Editorial: Calcium metabolism and treatment of hypercalcemia

Calcium is essential for many physiologic process, including nerve function, muscle contraction, and blood clotting. It is the main mineral constituent of bones, and regulates several enzymatic activities, and cellular membranes excitability. Calcium-sensing receptors (CASR) are the key mediator of Ca2+ actions on parathyroid glands and kidney, regulating homeostatic responses that restore normal Ca2+ levels. However, the function of other actors, such as fibroblast growth factor-23 (FGF23), Klotho, and the transient receptor potential cation channel, subfamily V (TRPV), which are essential for maintaining calcium-phosphate homeostasis and regulating calcium metabolism, should be considered. FGF23 is involved in the molecular mechanism of renal phosphate reabsorption, increases urinary excrection of phosphorus, and inhibits both renal tubular phosphate transport and renal production of 1,25(OH)2D3, thereby decreasing PTH serum levels and its secretion. Klotho is a transmembrane protein which regulates transepithelial Ca2+ transport, PTH secretion and subsequent serum Ca2+ increase, signal transduction of FGF23, and downregulation of 1,25(OH)2D3 production. Apical Ca2+ entry via TRPV-calcium channels, induced by 1,25(OH)2D3, represents the first step of intestinal and renal epithelial Ca2+ transport mechanisms. Uncontrolled hypercalcemia may cause renal impairment, both temporary (alteration of renal tubular function) and progressive (relapsing nephrolithiasis), leading to a progressive loss of renal function, as well as severe bone diseases, and heart damages. Primary hyperparathyroidism (PHPT) and malignancy-associated hypercalcemia (MAH) are responsible for more than 90% of all causes of hypercalcemia, usually presenting with chronic hypercalcemia. PTHrP also stimulates stromal bone cells and osteoblasts production of RANKL, a potent inducer of osteoclast maturation, and acts locally to induce bone lesions. RANK, its ligand RANKL, and osteoprotegerin, the natural decoy receptor for RANKL, represent the three essential molecules that control osteoclast function. There are five keystones of therapy of acute hypercalcemia: (1) restore normovolemia to prevent renal impairment, (2) restore renal function and enhance renal excretion of calcium, (3) dialysis, (4) inhibit osteoclastic bone resorption, and (5) reduce intestinal calcium absorption. Due to their antiresorptive action, bisphosphonates are currently the treatment of choice especially in cancer-related bone diseases. However, their clinical efficacy is usually short-lived and sometimes incomplete. This is due to the increased distal tubular calcium reabsorption mainly driven by paraneoplastic release of PTHrP by the cancer tissue. A monoclonal antibody against human RANKL (denosumab) is currently available, and it seems to be more effective than bisphosphonates to suppress bone resorption. Denosumab prevents the binding between RANKL and RANK receptor on the surface of both osteoclasts and osteoclast precursors, and reduces the differentiation, activation, and survival of osteoclasts, slowing the rate of bone resorption. A humanized monoclonal antibody against human PTHrP has also been generated, and is still under evaluation. Cathepsin K is the most abundant cysteine protease expressed in osteoclasts, and a cathepsin K inhibitor (odanacatib) may suppress bone resorption in patients with bone metastases from breast cancer. In conclusion, advances in the understanding of all actors of calcium metabolism may have several practical consequences in the treatment and prevention of hypercalcemia.