrast, low serum magnesium stimulates PTH secretion.

Table 1: Role of vitamins and hormones in magnesium homeostasis.

Hormone/vitamin
Role of hormones/vitamins
Comments

Vitamin D
1,25-Dihydroxyvitamin D3 can stimulate intestinal magnesium absorption.
Mg is required for metabolism of vitamin D in the liver and the kidneys and also for its transportation in serum.

PTH
Helps in the reabsorption of Mg in the kidney, absorption in the gut, and release from the bone.
Hypercalcemia interferes with the role of PTH in magnesium regulation.

Estrogen
Enhances Mg reabsorption in the kidney and absorption in the gut by stimulating TRPM6 expression.

Mg: magnesium; PTH: parathyroid hormone.

Magnesium has important role in adenylate cyclase activity required for cyclic adenosine monophosphate (cAMP) which is involved in PTH secretion and end organ effects of PTH. Severe hypomagnesemia (<0.4 mmol/L) causes reduced cAMP levels which can result in reduced secretion of PTH and increased peripheral resistance [9, 10]. In addition, molecular studies have suggested that severe hypomagnesemia causes blockage of PTH secretion by disinhibition of G[α] subunits and subsequently activation of the CaSR [11]. This paradoxical effect of hypomagnesemia can result in hypocalcemia in patients with severe hypomagnesemia [12]. On the other hand, PTH enhances the reabsorption of magnesium in the distal convoluted tubule and the gut and increases the release of magnesium from the bone [2].

4. Magnesium Storage and Circulation

The total body magnesium in the average adult is around 1000 mmol or 24 g, that is, 20 mmol/kg of lean body mass [4]. The bones store about 50–60% of the total magnesium content while muscles and other soft tissues store around 40–50% [3]. Around one-third of the bone magnesium content is available for exchange to maintain the levels of extracellular magnesium [4]. Less than 2% of magnesium in the body is available in serum and red blood cells, accounting for the extracellular magnesium in the body [3].

5. Magnesium Transcellular Transportation

Due to the very important role of magnesium in the human body, the levels of cellular magnesium need to be strictly regulated. Several specific transporters controlling the cellular movements of magnesium have been identified [13]. Using the electrochemical gradient of Na⁺ and through cations channels, magnesium enters cells via Mg²⁺/anion cotransport. Eight cation channels have been identified including transient receptor potential melastatin cation channels 6 and 7 (TRPM6, TRPM7), members 1 and 2 (SLC41A1, SLC41A2) channels, ancient conserved domain protein 2 (ACDP2), the mitochondrial RNA splicing 2 protein (Mrs2p), magnesium transporter 1 (MagT1), the human solute carrier family 41, and paracellin-1 [13]. TRPM7 is the most selective channel for magnesium, and it has been identified in the heart, blood vessels, lungs, liver, brain, intestine, and spleen. It is essential for regulating intracellular magnesium level, cell survival, and function [14]. On the other hand, TRPM6 is mainly responsible for regulating the total body magnesium level via the kidney and intestines [15]. Mrs2p, SLC41A1, and SLC41A2 are implicated in magnesium transportation in the mitochondria and hence have a regulatory role related to metabolic, cardiovascular, and neurological functions [16]. Magnesium efflux involves several exchanges including Na⁺/Mg²⁺, Ca²⁺/Mg²⁺, Mn²⁺/Mg²⁺ antiporter, and Cl⁻/Mg²⁺ cotransporter [13]. The most important exchanger is Na⁺/Mg²⁺ exchanger which has been identified in many cells including cardiac and vascular smooth cells. Several factors have been found to effect the function of this exchanger such as vasopressin, angiotensin II, and insulin [13, 17].

6. Role of Magnesium in the Human Body

Magnesium is the fourth most abundant cation in the body and the second most abundant intracellular cation after potassium [18]. Magnesium is an essential cofactor for a diverse metabolic reactions involving more than 300 enzymes within the human body [19]. It acts as counter ion for the energy-rich ATP and nucleic acids, regulates transmembrane transport [20], and has various roles in function and structure of proteins, nucleic acid, and mitochondria [2]. Magnesium is an important mineral for bone mineralization, muscular relaxation, and several other cellular functions [18] (Table 2).

Table 2: Role of magnesium in the human body.

Cofactor for enzymes involved in

Protein synthesis, muscle and nerve transmission, neuromuscular conduction, and blood glucose and blood pressure regulation.

Role in active transport

Facilitates active transport of calcium and potassium ions across cell membranes, which is essential for the conduction of nerve impulses, muscle contraction, maintaining vasomotor tone, and normal heart rhythm.

Structural roles

Important for the structure of bones, proteins, many enzymes, mitochondria, DNA, and RNA.

Role in immunological functions

Involved in macrophage activation, adherence, and bactericidal activity of granulocyte oxidative burst, lymphocyte proliferation, and endotoxin binding to monocytes.

7. Assessment of Magnesium Status

In clinical practice, serum magnesium concentration is the most commonly used test to assess the magnesium status, and the normal reference range is usually 0.7–1 mmol/L (equivalent to 1.5–2 mEq/L or 1.7–2.4 mg/dL) [21]. However, the normal value varies from laboratory to laboratory, and different studies have used slightly different ranges. This may partially explain the differences in the prevalence of magnesium imbalances reported in different groups of patients with similar characteristics [4].

Normal serum magnesium does not necessarily mean adequate content of total body magnesium because only less than 0.3% of total body magnesium is found in serum [4]. Serum magnesium is in most places not part of routine blood tests, and it should be assessed in the relevant clinical conditions such as arrhythmia, hypokalemia, hypocalcemia, diarrhea, and chronic alcoholism that tend to be associated with magnesium derangement [20]. Assessment is also recommended if the patient is critically ill or when being administered certain medications known to cause hypomagnesemia. Table 3 lists other more accurate but lesser used measures of assessing magnesium status [2, 22].

Table 3: Assessment of magnesium status.

Test
Comments

Serum magnesium
Sometimes not adequate since less than 0.3% of total body magnesium is found in serum. However, it is easy, accessible, and cheap.

24 hours excretion in urine or the fractional excretion of magnesium
Helps in differentiating renal wasting of magnesium from inadequate intake or poor absorption as an etiology for hypomagnesemia.

Magnesium loading test
Identifies patients with normomagnesic magnesium deficiency.

Assesses intestinal absorption of magnesium.

Indirectly assesses bone status of magnesium.

Magnesium concentration in RBCs
Can give early indication of magnesium deficiency.

Isotopic analysis of magnesium
Assesses the absorption of magnesium from the gastrointestinal tract in research setting.

Ionized magnesium
More accurate, especially in critically ill patients with rapid change in hemodynamics.

Not effected by low albumin.

RBCs: red blood cell counts.

8. Hypomagnesemia

Several studies have shown that hypomagnesemia is a common electrolyte derangement in clinical setting especially in patients admitted to intensive care unit (ICU) where it was found to be associated with increased mortality and hospital stay [23–25] (Table 4).

Table 4: Prevalence of hypomagnesemia in different populations and under different clinical settings.

Authors
Country and year
Definition
Sample
Sample size
Prevalence

Chernow [23]
USA, 1989
<0.75 mmol/L
ICU
193
61%

Schimatschek and Rempis [24]
Germany, 2001
<0.76 mmol/L
Unselected population
16,000
14.5%

Cheungpasitporn et al. [25]
USA, 2015
<0.70 mmol/L
Hospitalized patients
65,974
20.2%

ICU: intensive care unit.

8.1. Symptoms of Hypomagnesemia

Symptoms of magnesium deficiency can be nonspecific and usually overlap with symptoms of other electrolyte imbalances. The severity of symptoms and signs depends on the degree of magnesium depletion and rate of magnesium decline. The symptoms usually occur when serum magnesium levels fall below 0.5 mmol/L (1.2 mg/dL) [26]. The clinical manifestations of hypomagnesemia may affect every system including neuromuscular, cardiovascular, renal, and gastrointestinal systems (Table 5) [4, 18]. The impact of chronic magnesium (Figure 2) depletion will be discussed in more depth later.

Table 5: Clinical and laboratory manifestations of hypomagnesemia.

System
Manifestations

Neuromuscular
Tremors, muscle fasciculation, muscle spasms and cramps, muscle contractions, numbness, tingling, and weakness.

Central nervous
Agitation, depression, sudden change in behavior, encephalopathy, and seizures.

Cardiovascular
Cardiac arrhythmia and ECG changes.

Gastrointestinal
Loss of appetite, nausea, and vomiting.

Metabolic
Hypokalemia and hypocalcemia.

Figure 2: Impact of hypomagnesemia.

8.2. Causes of Hypomagnesemia

Causes of hypomagnesemia can be categorized into genetic causes [19] (Table 6) and acquired causes. The acquired causes can be attributed to decreased oral intake or GI absorption, increased renal loss, or redistribution triggered by severe illness [2]. Several medications are also known to influence serum magnesium levels by different mechanisms [4, 6, 27–31] (Table 7).

Table 6: The most common genetic disorders causing hypomagnesemia.

Disorder
Inheritance
Gene
Other features (other than hypomagnesemia)

Hypercalciuric hypomagnesemias
Hypercalciuria and nephrocalcinosis

FHHNC type 1
AR
CLDN16
Polyuria/polydipsia, elevated serum PTH, and renal failure

FHHNC type 2
AR
CLDN19
Besides FHHNC type 1 features, patient has ocular abnormalities

ADHH Bartter syndrome type 5
AD
CASR
Hypocalcemia with normal or low PTH

Bartter syndrome type 3 (classical type)
AR
CLCNKB
Gitelman-like phenotype possible, rarely nephrocalcinosis

Gitelman-like hypomagnesemias
Hypocalciuria, hypokalemia, and metabolic alkalosis

Gitelman syndrome
AR
SLC12A3
Chondrocalcinosis at older age

ADTKD/RCAD
AD
HNF1B
Renal, genital, and pancreatic abnormalities

Mitochondrial hypomagnesemias

KSS
Mt
Mitochondrial deletion
External ophthalmoplegia, retinopathy, and cardiac conduction defects

ADHH: autosomal dominant hypocalcemia with hypocalciuria; ADTKD: autosomal dominant tubulointerstitial kidney disease; FHHNC: familial hypomagnesemia with hypocalcemia and nephrocalcinosis; RCAD: renal cysts and diabetes; KSS: Kearns-Sayre syndrome; AR: autosomal recessive; AD: autosomal dominant.

