We have investigated the pharmacologic effects of a new bisphosphonate compound, CGP 42'446 [2-(imidazol-1-yl)-1-hydroxyethylidene-1,1-bisphosphonate], on bone metabolism. The compound exhibited potent inhibitory activity on the bone resorption induced by 1,25-dihydroxyvitamin D3 both in vivo in the thyroparathyroidectomized rat (ED50 0.072 microgram/kg SC) and in vitro in mouse calvarial cultures (IC50 0.002 microM). 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-1 beat. Short-term treatment of growing rats with CGP 42'H446 dose-dependently increased the radiographic density of the tibial proximal metaphysis (ED50 1.7 micrograms/kg SC) as well as increasing the calcium and hydroxyproline content of femoral trabeculae (ED50 values 0.17 and 1.1 micrograms/kg 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'H446 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.