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A method is presented for flexibly aligning small molecules. The method accepts a collection of small molecules with 3D coordinates as input and computes a collection of alignments. Each alignment is given a score, which quantifies the quality of the alignment both in terms of internal strain and overlap of molecular features. The results of several computational experiments on pairs of compounds with known binding conformations are used to systematically and objectively tune the parameters for the method. The results indicate the method's utility for the elucidation of pharmacophores and comparative field analysis.
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PATIENTS were classified into the alendronate, calcitonin, or raloxifene group according to exposure after follow-up.
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Raloxifene and alendronate are anti-resorptive therapies approved for the prevention and treatment of postmenopausal osteoporosis. Raloxifene is also indicated to reduce the risk of invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk of invasive breast cancer. A definitive study comparing the fracture effectiveness and rate of breast cancer for raloxifene and alendronate has not been published. The purpose of this retrospective cohort study was to evaluate fracture and breast cancer rates among patients treated with raloxifene or alendronate.
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This commentary explores the recent experience with and the basis for the use of selective estrogen receptor modulators (SERMs) to prevent breast cancer. Chemoprevention has been a goal for many years. As newer agents are unveiled, they will continue to be tested against tamoxifen, the current standard for the treatment and prevention of breast cancer. Raloxifene holds the promise of treating osteoporosis with the beneficial side effect of breast cancer prevention. The Study of Tamoxifen and Raloxifene (STAR) trial and prior prevention studies will be discussed in an attempt understand the bridge from the laboratory to the clinic.
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To assess the effect of raloxifene 60 mg/day (RLX) on year-by-year cardiovascular (CV) events in postmenopausal women participating in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, a double-blind, placebo-controlled osteoporosis treatment trial.
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This study was aimed to investigate the reversible effect of cyclosporine A, raloxifene and their combination on multidrug resistance cell line K562/A02. The IC(50) (the concentration causing 50% inhibition of cell growth) of DNR were assayed by MTT method, the expression level of mdr-1 mRNA was assayed by RT-PCR, p-glycoprotein (P-gp) expression and intracellular DNR concentration were detected by flow cytometry. The results showed that the IC(50) of DNR on K562/A02 and K562 cells were 23.51 mg/L and 0.29 mg/L, respectively. The IC(50) of DNR on K562/A02 cells in treatment with raloxifene CsA and both combination were 5.98, 8.15 and 3.68 mg/L respectively, but both drugs not influenced IC(50) of DNR on K562 cells. Pretreating K562/A02 cells with raloxifene (2.5 mg/L) or CsA (1 mg/L) for 48 hours partially restored the sensitivity of K562/A02 cells to DNR. Cyclosporine A and raloxifene (alone or combination) elevated the intracellular DNR concentration in K562/A02, down regulated P-gp and mdr-1 mRNA expressions. It is concluded that multidrug resistance (MDR) can be partially reversed by CsA or raloxifene, the combination of both drugs shows a great synergistic reversal effect.
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Hypothalamic differentiation in the female rat during the neonatal period is critically dependent on the steroid milieu, as permanent changes in reproductive function are observed after administration of oestradiol and testosterone during such a critical stage. Selective oestrogen modulators (SERMs) constitute a family of drugs that, depending on the tissue, are able to exert oestrogenic or antioestrogenic actions. The present experiments were conducted to analyse whether the SERMs, tamoxifen and raloxifene, can cause oestrogenic actions during the hypothalamic differentiation period. Postnatal female rats were injected between days 1 and 5 with 100 microg/day tamoxifen, raloxifene or ICI 182,780 (a pure antioestrogen). Other groups of animals were injected on day 1 of age with 100 microg oestradiol benzoate (OeB) or 1.25 mg testosterone propionate (TP) alone or in combination with raloxifene (500 microg/day between days 1 and 5). In all experimental groups, the age, body weight and concentrations of serum gonadotrophins at vaginal opening were recorded, whereas vaginal cyclicity and the negative and positive feedback between oestradiol and LH were monitored in adulthood. The results obtained confirmed the ability of high doses of OeB or TP to alter the normal differentiation of the brain permanently. They also reinforced the hypothesis that oestrogens are also necessary for normal brain differentiation in female rats because administration of a pure antioestrogen, such as ICI 182,780 permanently altered the function of the reproductive axis. In addition, our data provided evidence for different actions of the two SERMs under analysis (raloxifene and tamoxifen) upon peripheral targets, as raloxifene advanced vaginal opening whereas tamoxifen did not. In contrast, their actions on brain differentiation appeared similar and analogous to those obtained after neonatal administration of oestradiol, as evidenced by vaginal acyclicity, ovarian atrophy, sterility and abolition of negative and positive feedback between oestradiol and LH, thus suggesting an oestrogenic action of these SERMs on hypothalamic differentiation. Moreover, the oestrogenic activity of raloxifene was supported by its inability to block the effects of OeB and TP administered neonatally. In conclusion, the present results indicated that the SERMs, tamoxifen and raloxifene, exert an oestrogen-like effect upon hypothalamic differentiation of the neonatal female rat.