Table 7: Medications associated with hypomagnesemia.

Medications
System
Pathophysiology

Aminoglycoside antibiotics
Renal
Impair renal tubular reabsorption ± acute tubular necrosis (ATN)

Amphotericin B
Renal
Renal toxicity and impaired magnesium reabsorption

Antiepidermal growth factor (EGF) receptor (e.g., cetuximab)
Renal
Impairs magnesium reabsorption

Calcineurin inhibitors (e.g., cyclosporine and tacrolimus)
Renal
Impair magnesium reabsorption

Platinum derivatives (e.g., cisplatin and carboplatin)
Renal
Impair magnesium reabsorption

Loop and thiazide diuretics
Renal
Impair magnesium reabsorption

Pentamidine
Renal
Impairs magnesium reabsorption

Proton pump inhibitors (PPI)
GI
Reduce intestinal absorption of magnesium by downregulating the TRPM6 transporters.

GI: gastrointestinal.

8.2.1. Decreased Intake

Several dietary surveys have shown that people in North America and Europe consume less than recommended daily allowance (RDA) for magnesium as a result of food processing and the use of poor soil for agriculture [2, 5, 32]. Hypomagnesemia can also occur in times of prolonged fasting, total parenteral nutrition, or prolonged nasogastric suctioning [33].

8.2.2. Impaired Gastrointestinal Absorption

Impaired gastrointestinal absorption of magnesium can be caused by a number of factors including chronic diarrhea, pancreatic insufficiency, celiac disease, chronic alcoholism, inflammatory bowel diseases, and short gut syndrome [26].

8.2.3. Redistribution and Intracellular Magnesium Shift

Acute pancreatitis associated with fat necrosis can cause hypomagnesemia via saponification. Additionally, there are certain conditions that can result in an intracellular shift in magnesium distribution. These include the refeeding syndrome, pregnancy, lactation, and cardiopulmonary surgeries [26].

8.2.4. Increased Renal Loss of Magnesium

Conditions such as diabetes mellitus, acute tubular necrosis, postobstructive diuresis, post kidney transplantation, excessive volume expansion, and chronic metabolic acidosis can all lead to hyperfiltration and increased renal loss of magnesium [26, 27]. Reduced renal reabsorption of magnesium can be triggered by hypokalemia, hypercalcemia, and hypophosphatemia [26]. Chronic alcoholism has been associated with reversible renal tubular dysfunction and hypomagnesemia [34]. Moreover, there are many genetic conditions (Table 6) and medications (Table 7) that have been associated with reduced renal reabsorption of magnesium.

8.2.5. Drug-Induced Hypomagnesemia

Around 50 medications have been found to cause hypomagnesemia [4, 6, 27–31, 35, 36]. Table 7 lists the most commonly prescribed medications associated with hypomagnesemia.

8.3. Hypomagnesemia in Critically Ill Patients

Hypomagnesemia is common in critically ill patients admitted to ICU, with a prevalence between 9% and 79% in different observational studies [37–43]. It is more common in postoperative ICU patients. Hypomagnesemia in critically ill patients might be explained by many factors such as impaired magnesium absorption secondary to impaired gastrointestinal activity, malnutrition, diabetes mellitus, and other electrolyte imbalances (e.g., hypokalemia and hypocalcemia) along with medications (e.g., loop diuretics, gentamycin, and proton pump inhibitors) [41]. According to previous studies, hypomagnesemia has been shown to be strongly associated with the increased need for mechanical ventilation, increased risk of sepsis and lactic acidosis, prolonged ICU stay, and increase in mortality [43–46]. A meta-analysis including 6 studies with total of 1550 participant reported that there was a significantly higher risk of mortality (relative risk 1.9), need for mechanical ventilation (relative risk 1.56), and prolonged ICU stay in patients admitted to ICU with hypomagnesemia [47]. Several studies have shown a weak relationship between serum magnesium concentration and total body magnesium in critically ill patients. Measuring ionized magnesium was found to better represent the actual magnesium status in this group of patients [46, 48].

Due to the high prevalence of hypomagnesemia in ICU patients, it is recommended to monitor serum magnesium closely [41, 49]. Intravenous magnesium sulfate replacement has been shown to have antiarrhythmic and neuroprotective effect and might be associated with decrease mortality and length of ICU stay [50–53].

8.4. Hypo- and Hypermagnesemia in Hospitalized Patients

There are only a limited number of studies that have analyzed the prevalence of hypo- and hypermagnesemia in hospitalized patients in general, including non-ICU patients. A recent study from Mayo Clinic included all patients (288,120 admissions) admitted to the hospital between 2009 and 2013 and assessed the prevalence and prognostic impact of dysmagnesemia [25]. Magnesium status was evaluated in only 40% of admitted patients on the first day of admission. Of the analyzed patients, 31.5% had hypermagnesemia (Mg > 0.91 mmol/L) while 20.2% had hypomagnesemia, which was more common in patients with oncologic/hematological disorders. On the other hand, hypermagnesemia was commonly observed for patients with cardiovascular diseases, which can be attributed to the increased trend of consuming magnesium supplements in this group due to increased awareness of the beneficial impacts of magnesium on the cardiovascular system. The study found that both hypomagnesemia and hypermagnesemia were associated with increased risk of hospital mortality and prolonged length of stay when adjusted for all variables except the admission diagnosis. Since Mayo Clinic is a major referral center for the entire US continent, some of these results may not be generalizable to other hospitals.

9. Hypermagnesemia

Although generally rare, the prevalence of hypermagnesemia in hospitalized patients can approach >30%, and similar to hypomagnesemia, hypermagnesemia has been found to be associated with higher mortality and longer hospital stay [25]. Hypermagnesemia is usually iatrogenic and is reported along with impaired kidney function, bowel disorders, and old age. Other uncommon causes of hypermagnesemia include lithium therapy, hypothyroidism, Addison’s disease, familial hypocalciuric hypercalcemia, and milk alkali syndrome [33]. Clinical consequences of hypermagnesemia vary according the serum magnesium level [54, 55] (Table 8).

Table 8: Clinical manifestations of hypermagnesemia.

Serum magnesium levels
Manifestations

0.70–1.0 mmol/L
Normal level.

2.2–3.5 mmol/L
Nausea, vomiting, facial flushing, urinary retention, ileus, and hypotension.

3.9–5.2 mmol/L
Somnolence, absence of the deep tendon reflex, and complete heart blockage.

>6.5 mmol/L
Respiratory depression, paralysis, and complete heart blockage.

>8.7 mmol/L
Asystole.

10. Hypomagnesemia and Endocrine Diseases

10.1. Diabetes Mellitus

Magnesium is an essential cofactor of several enzymes involved in carbohydrate metabolism [56]. Magnesium works as an insulin sensitizer by autophosphorylation of insulin receptors and regulating tyrosine kinase activity on these receptors [57]. In addition, magnesium blocks entry of calcium into adipocytes through the L-type calcium channel. Reduced intracellular magnesium level can lead to increased calcium entry into adipocytes followed by increase oxidative stress, inflammation, and increase insulin resistance [58, 59]. On the other hand, previous studies have shown that insulin facilitates shift of magnesium from the extracellular to the intracellular space [60, 61] and reduces the tubular reabsorption of magnesium, which can lead to hypomagnesemia in people with poorly controlled diabetes and hyperinsulinemia [62].

Magnesium-deficient diet was found to be significantly associated with reduced insulin-dependent glucose uptake [63, 64] and increase incidence of diabetes mellitus [65]. Also, several studies have shown inverse relationship between serum magnesium levels and incidence of type 2 diabetes mellitus [65–67]. A meta-analysis examining the relationship between magnesium intake and type 2 diabetes involving seven cohort studies with a total of 286,668 participants concluded that four out of the seven studies showed a significant inverse relationship between magnesium intake and the risk of type 2 diabetes. It was estimated that 100 mg/day of magnesium reduces the risk of type 2 diabetes by 15% [68]. Moreover, magnesium supplements reduced the risk of developing type 2 diabetes in high-risk population, as demonstrated in a prospective study involved 2582 community-dwelling participants followed up for 7 years [69]. Oral magnesium supplementation could reduce plasma glucose levels and improve the glycemic status in a randomized controlled trial (RCT) involving 116 adults with prediabetes and hypomagnesemia [70]. Similar beneficial effects of oral magnesium have been demonstrated in people with type 2 diabetes and hypomagnesemia [71]. An observational study concluded that low serum magnesium was significantly associated with higher prevalence of diabetic nephropathy, and hypomagnesemia can be used as a marker for the risk of development of diabetic nephropathy [72]. Additionally, hypomagnesemia was associated with poor glycemic control [73], reduced HDL cholesterol, increased triglycerides, and total cholesterol levels [74, 75].

In regard to gestational diabetes, a RCT involving 70 women reported that oral magnesium supplementation provided multiple beneficial effects on metabolic status and fetal and pregnancy outcomes [76]. In addition, a recent RCT demonstrated that oral magnesium supplementation (250 mg/day) to women with gestational diabetes significantly reduced fasting plasma glucose compared with placebo. Moreover, it had beneficial effect on lipid profile by upregulating gene expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) and glucose transporter 1 (GLUT-1) and downregulating gene expression of oxidized low-density lipoprotein receptor (LDLR) [77].

The level of magnesium was found to be lower in patients with type 1 diabetes mellitus compared to healthy individuals [78]. Hypomagnesemia was also associated with poor glycemic control [79], poor lipid profile [80], and high risk of atherosclerosis [81]. In addition, some studies in type 1 diabetes have shown a beneficial effect of magnesium supplementation in improving HbA1c and lipid profile [82] and slowing the progression of neuropathy [83].

10.2. Metabolic Syndrome

Several studies have linked hypomagnesemia with chronic inflammation and the metabolic syndrome. It has been proposed that hypomagnesemia can trigger low-grade chronic inflammation by contributing to activation of leukocyte and macrophage, release of acute-phase proteins and cytokines, as well as production of free radicals [59, 84, 85]. In addition, several clinical and epidemiological studies have demonstrated inverse relationships between serum magnesium and C-reactive protein (CRP) which is an important marker of inflammation [86–88]. However, it should be taken into account that oxidative stress has several causes starting with unbalanced diet involving not only magnesium but many other nutrients related with similar diseases than the ones attributed to hypomagnesemia. Nevertheless, a recent systemic review evaluated the effect of magnesium supplementation on insulin resistance. Twelve studies were identified, and it was concluded that oral magnesium supplementation had beneficial effect on insulin resistance in patients with hypomagnesemia compared to patients with normal serum magnesium [89]. Moreover, oral magnesium supplementation may have positive effect on lipid profile in individuals with and without diabetes [90, 91]. Furthermore, magnesium supplementation improves metabolic control and reduces insulin resistance in patients with type 2 diabetes and hypomagnesemia [71].

