Key words: Bisphosphonates — Estrogens — Conjugates — Osteoporosis therapy.
Springer Online Journal Archives 1860-2000
Abstract. In order to target 17β-estradiol directly at bone we synthesized three 17β-estradiol-bisphosphonate conjugates (E2-BPs) with different esterase-sensitive linkers between both molecular moieties. The systemic administration of these compounds should result primarily in local estrogenic effects on bone with no or negligible systemic hormonal effects. Only if a considerable margin exists between the doses required for inhibition of bone loss and those for systemic hormonal effects can such a pro-drug be considered acceptable for patients refusing systemic estrogen replacement therapy for several reasons. The conjugates were tested in vitro for their 17β-estradiol release in rat serum and in vivo for their local and systemic effects in rats: in vitro, 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 17β-estradiol serum half-life (3.78 hours) whereas the high-cleavage conjugate resulted in approximately four times higher serum half-life (8.36 hours) when compared with free 17β-estradiol. In ovariectomized rats, bone loss was optimally prevented by 50 nmol/kg/day of 17β-estradiol when administered S.C. over a period of 5 weeks, and protection against uterine atrophy was achieved at doses as low as 5 nmol/kg/day. The cleavage-resistant conjugate was ineffective in preserving bone and uterus in doses ranging from 5 to 150 nmol/kg/day. The other two E2-BPs revealed a dose-dependent inhibition of bone loss which was paralleled by the respective uterus weight with a dose range of 1.5–150 nmol/kg/day being fully effective in a range similar to 17β-estradiol alone. The higher sensitivity of the uterus versus bone to protective estrogenic effects (1:10) was abolished by the conjugates. We conclude that E2-BPs containing esterase-sensitive linkers failed to act as bone-seeking pro-drugs expressing primarily local effects on bone without systemic effects.
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