EFFECT OF 17-BETA-ESTRADIOL-BISPHOSPHONATE CONJUGATES, POTENTIAL BONE-SEEKING ESTROGEN PRO-DRUGS, ON 17-BETA-ESTRADIOL SERUM KINETICS AND BONE MASS IN RATS

In order to target 17 beta-estradiol directly at bone we synthesized t hree 17 beta-estradiol-bisphosphonate conjugates (E(2)-BPs) with diffe rent esterase-sensitive linkers be tween both molecular moieties. The systemic administration of these compounds should result primarily in local estrogenic effects on bone with no or negligible systemic hormon al effects. Only if a considerable margin exists between the doses req uired for inhibition of bone loss and those for systemic hormonal effe cts can such a pro-drug be considered acceptable for patients refusing systemic estrogen replacement therapy for several reasons. The conjug ates were tested in vitro for their 17 beta-estradiol release in rat s erum and in vivo for their local and systemic effects in rats: in vitr o, the conjugates expressed cleavage resistance, low cleavage (4.8%), or high cleavage (33.1%) within 48 hours of incubation. The conjugate with the low-cleavage doubled 17 beta-estradiol serum half-life (3.78 hours) whereas the high-cleavage conjugate resulted in approximately f our times higher serum half-life (8.36 hours) when compared with free 17 beta-estradiol. In ovariectomized rats, bone loss was optimally pre vented by 50 nmol/kg/day of 17 beta-estradiol when administered S.C. o ver a period of 5 weeks, and protection against uterine atrophy was ac hieved at doses as low as 5 nmol/kg/day. The cleavage-resistant conjug ate was ineffective in preserving bone and uterus in doses ranging fro m 5 to 150 nmol/kg/day. The other two E(2)-BPs revealed a dose-depende nt inhibition of bone loss which was paralleled by the respective uter us weight with a dose range of 1.5-150 nmol/kg/day being fully effecti ve in a ran, to 17 beta-estradiol alone. The higher sensitivity of the uterus versus bone to protective estrogenic effects (1:10) was abolis hed by the conjugates. We conclude that E(2)-BPs containing esterase-s ensitive linkers failed to act as bone-seeking pro-drugs expressing pr imarily local effects on bone without systemic effects.