10.3. Magnesium and Osteoporosis

Bones store around 60% of total body magnesium, of which 30% is skeletal magnesium in the hydration shell or on the surface of hydroxyapatite [92]. Magnesium on the surface of the bones is available for exchange with serum magnesium. The remaining skeletal magnesium forms an integral part of the bones, and its release is dependent on the bone resorption [93].

Low serum magnesium has been demonstrated to be associated with low bone density in pre- and postmenopausal women [92, 94–96], and magnesium intake is found to be positively correlated with a greater bone mineral density in both men and women [97]. Furthermore, magnesium supplements have been shown to improve BMD in osteoporotic women [98, 99] and in young people [100–102]. Moreover, high dietary magnesium intake reduced prospectively the risk of osteoporotic fractures in middle-aged men and women [103]. The relationship between magnesium and bone health can be explained by different mechanisms. Low magnesium can lead to alteration of trabecular bone by formation of large but fragile crystals [104]. Moreover, low magnesium can reduce the vascular supply of bones [105] and increase inflammatory cytokines [106], which can trigger bone remodeling and osteopenia. Furthermore, reduced body magnesium can cause a reduction in PTH levels, increase in tissue resistance to PTH, and decrease in vitamin D levels [92]. On the other hand, hypermagnesemia has been associated with osteopenia and osteoporosis in postmenopausal women and people with chronic kidney diseases [92].

10.4. Magnesium-Dependent Vitamin D-Resistant Rickets

Magnesium acts as a cofactor for binding of vitamin D to its transport protein (vitamin D-binding protein), and it is required for conversion of vitamin D into the active form in the liver and the kidneys [2]. 1,25-Dihydroxyvitamin D has been shown to stimulate the absorption of magnesium from the intestines. Magnesium deficiency can cause magnesium-dependent vitamin D-resistant rickets by reducing the synthesis of vitamin D and impairing PTH function [2]. Adequate replacement of magnesium is essential for the treatment of magnesium-dependent rickets [107].

11. Hypo- and Hypermagnesemia in Cardiovascular Health

Magnesium has an important role in the regulation of cardiac rhythm, influencing vascular tone, peripheral vascular resistance, and endothelial function [3]. Table 9 summarizes the effect of magnesium on cardiovascular health [87, 108–111].

Table 9: Magnesium effects on the cardiovascular system.

Improvement in endothelial function.

Induction of direct and indirect vasodilation.

Improvement in blood pressure.

Beneficial effects on arrhythmias, inflammatory reactions, and platelet aggregation.

Potential effect in improving exercise tolerance in patients with stable coronary artery disease.

Improvement of insulin homeostasis and lipid metabolism.

Reduces platelets activation and thrombosis.

Reduces cellular ischemic injury by reducing calcium overload in coronary arteries.

11.1. Risk of Arrhythmia

Hypomagnesemia is associated with an increased risk of cardiac arrhythmia via the following possible mechanisms: decreased effect of magnesium against calcium at the atrioventricular node (AV node); low magnesium causes impairment of Na⁺/K⁺-ATPase, which decreases the levels of intracellular potassium, increases intracellular sodium, and creates a less negative resting membrane potential. Both mechanisms lead to unstable membrane potentials and conduction of impulses and increase the susceptibility to arrhythmia [112]. Changes in the electrocardiograms (ECG) associated with hypomagnesemia vary according to the levels of magnesium. Mild hypomagnesemia leads to sinus tachycardia, high-peaked T waves, and ST segment depression, while severe hypomagnesemia causes shortening of the PQ interval, QRS duration, and QTc [113].

In a large scale population study, hypomagnesemia was associated with an increase in the incidence of atrial fibrillation over a 20-year follow-up [114]. Hypomagnesemia also increased the risk of atrial fibrillation postcardiac surgery [115].

Several studies have demonstrated the association between low serum magnesium and an increased risk of premature ventricular contractions, ventricular tachycardia, and polymorphic ventricular tachycardia (torsades de pointes) [112, 116–119]. A RCT showed that oral magnesium supplementation reduced the intensity of premature ventricular and supraventricular arrhythmia in patients without underlying ischemic or structural heart disease [120].

Digoxin inhibits Na⁺/K⁺-ATPase causing an increase in the intracellular concentration of sodium and calcium. Magnesium is an essential cofactor for Na⁺/K⁺-ATPase, and hence, magnesium deficiency can cause further increase in intracellular sodium, while decreasing the intracellular potassium [113]. Hypomagnesemia has been associated with increased risk of digoxin toxicity [121], which can precipitate life-threatening dysrhythmia in patients with normal digoxin and potassium level [122, 123]. It has also been shown that treatment with oral magnesium supplements may be associated with a reduction in ventricular ectopy in patients with low serum magnesium treated with digoxin for chronic atrial fibrillation [124].

11.2. Risk of Coronary Artery Disease

Experimental animal models have demonstrated that magnesium deficiency promotes atherosclerotic lesions in arteries, and the degree of atherosclerotic lesions was inversely related to the magnesium intake. Furthermore, low magnesium could cause endothelial dysfunction and hypercoagulability and increase the deposition of lipids and calcium in atheromatous lesions [113].

In human studies, an inverse relationship has been observed between dietary magnesium intake and serum magnesium levels and overall risk of cardiovascular diseases [125–127]. A meta-analysis on more than 77,000 cases found an inverse association between magnesium levels in the drinking water and cardiovascular mortality risk [128]. Another meta-analysis reviewing 19 studies with a total of 532,979 participants showed that dietary magnesium intake and serum magnesium concentrations were inversely associated with the risk of total cardiovascular events [111]. Moreover, hypomagnesemia was found to be associated with increased risk of coronary artery disease in a study involving 13,922 healthy subjects followed up for 4–7 years [129]. Other small RCTs have shown that oral magnesium supplementation reduced platelet-induced thrombosis [108] and improved endothelial function [130].

With regard to acute ischemia, hypomagnesemia was found to be associated with increased mortality and malignant arrhythmia in patients admitted with acute myocardial infraction. A large retrospective cohort study involving 10,806 patients with acute myocardial infraction found a U-shaped relationship between the most recent magnesium levels and mortality. Lowest mortality was seen with serum magnesium levels of ∼0.74 to 0.83 mmol/L [131]. However, several RCTs have shown conflicting results regarding the role of intravenous magnesium administration in reducing mortality in patients with acute myocardial infarction [132]. In a prospective study involving 414 patients with a median follow-up of 24 months, hypomagnesemia was associated with an increase in major adverse cardiac events in patients treated with drug-eluting stents for acute myocardial infarction [133].

Thus, there is strong evidence to support the role of magnesium in the risk of developing coronary artery diseases. Furthermore, treatment of hypomagnesemia is important in the prevention of arrhythmia in patients with acute myocardial ischemia. Previous research has suggested that consumption of water with high amount of magnesium could decrease mortality from cardiovascular disease by 30–35% [134]. Supplementing drinking water with magnesium, 25 to 50 ppm, may provide protection against cardiovascular disease and probably many other health problems [135–137].

11.3. Hypertension

Low dietary magnesium and hypomagnesemia might be a contributing factor in the pathophysiology of hypertension. Magnesium reduces vascular tone and resistance by enhancing vasodilator effect of nitric oxide, antagonizing the vasoconstrictor effect of calcium, bradykinin, angiotensin II, serotonin, and prostaglandin in F2α, and protecting the vascular endothelium through its antioxidant effect [138]. Several clinical trials have been conducted to study the effect of magnesium supplementation on the blood pressure, and at present, there is no strong evidence to support the use of magnesium supplementation in the routine management of hypertension [3, 113].

11.4. Magnesium and Preeclampsia

Intravenous magnesium sulfate has been used to treat preeclampsia and eclampsia for a long time. The underlying mechanisms of action can be explained by the vasodilating effect of magnesium in the vasculature and its protective role against oxidative damage during severe preeclampsia [139]. Furthermore, the anticonvulsant effect of magnesium can be explained by the role of magnesium in blocking N-methyl-D-aspartate (NMDA) receptors [3]. A recent meta-analysis concludes that magnesium sulfate for treatment of preeclampsia can reduce the risk of eclampsia by 50% [140].

11.5. Heart Failure

Patients with congestive heart failure are more prone to having low serum levels of potassium and magnesium due to multiple factors. These include poor oral intake, impaired gastrointestinal absorption, chronic overstimulation of the renin-angiotensin-aldosterone system, and the use of medications such as diuretics [141]. Some studies indicate the prevalence of hypomagnesemia in patients with heart failure to exceed 30% [141, 142]. A RCT has shown the association of hypomagnesemia with increased rate of ventricular ectopic beats, couplets, and episodes of nonsustained ventricular tachycardia in inpatients with heart failure. When treated for hypomagnesemia using intravenous magnesium sulfate, the same group had significantly reduced rate of arrhythmias [141]. A recent meta-analysis of seven prospective studies with total 5172 heart failure patients showed that hypermagnesemia (≥1.05 mmol/L) was associated with an increased risk of cardiovascular mortality and all-cause mortality in elderly patients with chronic heart failure and reduced left ventricular function. These findings were not observed in patients with hypomagnesemia [143].

12. Hypomagnesemia and Neurological Diseases

Extracellular magnesium has an inhibitory role on NMDA receptors, γ-aminobutyric acid (GABA) receptors, and glutamate release from NMDA receptor-rich neurons [3, 144]. Low extracellular magnesium can result in an abnormal opening of NMDA-coupled calcium channels, leading to increased calcium influx, hyperexcitability of neurons, and an increase in the production of toxic nitric oxide radicals [3, 145].

