Why Serum Magnesium Fails: A Narrative Review of Magnesium Biochemistry, Compartmental Exchange, and Endpoint Selection for Supplementation Trials.

Magnesium is an obligate cofactor in more than 600 enzymatic reactions, yet population-level inadequacy is widespread and rarely detected. The reason is largely methodological. Serum magnesium, used in routine care and in most supplementation trials, holds less than one percent of total body magnesium and is homeostatically defended by renal reabsorption and bone exchange, so individuals with substantial tissue depletion may present with values inside the reference range. This narrative review addresses a specific problem: the biochemical endpoints of oral magnesium supplementation trials are poorly matched to the compartments in which magnesium acts. The mismatch has attenuated the evidence in five clinical areas-essential hypertension, insulin resistance and type 2 diabetes, insomnia and disordered sleep, skeletal muscle cramping, and migraine prophylaxis-in each of which clinical benefit is reported without commensurate serum change. The review first establishes the biochemistry of magnesium essentiality, identifying the enzyme classes for which Mg-ATP is the physiological substrate and the systems in which the free ion acts as a structural or gating element. It then proposes an integrated model in which absorption, renal handling, bone exchange and intracellular distribution operate on distinct timescales, from hours for renal conservation to months for bone. Against that model, serum, erythrocyte, ionized, urinary and loading-test measurements are appraised, and candidate biomarkers mapped compartment by compartment. Published biological variation gives a reference change value of approximately 12% for serum magnesium and a critical difference of approximately 22% for erythrocyte magnesium, while the change reported with oral repletion is comparable or smaller. This arithmetic makes trial endpoints underpowered by construction and explains the recurring pattern of null biochemical findings alongside positive clinical ones. The review closes with a context-dependent hierarchy of methods and identifies harmonization of erythrocyte reference intervals as the most pressing methodological priority.