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  2. October 2015 Vol. 7 Issue 10

Identifying and Treating Magnesium Deficiency in Cancer Patients Receiving Platinum-based Chemotherapy

A review of the literature on hypomagnesemia in cancer patients

By Jen Green, ND, FABNO, Meighan Valero, ND, and Laura Perkowski, ND

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Abstract 

Purpose. In this article, we review the prevalence of magnesium (Mg) deficiency in patients undergoing platinum-based chemotherapy (PBC), summarize research on IV and oral Mg in supportive care, discuss the role of Mg in carcinogenesis, explore different forms of oral Mg, investigate current best evidence on the effect of Mg on survivorship, and review ways for clinicians to identify and remedy early signs of Mg depletion. Methods. PubMed, Natural Medicines Comprehensive Database, Natural Standard Database, Google Scholar, and the book Herb, Nutrient, and Drug Interactions were used to locate relevant studies with publication dates up to May 15, 2015. Results. Hypomagnesemia is known to occur in 29% to 100% of patients undergoing PBC. While serum Mg does not appear to be a reliable indicator of Mg deficiency, there are a wide variety of clinical signs and symptoms that can be used for screening. These include loss of appetite, nausea, vomiting, headache, weakness, numbness, tingling, muscle cramps, constipation, fatigue, anxiety, restless legs, insomnia, depression, irritability, asthma, refractory hypocalcemia and hypokalemia, high blood pressure, tremor, tetany, prolonged QT interval, cardiac arrhythmias, ataxia, carpopedal spasms, seizures, metabolic alkylosis, psychiatric disturbances, and cortical blindness. Prophylactic IV Mg in pre- and posthydration followed by oral Mg supplementation can play an important role in preventing platinum (Pt)-induced serum hypomagnesemia. Mg supplementation with PBC is safe because it does not appear to affect progression-free survival, overall survival, antitumor activity, or blood concentrations of chemotherapy. Conclusions. Prophylactic IV Mg followed by oral Mg can prevent Pt-induced hypomagnesemia and alleviate Mg deficiency symptoms in cancer patients.

Background

Magnesium (Mg) deficiency is a relatively common nutritional deficiency, with up to 75% of the US population falling below the recommended daily allowance in dietary Mg.1 Cancer patients may be at additional risk of deficiency either from gastrointestinal loss of Mg or related to drug-induced depletions. There is dispute regarding the usefulness of serum Mg to identify deficiency, and there is lack of clarity regarding which clinical symptoms suggest low tissue Mg levels. In this article, we discuss the potential causes of Mg deficiency in patients receiving platinum-based chemotherapy (PBC), review the signs and symptoms of Mg deficiency, explore how to best screen for Mg deficiency, and summarize the research available on combining Mg with PBC.

Causes and Prevalence of Magnesium Deficiency in Oncology Patients

Mg deficiency may occur from low stomach acid, loss of Mg in the gastrointestinal tract, or renal wasting. Mg deficiency can be induced by a number of chemotherapeutic agents commonly used in cancer care. Specific conditions and therapeutic agents that may cause Mg deficiency in oncology patients are listed in Table 1.
 
Table 1. Causes of Magnesium Deficiency in Oncology Patients
Routes of Magnesium Deficiency Conditions and Medications
Gastrointestinal Diarrhea, pancreatitis, irritable bowel disease, bowel resection, protein-calorie malnutrition, total parenteral nutrition, bowel fistula1
Renal Postobstructive diuresis, postacute tubular necrosis, renal transplantation, interstitial nephropathy, Bartter syndrome, Gitelman’s syndrome1
Medications Proton pump inhibitors, corticosteroids, laxatives, loop and thiazide diuretics, foscarnet, digoxin, amphotericin B, colchicines, theophylline, macrolide antibiotics, petamidine, tobramycin, amikacin1; tacrolimus1,2
Chemotherapeutic agents Aminoglycosides (gentamicin, streptomycin)1; cyclosporine, cisplatin3; carboplatin4; cetuximab5; panitumumab6
Other Burns1; alcoholism, diabetes7
 
