Modeling calcium and magnesium balance: effects of diuretics

Calcium (Ca²⁺) and magnesium (Mg²⁺) are important for bone formation, muscle contraction and mass, and nerve function. Processes regulating Ca²⁺, Mg²⁺, parathyroid hormone (PTH), and vitamin D₃ are tightly coupled, ensuring proper bone metabolism and intestinal and renal absorption of Mg²⁺ and Ca²⁺. To better understand the synergy among these processes, mathematical modeling can be used in conjunction with experimental studies. Although several Ca²⁺ homeostasis models exist, computational models for studying Mg²⁺ homeostasis are much more limited. To fill this knowledge gap, we developed a model of Ca²⁺ and Mg²⁺ homeostasis in humans (more specifically, men), based on a previously published model in male rats. The model describes the exchanges of Ca²⁺, Mg²⁺, PTH, and calcitriol among five compartments: plasma, parathyroid gland, intestine, kidney, and bone. Given the increasing prevalence of dietary Mg²⁺ deficiency and its clinical importance as a risk factor for osteoporosis, we simulated severe dietary Mg²⁺ deficiency. Our model predicted a significant drop in PTH and calcitriol levels and an increase in bone resorption. In addition, we analyzed the systemic effects of diuretics, commonly used for the management of blood pressure and fluid balance. Although the pharmacological targets of diuretics typically directly mediate Na⁺ transport, they also indirectly alter renal Ca²⁺ and Mg²⁺ handling through changes in the transepithelial electrochemical gradient, thus affecting Ca²⁺ and Mg²⁺ balance. Model results suggest that acute administration of these three diuretics may not significantly perturb plasma concentrations of Ca²⁺, Mg²⁺, and the calciotropic hormones, whereas chronic administration can cause electrolyte and hormonal dyshomeostasis and affect bone mineral content.<b>NEW & NOTEWORTHY</b> The kidneys play an important role in maintaining the homeostasis of calcium and magnesium. Although diuretics directly affect the kidney's handling of sodium, they also indirectly affect renal calcium and magnesium reabsorption through changes in electrochemical gradients. How do diuretics affect whole body calcium and magnesium balance? To answer this question, we simulate the effect of acute and chronic administration of loop, thiazide, and K-sparing diuretics on renal transport and homeostasis of calcium and magnesium.