Upacicalcet was developed by Ajinomoto Co., Inc. during research on the umami taste receptor, which, like the calcium-sensing receptor (CaSR), belongs to the class C G protein-coupled receptor family. Long-term clinical data have demonstrated that dose reduction or temporary treatment interruption is rarely required, highlighting its favorable tolerability profile (Hamano T, Am J Nephrol. 2025). Notably, upacicalcet was associated with a very low incidence of hypocalcemia despite no significant increase in the use of active vitamin D analogues or calcium-containing agents.

This favorable safety profile may be attributable to its unique calcium concentration-dependent pharmacological activity. Unlike etelcalcetide, in vitro studies have demonstrated that the CaSR agonistic activity of upacicalcet diminishes as extracellular calcium concentrations decrease. This property may serve as an intrinsic “safety valve” against hypocalcemia. Indeed, upacicalcet reduced the calcium–phosphate product with little hypocalcemia even in patients with iPTH levels below 300 pg/mL. These findings raise the possibility that upacicalcet could be used even in mild secondary hyperparathyroidism to attenuate vascular calcification and potentially reduce cardiovascular events.

Supporting this concept, upacicalcet reduced aortic medial calcification even in Klotho-deficient mice, a model characterized by elevated 1,25-dihydroxyvitamin D levels and suppressed PTH. This effect was reported to involve preservation of elastic fiber integrity through suppression of elastin-degrading enzymes (Hasegawa T, Scientific Reports 2026).

Recent clinical studies have further suggested that upacicalcet suppresses bone turnover irrespective of baseline PTH levels (Yamamoto S, JBMR Plus. 2025) and may attenuate the decline in serum albumin in patients with secondary hyperparathyroidism (Komaba H, Am J Nephrol. 2026). Collectively, these findings suggest that the potential clinical benefits of upacicalcet may extend beyond PTH lowering and may reflect its distinctive calcium concentration-dependent pharmacological properties.