Antiresorptive dose-response relationships across three generations of bisphosphonates

The first generation of bisphosphonates was discovered in the late 1960s and is characterized by short alkyl or halide side-chains. Well known representatives of this class are 1-hydroxyethane-1,1-bisphosphonate (etidronate) and dichloromethane bisphosphonate (clodronate). The antiresorptive activity of these and other analogues was measured in an assay in which a drug was administered for 7 days to growing rats, followed by a morphological assessment of bone volume. In this model, the first generation analogues have antiresorptive activity at dose levels from 0.1 to 10 mg P/kg. Some first generation analogues are now used to treat metabolic bone disease but, when given orally, their efficacy in aggressive resorptive disease may be limited because of low potency. A second generation of bisphosphonates, characterized by an amino terminal group and a higher antiresorptive potency, includes 3-amino-1-hydroxypropane-1,1-bisphosphonate (pamidronate) and 4-amino-1-hydroxybutane-1,1-bisphosphonate. Their antiresorptive activity in growing rats ranges from 0.01 to 1 mg P/kg. In the 1980s a third generation of bisphosphonates, characterized by a cyclic chain, was synthesized. It includes series of pyridinyl ethane bisphosphonates, pyridinyl aminomethane bisphosphonates, indan bisphosphonates, cyclopentane bisphosphonates, piperidyl ethane bisphosphonates, pyridinyl and piperidyl hydroxyethane bisphosphonates, piperidinylidene aminomethane bisphosphonates, and pyridinyl oxa- and thiomethane bisphosphonates. Several of these show antiresorptive activity in growing rats as low as 0.001 mg P/kg. Many of the first-, second- and third-generation bisphosphonates have been tested in a model of retinoid-induced bone resorption, and in this model the rank ordering of potency is similar, though somewhat larger doses of bisphosphonate are required to block the resorption induced by the retinoid.(ABSTRACT TRUNCATED AT 250 WORDS)