Application of an in vitro model and a clinical protocol in the assessment of the potency of a new bisphosphonate.
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)
Papapoulos
S E
SE
Department of Endocrinology, University Hospital, Leiden, The Netherlands.
Hoekman
K
K
Löwik
C W
CW
Vermeij
P
P
Bijvoet
O L
OL
D000284:Administration, Oral; D000368:Aged; D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy; D001842:Bone and Bones / Q000187:drug effects; D002985:Clinical Protocols; D004164:Diphosphonates / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D006909:Hydroxyproline / Q000652:urine; D007262:Infusions, Intravenous; D051379:Mice; D008875:Middle Aged; D008954:Models, Biological; D009924:Organ Culture Techniques; D010001:Osteitis Deformans / Q000188:drug therapy* / Q000378:metabolism; D000077268:Pamidronate; D011446:Prospective Studies
D004164:Diphosphonates; C055774:olpadronic acid; D000077268:Pamidronate; D006909:Hydroxyproline