Divergent effects of strontium and calcium-sensing receptor positive allosteric modulators (calcimimetics) on human osteoclast activity

BACKGROUND AND PURPOSE: Strontium ranelate, a drug approved and until recently used for the treatment of osteoporosis, mediates its effects on bone at least in part via the calcium‐sensing (CaS) receptor. However, it is not known whether bone‐targeted CaS receptor positive allosteric modulators (PAMs; calcimimetics) represent an alternative (or adjunctive) therapy to strontium (Sr(2+) (o)). EXPERIMENTAL APPROACH: We assessed three structurally distinct calcimimetics [cinacalcet, AC‐265347 and a benzothiazole tri‐substituted urea (BTU‐compound 13)], alone and in combination with extracellular calcium (Ca(2+) (o)) or Sr(2+) (o), in G protein‐dependent signalling assays and trafficking experiments in HEK293 cells and their effects on cell differentiation, tartrate‐resistant acid phosphatase (TRAP) activity and hydroxyapatite resorption assays in human blood‐derived osteoclasts. KEY RESULTS: Sr(2+) (o) activated CaS receptor‐dependent signalling in HEK293 cells in a similar manner to Ca(2+) (o), and inhibited the maturation, TRAP expression and hydroxyapatite resorption capacity of human osteoclasts. Calcimimetics potentiated Ca(2+) (o)‐ and Sr(2+) (o)‐mediated CaS receptor signalling in HEK293 cells with distinct biased profiles, and only cinacalcet chaperoned an endoplasmic reticulum‐retained CaS mutant receptor to the cell surface in HEK293 cells, indicative of a conformational state different from that engendered by AC‐265347 and BTU‐compound 13. Intriguingly, only cinacalcet modulated human osteoclast function, reducing TRAP activity and profoundly inhibiting resorption. CONCLUSION AND IMPLICATIONS: Although AC‐265347 and BTU‐compound 13 potentiated Ca(2+) (o)‐ and Sr(2+) (o)‐induced CaS receptor activation, they neither replicated nor potentiated the ability of Sr(2+) (o) to inhibit human osteoclast function. In contrast, the FDA‐approved calcimimetic, cinacalcet, inhibited osteoclast TRAP activity and hydroxyapatite resorption, which may contribute to its clinical effects on bone mineral density LINKED ARTICLES: This article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.21/issuetoc