Serum hypomagnesemia is frequently observed in more than 10% of hospitalized patients, and occurrences can be as high as 65% in patients in intensive care.8 Patients at particularly high risk include those with leukemia who are receiving arsenic trioxide or cisplatin. In particular, patients with acute promyelocytic leukemia who receive arsenic trioxide as part of induction therapy are at high risk for hypomagnesemia, which can subsequently cause an increased risk for QT prolongation and possible progression to torsade de pointes. Arsenic trioxide itself can cause QT interval prolongation and lead to complete atrioventricular block and ultimately death. For these patients, it is recommended that they maintain serum potassium and Mg levels at or above 4 mEq/dL and 1.8 mg/dL, respectively.9

Prevalence of Magnesium Deficiency With Platinum-based Chemotherapy

Increasing evidence points to routine depletion of Mg by PBC. Cisplatin’s nephrotoxicity causes increased Mg excretion10-12 even before renal function is affected.13 The reported incidence in studies varies between 29% and 100% of patients.14 Buckley et al reported the incidence of hypomagnesemia to be 41% after 1 course of treatment and 100% after 6 courses of treatment with cisplatin.15 Hodkinson et al reported the incidence of hypomagnesemia to be 43% at any point during cisplatin treatment.14 Schilsky and Anderson reported that most adults receiving cisplatin will develop hypomagnesemia at some time during their treatment16 and that in children, hypomagnesemia was virtually inevitable.16 Hypomagnesemia typically persists for 4 to 5 months after the cessation of chemotherapy,15 but in children can even persist for months or years after cancer treatment.16
 
The incidence and severity of low serum Mg with treatment with cisplatin is dose-dependent and worsens with increasing cumulative doses.14 Martin et al suggested that most patients who receive cumulative doses of cisplatin in excess of 400 mg/m2 will develop some degree of hypomagnesemia.17 Deficiency is often noted after 2 or 3 cycles of therapy, although hypomagnesemia can occur after a single treatment.18 The frequency of administration of cisplatin may also be important. A study by Buckley et al showed a lower incidence of hypomagnesemia in patients receiving cisplatin every 8 weeks vs with cisplatin every 4 weeks.15 Patients receiving larger doses of cisplatin (80-100 mg/m2 compared with 50-60 mg/m2) developed hypomagnesemia more quickly.19 Although hypomagnesemia is usually mild, the concentration of Mg in the serum can fall to potentially dangerous levels after only the second cycle of treatment with cisplatin.20
 
Studies previously estimated that only 10% of patients treated with carboplatin develop hypomagnesemia.21 However, in a study of patients with gynecological cancer who received carboplatin, 46% were noted to be hypomagnesemic, with 14% developing toxicity of grade 2 or greater. Carboplatin was associated with the risk of hypomagnesemia compared with noncarboplatin regimens (P=0.05).4
 
Cancer patients receiving PBC alongside aminoglycoside antibiotics may be at particularly high risk for severe symptoms. Keating et al reported that of the 17 cancer patients who received an aminoglycoside and doxorubicin or a PCB and developed complex metabolic syndromes,12 died and 5 developed progressive renal impairment. Aminoglycoside antibiotics can cause renal tubular damage and renal insufficiency, which can add to the nephrotoxic effects of platinum (Pt).1

Laboratory Testing for Magnesium

Evaluating Mg levels in oncology patients is challenging because Mg is largely intracellular. Only 0.3% of Mg is present in the plasma and less than 1% is located in the extracellular space. A deficit can easily be present with normal serum Mg. In 1 study of patients receiving cisplatin, serum Mg was not a sensitive or reliable indicator of depletion compared to skeletal muscle Mg levels.22 Despite the apparent lack of sensitivity of serum Mg to tissue depletion, hypomagnesemia is still very prevalent, highlighting how severe Mg deficiency can be in this population. 
 
Urinary Mg may provide a sensitive measure of Mg status for patients treated with PBC (less than 1 mmol/d indicates a deficiency) and can be considered for future trials. The parenteral Mg load test is another potentially more accurate measure. The test consists of administering a loading dose of Mg sulphate (0.25 mmol per 1 kg body weight) in 250 mL 0.9% saline over 1 hour and collecting urine for 24 hours. Excretion of less than 80% of the loading dose indicates deficiency. Both tests require lengthy urine collections and are not realistic for daily practice. Clinical screening for Mg deficiency is advised by the authors as an adjunct to current testing of serum Mg.