12.1. Headache

Observational studies have concluded that patients with migraine tend to have lower serum [146, 147] and brain [148] magnesium when compared to healthy subjects. Several mechanisms have been described to explain the relationship between low magnesium levels and migraine. Low magnesium levels can increase the aggregation of platelets and promote the secretion of serotonin, resulting in vasoconstriction which can trigger acute migraine. Furthermore, low magnesium increases neuronal excitability and triggers cortical spreading depression by increasing NMDA receptor activation, intracellular calcium, glutamate secretion, and the levels of extracellular potassium [147, 149]. Intravenous magnesium has been shown to have a beneficial additive effect in alleviating acute migraine [150, 151] and other types of acute headaches [152, 153]. To this end, oral magnesium supplements have been tried as a prophylactic agent for migraine with a significant beneficial effect [154, 155]. A recent quasi-experimental study including 70 patients concluded that both intravenous magnesium sulfate and intravenous caffeine can significantly reduce the severity of acute migraine headache, with better improvements observed with magnesium [145]. However, a meta-analysis on five RCTs with 295 patients failed to find a significant beneficial effect of magnesium sulfate in alleviating migraines, although the results need to interpreted with caution given the small sample size [156].

12.2. Seizures

Severe hypomagnesemia can cause a generalized tonic-clonic seizure in children and adults. Seizures are usually preceded by symptoms related to neuromuscular irritability and CNS hyperexcitability [157, 158]. Magnesium sulfate has been used as a drug of choice for seizure management, treatment, and prophylaxis in women with preeclampsia and eclampsia [157, 159–161]. It is suggested that oral magnesium supplements might have a beneficial effect when used as an adjunctive medication in the treatment of drug-resistant epilepsy [162]. The anticonvulsant effect of magnesium can be explained by its role in inhibiting NMDA glutamate receptors, increasing production of vasodilator prostaglandins, and stabilizing the neuronal membrane [157].

12.3. Stroke

Low magnesium intake is associated with an increased risk of stroke in several observational studies [163–165], which can be explained by the beneficial role of magnesium in endothelial function, platelet aggregation, blood pressure, and glycemic control as discussed in the previous section. Patients suffering acute ischemic stroke and admitted with low magnesium levels have an increased inpatient mortality risk [166] and increased intensity of neurological deficit [167]. This might be attributed to the cerebral vasoconstriction triggered by hypomagnesemia. On the other hand, a large double-blinded RCT reported that intravenous magnesium sulfate administration for patients with acute stroke within 2 hours of onset of stroke symptoms had no impact on the improvement of disability outcomes at 90 days of poststroke [168].

13. Hypomagnesemia and Respiratory Diseases

Several studies have indicated that dietary magnesium and intravenous magnesium sulfate infusion were associated with an improvement in lung function, as measured by forced vital capacity (FVC) and forced expiratory volume (FEV) [169, 170]. While the mechanism of action is not entirely understood, it is possible that magnesium acts via anti-inflammatory effect and reduces lung inflammation along with the role of magnesium in regulating bronchoconstrictors such as acetylcholine (ACh) and histamine, as well as the vasodilatory and the bronchodilatory effect of magnesium [3].

13.1. Bronchial Asthma

A single dose of intravenous magnesium sulfate (1.2 g) has been recommended for the management of acute severe and life-threatening exacerbation of asthma [171]. A Cochrane review analyzing the findings of 14 RCTs including 2313 adult patients presented to the Emergency Department with acute exacerbation of bronchial asthma concluded that intravenous magnesium sulfate reduced the need for hospital admission and improves lung function test [172]. Another RCT also showed that the use of inhaled isotonic magnesium as adjuvant therapy in treatment of severe acute exacerbation of bronchial asthma was associated significant improvement of FEV1 at 90 minutes [173]. The role of magnesium in antagonizing the effect of calcium and altering intracellular cAMP and thereby reducing the neutrophil respiratory burst is believed to be the mechanism of action of magnesium sulfate, which helps in controlling airway inflammation during asthma [174].

13.2. Chronic Obstructive Pulmonary Disease (COPD)

Hypomagnesemia is associated with advanced chronic lung diseases, increased severity of the disease, and the length of hospital stay, according to observational studies [175, 176]. However, a systemic review of four RCTs has failed to show any significant therapeutic effect of intravenous or inhaled magnesium used in the treatment of COPD [177]. Overall, there are only a few experimental trials evaluating the effect of magnesium on COPD, and the existing trials have several limitations [178]. Therefore, further studies are required to elaborate the impact of magnesium on COPD.

14. Magnesium Disorders and Kidney Disease

The kidney has a very important role in magnesium homeostasis. Mild and moderate renal impairment can increase the fractional excretion of magnesium to compensate for the loss of glomerular filtration [179]. However, with advanced chronic kidney disease (creatinine clearance < 30 mL/min), this compensatory mechanism fails to maintain the homeostasis, resulting in hypermagnesemia [180]. In addition, magnesium homeostasis can be affected by vitamin D, PTH, and calcium abnormalities associated with advanced chronic kidney disease. In peritoneal hemodialysis patients, the use of higher concentration of magnesium dialysate can cause hypermagnesemia [179, 180]. In contrast, hypomagnesemia might be observed in patients as a result of the use of low magnesium dialysate, secondary to medications used or as a result of an underlying medical problem such as malnutrition or alcohol abuse [181]. Patients with chronic kidney disease and hypomagnesemia may have higher risk of osteoporosis [182], cardiovascular morbidity, and an all-cause mortality [183].

15. Future Perspectives

Further research would be valuable in assessing the utility of magnesium level as a marker of disease severity, especially in hospitalized patients. More importantly, much previous research focused on diseases caused by hypomagnesemia and the therapeutic role of magnesium. However, many diseases discussed in this review could be a reflection of the modern magnesium-deficient diet. We suggest that more focus should be on the preventive role of magnesium on alleviating the burden of disease.

16. Conclusion

Magnesium is an essential cation involved in numerous enzymatic reactions and important for many vital physiological functions. Magnesium disorders, especially hypomagnesemia, are common in clinical settings and are associated with many adverse health outcomes. Magnesium has been used successfully in treatment of medical conditions such as bronchial asthma, cardiac arrhythmia, eclampsia, and preeclampsia, and oral magnesium supplements have indicated beneficial health outcomes. Further research is needed to evaluate to feasibility and effectiveness of magnesium supplementation on overall morbidity and mortality.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

References

J. Bertinato, C. Wu Xiao, W. M. Ratnayake et al., “Lower serum magnesium concentration is associated with diabetes, insulin resistance, and obesity in South Asian and white Canadian women but not men,” Food & Nutrition Research, vol. 59, no. 1, article 25974, 2015.

U. Grober, J. Schmidt, and K. Kisters, “Magnesium in prevention and therapy,” Nutrients, vol. 7, no. 9, pp. 8199–8226, 2015.

J. H. F. de Baaij, J. G. J. Hoenderop, and R. J. M. Bindels, “Magnesium in man: implications for health and disease,” Physiological Reviews, vol. 95, no. 1, pp. 1–46, 2015.

W. Jahnen-Dechent and M. Ketteler, “Magnesium basics,” Clinical Kidney Journal, vol. 5, Supplement 1, pp. i3–i14, 2012.

J. Olza, J. Aranceta-Bartrina, M. Gonzalez-Gross et al., “Reported dietary intake, disparity between the reported consumption and the level needed for adequacy and food sources of calcium, phosphorus, magnesium and vitamin D in the Spanish population: findings from the ANIBES study †,” Nutrients, vol. 9, no. 2, 2017.

J. H. William and J. Danziger, “Proton-pump inhibitor-induced hypomagnesemia: current research and proposed mechanisms,” World Journal of Nephrology, vol. 5, no. 2, pp. 152–157, 2016.

Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride, National Academies Press, Washington, DC, USA, 1997.

W. M. Groenestege, J. G. Hoenderop, L. van den Heuvel, N. Knoers, and R. J. Bindels, “The epithelial Mg²⁺ channel transient receptor potential melastatin 6 is regulated by dietary Mg²⁺ content and estrogens,” Journal of the American Society of Nephrology, vol. 17, no. 4, pp. 1035–1043, 2006.

E. M. Brown and R. J. MacLeod, “Extracellular calcium sensing and extracellular calcium signaling,” Physiological Reviews, vol. 81, no. 1, pp. 239–297, 2001.

S. Mutnuri, I. Fernandez, and T. Kochar, “Suppression of parathyroid hormone in a patient with severe magnesium depletion,” Case Reports in Nephrology, vol. 2016, Article ID 2608538, 3 pages, 2016.

T. Vetter and M. J. Lohse, “Magnesium and the parathyroid,” Current Opinion in Nephrology and Hypertension, vol. 11, no. 4, pp. 403–410, 2002.

U. Quitterer, M. Hoffmann, M. Freichel, and M. J. Lohse, “Paradoxical block of parathormone secretion is mediated by increased activity of Gα subunits,” The Journal of Biological Chemistry, vol. 276, no. 9, pp. 6763–6769, 2001.

B. Sontia and R. M. Touyz, “Magnesium transport in hypertension,” Pathophysiology, vol. 14, no. 3-4, pp. 205–211, 2007.

M. K. Monteilh-Zoller, M. C. Hermosura, M. J. S. Nadler, A. M. Scharenberg, R. Penner, and A. Fleig, “TRPM7 provides an ion channel mechanism for cellular entry of trace metal ions,” The Journal of General Physiology, vol. 121, no. 1, pp. 49–60, 2002.

K. P. Schlingmann and T. Gudermann, “A critical role of TRPM channel-kinase for human magnesium transport,” The Journal of Physiology, vol. 566, no. 2, pp. 301–308, 2005.

I. Pilchova, K. Klacanova, Z. Tatarkova, P. Kaplan, and P. Racay, “The involvement of Mg²⁺ in regulation of cellular and mitochondrial functions,” Oxidative Medicine and Cellular Longevity, vol. 2017, Article ID 6797460, 8 pages, 2017.

M. E. Gold, G. M. Buga, K. S. Wood, R. E. Byrns, G. Chaudhuri, and L. J. Ignarro, “Antagonistic modulatory roles of magnesium and calcium on release of endothelium-derived relaxing factor and smooth muscle tone,” Circulation Research, vol. 66, no. 2, pp. 355–366, 1990.

K. J. Martin, E. A. Gonzalez, and E. Slatopolsky, “Clinical consequences and management of hypomagnesemia,” Journal of American Society of Nephrology, vol. 20, no. 11, pp. 2291–2295, 2009.

D. H. H. M. Viering, J. H. F. de Baaij, S. B. Walsh, R. Kleta, and D. Bockenhauer, “Genetic causes of hypomagnesemia, a clinical overview,” Pediatric Nephrology, vol. 32, no. 7, pp. 1123–1135, 2017.

