Short- and long-term effects of a single dose of bisphosphonates on retinoid-induced bone resorption in thyroparathyroidectomized rats.

ABSTRACT

The inhibitory effect of a single subcutaneous (s.c.) dose of three different bisphosphonates (Bps)--4-amino-1-hydroxybutylidene-1,1-bisphosphonate (AHBuBP), 2-(2-pyridinyl)-ethylidene-1,1-bisphosphonate (2-PEBP), and dichloromethylene-bisphosphonate (Cl2MBP)--was studied in a model of retinoid-induced bone resorption, which consists of assessing the hypercalcemic effect of the arotinoid Ro 13-6298 given s.c. for three days in thyroparathyroidectomized (TPTX) rats. The retinoid was given on day 0, 1, and 2. Bps were administered together with or at different times prior to the first dose of retinoid. A dose-dependent inhibition was obtained with all three compounds. AHBuBP produced complete inhibition which remained for 3 weeks at 0.1 mg P/kg. The dose-response curves were identical when the compound was given on the first day of retinoid administration (day 0) or 6 days earlier. With 2-PEBP, the dose-response curve was the same as that for AHBuBP when given on day 0. When given 6 days earlier, the curve was shifted to 30 times less potency. Cl2MBP was about 100 times less potent than AHBuBP when given on day 0, with 3 mg P/kg producing complete inhibition. When given 6 days earlier, the curve was also shifted to 10 times less potency, and even 30 mg P/kg failed to produce complete inhibition. With 10 mg P/kg, the inhibitory effect was maintained partially for up to 3 weeks. This study shows that in this model of bone resorption the inhibitory effect of a single dose of certain Bps is effective for at least 3 weeks and that the compounds vary in their activity over time.