title: The estrogen receptor ligand ICI 182,780 does not impair the bone-sparing effects of testosterone in the young orchidectomized rat model.
abstract: Testosterone (T) can affect bone metabolism not only directly, but also via its metabolites, estrogen or dihydrotestosterone, produced by enzymes present in bone. Therefore, the aim of this study was to investigate whether the high-affinity estrogen receptor ligand ICI 182,780 (ICI) impaired the bone-protective action of T in 3-month-old orchidectomized (Orch) rats, studied during an experimental period of 3 months. As expected, Orch significantly decreased trabecular bone volume in the proximal tibial metaphysis (-52%), as measured by histomorphometry, and had a similar negative effect on volumetric bone mineral density (BMD) in the distal femoral metaphysis (-53%), as assessed by peripheral quantitative computed tomography (pQCT). The loss of bone induced by Orch was completely prevented by T administration. Moreover, the Orch-associated increases of biochemical markers of bone turnover (serum osteocalcin, urinary deoxypyridinoline, and calcium excretion) did not occur when Orch rats received T. Administration of ICI in combination with T did not impair this bone-sparing effect. Cortical bone parameters (as determined by pQCT), body weight gain, and body composition (as measured by dual-energy X-ray absorptiometry) were not affected by T or ICI in combination with T. Furthermore, no differences were observed in serum concentrations of insulin-like growth factor-I or glucose homeostasis. In conclusion, ICI does not impair the long-term bone-protective effects of T in orchidectomized male rats, suggesting that testosterone can mediate its effect on the male skeleton directly via the androgen receptor. The absence of effects on body growth via the growth hormone--insulin-like growth factor-I axis may be a possible explanation for the lack of skeletal effects of this selective estrogen receptor antagonist.
authors.affiliation: Laboratorium voor Experimentele Geneeskunde en Endocrinologie, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Vandenput
authors.forename: J V
authors.initials: JV
authors.lastname: Swinnen
authors.forename: E
authors.initials: E
authors.lastname: Van Herck
authors.forename: A
authors.initials: A
authors.lastname: Verstuyf
authors.forename: S
authors.initials: S
authors.lastname: Boonen
authors.forename: R
authors.initials: R
authors.lastname: Bouillon
authors.forename: D
authors.initials: D
authors.lastname: Vanderschueren
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism; D004347:Drug Interactions; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism; D005500:Follow-Up Studies; D000077267:Fulvestrant; D008024:Ligands; D008297:Male; D023421:Models, Animal; D009919:Orchiectomy / Q000009:adverse effects; D051381:Rats; D017208:Rats, Wistar; D011944:Receptors, Androgen / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D013739:Testosterone / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D015415:Biomarkers; D004965:Estrogen Antagonists; D004967:Estrogens; D008024:Ligands; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D000077267:Fulvestrant; D013739:Testosterone; D004958:Estradiol