Calcimimetics are ligands that mimic or potentiate the actions of extracellular Ca2+ at the calcium receptor (CaR). They are structurally diverse and act as either agonists or positive allosteric modulators (PAMs) at the CaR. Small molecule and peptide PAMs are used to treat primary and/or secondary hyperparathyroidism (HPT). These calcimimetics increase the sensitivity of the CaR for extracellular Ca2+ and thereby shift the concentration-response curve for extracellular Ca2+ to the left. Calcimimetics have minimal effects on blood levels of parathyroid hormone (PTH) in primary HPT or parathyroid carcinoma yet significantly lower blood levels of calcium. Calcimimetics are similarly effective in lowering blood calcium levels and diminishing hypocalcemic symptoms in familiar forms of HPT and in neonatal HPT arising from heterozygous variants in the CaR gene. Calcimimetics are, however, very effective in lowering blood levels of PTH from hyperplastic parathyroid cells that characterize secondary HPT and this is their major clinical use.
Calcilytics are CaR antagonists and, with the exception of phosphate, all are synthetic small molecules that act as negative allosteric modulators – they shift the set-point for systemic calcium homeostasis to the right. As such, they are tailored made for treating genetic set-point disorders like autosomal dominant hypocalcemia (ADH) type 1 and type 2. In ADH1 patients, the orally-active calcilytic encaleret has been shown to normalize blood and urine mineral metabolism. Because calcilytics also block renal CaRs, they can increase blood calcium levels in post-surgical hypoparathyroid patients in the absence of any increase in blood PTH levels.
It’s possible that future calcimimetics and calcilytics with different mechanisms of action may be clinically useful but currently, these two pharmaceutical classes effectively treat several genetic or acquired disorders of mineral metabolism by increasing or decreasing the sensitivity of the CaR to activation by extracellular Ca2+.