JOURNAL OF BONE: AND MINERAL RESEARCH Volume 4, Number 5, 1989 Mary Ann Liebert. Inc., Publishers zyxwvutsrqpo Application of an In Vitro Model and a Clinical Protocol in the Assessment of the Potency of a New Bisphosphonate SOCRATES E. PAPAPOULOS, KLAAS HOEKMAN, CLEMENS W.G.M. LOWIK, PIETER VERMEIJ, and OLAV L.M. BIJVOET ABSTRACT 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 co- culture 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 treat- ment 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 antire- sorptive potency of the new bisphosphonate zyxwvu (3-dimethylamino-l-hydroxypropylidene)-l,l-bisphosphonate (dimethyl-APD). A total zyxwvut of zyxwvuts 42 patients with Paget’s disease of bone received dimethyl-APD in doses pre- dicted 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 hydroxypro- line excretion reached 30.9 f 5.6, 17.1 f 3.1, and 2.1 f 5.3% of initial excess after 10 days treatment with intravenous dimethyl-APD, 2, 4, and 8 mg/day, and 37.4 f 18,10.4 zyxw f 8.5, and 13 f 4.1% with oral ther- apy, 100, zyxwvutsrq 200, and 400 mg/day zyxwvuts , 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. These results demonstrate the predictive power of the coculture mouse metacarpal resorption assay and the use of a standardized protocol in Paget’s disease for the introduction of new bisphosphonates into clinical practice. Full treatment efficacy in a simple and convenient way can be achieved with oral dimethyl- APD, which can be considered representative of third-generation bisphosphonates. INTRODUCTION INCE THE INTRODUCTION Of the first bisphosphonate S into clinical practice some 20 years ago, a number of variants have appeared.‘’) The differences among these compounds, however, are far larger than the term “vari- ants’’ suggest. Although all possess a bisphosphonate group to adsorb to bone, the remainder of the structure may be quite dissimilar. Restructuring this part of the molecule has resulted in the development of compounds with different molar potencies and activity/toxicity ratios. The early phase of clinical application in which significant but incomplete effects were observed is being replaced by a stage in which new bisphosphonates with sufficient po- tency to allow predictable modulation of bone resorption are developed. This development has been slow, however, the main reason being that the in vitro cell and bone re- sorption systems used not only provided widely different Clinical Investigation Unit, Department of Endocrinology and Hospital Pharmacy (PV), University Hospital, teiden, The Nether- lands. 775