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.)

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Tamoxifen has been shown to reduce the risk of developing estrogen receptor (ER)-positive breast cancer by at least 50%, in both pre- and postmenopausal women. The current challenge is to find new agents with fewer side effects and to find agents that are specifically suitable for premenopausal women with ER-negative breast cancer. Other selective estrogen receptor modulators (SERMs), such as raloxifene, arzoxifene, and lasofoxifene, have been shown to reduce the incidence of breast cancer by 50%-80%. SERMs are interesting agents for the prevention of breast cancer, but longer follow-up is needed for some of them for a complete risk-benefit profile of these drugs. Aromatase inhibitors have emerged as new drugs in the prevention setting for postmenopausal women. In the Mammary Prevention 3 (MAP3) trial, a 65% reduction in invasive breast cancer with exemestane was observed, and the Breast Cancer Intervention Study-II trial, which compared anastrozole with placebo, reported a 60% reduction in those cancers. Although SERMs and aromatase inhibitors have been proven to be excellent agents in the preventive setting specifically for postmenopausal women and ER-positive breast cancer, newer agents have to be found specifically for ER-negative breast cancers, which mostly occur in premenopausal women.
    Cancer Management and Research 01/2014; 6:423-30. DOI:10.2147/CMAR.S55219
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The incidence of osteoporosis-related fractures in Asian countries is steadily increasing. Optimizing osteoporosis treatment is especially important in Japan, where the rate of aging is increasing rapidlyelderly population is increasing rapidly and life expectancy is among the longest in the world. There are several therapies currently available in Japan for the treatment of postmenopausal osteoporosis, each with a unique risk/benefit profile. A novel selective estrogen receptor modulator, bazedoxifene (BZA), was recently approved for the treatment of postmenopausal osteoporosis in Japan. Results from a 2-year, phase 2 trial in postmenopausal Japanese women showed that BZA significantly improved lumbar spine and total hip bone mineral density compared with placebo, while maintaining endometrial and breast safety, consistent with results from 2 global, phase 3 trials including a 2-year osteoporosis prevention study and a 3-year osteoporosis treatment study. In the pivotal 3-year treatment study, BZA significantly reduced the incidence of new vertebral fractures compared with placebo; in a post hoc analysis of a subgroup of women at higher risk of fractures, BZA significantly reduced the risk of nonvertebral fractures compared with placebo and raloxifene. A 2-year extension of the 3-year treatment study demonstrated the sustained efficacy of BZA over 5 years of treatment. BZA was generally safe and well tolerated in these studies. In a "super-aging" society such as Japan, long-term treatment for postmenopausal osteoporosis is a considerable need. BZA may be considered as a first choice for younger women anticipating long-term treatment, and also an appropriate option for older women who are unable or unwilling to take bisphosphonates.
    Osteoporosis International 12/2014; 26(3). DOI:10.1007/s00198-014-2940-x · 4.17 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This study aims to explore the effects of exercise on postmenopausal osteoporosis and the mechanisms by which exercise affects bone remodeling. Sixty-three Wistar female rats were randomly divided into five groups: (1) control group, (2) sham-operated group, (3) OVX (Ovariectomy) group, (4) DES-OVX (Diethylstilbestrol-OVX) group, and (5) Ex-OVX (Exercise-OVX) group. The rat osteoporosis model was established through ovariectomy. The Ex-OVX rats were made to run 251.2 meters every day, 6 d/wk for 3 months in a running wheel. Trabecular bone volume (TBV%), total resorption surface (TRS%), trabecular formation surface (TFS%), mineralization rate (MAR), bone cortex mineralization rate (mAR), and osteoid seam width (OSW) were determined by bone histomorphometry. The mRNA and protein levels of interleukin-1β (IL-1β2), interleukin-6 (IL-6), and cyclooxygenase-2 (Cox-2) were determined by in situ hybridization and immunohistochemistry, respectively. Serum levels of estrogen estradiol (E2), calcitonin (CT), osteocalcin (BGP), and parathyroid hormone (PTH) were determined by ELISA assays. The investigation revealed that compared to the control and the sham-operated groups, the OVX group showed significantly lower levels of TBV%, E2, and CT, but much higher levels of TRS%, TFS%, MAR, OSW, BGP, and PTH. The Ex-OVX group showed increased TBV% and serum levels of E2 and CT compared to the OVX group. Ovariectomy also led to a significant increase in IL-1β mRNA and protein levels in the bone marrow and IL-6 and Cox-2 protein levels in tibias. In addition, the Ex-OVX group showed lower levels of IL-1 mRNA and protein, IL-6 mRNA, and Cox-2 mRNA and protein than those in the OVX group. The upshot of the study suggests that exercise can significantly increase bone mass in postmenopausal osteoporosis rat models by inhibiting bone resorption and increasing bone formation, especially in trabecular bones.
    PLoS ONE 11/2014; 9(11):e112845. DOI:10.1371/journal.pone.0112845 · 3.53 Impact Factor

Full-text (2 Sources)

Available from
Jun 1, 2014