Selective estrogen receptor modulator inhibits osteocyte apoptosis during abrupt estrogen withdrawal: implications for bone quality maintenance.
Estrogens exert positive effects on the quantity and quality of bone, including the maintenance of osteocytes through the inhibition of their apoptosis. Ideally, selective estrogen receptor modulators (SERMs) confer all of the positive bone-associated effects of estrogens without any adverse effects. In a similar way to estrogen, the raloxifene analog LY 117018 has been shown to prevent bone loss in ovariectomized (OVX) rats. In this study, we investigated whether the osteocyte-sparing effect of 17beta-estradiol can be mimicked by the SERM LY 117018 in a rat model of OVX. Twenty-four juvenile female rats were divided into four treatment groups: sham-operated (SHAM), OVX, OVX + 17beta-estradiol (OVX+E(2)), and OVX + LY 117018 (OVX+SERM). At 7 or 14 days following the start of treatment, the radius and ulna were removed. The percentage of apoptotic osteocytes, determined using an in situ nick-translation method, was increased (2.5-fold at 7 days and sixfold at 14 days) in the OVX group compared with SHAM in both the radius and ulna. Treatment of OVX animals with either 17beta-estradiol at a dose rate of 0.125 mg/kg/day or LY 117018 at a dose rate of 3 mg/kg/day prevented these increases in osteocyte apoptosis similarly. These observations demonstrate that LY 117018 exerts a powerful inhibitory effect upon osteocyte apoptosis directly after estrogen loss, in a similar way to the known effect of 17beta-estradiol replacement. These results point to the potential benefits of SERMs on both the quantity and quality of bone in E(2)-depleted rats.
Huber
C
C
Musculoskeletal Tissue Engineering Collaboration, Department of Medicine, University of Edinburgh, 49 Little France Crescent, Chancellor's Building, University of Edinburgh, Edinburgh, EH16 4SB, UK.
Collishaw
S
S
Mosley
J R
JR
Reeve
J
J
Noble
B S
BS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D015519:Bone Density / Q000187:drug effects / Q000502:physiology; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology / Q000627:therapeutic use; D047628:Estrogen Receptor alpha / Q000187:drug effects* / Q000378:metabolism; D004967:Estrogens / Q000819:agonists / Q000172:deficiency*; D005260:Female; D006801:Humans; D010011:Osteocytes / Q000187:drug effects* / Q000378:metabolism; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D011759:Pyrrolidines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology* / Q000627:therapeutic use; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
D047628:Estrogen Receptor alpha; D004967:Estrogens; D011759:Pyrrolidines; D020845:Selective Estrogen Receptor Modulators; D013876:Thiophenes; D004958:Estradiol; C025430:LY 117018