Effect of diphosphonates on adenosine 3':5'-cyclic monophosphate in mouse calvaria after stimulation by parathyroid hormone in vitro.

1. The diphosphonates, disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) and disodium dichloromethylene diphosphonate (Cl2MDP), inhibit bone resorption in animals and in explanted bone in tissue culture. The possibility that these effects might be due to inhibition of skeletal adenylate cyclase has been studied. 2. EHDP and Cl2MDP, added for 30 min to the incubation medium at concentrations known to inhibit bone resorption, had no effect on basal content of adenosine 3':5'-cyclic monophosphate (cyclic AMP) of mouse calvaria incubated in vitro, nor did they inhibit the rise in cyclic AMP induced by bovine parathyroid hormone. 3. Pretreatment of mice for 3 days with Cl2MDP also had no effect on cyclic AMP under basal conditions or after incubation of explanted calvaria with parathyroid hormone in vitro. EHDP under similar conditions slightly inhibited the increase induced by parathyroid hormone but had no effect on basal concentrations of cyclic AMP. 4. It is suggested that the inhibition of adenylate cyclase is not an essential feature of the reduction of bone resorption by diphosphonates, which may act by direct inhibitory effects on the dissolution of hydroxyapatite and perhaps by other unidentified effects on bone cells. Key words: adenosine 3':5'-cyclic monophosphate, bone, dichloromethylene diphosphonate, diphosphonates, ethane-1-hydroxy-1,1-diphosphonate, parathyroid hormone.