M. F. Ryan, “The role of magnesium in clinical biochemistry: an overview,” Annals of Clinical Biochemistry: International Journal of Laboratory Medicine, vol. 28, no. 1, pp. 19–26, 1991.

M. A. Williamson, L. M. Snyder, and J. B. Wallach, Wallach's Interpretation of Diagnostic Tests, Wolters Kluwer/Lippincott Williams & Wilkins, Philadelphia, PA, USA, 9th edition, 2011, xvi, 1143.

H. Millart, V. Durlach, and J. Durlach, “Red blood cell magnesium concentrations: analytical problems and significance,” Magnesium Research, vol. 8, no. 1, pp. 65–76, 1995.

B. Chernow, “Hypomagnesemia in intensive care correction of units,” Chest, vol. 95, no. 6, p. 1362, 1989.

H. F. Schimatschek and R. Rempis, “Prevalence of hypomagnesemia in an unselected German population of 16,000 individuals,” Magnesium Research, vol. 14, no. 4, pp. 283–290, 2001.

W. Cheungpasitporn, C. Thongprayoon, and Q. Qian, “Dysmagnesemia in hospitalized patients: prevalence and prognostic importance,” Mayo Clinic Proceedings, vol. 90, no. 8, pp. 1001–1010, 2015.

P. C. Pham, P. A. Pham, S. V. Pham, P. T. Pham, P. M. Pham, and P. T. Pham, “Hypomagnesemia: a clinical perspective,” International Journal of Nephrology and Renovascular Disease, vol. 7, pp. 219–230, 2014.

Z. S. Agus, “Hypomagnesemia,” Journal of the American Society of Nephrology, vol. 10, no. 7, pp. 1616–1622, 1999.

H. Lajer and G. Daugaard, “Cisplatin and hypomagnesemia,” Cancer Treatment Reviews, vol. 25, no. 1, pp. 47–58, 1999.

C. I. Bagnis and G. Deray, “Amphotericin B nephrotoxicity,” Saudi Journal of Kidney Diseases and Transplantation, vol. 13, no. 4, pp. 481–491, 2002.

C. H. Lee and G. H. Kim, “Electrolyte and acid-base disturbances induced by clacineurin inhibitors,” Electrolyte & Blood Pressure, vol. 5, no. 2, pp. 126–130, 2007.

J. Sivakumar, “Proton pump inhibitor-induced hypomagnesaemia and hypocalcaemia: case review,” International Journal of Physiology, Pathophysiology and Pharmacology, vol. 8, no. 4, pp. 169–174, 2016.

C. Bergman, D. Gray-Scott, J. J. Chen, and S. Meacham, “What is next for the dietary reference intakes for bone metabolism related nutrients beyond calcium: phosphorus, magnesium, vitamin D, and fluoride?” Critical Reviews in Food Science and Nutrition, vol. 49, no. 2, pp. 136–144, 2009.

J. W. Seo and T. J. Park, “Magnesium metabolism,” Electrolyte Blood Pressure, vol. 6, no. 2, pp. 86–95, 2008.

S. De Marchi, E. Cecchin, A. Basile, A. Bertotti, R. Nardini, and E. Bartoli, “Renal tubular dysfunction in chronic alcohol abuse--effects of abstinence,” The New England Journal of Medicine, vol. 329, no. 26, pp. 1927–1934, 1993.

J. D. Gradon, L. Fricchione, and D. Sepkowitz, “Severe hypomagnesemia associated with pentamidine therapy,” Reviews of Infectious Diseases, vol. 13, no. 3, pp. 511-512, 1991.

J. Atsmon and E. Dolev, “Drug-induced hypomagnesaemia: scope and management,” Drug Safety, vol. 28, no. 9, pp. 763–788, 2005.

E. Fiaccadori, S. Del Canale, E. Coffrini et al., “Muscle and serum magnesium in pulmonary intensive care unit patients,” Critical Care Medicine, vol. 16, no. 8, pp. 751–760, 1988.

C. Guerin, C. Cousin, F. Mignot, M. Manchon, and G. Fournier, “Serum and erythrocyte magnesium in critically ill patients,” Intensive Care Medicine, vol. 22, no. 8, pp. 724–727, 1996.

M. P. Escuela, M. Guerra, J. M. Anon et al., “Total and ionized serum magnesium in critically ill patients,” Intensive Care Medicine, vol. 31, no. 1, pp. 151–156, 2005.

O. C. Dabbagh, A. S. Aldawood, Y. M. Arabi, N. A. Lone, R. Brits, and M. Pillay, “Magnesium supplementation and the potential association with mortality rates among critically ill non-cardiac patients,” Saudi Medical Journal, vol. 27, no. 6, pp. 821–825, 2006.

M. S. H. Zafar, J. I. Wani, R. Karim, M. M. Mir, and P. A. Koul, “Significance of serum magnesium levels in critically ill-patients,” International Journal of Applied Basic Medical Research, vol. 4, no. 1, pp. 34–37, 2014.

M. Chen, R. Sun, and B. Hu, “The influence of serum magnesium level on the prognosis of critically ill patients,” Zhonghua Wei Zhong Bing Ji Jiu Yi Xue, vol. 27, no. 3, pp. 213–217, 2015.

A. Moskowitz, J. Lee, M. W. Donnino, R. Mark, L. A. Celi, and J. Danziger, “The association between admission magnesium concentrations and lactic acidosis in critical illness,” Journal of Intensive Care Medicine, vol. 31, no. 3, pp. 187–192, 2016.

H. M. Soliman, D. Mercan, S. S. M. Lobo, C. Melot, and J. L. Vincent, “Development of ionized hypomagnesemia is associated with higher mortality rates,” Critical Care Medicine, vol. 31, no. 4, pp. 1082–1087, 2003.

C. S. Limaye, V. A. Londhey, M. Y. Nadkart, and N. E. Borges, “Hypomagnesemia in critically ill medical patients,” The Journal of the Association of Physicians of India, vol. 59, pp. 19–22, 2011.

D. Velissaris, V. Karamouzos, C. Pierrakos, D. Aretha, and M. Karanikolas, “Hypomagnesemia in critically III sepsis patients,” Journal of Clinical Medicine Research, vol. 7, no. 12, pp. 911–918, 2015.

S. Upala, V. Jaruvongvanich, K. Wijarnpreecha, and A. Sanguankeo, “Hypomagnesemia and mortality in patients admitted to intensive care unit: a systematic review and meta-analysis,” QJM: An International Journal of Medicine, vol. 109, no. 7, pp. 453–459, 2016.

A. Arnold, J. Tovey, P. Mangat, W. Penny, and S. Jacobs, “Magnesium deficiency in critically ill patients,” Anaesthesia, vol. 50, no. 3, pp. 203–205, 1995.

B. S. Charles, I. Menon, T. S. Girish, and A. M. Cherian, “Hypomagnesemia in the ICU - does correction matter?” The Journal of the Association of Physicians of India, vol. 64, no. 11, pp. 15–19, 2016.

J. L. Moran, J. Gallagher, S. L. Peake, D. N. Cunningham, M. C. N. Salagaras, and P. Leppard, “Parenteral magnesium sulfate versus amiodarone in the therapy of atrial tachyarrhythmias: a prospective, randomized study,” Critical Care Medicine, vol. 23, no. 11, pp. 1816–1824, 1995.

S. Kasaoka, R. Tsuruta, K. Nakashima et al., “Effect of intravenous magnesium sulfate on cardiac arrhythmias in critically III patients with low serum ionized magnesium,” Japanese Circulation Journal, vol. 60, no. 11, pp. 871–875, 1996.

M. E. Sleeswijk, J. E. Tulleken, T. Van Noord, J. H. J. M. Meertens, J. J. M. Ligtenberg, and J. G. Zijlstra, “Efficacy of magnesium-amiodarone step-up scheme in critically ill patients with new-onset atrial fibrillation: a prospective observational study,” Journal of Intensive Care Medicine, vol. 23, no. 1, pp. 61–66, 2008.

Y. Panahi, M. Mojtahedzadeh, A. Najafi et al., “The role of magnesium sulfate in the intensive care unit,” EXCLI Journal, vol. 16, pp. 464–482, 2017.

M. A. Karahan, A. Kucuk, E. Buyukfirat, and F. Yalcin, “Acute respiratory and renal failure due to hypermagnesemia, induced by counter laxatives in an elderly man,” Journal of Clinical and Diagnostic Research, vol. 9, no. 12, article UL01, 2015.

M. Sugiyama, E. Kusumoto, M. Ota et al., “Induction of potentially lethal hypermagnesemia, ischemic colitis, and toxic megacolon by a preoperative mechanical bowel preparation: report of a case,” Surgical Case Reports, vol. 2, no. 1, p. 18, 2016.

K. J. C. Cruz, A. R. S. de Oliveira, D. P. Pinto et al., “Influence of magnesium on insulin resistance in obese women,” Biological Trace Element Research, vol. 160, no. 3, pp. 305–310, 2014.

F. Guerrero-Romero and M. Rodriguez-Moran, “Magnesium improves the beta-cell function to compensate variation of insulin sensitivity: double-blind, randomized clinical trial,” European Journal of Clinical Investigation, vol. 41, no. 4, pp. 405–410, 2011.

F. H. Nielsen, D. B. Milne, S. Gallagher, L. Johnson, and B. Hoverson, “Moderate magnesium deprivation results in calcium retention and altered potassium and phosphorus excretion by postmenopausal women,” Magnesium Research, vol. 20, no. 1, pp. 19–31, 2007.

F. H. Nielsen, “Magnesium deficiency and increased inflammation: current perspectives,” Journal of Inflammation Research, vol. 11, pp. 25–34, 2018.

G. Paolisso, S. Sgambato, N. Passariello et al., “Insulin induces opposite changes in plasma and erythrocyte magnesium concentrations in normal man,” Diabetologia, vol. 29, no. 9, pp. 644–647, 1986.

L. H. R. Xu and N. M. Maalouf, “Effect of acute hyperinsulinemia on magnesium homeostasis in humans,” Diabetes/Metabolism Research and Reviews, vol. 33, no. 2, 2017.

P. McNair, M. S. Christensen, C. Christiansen, S. Madsbad, and I. Transbol, “Renal hypomagnesaemia in human diabetes mellitus: its relation to glucose homeostasis,” European Journal of Clinical Investigation, vol. 12, no. 1, pp. 81–85, 1982.

