Calcilytic actions on PTH secretion from normal human parathyroid cells — ASN Events
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Calcilytic actions on PTH secretion from normal human parathyroid cells (#152)

Hee-chang (Ryan) Mun 1 , Katie Leach 2 , Stan Sidhu 3 , Leigh Delbridge 3 , Arthur D Conigrave 1
  1. School of Life & Environmental Sciences, Charles Perkins Centre, University of Sydney, NSW 2006, Australia
  2. Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052 , Australia
  3. Endocrine Surgery, Royal North Shore Hospital, St Leonards, NSW 2065, Australia

Calcilytics are negative modulators of the calcium-sensing receptor (CaSR), which elevate serum PTH levels and have thus been developed for the treatment of human osteoporosis. However, orally active calcilytics have been disappointing in human trials. While it is possible that these calcilytics have unintended ‘off-target’ effects on bone e.g., by suppressing osteoblast differentiation and/or survival, their key failing appears to be inadequate elevation of serum PTH levels when compared to the levels achieved by subcutaneous administration of human PTH1-34 (teriparatide). In the current study, we set out to investigate the underlying reasons for the poor serum PTH responses and contrasted the cellular effects of various calcilytics including NPS-2143, Calhex231, Ronacaleret, and ATF936 in the presence of a physiological saline solution (1.2 mM Ca2+). All four calcilytics promptly elevated PTH secretion from normal human parathyroid cells perifused in vitro but we noted marked differences in their potencies and maximal responses. The order of calcilytic potency was Ronacaleret > ATF936 > NPS 2143 and the order of maximal effectiveness was NPS-2143 > Ronacaleret > ATF936 > Calhex231. The maximum elevation in PTH secretion above the control level observed with NPS-2143 was 5-fold, still 3-4 fold below that required to emulate the serum PTH levels obtained with teriparatide. Surprisingly, Calhex231 had calcimimetic activity at low concentrations. Comparative analyses of the actions of calcilytics on various signaling pathways in CaSR-expressing HEK-293 cells including PI-PLC, intracellular Ca2+ mobilisation and ERK1/2 phosphorylation indicate that none of the agents tested achieved greater than 70-80% inhibition of CaSR signaling in the presence of physiological concentrations of Ca2+. The findings raise the possibility that a new generation of calcilytics could be developed that achieve 100% inhibition of CaSR signaling together with the 15-20-fold elevations in serum PTH level required to induce bone anabolic actions in osteoporosis patients in vivo.