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Effects of raloxifene hydrochloride on endometrial cancer cells in vitro.

Hibner M, Magrina JF, Lefler SR, Cornella JL, Pizarro AR, Loftus JC.

Department of Obstetrics and Gynecology, Mayo Clinic, Scottsdale, AZ 85259, USA.

OBJECTIVE: Determine effects of raloxifene hydrochloride, a selective estrogen receptor modulator (SERM), on growth and proliferation of an estrogen-responsive endometrial cancer cell line in vitro. MATERIALS AND METHODS: Studies were performed with Ishikawa endometrial adenocarcinoma cells, a well-differentiated cancer that expresses estrogen receptors and progesterone receptors. Raloxifene was purified as the hydrochloride salt. The four arms of the study were cells grown (1) without any further addition (control), (2) with estradiol only, (3) with raloxifene only, or (4) with estradiol and raloxifene. Three concentrations of estradiol (10, 100, 1000 pg/ml) and raloxifene (1, 10, 100 ng/ml) were used. After 1 week of culturing, the number of living cells for each experimental group was determined and expressed as a percentage of the control group. RESULTS: Cells treated with raloxifene 10 or 100 ng/ml alone grew significantly faster than control cells: 10 ng/ml [115.25%; SD, 11.05; 95% confidence interval (CI), 107.35-123.16; P = 0.002] and 100 ng/ml (111.14%; SD, 14.19; 95% CI, 100.98-121.29; P = 0.03). Estradiol 10 or 100 pg/ml did not stimulate cell growth, whereas cells treated with 1000 pg/ml grew significantly faster than control cells (114.69%; SD, 16.84; 95% CI, 102.65-126.74; P = 0.02). Raloxifene and estradiol together in any concentration did not affect cell growth. CONCLUSIONS: Raloxifene did not inhibit the growth of endometrial cancer cells in vitro. High concentrations even promoted cell growth. Estradiol in physiologic concentrations did not stimulate the growth of endometrial cancer cells in vitro.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15196858&dopt=Abstract raloxifene Evista



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Effects of ovarian steroids and raloxifene on proteins that synthesize, transport, and degrade serotonin in the raphe region of macaques.

Smith LJ, Henderson JA, Abell CW, Bethea CL.

Division of Reproductive Sciences, Oregon National Primate Research Center, Beaverton, OR, USA.

In the monkey dorsal raphe, we reported that 1-month (mo) of estrogen replacement, with or without progesterone supplementation for 14 days, significantly increased tryptophan hydroxylase-1 (TPH-1) mRNA; decreased serotonin reuptake transporter (SERT) mRNA and decreased monoamine oxidase (MAO)-A mRNA, but had no effect on MAO-B mRNA. Here, we questioned what effect would 1 or 5 mo of ovarian hormones or the selective estrogen receptor modulator (SERM), raloxifene, have on TPH protein and phosphorylation, and on protein expression of SERT, MAO-A or MAO-B? Raloxifene antagonizes estrogen in breast or uterus, but estrogen-like activities in the brain have been reported. Cytoplasmic and membrane extracts of the dorsal raphe region were processed for Western blotting. TPH, phosphoserine, SERT, MAO-A, and MAO-B were detected with specific antibodies. The optical densities of the signals were measured with NIH image and analyzed by ANOVA. Both 1 and 5 mo of estrogen, with or without progesterone, and 5 mo of raloxifene significantly increased TPH protein. Administration for 5 mo of estrogen plus progesterone and raloxifene also increased TPH phosphorylation. Estrogen, with or without progesterone, for 1 mo had no effect on SERT protein. However, 5 mo of estrogen and 5 mo of raloxifene increased SERT protein. Estrogen alone or combined with progesterone for 1 mo caused a significant reduction in MAO-A. Yet, after 5 mo of the same treatments, MAO-A was not different from spayed controls. Estrogen alone had no effect on MAO-B. However, the addition of progesterone significantly increased MAO-B. Raloxifene for 5 mo had no effect on MAO-A or MAO-B. Thus, to various extents, estrogen, progesterone, and raloxifene may increase serotonin production and transport. The expression of the degradative enzymes suggests a complex combination of gene transcription, post-transcriptional processing, and substrate feedback mechanisms.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15199371&dopt=Abstract raloxifene Evista



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A new selective estrogen receptor modulator HMR-3339 fully corrects bone alterations induced by ovariectomy in adult rats.