S. Matsunobu, Y. Terashima, T. Senshu, H. Sano, and H. Itoh, “Insulin secretion and glucose uptake in hypomagnesemic sheep fed a low magnesium, high potassium diet,” The Journal of Nutritional Biochemistry, vol. 1, no. 3, pp. 167–171, 1990.

A. Suárez, N. Pulido, A. Casla, B. Casanova, F. J. Arrieta, and A. Rovira, “Impaired tyrosine-kinase activity of muscle insulin receptors from hypomagnesaemic rats,” Diabetologia, vol. 38, no. 11, pp. 1262–1270, 1995.

W. H. L. Kao, A. R. Folsom, F. J. Nieto, J. P. Mo, R. L. Watson, and F. L. Brancati, “Serum and dietary magnesium and the risk for type 2 diabetes mellitus: the atherosclerosis risk in communities study,” Archives of Internal Medicine, vol. 159, no. 18, pp. 2151–2159, 1999.

L. M. Resnick, B. T. Altura, R. K. Gupta, J. H. Laragh, M. H. Alderman, and B. M. Altura, “Intracellular and extracellular magnesium depletion in type 2 (non-insulin-dependent) diabetes mellitus,” Diabetologia, vol. 36, no. 8, pp. 767–770, 1993.

M. Barbagallo, L. J. Dominguez, A. Galioto et al., “Role of magnesium in insulin action, diabetes and cardio-metabolic syndrome X,” Molecular Aspects of Medicine, vol. 24, no. 1–3, pp. 39–52, 2003.

S. C. Larsson and A. Wolk, “Magnesium intake and risk of type 2 diabetes: a meta-analysis,” Journal of Internal Medicine, vol. 262, no. 2, pp. 208–214, 2007.

A. Hruby, J. B. Meigs, C. J. O'Donnell, P. F. Jacques, and N. M. McKeown, “Higher magnesium intake reduces risk of impaired glucose and insulin metabolism and progression from prediabetes to diabetes in middle-aged Americans,” Diabetes Care, vol. 37, no. 2, pp. 419–427, 2014.

F. Guerrero-Romero, L. E. Simental-Mendia, G. Hernandez-Ronquillo, and M. Rodriguez-Moran, “Oral magnesium supplementation improves glycaemic status in subjects with prediabetes and hypomagnesaemia: a double-blind placebo-controlled randomized trial,” Diabetes & Metabolism, vol. 41, no. 3, pp. 202–207, 2015.

M. Rodriguez-Moran and F. Guerrero-Romero, “Oral magnesium supplementation improves insulin sensitivity and metabolic control in type 2 diabetic subjects: a randomized double-blind controlled trial,” Diabetes Care, vol. 26, no. 4, pp. 1147–1152, 2003.

S. Bherwani, S. B. Jibhkate, A. S. Saumya, S. K. Patel, R. Singh, and L. H. Ghotekar, “Hypomagnesaemia: a modifiable risk factor of diabetic nephropathy,” Hormone Molecular Biology and Clinical Investigation, vol. 29, no. 3, pp. 79–84, 2017.

S. Ramadass, S. Basu, and A. R. Srinivasan, “Serum magnesium levels as an indicator of status of diabetes mellitus type 2,” Diabetes & Metabolic Syndrome: Clinical Research & Reviews, vol. 9, no. 1, pp. 42–45, 2015.

F. Guerrero-Romero and M. Rodriguez-Moran, “Hypomagnesemia is linked to low serum HDL-cholesterol irrespective of serum glucose values,” Journal of Diabetes and its Complications, vol. 14, no. 5, pp. 272–276, 2000.

F. Corica, A. Corsonello, R. Ientile et al., “Serum ionized magnesium levels in relation to metabolic syndrome in type 2 diabetic patients,” Journal of the American College of Nutrition, vol. 25, no. 3, pp. 210–215, 2006.

Z. Asemi, M. Karamali, M. Jamilian et al., “Magnesium supplementation affects metabolic status and pregnancy outcomes in gestational diabetes: a randomized, double-blind, placebo-controlled trial,” The American Journal of Clinical Nutrition, vol. 102, no. 1, pp. 222–229, 2015.

M. Jamilian, M. Samimi, A. E. Faraneh et al., “Magnesium supplementation affects gene expression related to insulin and lipid in patients with gestational diabetes,” Magnesium Research, vol. 30, no. 3, pp. 71–79, 2017.

C. C. Lin and Y. L. Huang, “Chromium, zinc and magnesium status in type 1 diabetes,” Current Opinion in Clinical Nutrition and Metabolic Care, vol. 18, no. 6, pp. 588–592, 2015.

A. Galli-Tsinopoulou, I. Maggana, I. Kyrgios et al., “Association between magnesium concentration and HbA1c in children and adolescents with type 1 diabetes mellitus,” Journal of Diabetes, vol. 6, no. 4, pp. 369–377, 2014.

M. S. Djurhuus, N. A. H. Klitgaard, K. K. Pedersen et al., “Magnesium reduces insulin-stimulated glucose uptake and serum lipid concentrations in type 1 diabetes,” Metabolism, vol. 50, no. 12, pp. 1409–1417, 2001.

M. E. Atabek, S. Kurtoglu, O. Pirgon, and M. Baykara, “Serum magnesium concentrations in type 1 diabetic patients: relation to early atherosclerosis,” Diabetes Research and Clinical Practice, vol. 72, no. 1, pp. 42–47, 2006.

D. Shahbah, T. Hassan, S. Morsy et al., “Oral magnesium supplementation improves glycemic control and lipid profile in children with type 1 diabetes and hypomagnesaemia,” Medicine, vol. 96, no. 11, article e6352, 2017.

I. De Leeuw, W. Engelen, C. De Block, and L. Van Gaal, “Long term magnesium supplementation influences favourably the natural evolution of neuropathy in Mg-depleted type 1 diabetic patients (T1dm),” Magnesium Research, vol. 17, no. 2, pp. 109–114, 2004.

A. M. Freedman, I. T. Mak, R. E. Stafford et al., “Erythrocytes from magnesium-deficient hamsters display an enhanced susceptibility to oxidative stress,” American Journal of Physiology-Cell Physiology, vol. 262, no. 6, pp. C1371–C1375, 1992.

F. Guerrero-Romero, C. Bermudez-Pena, and M. Rodriguez-Moran, “Severe hypomagnesemia and low-grade inflammation in metabolic syndrome,” Magnesium Research, vol. 24, no. 2, pp. 45–53, 2011.

F. Guerrero-Romero and M. Rodriguez-Moran, “Relationship between serum magnesium levels and C-reactive protein concentration, in non-diabetic, non-hypertensive obese subjects,” International Journal of Obesity and Related Metabolic Disorders, vol. 26, no. 4, pp. 469–474, 2002.

Y. Song, T. Y. Li, R. M. van Dam, J. A. E. Manson, and F. B. Hu, “Magnesium intake and plasma concentrations of markers of systemic inflammation and endothelial dysfunction in women,” The American Journal of Clinical Nutrition, vol. 85, no. 4, pp. 1068–1074, 2007.

D. T. Dibaba, P. Xun, and K. He, “Dietary magnesium intake is inversely associated with serum C-reactive protein levels: meta-analysis and systematic review,” European Journal of Clinical Nutrition, vol. 68, no. 4, pp. 510–516, 2014.

J. B. S. Morais, J. S. Severo, G. R. R. de Alencar et al., “Effect of magnesium supplementation on insulin resistance in humans: a systematic review,” Nutrition, vol. 38, pp. 54–60, 2017.

K. Kisters, C. Spieker, M. Tepel, and W. Zidek, “New data about the effects of oral physiological magnesium supplementation on several cardiovascular risk factors (lipids and blood pressure),” Magnesium Research, vol. 6, no. 4, pp. 355–360, 1993.

K. Yokota, M. Kato, F. Lister et al., “Clinical efficacy of magnesium supplementation in patients with type 2 diabetes,” Journal of the American College of Nutrition, vol. 23, no. 5, pp. 506S–509S, 2004.

S. Castiglioni, A. Cazzaniga, W. Albisetti, and J. A. Maier, “Magnesium and osteoporosis: current state of knowledge and future research directions,” Nutrients, vol. 5, no. 8, pp. 3022–3033, 2013.

A. C. Alfrey and N. L. Miller, “Bone magnesium pools in uremia,” The Journal of Clinical Investigation, vol. 52, no. 12, pp. 3019–3027, 1973.

N. Saito, N. Tabata, S. Saito et al., “Bone mineral density, serum albumin and serum magnesium,” Journal of the American College of Nutrition, vol. 23, no. 6, pp. 701S–703S, 2004.

M. Mahdavi-Roshan, M. Ebrahimi, and A. Ebrahimi, “Copper, magnesium, zinc and calcium status in osteopenic and osteoporotic post-menopausal women,” Clinical Cases in Mineral and Bone Metabolism, vol. 12, no. 1, pp. 18–21, 2015.

A. Czeczuk, E. Huk-Wieliczuk, A. Dmitruk, and H. Poplawska, “An analysis of selected risk factors of osteoporosis - dietary patterns and physical activity - in pubescent girls from the Lubelskie province,” Przegla̧d Epidemiologiczny, vol. 71, no. 1, pp. 99–110, 2017.

K. L. Tucker, M. T. Hannan, H. Chen, L. A. Cupples, P. W. F. Wilson, and D. P. Kiel, “Potassium, magnesium, and fruit and vegetable intakes are associated with greater bone mineral density in elderly men and women,” The American Journal of Clinical Nutrition, vol. 69, no. 4, pp. 727–736, 1999.

A. L. Tranquilli, E. Lucino, G. G. Garzetti, and C. Romanini, “Calcium, phosphorus and magnesium intakes correlate with bone mineral content in postmenopausal women,” Gynecological Endocrinology, vol. 8, no. 1, pp. 55–58, 1994.

T. S. Orchard, J. C. Larson, N. Alghothani et al., “Magnesium intake, bone mineral density, and fractures: results from the Women’s Health Initiative Observational Study,” The American Journal of Clinical Nutrition, vol. 99, no. 4, pp. 926–933, 2014.

M. C. Wang, E. C. Moore, P. B. Crawford et al., “Influence of pre-adolescent diet on quantitative ultrasound measurements of the calcaneus in young adult women,” Osteoporosis International, vol. 9, no. 6, pp. 532–535, 1999.