Clinical Symptoms of Magnesium Deficiency

Identifying Mg deficiency during a clinical encounter can be particularly challenging in oncology patients. Mg deficiency can cause a wide variety of symptoms, and some of the earlier signs of Mg deficiency—such as nausea, vomiting, weakness, tingling, depression, irritability, constipation, and ataxia—are also commonly seen side effects from chemotherapy. Since serum levels of Mg are such poor indicators of Mg status, clinicians must use alternative screening methods to identify Mg deficiency. Identification of hypomagnesemia by medical personnel in the early phases of deficiency can prevent life-threatening conditions. 
 
Suboptimal Mg levels affect a wide range of tissues, especially smooth muscle (uterine, cardiac, arterial, and intestinal), nerves, heart, and kidneys. Table 2 provides a comprehensive list of symptoms associated with Mg deficiency. 
 
Table 2. Symptoms of Magnesium Deficiency
Mild Muscle cramps, constipation, fatigue, anxiety, restless legs, insomnia, irritability, insulin resistance1; loss of appetite, nausea, vomiting, headache, weakness, numbness, tingling23; depression24
Major Refractory hypocalcemia and hypokalemia7; high blood pressure, tremor, prolonged QT interval, cardiac arrhythmias, hyperreflexia, ataxia, carpopedal spasms14; migraine headache, asthma, hypoparathyroidism25; tetany and/or convulsions14,26
Severe Seizures, metabolic alkylosis, psychiatric disturbances27; cortical blindness28
 
In the oncology setting, case reports have indicated that PBC-induced Mg deficiency leads to a wide array of clinical signs and symptoms. One case report described a patient with cervical cancer who received cisplatin and developed sudden cortical blindness. When hypomagnesemia was discovered and treated, her vision was restored.29 Three case reports in which cisplatin was identified as triggering cardiac arrhythmias resolved with Mg repletion.30 Two cases were published in which refractory hypokalemia responded only with Mg supplementation.29 A recent review by Centeno and Lopez-Saca found that many of the clinical symptoms of hypomagnesemia in patients with advanced cancer, as well as other chronic illnesses, were alleviated with intravenous (IV) and oral administration of Mg.31 By recognizing early signs of Mg deficiency, health professionals may prevent a number of potentially severe sequelae.

Magnesium and Carcinogenesis

In addition to the research involving hypomagnesemia induced by PBC, recent literature describes a role of Mg in carcinogenesis. Tumor biology is characterized by high energy requirements due to rapid proliferation, dedifferentiation, and cell immortality, and Mg is necessary in the cellular processes of tumor cells. As such, tumor tissue often stores Mg and can lead to low plasma Mg.33 The relationship between Mg and carcinogenesis is complex and multifactorial, but can it be said that Mg could propagate tumor growth?
 
Mg deficiency can contribute to the development of an oncogenic milieu by inducing inflammation, oxidative stress, and by inhibiting DNA repair enzymes. Less than optimal intake of Mg is linked with systemic inflammation,33,34 oxidative injury, and increased lipid peroxidation.34,35 Adequate levels of Mg stabilize the structure of DNA and its repair mechanism, act as a cofactor in nucleic acid metabolism, and are important in DNA replication and repair.36-38 The checkpoints in DNA replication and stability help prevent mutations from occurring. It has been hypothesized that a decrease in Mg activates the gene TRPM7, which increases intracellular calcium (Ca) levels while decreasing the nucleotide MgATP. This overall change in ATP and Ca levels can activate Ca-dependent cell proliferation, leading to oncogenesis.39 In vivo studies conducted by Wolf et al noted that the development of lung metastasis nearly doubled in Mg-deficient mice, compared to that of mice with a normal diet.34 Mg has also been demonstrated to prevent lead- and nickel-induced lung tumors in mice and to protect against 3-methyl-cholantrene-induced fibrosarcomas in rats.40-42 Solanki et al found that Mg supplementation protects against cisplatin-induced acute kidney injury in human ovarian tumor xenograft mouse models without compromising the cytotoxic effects by cisplatin.43 These in vitro and in vivo studies of Mg support its role in cancer prevention and treatment. 
 