Ammann P, Bourrin S, Brunner F, Meyer JM, Clement-Lacroix P, Baron R, Gaillard M, Rizzoli R.

Department of Rehabilitation and Geriatrics, Service of Bone Diseases (WHO Collaborating Center for Osteoporosis Prevention), University Hospital, CH-1211 Geneva 14, Switzerland. Patrick.Ammann medecine.unige.ch

The selective estrogen receptor modulator (SERM) raloxifene has been shown to reduce the risk of vertebral fracture, but without significant effect on nonvertebral fractures. However, there is a need for SERMs capable of improving mechanical competence and reducing the risk of fractures at multiple skeletal sites, with minimal side effects. We investigated the effects of a new steroidal SERM, HMR-3339, compared to raloxifene, on bone strength and its determinants (BMD, microarchitecture, dimensions) at various skeletal sites (lumbar spine, tibia, and femur) of adult ovariectomized rats in both prevention and intervention protocols. In a prevention study, HMR-3339 and raloxifene treatments fully prevented alterations of bone strength. In an intervention protocol, where treatment was started 8 weeks after ovariectomy, HMR-3339 fully restored mechanical properties by influencing both areal BMD and outer diameter. This effect was observed at skeletal sites formed of cancellous and cortical bone or of cortical bone only. In contrast, raloxifene positively influenced structures containing mainly cancellous bone. In HMR-3339-treated rats, IGF-I plasma levels were higher than in ovariectomized controls; this was not observed with raloxifene. In conclusion, these results indicate that HMR-3339 increased not only bone mineral mass, but also restored bone mechanical strength at multiple sites in adult osteoporotic rats. In contrast to raloxifene, HMR-3339 also influenced skeletal sites predominantly formed of cortical bone.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15207751&dopt=Abstract raloxifene Evista



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Modulation of survival in osteoblasts from postmenopausal women.

Garcia-Moreno C, Catalan MP, Ortiz A, Alvarez L, De la Piedra C.

Bone Pathophysiology Laboratory, Jimenez-Diaz Foundation, Madrid, Spain.

Osteoblast survival is one of the determinants of postmenopausal osteoporosis development. Recent data from animal experiments suggest that cytokines, in particular Fas ligand (FasL), contribute to postmenopausal osteoporosis. We now address the effect of Fas activation in postmenopausal osteoblast survival and the potential modulatory effect of estrogen and raloxifene analog (LY117018). The expression of Fas mRNA, Fas protein, and the sensitivity to Fas-induced apoptosis were studied in primary cultures of human osteoblasts from postmenopausal women and in osteoblastic MG-63 cells. Human postmenopausal osteoblasts constitutively expressed Fas receptors in the cell surface. TNFalpha increased the expression of Fas mRNA and cell surface Fas expression. Neither estradiol nor raloxifene analog prevented this increase in Fas expression. In addition, activation of Fas receptor resulted in apoptosis of postmenopausal osteoblasts. While TNFalpha did not induce human osteoblast apoptosis, it did increase the lethal effect of Fas activation. Therapeutic concentrations of estradiol or raloxifene analog did not modulate lethal cytokine-induced apoptosis. Both postmenopausal osteoblasts and MG-63 cells express FasL. FasL expression was not modulated by TNFalpha. In conclusion, estrogen and raloxifene analog do not appear to affect the sensitivity of postmenopausal osteoblasts to Fas-mediated apoptosis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15207753&dopt=Abstract raloxifene Evista



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Compliance with drug therapies for the treatment and prevention of osteoporosis.

McCombs JS, Thiebaud P, McLaughlin-Miley C, Shi J.

