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IOF World Congress Abstracts Animal trials for a new SERM show prevention of bone loss and reduction of serum cholesterol Preclinical results of lasofoxifene, a third generation SERM (Selective Estrogen Receptor Modulator), were presented at the IOF World Congress on Osteoporosis. SERMs are increasingly challenging hormone replacement therapy (HRT), for treatment and prevention of postmenopausal osteoporosis. David Thompson from Pfizer Global Research and Development reviewed preclinical results obtained with lasofoxifene, noted in ovariectomized rats and in aged intact female rats, lasofoxifene blocked bone loss at doses as low as 10 mcg/kg/day p.o. Like estrogen, the study drug prevented bone loss by increasing cell apoptosis in osteoclasts. Lasofoxifene also reduced serum cholesterol levels in both male and female rodents at nearly the same doses required for bone preservation. In ovariectomized primates treated for two years, lasofoxifene inhibited bone turnover and prevented bone loss. In these preclinical models, no uterine hypertrophy was observed among animals treated with the investigational agent. "The preclinical perspective offers very interesting prospects to proceed forward with a human clinical profile, says Thompson. It is well characterized in multiple animal models and offers excellent efficacy demonstrated in bone, lipids and breast cancer." Dr. Alfred Moffett, Jr. of the University of South Florida College of Medicine reviewed phase I and phase II clinical trials conducted to date with lasofoxifene, demonstrating the SERM's good tolerability and favorable effects on bone and lipid metabolism in postmenopausal women. Six- and 12-month trial data demonstrate significant improvements in bone mineral density of the spine and hip after one year of drug therapy as compared to placebo, as well as sustained reductions in LDL cholesterol beginning as soon as six weeks after beginning treatment and lasting for up to one year. The drug has been administered safely for one year at doses of up to 10 mg/day, with no endometrial atypia, hyperplasia or cancer detected in any subjects treated. Lasofoxifene is now undergoing phase III evaluation. Hormone replacement therapy (HRT), long considered a standard in the treatment and prevention of postmenopausal osteoporosis, is quickly losing favor in the face of competition from newer tissue-selective estrogens, or SERMs. Compounds in the Selective Estrogen Receptor Modulator class, including the marketed drug raloxifene and investigational compounds such as lasofoxifene, act as estrogen receptor agonists in some tissues and as estrogen receptor antagonists in others. Pfizer's third-generation SERM lasofoxifene was the subject of a satellite symposium held in conjunction with the IOF World Congress on Osteoporosis in Lisbon, Portugal. Like other members of the SERM class, lasofoxifene acts as an estrogen antagonist in breast and uterine tissues and as an estrogen agonist in bone and other tissues. Lasofoxifene binds to estrogen receptors with an affinity comparable to that of 17beta-estradiol and, in bone, duplicates many of the effects obtained following administration of estrogen.
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