T. O. Carpenter, M. C. DeLucia, J. H. Zhang et al., “A randomized controlled study of effects of dietary magnesium oxide supplementation on bone mineral content in healthy girls,” The Journal of Clinical Endocrinology & Metabolism, vol. 91, no. 12, pp. 4866–4872, 2006.

C. N. Matias, D. A. Santos, C. P. Monteiro et al., “Magnesium intake mediates the association between bone mineral density and lean soft tissue in elite swimmers,” Magnesium Research, vol. 25, no. 3, pp. 120–125, 2012.

N. Veronese, B. Stubbs, M. Solmi et al., “Dietary magnesium intake and fracture risk: data from a large prospective study,” British Journal of Nutrition, vol. 117, no. 11, pp. 1570–1576, 2017.

L. Cohen and R. Kitzes, “Infrared spectroscopy and magnesium content of bone mineral in osteoporotic women,” Israel Journal of Medical Sciences, vol. 17, no. 12, pp. 1123–1125, 1981.

D. E. Warburton, C. W. Nicol, S. N. Gatto, and S. S. Bredin, “Cardiovascular disease and osteoporosis: balancing risk management,” Vascular Health and Risk Management, vol. 3, no. 5, pp. 673–689, 2007.

A. Mazur, J. A. M. Maier, E. Rock, E. Gueux, W. Nowacki, and Y. Rayssiguier, “Magnesium and the inflammatory response: potential physiopathological implications,” Archives of Biochemistry and Biophysics, vol. 458, no. 1, pp. 48–56, 2007.

V. Reddy and B. Sivakumar, “Magnesium-dependent vitamin-D-resistant rickets,” Lancet, vol. 1, no. 7864, pp. 963–965, 1974.

M. Shechter, C. N. B. Merz, M. Paul-Labrador et al., “Oral magnesium supplementation inhibits platelet-dependent thrombosis in patients with coronary artery disease,” The American Journal of Cardiology, vol. 84, no. 2, pp. 152–156, 1999.

M. Shechter, C. N. Bairey Merz, H. G. Stuehlinger, J. Slany, O. Pachinger, and B. Rabinowitz, “Effects of oral magnesium therapy on exercise tolerance, exercise-induced chest pain, and quality of life in patients with coronary artery disease,” The American Journal of Cardiology, vol. 91, no. 5, pp. 517–521, 2003.

R. Pokan, P. Hofmann, S. P. von Duvillard et al., “Oral magnesium therapy, exercise heart rate, exercise tolerance, and myocardial function in coronary artery disease patients,” British Journal of Sports Medicine, vol. 40, no. 9, pp. 773–778, 2006.

X. Qu, F. Jin, Y. Hao et al., “Magnesium and the risk of cardiovascular events: a meta-analysis of prospective cohort studies,” PLoS One, vol. 8, no. 3, article e57720, 2013.

L. C. Del Gobbo, Y. Song, P. Poirier, E. Dewailly, R. J. Elin, and G. M. Egeland, “Low serum magnesium concentrations are associated with a high prevalence of premature ventricular complexes in obese adults with type 2 diabetes,” Cardiovascular Diabetology, vol. 11, no. 1, p. 23, 2012.

G. Efstratiadis, M. Sarigianni, and I. Gougourelas, “Hypomagnesemia and cardiovascular system,” Hippokratia, vol. 10, no. 4, pp. 147–152, 2006.

N. Markovits, D. Kurnik, H. Halkin et al., “Database evaluation of the association between serum magnesium levels and the risk of atrial fibrillation in the community,” International Journal of Cardiology, vol. 205, pp. 142–146, 2016.

R. Y. Klinger, C. A. Thunberg, W. D. White et al., “Intraoperative magnesium administration does not reduce postoperative atrial fibrillation after cardiac surgery,” Anesthesia & Analgesia, vol. 121, no. 4, pp. 861–867, 2015.

L. F. Janeira, “Torsades de pointes and long QT syndromes,” American Family Physician, vol. 52, no. 5, pp. 1447–1453, 1995.

S. Isayama, K. Ushijima, Y. Sakanashi, T. Yano, and H. Terasaki, “Sudden ventricular tachyarrhythmia immediately following hepatectomy in a patient with hypomagnesemia,” Masui, vol. 47, no. 4, pp. 470–474, 1998.

T. Onagawa, A. Ohkuchi, R. Ohki et al., “Woman with postpartum ventricular tachycardia and hypomagnesemia,” The Journal of Obstetrics and Gynaecology Research, vol. 29, no. 2, pp. 92–95, 2003.

A. D. Kaye, J. Volpi-Abadie, J. M. Bensler, A. M. Kaye, and J. H. Diaz, “QT interval abnormalities: risk factors and perioperative management in long QT syndromes and Torsades de Pointes,” Journal of Anesthesia, vol. 27, no. 4, pp. 575–587, 2013.

C. N. M. L. De Falco, C. Grupi, E. Sosa et al., “Successful improvement of frequency and symptoms of premature complexes after oral magnesium administration,” Arquivos Brasileiros de Cardiologia, vol. 98, no. 6, pp. 480–487, 2012.

I. S. Young, E. M. Goh, U. H. McKillop, C. F. Stanford, D. P. Nicholls, and E. R. Trimble, “Magnesium status and digoxin toxicity,” British Journal of Clinical Pharmacology, vol. 32, no. 6, pp. 717–721, 1991.

L. Cohen and R. Kitzes, “Magnesium sulfate and digitalis-toxic arrhythmias,” Journal of the American Medical Association, vol. 249, no. 20, pp. 2808–2810, 1983.

M. P. Raja Rao, P. Panduranga, K. Sulaiman, and M. Al-Jufaili, “Digoxin toxicity with normal digoxin and serum potassium levels: beware of magnesium, the hidden malefactor,” The Journal of Emergency Medicine, vol. 45, no. 2, pp. e31–e34, 2013.

R. V. Lewis, B. Tregaskis, J. McLay, E. Service, and D. G. McDevitt, “Oral magnesium reduces ventricular ectopy in digitalised patients with chronic atrial fibrillation,” European Journal of Clinical Pharmacology, vol. 38, no. 2, pp. 107–110, 1990.

E. S. Ford, “Serum magnesium and ischaemic heart disease: findings from a national sample of US adults,” International Journal of Epidemiology, vol. 28, no. 4, pp. 645–651, 1999.

K. He, K. Liu, M. L. Daviglus et al., “Magnesium intake and incidence of metabolic syndrome among young adults,” Circulation, vol. 113, no. 13, pp. 1675–1682, 2006.

B. C. T. Kieboom, M. N. Niemeijer, M. J. G. Leening et al., “Serum magnesium and the risk of death from coronary heart disease and sudden cardiac death,” Journal of the American Heart Association, vol. 5, no. 1, article e002707, 2016.

L. Jiang, P. He, J. Chen et al., “Magnesium levels in drinking water and coronary heart disease mortality risk: a meta-analysis,” Nutrients, vol. 8, no. 1, 2016.

F. Liao, A. R. Folsom, and F. L. Brancati, “Is low magnesium concentration a risk factor for coronary heart disease? The Atherosclerosis Risk in Communities (ARIC) Study,” American Heart Journal, vol. 136, no. 3, pp. 480–490, 1998.

M. Shechter, M. Sharir, M. J. P. Labrador, J. Forrester, B. Silver, and C. N. Bairey Merz, “Oral magnesium therapy improves endothelial function in patients with coronary artery disease,” Circulation, vol. 102, no. 19, pp. 2353–2358, 2000.

A. Shafiq, A. Goyal, P. G. Jones et al., “Serum magnesium levels and in-hospital mortality in acute myocardial infarction,” Journal of the American College of Cardiology, vol. 69, no. 22, pp. 2771-2772, 2017.

J. Li, Q. Zhang, M. Zhang, and M. Egger, “Intravenous magnesium for acute myocardial infarction,” The Cochrane Database of Systematic Reviews, no. 2, article CD002755, 2007.

G. An, Z. Du, X. Meng et al., “Association between low serum magnesium level and major adverse cardiac events in patients treated with drug-eluting stents for acute myocardial infarction,” PLoS One, vol. 9, no. 6, article e98971, 2014.

S. Monarca, I. Zerbini, C. Simonati, and U. Gelatti, “Drinking water hardness and chronic degenerative diseases. II. Cardiovascular diseases,” Annali di Igiene, vol. 15, no. 1, pp. 41–56, 2003.

C. Y. Yang, H. F. Chiu, J. F. Chiu, T. N. Wang, and M. F. Cheng, “Magnesium and calcium in drinking water and cerebrovascular mortality in Taiwan,” Magnesium Research, vol. 10, no. 1, pp. 51–57, 1997.

E. Rubenowitz, I. Molin, G. Axelsson, and R. Rylander, “Magnesium in drinking water in relation to morbidity and mortality from acute myocardial infarction,” Epidemiology, vol. 11, no. 4, pp. 416–421, 2000.

A. Rosanoff, “The high heart health value of drinking-water magnesium,” Medical Hypotheses, vol. 81, no. 6, pp. 1063–1065, 2013.

T. M. Paravicini, A. Yogi, A. Mazur, and R. M. Touyz, “Dysregulation of vascular TRPM7 and annexin-1 is associated with endothelial dysfunction in inherited hypomagnesemia,” Hypertension, vol. 53, no. 2, pp. 423–429, 2009.

C. Abad, F. R. Vargas, T. Zoltan et al., “Magnesium sulfate affords protection against oxidative damage during severe preeclampsia,” Placenta, vol. 36, no. 2, pp. 179–185, 2015.

S. D. McDonald, O. Lutsiv, N. Dzaja, and L. Duley, “A systematic review of maternal and infant outcomes following magnesium sulfate for pre-eclampsia/eclampsia in real-world use,” International Journal of Gynecology & Obstetrics, vol. 118, no. 2, pp. 90–96, 2012.

L. Ceremuzynski, J. Gebalska, R. Wolk, and E. Makowska, “Hypomagnesemia in heart failure with ventricular arrhythmias. Beneficial effects of magnesium supplementation,” Journal of Internal Medicine, vol. 247, no. 1, pp. 78–86, 2000.

P. O. Wester and T. Dyckner, “Intracellular electrolytes in cardiac failure,” Acta Medica Scandinavica, vol. 219, no. S707, pp. 33–36, 1986.

T. Angkananard, T. Anothaisintawee, S. Eursiriwan et al., “The association of serum magnesium and mortality outcomes in heart failure patients: a systematic review and meta-analysis,” Medicine, vol. 95, no. 50, article e5406, 2016.