Department of Pharmaceutical Economics and Policy, School of Pharmacy, University of Southern California, Los Angeles, CA, USA. jmccombs usc.edu

OBJECTIVES: This study used paid claims data from real-world treatment settings to investigate the impact of hormone replacement therapy (HRT), bisphosphonate and raloxifene on patients with a recorded diagnosis of osteoporosis. METHODS: Data from a large health insurer were used to identify 58,109 osteoporosis patients who initiated drug therapy for osteoporosis. Multivariate statistical models were developed for duration of therapy, compliance at 1 year, time to discontinuation or a change in therapy, health care costs and risk of fracture over 1 year. RESULTS: One-year compliance rates were below 25% for all osteoporosis therapies. The mean unadjusted duration of continuous therapy was 221 days for raloxifene, 245 days for bisphosphonate, 262 for estrogen-only and 292 days for estrogen plus progestin. Raloxifene patients were consistently less compliant than estrogen-only patients after adjusting for differences in patient characteristics. Estrogen plus progestin patients were generally more compliant while bisphosphonate did not differentiate from estrogen-only. Compliance reduced the risk of hip fracture (o.r. = 0.382, P < 0.01) and vertebral fracture (o.r. = 0.601, P < 0.05). Compliant patients used fewer physicians services (-US dollars 56, P < 0.0001), hospital outpatient services (-US dollars 38, P < 0.05) and hospital care (-US dollars 155, P < 0.01). Bisphosphonate patients were twice as likely as estrogen-only patients to experience vertebral, Colles and other fractures and experienced higher health care costs (+US dollars 420, P < 0.01). The effectiveness of both raloxifene and bisphosphonate medications relative to estrogen-only improved significantly with the age of the patient. CONCLUSIONS: Compliance with drug therapies for osteoporosis over 1 year is poor leaving patients at risk for fractures and higher health care costs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15207894&dopt=Abstract raloxifene Evista



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Risk-benefit profile for raloxifene: 4-year data From the Multiple Outcomes of Raloxifene Evaluation (MORE) randomized trial.

Barrett-Connor E, Cauley JA, Kulkarni PM, Sashegyi A, Cox DA, Geiger MJ.

Division of Epidemiology, Department of Family and Preventive Medicine, University of California at San Diego, La Jolla, California 92093-0607, USA. ebarrettconnor ucsd.edu

Posthoc analysis of the MORE osteoporosis treatment trial assessed risk-benefit profile of raloxifene in 7705 postmenopausal women. A major disease outcomes global index resulted in annual rates of 1.39% and 1.83% in the raloxifene and placebo groups, respectively (HR, 0.75; 95% CI, 0.62-0.92), compatible with a favorable risk-benefit profile for raloxifene for treating postmenopausal osteoporosis. INTRODUCTION: The Women's Health Initiative (WHI) trial reported overall risks that exceeded benefits from use of estrogen-progestin in healthy postmenopausal women. The objective of this posthoc analysis of the Multiple Outcomes of Raloxifene Evaluation (MORE) trial was to assess the safety profile of raloxifene, a selective estrogen receptor modulator indicated for the prevention and treatment of osteoporosis, using the global index method from the WHI trial. MATERIALS AND METHODS: A total of 7705 postmenopausal women (mean age, 67 years) were enrolled in the MORE osteoporosis treatment trial and randomly assigned to receive placebo or one of two doses of raloxifene (60 or 120 mg/day) for 4 years. A global index of clinical outcomes, defined as described for the WHI trial (the earliest occurrence of coronary heart disease, stroke, pulmonary embolism, invasive breast cancer, endometrial cancer, colorectal cancer, hip fracture, or death because of other causes) was applied to the MORE trial data. Physicians blinded to treatment assignment adjudicated events. Intention-to-treat survival analysis of time-to-first-event was performed using a proportional hazards model. RESULTS AND CONCLUSIONS: The annualized rate of global index events was 1.83% in the placebo group and 1.39% in the combined raloxifene dose groups (hazard ratio [HR], 0.75; 95% CI, 0.62-0.92). Analyzing individual dose groups separately yielded the same results (HR for 60 mg/day, 0.75; 95% CI, 0.60-0.96: HR for 120 mg/day, 0.75; 95% CI, 0.59-0.95). Subgroup analyses showed no significant interactions between age or hysterectomy status and the effect of raloxifene on the global index (interaction p > 0.1), whereas the global index risk reduction seemed to be greater in obese women compared with nonobese women (interaction p = 0.03). The significant 25% reduction in global index is compatible with a favorable risk-benefit safety profile when raloxifene is used for osteoporosis treatment in postmenopausal women. These results require confirmation in ongoing clinical trials.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15231013&dopt=Abstract raloxifene Evista