ABSTRACT:We have investigated the pharmacologic effects of a new bisphosphonate compound, CGP 42'446 [2-(imidazol- I-yl)-1-hydroxyethylidene-,1I -bisphosphonate], on bone metabolism. The compound exhibited potent inhibitory activity on the bone resorption induced by 1,25-dihydroxyvitamin D, both in vivo in the thyroparathyroidectomized rat (ED,, 0.072 Fgkg SC) and in vitro in mouse calvarial cultures (ICso 0.002 FM). A comparison of the in vivo and in vitro inhibitory potencies of a total of nine bisphosphonates revealed an excellent correlation between the two assays (r = 0.97). CGP 42'446 also potently inhibited calvarial bone resorption induced by parathyroid hormone (1-34), parathyroid hormone-related protein (1-34). and recombinant human interleukin- lp. Short-term treatment of growing rats with CGP 42'446 dose-dependently increased the radiographic density of the tibia1 proximal metaphysis (ED,, 1.7 pgkg SC) as well as increasing the calcium and hydroxyproline content of femoral trabeculae (ED,, values 0.17 and 1.1 pgkg SC, respectively), but there was no detectable effect on cortical bone. On a molar basis in this range of in vivo screening assays, CGP 42' 446 was between 940-fold (thyroparathyroidectomized rat) and 87-fold (rat femoral trabecular calcium content) more potent than pamidronate. It is concluded that CGP 42'446 is a promising new, highly potent bisphosphonate for the suppression of the increased bone resorption associated with various diseases.