Estrogens are currently the first choice in the treatment of osteoporosis. Nevertheless, a lot of patients refuse them due to several reasons such as fear of cancer or others. In order to target estrogen directly to bone we tested several E 2 -BPs with different esterase-sensitive spacers for their local and systemic effects in vivo.Two E 2 -BPs expressing different serum cleavage in vitro were administered s.c. (15 nmol/kg) in male Wistar rats. Their serum kinetic of 17β-estradiol (E 2 ) was compared to that of non-conjugated E 2 (150 nmol/kg). Subsequently all compounds plus an additional cleavage-resistent conjugate (crE 2 BP) were investigated for their capacity to prevent bone loss and uterusatrophy in ovariectomized (Ovx) Wistar rats (n=8-10/group). The compounds were administered s.c. (E 2 BPs: 1.5-150 nmol/kg/d) for 5 weeks starting one day after bilateral Ovx or sham-operation. Controls received E 2 (50 nmol/kg/d) or saline. Uterus fresh weight was recorded and bone mass determined by X-ray densitometry, ash weight and calcium analysis of the femurs.Serum half-life of E 2 was found to be 2h whereas those of the E 2 -BPs were similar or increased up to 8.4h. Ovx-induced bone loss and uterusatrophy were prevented completely by E 2 whereas no effects on both parameters were seen by crE 2 BP. The two other E 2 BPs expressed a dose-dependent prevention of bone loss which was paralleled by uterine weight.We conclude that E 2 -BPs containing esterase-sensitive spacers failed to act as bone seeking agents expressing primarily local effects on bone without systemic effects.