M. L. Mayer, G. L. Westbrook, and P. B. Guthrie, “Voltage-dependent block by Mg²⁺ of NMDA responses in spinal cord neurones,” Nature, vol. 309, no. 5965, pp. 261–263, 1984.

A. Baratloo, S. Mirbaha, H. Delavar Kasmaei, P. Payandemehr, A. Elmaraezy, and A. Negida, “Intravenous caffeine citrate vs. magnesium sulfate for reducing pain in patients with acute migraine headache; a prospective quasi-experimental study,” The Korean Journal of Pain, vol. 30, no. 3, pp. 176–182, 2017.

J. Schoenen, J. Sianard-Gainko, and M. Lenaerts, “Blood magnesium levels in migraine,” Cephalalgia, vol. 11, no. 2, pp. 97–99, 1991.

A. Samaie, N. Asghari, R. Ghorbani, and J. Arda, “Blood magnesium levels in migraineurs within and between the headache attacks: a case control study,” The Pan African Medical Journal, vol. 11, p. 46, 2012.

N. M. Ramadan, H. Halvorson, A. Vande-Linde, S. R. Levine, J. A. Helpern, and K. M. A. Welch, “Low brain magnesium in migraine,” Headache, vol. 29, no. 9, pp. 590–593, 1989.

A. A. P. Leo, “Further observations on the spreading depression of activity in the cerebral cortex,” Journal of Neurophysiology, vol. 10, no. 6, pp. 409–414, 1947.

Y. Cete, B. Dora, C. Ertan, C. Ozdemir, and C. Oktay, “A randomized prospective placebo-controlled study of intravenous magnesium sulphate vs. metoclopramide in the management of acute migraine attacks in the emergency department,” Cephalalgia, vol. 25, no. 3, pp. 199–204, 2005.

A. Shahrami, F. Assarzadegan, H. R. Hatamabadi, M. Asgarzadeh, B. Sarehbandi, and S. Asgarzadeh, “Comparison of therapeutic effects of magnesium sulfate vs. dexamethasone/metoclopramide on alleviating acute migraine headache,” The Journal of Emergency Medicine, vol. 48, no. 1, pp. 69–76, 2015.

A. Mauskop, B. T. Altura, R. Q. Cracco, and B. M. Altura, “Intravenous magnesium sulfate rapidly alleviates headaches of various types,” Headache, vol. 36, no. 3, pp. 154–160, 1996.

S. M. Dorhout Mees, D. Bertens, H. B. van der Worp, G. J. E. Rinkel, and W. M. van den Bergh, “Magnesium and headache after aneurysmal subarachnoid haemorrhage,” Journal of Neurology, Neurosurgery, and Psychiatry, vol. 81, no. 5, pp. 490–493, 2010.

F. Facchinetti, G. Sances, P. Borella, A. R. Genazzani, and G. Nappi, “Magnesium prophylaxis of menstrual migraine: effects on intracellular magnesium,” Headache, vol. 31, no. 5, pp. 298–301, 1991.

J. Opavsky, “Magnesium and its combination with cinnarizine in the long-term treatment of headache,” Acta Universitatis Palackianae Olomucensis Facultatis Medicae, vol. 131, pp. 157–164, 1991.

H. Choi and N. Parmar, “The use of intravenous magnesium sulphate for acute migraine: meta-analysis of randomized controlled trials,” European Journal of Emergency Medicine, vol. 21, no. 1, pp. 2–9, 2014.

L. Castilla-Guerra, M. del Carmen Fernández-Moreno, J. M. López-Chozas, and R. Fernández-Bolaños, “Electrolytes disturbances and seizures,” Epilepsia, vol. 47, no. 12, pp. 1990–1998, 2006.

B. B. Chen, C. Prasad, M. Kobrzynski, C. Campbell, and G. Filler, “Seizures related to hypomagnesemia: a case series and review of the literature,” Child Neurology Open, vol. 3, article 2329048X16674834, 2016.

B. M. Sibai, “Magnesium sulfate is the ideal anticonvulsant in preeclampsia-eclampsia,” American Journal of Obstetrics and Gynecology, vol. 162, no. 5, pp. 1141–1145, 1990.

J. R. Barton, B. M. Sibai, R. A. Ahokas, W. D. Whybrew, and B. M. Mercer, “Magnesium sulfate therapy in preeclampsia is associated with increased urinary cyclic guanosine monophosphate excretion,” American Journal of Obstetrics and Gynecology, vol. 167, no. 4, pp. 931–934, 1992.

P. Chinayon, “Clinical management and outcome of eclampsia at Rajavithi Hospital,” Journal of the Medical Association of Thailand, vol. 81, no. 8, pp. 579–585, 1998.

P. A. Abdelmalik, N. Politzer, and P. L. Carlen, “Magnesium as an effective adjunct therapy for drug resistant seizures,” The Canadian Journal of Neurological Sciences, vol. 39, no. 3, pp. 323–327, 2012.

T. Ohira, J. M. Peacock, H. Iso, L. E. Chambless, W. D. Rosamond, and A. R. Folsom, “Serum and dietary magnesium and risk of ischemic stroke: the Atherosclerosis Risk in Communities Study,” American Journal of Epidemiology, vol. 169, no. 12, pp. 1437–1444, 2009.

S. N. Adebamowo, D. Spiegelman, W. C. Willett, and K. M. Rexrode, “Association between intakes of magnesium, potassium, and calcium and risk of stroke: 2 cohorts of US women and updated meta-analyses,” The American Journal of Clinical Nutrition, vol. 101, no. 6, pp. 1269–1277, 2015.

L. K. M. Bain, P. K. Myint, A. Jennings et al., “The relationship between dietary magnesium intake, stroke and its major risk factors, blood pressure and cholesterol, in the EPIC-Norfolk cohort,” International Journal of Cardiology, vol. 196, pp. 108–114, 2015.

S. You, C. Zhong, H. Du et al., “Admission low magnesium level is associated with in-hospital mortality in acute ischemic stroke patients,” Cerebrovascular Diseases, vol. 44, no. 1-2, pp. 35–42, 2017.

I. M. Cojocaru, M. Cojocaru, C. Burcin, and N. A. Atanasiu, “Serum magnesium in patients with acute ischemic stroke,” Romanian Journal of Internal Medicine, vol. 45, no. 3, pp. 269–273, 2007.

J. L. Saver, S. Starkman, M. Eckstein et al., “Prehospital use of magnesium sulfate as neuroprotection in acute stroke,” The New England Journal of Medicine, vol. 372, no. 6, pp. 528–536, 2015.

J. Britton, I. Pavord, K. Richards et al., “Dietary magnesium, lung function, wheezing, and airway hyperreactivity in a random adult population sample,” The Lancet, vol. 344, no. 8919, pp. 357–362, 1994.

A. F. do Amaral, A. L. Rodrigues-Junior, J. Terra Filho, H. Vannucchi, and J. A. Martinez, “Effects of acute magnesium loading on pulmonary function of stable COPD patients,” Medical Science Monitor, vol. 14, no. 10, pp. CR524–CR529, 2008.

E. M. Skobeloff, W. H. Spivey, R. M. McNamara, and L. Greenspon, “Intravenous magnesium sulfate for the treatment of acute asthma in the emergency department,” Journal of the American Medical Association, vol. 262, no. 9, pp. 1210–1213, 1989.

K. M. Kew, L. Kirtchuk, and C. I. Michell, “Intravenous magnesium sulfate for treating adults with acute asthma in the emergency department,” Cochrane Database of Systematic Reviews, vol. 5, article CD010909, 2014.

R. Hughes, A. Goldkorn, M. Masoli, M. Weatherall, C. Burgess, and R. Beasley, “Use of isotonic nebulised magnesium sulphate as an adjuvant to salbutamol in treatment of severe asthma in adults: randomised placebo-controlled trial,” The Lancet, vol. 361, no. 9375, pp. 2114–2117, 2003.

C. B. Cairns and M. Kraft, “Magnesium attenuates the neutrophil respiratory burst in adult asthmatic patients,” Academic Emergency Medicine, vol. 3, no. 12, pp. 1093–1097, 1996.

H. S. Aziz, A. I. Blamoun, M. K. Shubair, M. M. Ismail, V. A. DeBari, and M. A. Khan, “Serum magnesium levels and acute exacerbation of chronic obstructive pulmonary disease: a retrospective study,” Annals of Clinical and Laboratory Science, vol. 35, no. 4, pp. 423–427, 2005.

S. P. Bhatt, P. Khandelwal, S. Nanda, J. C. Stoltzfus, and G. T. Fioravanti, “Serum magnesium is an independent predictor of frequent readmissions due to acute exacerbation of chronic obstructive pulmonary disease,” Respiratory Medicine, vol. 102, no. 7, pp. 999–1003, 2008.

M. C. Shivanthan and S. Rajapakse, “Magnesium for acute exacerbation of chronic obstructive pulmonary disease: a systematic review of randomised trials,” Annals of Thoracic Medicine, vol. 9, no. 2, pp. 77–80, 2014.

A. Gumus, M. Haziroglu, and Y. Gunes, “Association of serum magnesium levels with frequency of acute exacerbations in chronic obstructive pulmonary disease: a prospective study,” Pulmonary Medicine, vol. 2014, Article ID 329476, 5 pages, 2014.

T. D. Mountokalakis, “Magnesium metabolism in chronic renal failure,” Magnesium Research, vol. 3, no. 2, pp. 121–127, 1990.

J. Cunningham, M. Rodriguez, and P. Messa, “Magnesium in chronic kidney disease stages 3 and 4 and in dialysis patients,” Clinical Kidney Journal, vol. 5, Supplement 1, pp. i39–i51, 2012.

J. Floridis, A. Abeyaratne, and S. W. Majoni, “Prevalence and clinical impact of magnesium disorders in end-stage renal disease: a protocol for a systematic review,” Systematic Reviews, vol. 4, no. 1, p. 76, 2015.

J. H. Huang, F. C. Cheng, and H. C. Wu, “Low magnesium exacerbates osteoporosis in chronic kidney disease patients with diabetes,” International Journal of Endocrinology, vol. 2015, Article ID 380247, 10 pages, 2015.

K. Cai, Q. Luo, Z. Dai et al., “Hypomagnesemia is associated with increased mortality among peritoneal dialysis patients,” PLoS One, vol. 11, no. 3, article e0152488, 2016.