Calcilytics

Calcilytics are a class of pharmacological agents that antagonize the calcium-sensing receptor (CaSR), a G-protein–coupled receptor that monitors extracellular calcium levels and regulates parathyroid hormone (PTH) secretion as well as renal calcium handling. By blocking CaSR, calcilytics decrease the receptor’s sensitivity to calcium, leading to increased release of PTH from the parathyroid glands and higher serum calcium in the short term. The goal in some research programs has been to induce pulsatile PTH secretion that could stimulate bone formation and be beneficial in osteoporosis or other disorders of bone turnover.

Mechanistically, CaSR is expressed in the parathyroids, kidneys, and various other tissues. Calcilytics reduce CaSR-mediated inhibition of PTH synthesis and release, while their effects on the kidney can alter calcium and phosphate reabsorption. Because PTH also drives bone remodeling, the intended therapeutic effect relies on carefully controlled, intermittent PTH stimulation to promote bone formation rather than resorption.

Historically, calcilytics emerged from an interest in exploiting CaSR signaling to treat osteoporosis and related conditions. Several compounds, such as NPS 2143 and other development candidates including ronacaleret, were studied in preclinical and early clinical settings. By the 2010s, development for osteoporosis largely waned due to mixed efficacy results and safety concerns, and no calcilytics have been approved for clinical use. Research continues in academic settings and for understanding calcium homeostasis, but the class is not represented in approved therapies.

See also: calcimimetics, which activate CaSR rather than block it.