A number of epidemiological studies have evaluated the levels of Mg in drinking water and cancer rates. One study suggested that high Mg content in drinking water offered protection from liver cancer and esophageal cancer.44,45 Mg levels in drinking water were also found to be inversely correlated with death rate from breast, prostate, and ovarian cancers.40,46 In Japan, an inverse correlation was found between dietary Mg intake and colon cancer. However, this finding was limited to men.47 In the United States, a cohort study of 61,433 women followed for 14.8 years found that women in the highest quintile of Mg intake (greater than 255 mg daily) relative to the lowest quintile (less than 209 mg daily) had a significantly reduced risk of colorectal cancer, with a relative risk of 0.59 (95% confidence interval: 0.40-0.87) after controlling for confounding variables.48 In the Nashville Men’s Health Study on prostate cancer involving 494 participants, serum Mg levels were significantly lower among high-grade cases vs controls (P=0.04).49 A case-control study on lung cancer with 1,139 patients and 1,210 matched healthy controls found that lower dietary Mg intake was associated with poorer DNA repair capacity and increased risk of lung cancer (P-trend<0.0001). Similar results were observed by histology and clinical stage of lung cancer.50 Overall, a number of studies have found correlations between low serum Mg and increased cancer risk and tumor aggressiveness. 
 
Clinical trial evidence regarding Mg supplementation with PBC and survivorship is sparse but encouraging. A small study with 33 participants found that infusions with Ca/Mg did not influence antitumor activity or blood concentrations of Pt chemotherapy.51 Sixteen patients with testicular cancer and 1 patient with ovarian dysgerminoma who were randomized to receive either oral and IV Mg or no supplementation showed no difference in tumor growth rates or outcome.20 A study of 36 patients with non-small cell lung carcinoma who were receiving cisplatin found that tumor response rates were 59.3% (16 of 27 patients) in the Mg group compared with 38.5% (10 of 26 patients) in the control.52 While none of these trials were powered to evaluate differences in survivorship, the current best evidence points to the safety of oral and IV Mg with PBC.
 
While Mg repletion seems to be important for preventing more severe symptoms of Mg deficiency, it is clear more research needs to be performed in this area to further elucidate the effects of Mg deficiency and Mg repletion on cancer progression. Clinicians will then be able to utilize these findings to better inform and treat their patients.

Intervention Studies Involving Magnesium and Platinum-based Chemotherapy 

The majority of published studies on IV or oral Mg demonstrate a high need for administration of Mg in conjunction with cisplatin, with a required dose escalation as cisplatin cycles progress. 
 
Table 3 summarizes studies on Mg supplementation with PBC. Note that for IV Mg sulphate, 1 g of Mg sulfate is equal to Mg 4.06 mmol.53

Table 3. Studies on Magnesium in Platinum-based Chemotherapy
Patients Randomized Intervention Control Outcome
40 patients with ovarian cancer receiving paclitaxel and cisplatin Yes (double- blind) 20.3 mmol IV Mg sulphate (5 g) every 3 wk plus oral Mg carbonate 500 mg 3x/d during the treatment intervals Placebo  Serum Mg varied significantly between supplemented and placebo groups (P<0.0001). Control group showed  significantly greater decrease of GFR assessed by serum levels of creatinine (P=0.0069), Cockroft-Gault (P=0.0077), and Modification Diet of Renal Disease (P=0.032)54
32 patients with upper GI malignancies receiving cisplatin/5-fluorouracil Yes

12 mmol IV Mg sulfate (2.96 g) prehydration and 16 mmol IV Mg sulfate (3.94 g) posthydration

 Mg only when the serum Mg below normal Mg supplements necessary in 50% of control group’s cycles, several instances of symptomatic hypomagnesemia requiring further IV supplements in midcycle55
201 patients with cervical cancer receiving cisplatin and radiation Yes

