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: 55.87). 02/2010; 362(8):686-96. DOI: 10.1056/NEJMoa0808692
Source: PubMed


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.)


Available from: Trevor J Powles
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    • "Nevertheless, raloxifene exhibited a fewer effectiveness than tamoxifen toward the prevention of invasive breast cancer (3). More recently, a third-generation SERM named lasofoxifene has evidenced high efficacy in reducing the incidence of ER-positive breast cancer, along with decreased side-effects compared to tamoxifen or raloxifene treatment (4). However, the use of lasofoxifene has not yet been approved by FDA in the prevention of breast cancer. "
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    ABSTRACT: The G-protein-coupled estrogen receptor-1 (GPER, formerly known as GPR30) has attracted increasing interest, considering its ability to mediate estrogenic signaling in different cell types, including the hormone-sensitive tumors like breast cancer. As observed for other GPCR-mediated responses, the activation of the epidermal growth factor receptor is a fundamental integration point in the biological action triggered by GPER. A wide number of natural and synthetic compounds, including estrogens and anti-estrogens, elicit stimulatory effects in breast cancer through GPER up-regulation and activation, suggesting that GPER function is associated with breast tumor progression and tamoxifen resistance. GPER has also been proposed as a candidate biomarker in triple-negative breast cancer, opening a novel scenario for a more comprehensive assessment of breast tumor patients.
    Frontiers in Endocrinology 05/2014; 5:66. DOI:10.3389/fendo.2014.00066
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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 · 3.97 Impact Factor
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    • "The incidence of non-vertebral fractures was only significantly reduced with LAS 0.5 mg compared with placebo at 5 years in the overall population47. Some endometrial safety findings with LAS include a small but significant increase in endometrial thickness and an increased incidence of endometrial polyps47,49. BZA 20 mg has shown a significant reduction in the risk of non-vertebral fractures compared with placebo and RLX 60 mg in a post hoc analysis of a subgroup of women at higher risk of fracture (baseline femoral neck BMD T-score ≤ –3.0 and/or at least one moderate or severe vertebral fracture or at least two mild fractures)51. "
    P Hadji ·
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    ABSTRACT: Selective estrogen receptor modulators (SERMs), which exhibit estrogen receptor agonist or antagonist activity based on the target tissue, have evolved through multiple generations for the prevention and/or treatment of postmenopausal osteoporosis. An ideal SERM would protect bone without stimulating the breast or endometrium. Raloxifene, lasofoxifene, and bazedoxifene have demonstrated unique preclinical profiles. Raloxifene, lasofoxifene, and bazedoxifene have shown significant reduction in the risk of vertebral fracture and improvement in bone mineral density versus placebo in postmenopausal women with osteoporosis. Raloxifene has been shown to reduce the risk of non-vertebral fractures in women with severe prevalent fractures at baseline. Lasofoxifene 0.5 mg, but not lasofoxifene 0.25 mg, has shown reduction in the incidence of non-vertebral fractures. Bazedoxifene 20 mg has been associated with a significant reduction in the risk of non-vertebral fracture versus placebo and raloxifene 60 mg in women at higher baseline fracture risk. Neither raloxifene, lasofoxifene, nor bazedoxifene has shown an increase in the incidence of endometrial hyperplasia or carcinoma. All SERMs have been associated with increased venous thromboembolic events and hot flushes. SERMs are effective alternatives for women who cannot tolerate or are unwilling to take bisphosphonates and may be appropriate for women at higher risk of fracture, particularly younger women who expect to remain on therapy for many years and are concerned about the long-term safety of bisphosphonates.
    Climacteric 08/2012; 15(6). DOI:10.3109/13697137.2012.688079 · 2.26 Impact Factor
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