The development of new
bisphosphonates for clinical use requires congruence between the results of basic and clinical investigations. We have previously shown that this can be achieved with the use of an in vitro coculture mouse metacarpal resorption system sensitive to the activation of osteoclast precursors together with a clinical protocol in which the rate of decrease in urinary
hydroxyproline excess with
bisphosphonate treatment is assessed in patients with Paget's disease. In these studies
bisphosphonates of known potencies were used. In the present study we have evaluated these approaches prospectively in the assessment of the antiresorptive potency of the new
bisphosphonate (3-dimethylamino-1-hydroxypropylidene)-1,1-bisphosphonate (dimethyl-APD). A total of 42 patients with
Paget's disease of bone received dimethyl-APD in doses predicted from the in vitro system. A total of 24 patients received the
bisphosphonate intravenously (2, 4, and 8 mg/day) in groups of 8 patients each and 18 orally (100, 200, and 400 mg/day) in groups of 6 patients each for 10 days. Dimethyl-APD
therapy was highly effective in inhibiting
bone resorption. Urinary
hydroxyproline excretion reached 30.9 +/- 5.6, 17.1 +/- 3.1, and 2.1 +/- 5.3% of initial excess after 10 days treatment with intravenous dimethyl-APD, 2, 4, and 8 mg/day, and 37.4 +/- 18, 10.4 +/- 8.5, and 13 +/- 4.1% with oral
therapy, 100, 200, and 400 mg/day, respectively. Comparison of the antiresorptive potency of dimethyl-APD with that of APD showed that the former is roughly five times more potent, as predicted in the in vitro study.(ABSTRACT TRUNCATED AT 250 WORDS)