Group 2: 8.12 mmol IV Mg sulphate (2 g) pre- and posthydration

Group 3: 8.12 mmol IV Mg sulphate (2 g) pre- and posthydration and then 12.18 mmol (3 g) pre- and posthydration after cycle 3

 Group 1: 4.06 mmol IV Mg sulphate (1 g) pre- and posthydration 62.8% (44/70) control vs 32.6% (22/70) group 2 patients with episodes of hypomagnesemia (P=0.007). Group 3 had a 49.6% decrease in the total number of episodes compared to control. Patients in the second intervention group showed a 100% improvement incidence of persistent hypomagnesemia over the 2 other cohorts (P=0.001)56
16 patients with testicular cancer and 1 with ovarian dysgerminoma receiving cisplatin Yes 8 mmol IV Mg sulphate followed by oral 246 mg Mg citrate 3x/d No treatment or placebo Significantly greater renal tubular damage (as assessed by urine N-acetyl-B-D-glucosaminidase) and lower serum Mg in controls. Trend towards reduced treatment delays in the supplemented group20
23 patients with advanced head and neck cancer receiving cisplatin Yes 123 mg oral MgAHa 3x/d continuously for 3-4 mo. If fell below <1.4 mg dL serum mg, dose doubled to 246 mg 3x/d

 

 123 mg oral MgAH 3x/d as needed Most controls required continuous Mg supplementation. 20% of continuous MgAH developed hypomagnesemia in a given cycle57
41 patients treated with cisplatin, mixed tumor types Yes 12.18 mmol IV Mg (3 g) before cisplatin or oral Mg pidolate, 2 g every 8 h on days 2 to 21 of cisplatin  No treatment Patients in both supplementation arms showed significantly higher Mg levels than controls from the second course on oral or from the third course on IV; 3 of 9 patients (33%) in the IV Mg arm and 4 of 9 (44%) in the oral Mg arm developed hypomagnesemia after the fourth course of cisplatin, compared with 9 of 10 (90%) patients in the control group17
33 metastatic patients with colon cancer receiving folinic acid, fluorouracil, and oxaliplatin-6 Yes Infusions with Ca gluconate 850 mg and Mg sulfate 720 mg Placebo No reduction in neurotoxicity with Ca/Mg infusions. No change in platinum concentrations52
401 patients receiving high dose (>60 mkg/m2) of cisplatin in firstline setting, mixed tumor types No 20 mEq Mg sulfate with 500 mL of one-quarter isotonic saline over 1 h after cisplatin administration No treatment Reduced risk of cisplatin nephrotoxicity (RR:0.175, P=0.0004) and reduced severity of renal toxicity (P=0.012) in Mg-supplemented group58
37 patients with NSCLC receiving cisplatin/ irinotecan;  matched with 32 controls No, case-control study Days 1 through 4 after irinotecan, orally administered alkalinizations with sodium bicarbonate, Mg oxide, basic water, and ursodeoxycholic acid. Controlled defecation with up to 4.0 g/d of Mg oxide and 2 L/d of excess basic water Matched controls taking cisplatin/ irinotecan  

Use of oral administration and controlled defecation reduced the incidence of delayed diarrhea (> or = grade 2: P=0.005), nausea (P=0.0001), vomiting (P=0.001), granulocytopenia (P=0.03), and lymphocytopenia (P=0.034). Dose intensification was well tolerated in patients receiving oral administration and controlled defecation, allowing dose escalation from 35.6±6.0 to 39.9±5.6 mg/m2/wk (P<0.001)52
8 patients with metastatic germ cell cancer and 8 matched controls taking high-dose cisplatin No 12.18 mmol IV Mg sulphate (3 g), 12 mmol prehydration, IV and oral as needed Matched controls received no treatment with Mg or placebo Mean serum Mg levels higher in supplemented patients (P<0.01)59
17 patients with cervical cancer receiving cisplatin No 20 mmol if Mg<0.62 mmol/L (4.9 g) N/A Incidence of serum hypomagnesemia reduced from 65% to 17.6%60
28 children receiving cisplatin, mixed tumor types No Unreported 16 given Mg after cisplatin, 12 pre- and postcisplatin Mg levels higher in pre- and postcisplatin group than postcisplatin only  (P<0.01)61
10 patients with  metastatic testicular cancer receiving cisplatin No 0.3 mmol Mg chloride/kg/day and 0.4 mmol potassium chloride/kg/day  5 given 0.4 mmol potassium chloride/kg/d only Mean serum Mg levels higher in supplemented patients (P<0.001)62
22 patients with upper GI cancer receiving epirubicin, cisplatin, and fluorouracil No IV Mg 25 mmol (6.15 g) pre- and posthydration  IV Mg 12.5 mmol (3 g) pre- and posthydration No significant difference69
214 consecutive patients with mixed tumor types receiving cisplatin  No Bleomycin, etoposide, cisplatin chemotherapy and 60 mmol IV Mg/cycle (14.78 g), POMBeACE chemotherapy received 20 mmol IV Mg/cycle (4.9 g) N/A

