Lasofoxifene in Postmenopausal Women with Osteoporosis

San Francisco Coordinating Center, California Pacific Medical Center Research Institute, and University of California, San Francisco, San Francisco, USA.
New England Journal of Medicine (Impact Factor: 54.42). 02/2010; 362(8):686-96. DOI: 10.1056/NEJMoa0808692
Source: PubMed

ABSTRACT The effects of lasofoxifene on the risk of fractures, breast cancer, and cardiovascular disease are uncertain.
In this randomized trial, we assigned 8556 women who were between the ages of 59 and 80 years and had a bone mineral density T score of -2.5 or less at the femoral neck or spine to receive once-daily lasofoxifene (at a dose of either 0.25 mg or 0.5 mg) or placebo for 5 years. Primary end points were vertebral fractures, estrogen receptor (ER)-positive breast cancer, and nonvertebral fractures; secondary end points included major coronary heart disease events and stroke.
Lasofoxifene at a dose of 0.5 mg per day, as compared with placebo, was associated with reduced risks of vertebral fracture (13.1 cases vs. 22.4 cases per 1000 person-years; hazard ratio, 0.58; 95% confidence interval [CI], 0.47 to 0.70), nonvertebral fracture (18.7 vs. 24.5 cases per 1000 person-years; hazard ratio, 0.76; 95% CI, 0.64 to 0.91), ER-positive breast cancer (0.3 vs. 1.7 cases per 1000 person-years; hazard ratio, 0.19; 95% CI, 0.07 to 0.56), coronary heart disease events (5.1 vs. 7.5 cases per 1000 person-years; hazard ratio, 0.68; 95% CI, 0.50 to 0.93), and stroke (2.5 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.64; 95% CI, 0.41 to 0.99). Lasofoxifene at a dose of 0.25 mg per day, as compared with placebo, was associated with reduced risks of vertebral fracture (16.0 vs. 22.4 cases per 1000 person-years; hazard ratio, 0.69; 95% CI, 0.57 to 0.83) and stroke (2.4 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.61; 95% CI, 0.39 to 0.96) Both the lower and higher doses, as compared with placebo, were associated with an increase in venous thromboembolic events (3.8 and 2.9 cases vs. 1.4 cases per 1000 person-years; hazard ratios, 2.67 [95% CI, 1.55 to 4.58] and 2.06 [95% CI, 1.17 to 3.60], respectively). Endometrial cancer occurred in three women in the placebo group, two women in the lower-dose lasofoxifene group, and two women in the higher-dose lasofoxifene group. Rates of death per 1000 person-years were 5.1 in the placebo group, 7.0 in the lower-dose lasofoxifene group, and 5.7 in the higher-dose lasofoxifene group.
In postmenopausal women with osteoporosis, lasofoxifene at a dose of 0.5 mg per day was associated with reduced risks of nonvertebral and vertebral fractures, ER-positive breast cancer, coronary heart disease, and stroke but an increased risk of venous thromboembolic events. ( number, NCT00141323.)

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Available from: Trevor J Powles, Aug 06, 2015
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    • "The first SERMs identified in this manner were lasofoxifene and bazedoxifene whose discovery utilized a series of in vitro molecular assays designed to report on ER-conformation [66]. Interestingly, in the Postmenopausal Evaluation and Risk-Reduction with Lasofoxifene (PEARL) trial, lasofoxifene was found to significantly reduce the risk of both vertebral and non-vertebral fractures, breast cancer, coronary events and stroke, although it was associated with an increased risk of thromboembolic events, hot flushes and benign endometrial changes [67] [68]. The second new SERM, bazedoxifene, has been approved for the treatment of postmenopausal osteoporosis in Europe and Japan, but is not registered in the United States. "
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    ABSTRACT: Estrogen Therapy and Hormone Therapy are effective options for the prevention and treatment of osteoporosis, although because of their significant side effect profile, long term use for these applications is not recommended. Whereas SERMs (Selective Estrogen Receptor Modulators) exhibit a more favorable side effect profile, the currently available medicines in this class are substantially less effective in bone than classical estrogens. However, the results of substantial efforts that have gone into defining the mechanisms that underlie the pharmacology of estrogens, antiestrogens and SERMs have informed the development of the next generation of SERMs and have led to the development of TSECs (Tissue Selective Estrogen Complexes), a new class of ER-modulator. Further, the recent determination that the oxysterol 27-hydroxycholesterol functions as an endogenous SERM has highlighted an unexpected link between hypercholesterolemia and bone biology and must be considered in any discussions of ER-pharmacology. This review considers the most recent progress in our understanding of ER pharmacology and how this has and will be translated into new medicines for the treatment and prevention of osteoporosis.
    Bone 11/2012; 53(1). DOI:10.1016/j.bone.2012.11.011 · 4.46 Impact Factor
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    • "Lasofoxifene received an initial US Food and Drug Administration nonapproval in 2005 due to a lack of large studies, although it was later approved by the European Medicines Agency in 2008. However, despite better fracture protection than raloxifene [Cummings et al. 2010], lasofoxifene was not commercialized because of a company decision. Only bazedoxifene survived the end of phase III trials and is available for prescription, in spite of an antifracture efficacy quite similar to raloxifene [Silverman et al. 2008]. "
    Therapeutic advances in musculoskeletal disease 04/2012; 4(2):55-9. DOI:10.1177/1759720X11435677
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    • "This versatile class of compounds includes tamoxifen and raloxifene, which are important endocrine therapies and preventive agents for ER-positive breast cancers (Martino et al. 2004; Fisher et al. 2005). Raloxifene and newer generation SERMs also have ER agonist activity in bone and are widely used clinically for prevention of osteoporosis in postmenopausal women (Siris et al. 2005; Silverman et al. 2008; Cummings et al. 2010). Apart from these beneficial applications, SERMs elicit a range of secondary, nontarget effects, including modulation of endocrine hormones (e.g., Rossi et al. 2009). "
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    ABSTRACT: Here, we report the effects of estrogen and the selective estrogen receptor modulator (SERM) levormeloxifene on adrenocortical measures in ovariectomized female cynomolgus monkeys (Macaca fascicularis). Animals were randomized into one of five treatment groups, each containing 23 to 26 animals: (1) placebo, (2) 0.016 mg/kg 17β-estradiol (E(2)), (3) 0.5 mg/kg levormeloxifene (L(1)), (4) 1.0 mg/kg levormeloxifene (L(2)), and (5) 5.0 mg/kg levormeloxifene (L(3)). Treatments were administered orally each day for 18 mo. All doses of levormeloxifene resulted in adrenal weights at least 50% greater than placebo (p < .0001 for all). The target dose of levormeloxifene (L(2)) resulted in higher serum concentrations of cortisol (+63%), dehydroepiandrosterone-sulfate (+73%), and androstenedione (+37%) compared with the placebo group (p < .05 for all). In contrast, E(2) resulted in no significant differences in adrenal weight or adrenocortical steroids. Oral E(2) and all SERM doses resulted in similar reductions in serum gonadotropins and at least threefold greater uterine weight versus placebo (p < .0001 for all). Results indicate that the SERM levormeloxifene, in contrast to E(2), may have robust stimulatory effects on adrenocortical hormones in a postmenopausal model. These findings warrant further investigation into long-term SERM effects on adrenocortical function.
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