<p>Calcium uptake in mammals depends on diffusion of calcium ions and calcium ions bound to hydroxycarboxylates like citrate or calcium ions bound to peptides. Such diffusion may lead to spontaneous isothermal supersaturation of calcium hydroxycarboxylates in homogeneous aqueous solution in vivo facilitiating para-cellular and trans-cellular calcium uptake in the intestines apparently violating principles of equilibrium thermodynamics. A number of such processes resulting in spontaneous supersaturation of calcium salts in homogeneous solution at constant temperature recently documented in vitro are in the present review analyzed each in terms of three stages: (i) diffusion separating calcium species according to diffusion rate locally increasing calcium concentrations above equilibrium solubility for specific species and equilibrium solubility for total calcium hydroxycarboxylate, (ii) prevention of equilibrization through reverse reactions as a consequence of Onsager reciprocal relations, and (iii) phase transitions like precipitation or membrane separation of specific calcium species. From the analysis, calcium bioavailability in biological systems may now be understood on the basis of thermodynamics of irreversible processes rather than on equilibrium thermodynamics considering ratios between forces and flux in system out of equilibrium but where local equilibria exists. Local entropy production for spontaneous non-equilibrium intermediate states seems to induce isothermal supersaturation.</p>