60 mmol IV Mg per cycle of 33 mg/m2/wk cisplatin sufficient to prevent hypomagnesemia; 20 mmol IV Mg per cycle of 40 mg/m2/wk cisplatin was insufficient to prevent hypomagnesemia14

 
23 patients with esophageal or hypopharyngeal cancer receiving fluorouracil and cisplatin; 10 patients received Mg supplementation No Mg sulphate (20 mEq) administered before fluorouracil (800mg/m2/24 h per days 1-5) and Cisplatin (80mg/m2/d) 13 patients did not receive Mg supplementation Mg supplementation successfully reduced the incidence of nephrotoxicity (P=0.038).64

Abbreviations: Ca, calcium; GFR, glomerular filtration rate; GI, gastrointestinal; IV, intravenous; Mg, magnesium; MgAH, Mg aspartate hydrochloride; NA, not available; NSCLC, non-small-cell lung carcinoma; RR, relative risk. 

aNote that Mg MgAH is not commonly used or available
 
A 2006 review on Mg in cisplatin-based chemotherapy concluded that it is effective to use Mg 40 mmol (9.8 g) per cycle of cisplatin dose 60 mg/m2, Mg 60 mmol (14.78 g) per cycle cisplatin dose 61 to 100 (mg/m2), and Mg 80 mmol (19.7 g) per cisplatin dose greater than 100 mg/m2 to prevent serum hypomagnesemia.14 The newer trials of higher quality suggest that 3 g to 5 g Mg sulfate in pre- and posthydration is sufficient with PBC, especially if oral Mg is used between cycles. In 2 small trials, the use of oral Mg alone helped to maintain serum Mg levels.20,54 The above studies suggest an important role for IV and oral Mg in preventing cisplatin-induced hypomagnesemia, improving tolerance of chemotherapy regimens, and preventing treatment delays.

Oral Magnesium Cautions and Nutrient/Drug Interactions

A number of clinical situations warrant caution in recommending oral Mg. Table 4 summarizes the nutrient/drug interactions and cautions regarding the use of Mg.
 
A 2006 review on Mg in cisplatin-based chemotherapy concluded that it is effective to use Mg 40 mmol (9.8 g) per cycle of cisplatin dose 60 mg/m2, Mg 60 mmol (14.78 g) per cycle cisplatin dose 61 to 100 (mg/m2), and Mg 80 mmol (19.7 g) per cisplatin dose greater than 100 mg/m2 to prevent serum hypomagnesemia.14 The newer trials of higher quality suggest that 3 g to 5 g Mg sulfate in pre- and posthydration is sufficient with PBC, especially if oral Mg is used between cycles. In 2 small trials, the use of oral Mg alone helped to maintain serum Mg levels.20,54 The above studies suggest an important role for IV and oral Mg in preventing cisplatin-induced hypomagnesemia, improving tolerance of chemotherapy regimens, and preventing treatment delays.

Oral Magnesium Cautions and Nutrient/Drug Interactions

A number of clinical situations warrant caution in recommending oral Mg. Table 4 summarizes the nutrient/drug interactions and cautions regarding the use of Mg.

