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Berardi et al. J Cancer Metastasis Treat 2019;5:79 I http://dx.doi.org/10.20517/2394-4722.2019.008 Page 25 of 33

Almost the complete amount (about 99%) of magnesium is placed in the intracellular compartment: about
50%-60% is in bone and 38% in soft tissues, while only 1% of total body magnesium is extracellular. Normal
serum magnesium concentration is between 1.5 and 1.9 mEq/L (1.7-2.2 mg/dL). Dietary magnesium
absorption takes place in intestinal tract, and it is negatively influenced by high protein, phosphate, and
fat. Magnesium elimination is mainly controlled by kidney. Several factors (hormonal: PTH, calcitonin,
glucagon, and vasopressin; and non-hormonal: acid-base balance, potassium reduction, and magnesium
plasma concentration) are involved in renal elimination [155] .

Hypomagnesemia
Definition and clinical implications
Hypomagnesemia is an electrolyte disorder characterized by reduced magnesium serum level (< 1.5 mEq/L).
Serum magnesium concentration lower than 1 mg/dL is defined as severe hypomagnesemia. It occurs
frequently (7%-12%) in hospitalized patients, and it is correlated to increased risk of death [156] .

Causes
Hypomagnesemia in cancer patients might result from different causes:
(1) Cancer: several conditions related to cancer might induce hypomagnesemia. Anorexia, malnutrition,
vomiting, intestinal injury, intestinal drainage/fistulae, diarrhea, and malabsorption syndrome are frequent
conditions in cancer patients inducing reduced magnesium intake.

(2) Cancer treatment: several drugs commonly used in cancer patients induce kidney damage and
secondary hypomagnesemia. Cisplatin might induce hypomagnesemia through distal renal tubular damage,
and it persists after treatment discontinuation. Therefore, intravenous supplementation of magnesium
is indicated to prevent hypomagnesemia and decrease risk of nephrotoxicity [157] . Hypomagnesemia was
also described in patients receiving EGFR inhibitors with an incidence of 34% in patients treated with
monoclonal anti-EGFR antibodies. In fact, EGFR activation is crucial for magnesium renal reabsorption
[158]
through TRPM-6 channel .

(3) Concomitant drugs: diuretics, antibiotics beta-adrenergic agonists, foscarnet, and amphotericin B might
induce hypomagnesemia.

(4) Concomitant diseases: hyperparathyroidism, hyperthyroidism, diabetes mellitus, dialysis, renal failure,
and hereditary disorders (e.g., Bartter’s syndrome and Gitelman’s syndrome) might induce hypomagnesemia.

Three main mechanisms are involved: reduced intake, redistribution into intracellular compartment, and
increased renal losses [Table 7].

The most common mechanism inducing hypomagnesemia is renal losses. However, reduced magnesium
intake is also frequent in cancer patients, mainly due to altered absorption secondary to diarrhea,
malabsorption syndromes, and extensive bowel resection, while rarely due to severe malnutrition.

Management
Treatment of hypomagnesemia depends on clinical manifestation and severity, and it should be focused on
hypomagnesemia correction and causes removal.

Patients with hypomagnesemia are usually asymptomatic, until magnesium concentration falls below
1.2 mg/dL, although symptoms usually do not correlate with serum magnesium levels [159] .

The earliest manifestations of magnesium deficiency are usually non-specific neuromuscular and
neuropsychiatric alterations such as weakness and muscle cramps. Severe hypomagnesemia might cause