title: Lasofoxifene (CP-336,156), a selective estrogen receptor modulator, prevents bone loss induced by aging and orchidectomy in the adult rat.
abstract: It has been well documented that selective estrogen receptor modulators (SERMs) can prevent bone loss in ovariectomized rats and postmenopausal women. The purposes of this study were to determine the effects of a potent and orally active SERM, lasofoxifene (CP-336,156), on bone mass, bone strength, total serum cholesterol, prostate weight, and histology in adult male orchidectomized (ORX) rats. Sprague Dawley male rats at 10 months of age were divided into 6 groups, with 10 rats/group. The first group was necropsied on day 0 and served as basal controls. The remaining rats were either sham operated (n = 10) and treated orally with vehicle, or ORX (n = 40) and treated with either vehicle or lasofoxifene at 1, 10, or 100 microg/kg x day for 60 days. Total serum cholesterol, prostate weight and histology, distal femoral bone mineral density (DFBMD) by dual energy x-ray absorptiometry, and static and dynamic bone histomorphometry of the third lumbar vertebral body were determined. Maximal load and stiffness of the fifth lumbar vertebral body were also determined by compression tests. Age-related decreases in DFBMD (-9%) and trabecular bone volume (TBV; -13%) of the third lumbar vertebral body were found in sham-operated rats compared with basal controls. ORX induced significant increases in total serum cholesterol (+31%), eroded surface (+48%), activation frequency of bone turnover (+103%) and significant decreases in prostate weight (-89%), DFBMD (-14%), TBV (-23%), and maximal load (-17%) compared with basal controls. Compared with sham controls, ORX induced significant increases in eroded perimeter and activation frequency. Lasofoxifene decreased body weight in all dose groups compared with both sham and ORX control values. Compared with ORX controls, ORX rats treated with lasofoxifene at 10 or 100 microg/kg x day had significantly lower percent eroded perimeter activation frequency and significantly higher DFBMD, TBV, and maximal load. Further, lasofoxifene at 10 and 100 microg/kg x day significantly decreased total serum cholesterol by 46% and 68% in ORX rats, whereas no effect was found in prostate weight and histology parameters compared with ORX control values. These data showed that lasofoxifene prevented bone loss by inhibiting bone turnover associated with aging and orchidectomy in 10-month-old male rats. Further, lasofoxifene decreased total serum cholesterol and did not affect the prostate in these rats. These results suggest that SERMs such as lasofoxifene may be useful therapeutic agents for preventing bone loss in elderly men with some degree of hypogonadism.
authors.affiliation: Department of Cardiovascular and Metabolic Diseases, Pfizer, Inc., Groton, Connecticut 06340, USA. huazhu@groton.pfizer.com
authors.forename: H Z
authors.initials: HZ
authors.lastname: Ke
authors.forename: H
authors.initials: H
authors.lastname: Qi
authors.forename: D T
authors.initials: DT
authors.lastname: Crawford
authors.forename: K L
authors.initials: KL
authors.lastname: Chidsey-Frink
authors.forename: H A
authors.initials: HA
authors.lastname: Simmons
authors.forename: D D
authors.initials: DD
authors.lastname: Thompson
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D001696:Biomechanical Phenomena; D001835:Body Weight / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005269:Femur / Q000378:metabolism; D008159:Lumbar Vertebrae / Q000033:anatomy & histology / Q000187:drug effects / Q000502:physiology; D008297:Male; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D010024:Osteoporosis / Q000209:etiology / Q000517:prevention & control*; D011467:Prostate / Q000033:anatomy & histology; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000187:drug effects; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
chemical_list: D004965:Estrogen Antagonists; D011759:Pyrrolidines; D011960:Receptors, Estrogen; D013764:Tetrahydronaphthalenes; C111332:Lasofoxifene; D002784:Cholesterol