Table 4. Interactions With the Use of Oral Magnesium
Contraindicated Patients with high grade atrioventricular blocks, bifascicular blocks1

Cautions and requires monitoring

 Patients with kidney failure, concomitant use with calcium channel blockers, neuromuscular blocking agents, antidiabetic agents1
Drug interactions requiring dose separation 

Tetracycline antibiotics (eg, demeclocycline, doxycycline) and aquinolone antibiotics (eg, ciprofloxacin, levofloxacin): 2 h before Mg or 4-6 h after Mg65

Warfarin: 2 h before Mg or 4-6 h after Mg65

Bisphosphanates: 30 min before Mg or 2 h after Mg1 (Note: Zometa and Aredia do not appear to have the interaction65)

Zinc: 1-2 h apart65
Synergistic Adrenergic bronchodilators

Abbreviation: Mg, magnesium.

Signs of Excess Magnesium

Since Mg levels are tightly controlled by the body, excess Mg is excreted in the urine and stool. There are no known reported cases of dietary Mg causing harm. However, excess supplemental Mg oxide or Mg citrate can cause diarrhea and cramping. There are 3 case reports of Mg toxicity resulting in unresponsiveness or death when more than 5,000 mg Mg per day was taken in the form of laxatives and antacids.25,66 Signs of excess Mg, which usually develop after serum concentrations exceed 1.74 mmol/L to 2.61 mmol/L, include thirst, change in mental status, hypotension, facial flushing, nausea, vomiting, diarrhea, muscle weakness, difficulty breathing, ileus, urinary retention, decreased tendon reflexes, irregular heartbeat, and atrioventricular block.26,27
 

Oral Magnesium: Rationale, Forms, and Dosing 

IV Mg quickly elevates plasma Mg; however, up to 50% of infused Mg is excreted in the urine due to the plasma surge that inhibits Mg reabsorption in the loop of Henle. In addition, Mg uptake by the cells is slow and therefore adequate repletion requires sustained administration. Because of these inefficiencies of IV Mg, oral replacement therapy is advised for asymptomatic patients whenever oral Mg supplements can be tolerated.27 According to the National Institutes of Health, the recommended dietary intake Mg is 310 mg to 420 mg, with a tolerable upper intake level of 350 mg of elemental Mg for supplementing in healthy adults.25 
 
There are many forms of oral Mg from which to choose. Because of the high prevalence of proton pump inhibitors use in the oncology population, liquid, powder, or capsule supplements are preferable to tablets for enhanced absorption. Small studies have found that Mg aspartate, Mg citrate, Mg lactate, and Mg chloride forms are more bioavailable than Mg oxide and Mg sulfate.25 While Mg oxide and Mg hydroxide (milk of magnesia) are poorly absorbed, these forms can function as an osmotic laxative when patients are experiencing constipation. The bioavailability of Mg oxide can also be doubled when taken as an effervescent in water vs a typical tablet to swallow.67 Mg citrate and Mg gluconate forms can trigger bowel movements, although not as easily as Mg oxide. Mg citrate dissolves well into liquids. Caution should be used in taking Mg orotate because orotic acid has been found to promote tumors in animal studie.68 Mg L-threonate, a new commercially available product, has been found in animal studies to support cognition and mood.69,70 Mg taurate has been used effectively to alleviate depression and anxiety as noted in case reports.71 Mg glycinate and Mg bisglycinate forms are useful for patients presenting with tingling and muscle cramps; the bioavailability of these forms and their affinity for nerves and muscles have a neutral impact on the bowel. Mg glycinate has also been found to have greater absorption than Mg carbonate by patients with intestinal resection.72 Table 5 summarizes the most common forms of oral Mg and recommended dosages.
 
Table 5. Oral Magnesium Forms and Doses

Form of Mg

 Percentage Elemental Mg25,73 Elemental Mg per Standard Pill Common Commercial Name and Dosing Laxative Effect
Mg citrate 16.2% 80 mg or 500 mg tablet NA; 1-2 2x/d Yes, mild
Mg glycinate 50.0% 100 mg-150 mg capsule Chelated Mg; 1-2 2x/d No
Mg oxide 60.3% 288 mg or 500 mg tablet NA; 1 2x/d-3x/d Yes
Mg chloride 12.0% 64 mg or 535 mg tablet Topical sprays, gels, “Slow Mag”; 1/d Yes
Mg taurate 9.0% 100 mg-125 mg tablet NA; 1 2x/d No
Mg L threonate Unknown 50 mg-75 mg capsule “Neuro Mag” or “Magtein”; 2x/d-4x/d   Yes, mild

Abbreviations: Mg, magnesium; NA, not available.

