Long-term treatment of lasofoxifene preserves bone mass and bone strength and does not adversely affect the uterus in ovariectomized rats.
The purpose of this study was to determine the long-term effects of lasofoxifene, a new selective estrogen receptor modulator, on bone mass, bone strength, and reproductive tissues in ovariectomized (OVX) rats. Sprague Dawley female rats at 3.5 months of age were OVX and treated orally with lasofoxifene (60, 150, or 300 microg/kg x d) for 52 wk. The urinary deoxypyridinoline/creatinine ratio was significantly lower in all lasofoxifene-treated OVX rats compared with OVX controls at wk 26. Peripheral quantitative computerized tomography analysis of proximal tibial metaphysis showed that the significant loss in trabecular content and density induced by OVX was significantly prevented by lasofoxifene treatment. Proximal tibial and lumber vertebral trabecular bone histomorphometric analysis showed that all doses of lasofoxifene significantly reduced OVX-induced bone loss by decreasing bone resorption and bone turnover. The ultimate strength, energy, and toughness of the fourth lumbar vertebral body in OVX rats treated with all doses of lasofoxifene were significantly higher compared with those in OVX controls, and did not differ significantly from those in sham controls. Uterine weight in OVX rats treated with lasofoxifene was slightly, but significantly, higher when compared with that in OVX controls, but was still much less than that in sham controls. No abnormal finding associated with lasofoxifene was observed with uterine histology examination. In summary, long-term treatment with lasofoxifene preserves bone mass and bone strength and does not adversely affect the uterus in OVX rats. These data suggest that lasofoxifene is an effective antiosteoporosis agent, and its efficacy and safety can be maintained over an extended period of time.
Ke
Hua Zhu
HZ
Pfizer Global Research and Development, Groton Laboratories, Groton, Connecticut 06340, USA. huazhu_ke@groton.pfizer.com
Foley
George L
GL
Simmons
Hollis A
HA
Shen
Victor
V
Thompson
David D
DD
D000596:Amino Acids / Q000652:urine; D000818:Animals; D001696:Biomechanical Phenomena; D001842:Bone and Bones / Q000033:anatomy & histology* / Q000187:drug effects / Q000502:physiology*; D019245:Compressive Strength; D003404:Creatinine / Q000652:urine; D004334:Drug Administration Schedule; D005260:Female; D005836:Genitalia, Female / Q000033:anatomy & histology / Q000187:drug effects; D008159:Lumbar Vertebrae / Q000033:anatomy & histology / Q000502:physiology; D009929:Organ Size / Q000187:drug effects; D015675:Osteocalcin / Q000097:blood; D010052:Ovariectomy; D011759:Pyrrolidines / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage*; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage*; D013977:Tibia / Q000033:anatomy & histology / Q000000981:diagnostic imaging; D014057:Tomography, X-Ray Computed; D014599:Uterus / Q000187:drug effects*
D000596:Amino Acids; D011759:Pyrrolidines; D020845:Selective Estrogen Receptor Modulators; D013764:Tetrahydronaphthalenes; D015675:Osteocalcin; C111332:Lasofoxifene; C036020:deoxypyridinoline; D003404:Creatinine