Pain and Hypomagnesemia

It is noteworthy that 2 common conditions in patients with a cancer diagnosis—neuropathic pain and depression—may be alleviated by Mg supplementation. In a double-blind randomized controlled study, 80 patients with chronic low-back pain with a neuropathic pain component were given IV Mg sulfate at 1 g daily for 2 weeks followed by oral Mg oxide at 400 mg for 4 weeks or placebo. Mg, which antagonizes N-methyl-D-aspartate receptors, significantly improved neuropathic pain.74 A systematic review of Mg to treat depression concluded that oral Mg supplementation may prevent depression and might be used as an adjunctive therapy.24
 
A review of 2 case studies by Lopez-Saca and Lopez-Picazo found that 2 oncology patients receiving palliative care with episodes of severe pain and hypomagnesemia achieved complete alleviation of pain via IV and oral administration of Mg.75 Dietary sources of Mg include seaweed, dark leafy vegetables, pumpkin seeds, cocoa, flaxseeds, Brazil nuts, almonds, cashews, avocados, and soy.76

Conclusions

The prevalence of Mg deficiency in patients diagnosed with cancer and undergoing treatment with PBC is high, with study findings ranging from 29% to 100%. While serum Mg does not appear to be a reliable indicator of Mg deficiency, there are a wide variety of signs and symptoms that can be used for screening. These include loss of appetite, nausea, vomiting, headache, weakness, numbness, tingling, muscle cramps, constipation, fatigue, anxiety, restless legs, insomnia, irritability, insulin resistance, migraine headache, asthma, hypoparathyroidism, refractory hypocalcemia and hypokalemia, high blood pressure, tremor, prolonged QT interval, cardiac arrhythmias, hyperreflexia, ataxia, carpopedal spasms, tetany and/or convulsions, seizures, metabolic alkylosis, psychiatric disturbances, and cortical blindness. Early identification of Mg deficiency can help prevent potentially severe sequelae. Published studies to date suggest a need for administration of IV Mg in conjunction with cisplatin, in the range of 3 g to 5 g total Mg sulfate in pre- and posthydration. Studies using oral Mg have demonstrated that prophylactic magnesium supplementation can also play an important role in preventing cisplatin-induced hypomagnesemia. Mg supplementation with PBC appears to be safe and does not negatively affect progression-free survival, overall survival, or blood concentrations of chemotherapy.

About the Authors

Jen Green, ND, FABNO, was born in Toronto, received her arts & science degree from McMaster University, and graduated from the Canadian College of Naturopathic Medicine in 2000. Green founded the Naturopathic Department at Beaumont Hospitals in 2008 and served as the department head for 5 years. Green was co-investigator in a trial on Essiac in breast cancer and wrote a systematic review on the use of probiotics in children. Green's publications include chapters in the book My Breasts, My Choice, the review Identifying & Treating Metabolic Syndrome in Breast Cancer, as well as articles in the Journal of Complementary & Integrative Medicine and Townsend Letters.

Meighan Valero, ND, worked as a cancer researcher at the University of Windsor, Ontario, for 5 years prior to graduating from the Canadian College of Naturopathic Medicine, Toronto, where she received special training in naturopathic oncology. She later became the first oncology research resident at the Ottawa Integrative Cancer Centre. Valero is a member of the Oncology Association of Naturopathic Physicians.

Laura Perkowski, ND, received her naturopathic doctorate from Bastyr University and has an undergraduate degree in physiology from Michigan State University’s Honors College. While at Bastyr, she interned at the Bastyr Integrative Oncology Research Center and studied with some of the top naturopathic oncologists in the Pacific Northwest. Previously, Perkowski served as both a writer and editor for an online natural health magazine. Perkowski provides naturopathic care to patients at Beaumont Hospital’s integrative medicine clinic in Michigan with a focus on oncology, gastrointestinal health, and autoimmune diseases.

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