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One hundred and twenty-three postmenopausal women with genotype 1b chronic hepatitis C were randomly assigned to one of two treatment groups: raloxifene hydrochloride (RLX) (60 mg/day) plus SOC (PegIFNα2a 180 μg/week and RBV 600-1,000 mg/day) (n=62) or SOC only (n=61). Genotyping was performed of the polymorphism in the interleukin-28B (IL28B) gene region (rs8099917) of DNA collected from each patient.
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Fluid shear stress and raloxifene, the selective estrogen receptor modulator, were verifed to be able to promote MC3T3-E1 proliferation, increase the expression of β-catenin and ERα, and the combination functioned synergicly significantly. Fluid shear stress and raloxifene may possiblely affect the osteoblast proliferation by regulating the signaling pathways of Wnt/β-catenin and ER.
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The following review article focuses on chemoprevention clinical trials of breast cancer. To date, SERMs (Selective Estrogen Receptor Modulators) have been the most studied drugs. Four randomized trials with tamoxifen vs. placebo have been performed and two with raloxifene are being carried out. Two tamoxifen trials showed between 30 and 50% reduction in breast cancer incidence. However, two other studies showed no statistical differences. Moreover, the real impact on mortality that these therapies could have is still unknown. This article includes a revision of trials that evaluated the relationship between daily vitamin intake and breast cancer. A follow up of these trials will give us answers about which patients will benefit from chemoprevention therapies.
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There were 373 women who participated in this study. Most women (86.3%) had a washout period between HT and RLX, and 55.2% had tapered their HT in some fashion. After beginning RLX, women who had had a washout duration of more than one week were found to be more likely to have an improvement in the severity of hot flashes (odds ratio [OR] = 6.3), and in the frequency of hot flashes (OR = 4.6), than women with a shorter washout or no washout period at all. The method of tapering of HT did not seem to affect either the severity or the frequency of hot flashes once on RLX. Women who had undergone a tapering period of more than one week's duration were more likely (OR = 2.6) to experience an improvement in the frequency (but not the severity) of hot flashes on RLX.
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A new method for the postprocessing of docking outputs has been developed, based on encoding putative 3D binding modes (docking solutions) as ligand-protein interactions into simple bit strings, a method analogous to the structural interaction fingerprint. Instead of employing traditional scoring functions, the method uses a series of new, knowledge-based scores derived from the similarity of the bit strings for each docking solution to that of a known reference binding mode. A GOLD docking study was carried out using the Bissantz estrogen receptor antagonist set along with the new scoring method. Superior recovery rates, with up to 2-fold enrichments, were observed when the new knowledge-based scoring was compared to the GOLD fitness score. In addition, top ranking sets of molecules (actives and potential actives or decoys) were structurally diverse with low molecular weights and structural complexities. Principal component analysis and clustering of the fingerprints permits the easy separation of active from inactive binding modes and the visualization of diverse binding modes.
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In a well-established model of postmenopausal RA, the raloxifene analog LY117018 potently inhibits the progression of arthritis and the associated development of osteoporosis, both in a prophylactic and in a therapeutic regimen. Since long-term HRT has been associated with significant side effects, raloxifene may be a useful adjuvant treatment for postmenopausal RA.
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The efficacy of estrogen therapy may be modified in women who smoke because of increased catabolism of estrogen and the interaction of tobacco products with the estradiol receptor. We examined whether the efficacy of raloxifene differed in smoking vs. nonsmoking women. We compared change in bone mineral density and biochemical markers of bone turnover, and incidence of new vertebral fracture in postmenopausal women of the Multiple Outcomes on Raloxifene Efficacy trial, who were randomized to either raloxifene (60 or 120 mg/d) or placebo. In the 17% of women who were current smokers, we found, compared with nonsmokers, lowered baseline trochanter bone mineral density (0.540 vs. 0.557 g/cm(2); P < 0.001) and serum osteocalcin (24.8 vs. 26.6 ng/liter; P < 0.001). Baseline urinary type I collagen breakdown products was increased among smokers (291.8 vs. 276.9 micromol/liter; P = 0.04). Body mass index was also lower in smokers (24.3 vs. 25.4; P < 0.001). After 6 months of treatment, there was no significant difference in reduction of bone turnover between smokers and nonsmokers. After 4 yr of treatment, the smoking-treatment interaction was not significant between smokers and nonsmokers for the percent increase in femoral neck bone mineral density (P = 0.25), trochanter bone mineral density (P = 0.24), and spine bone mineral density (P = 0.37). The smoking-treatment interaction for reduction in vertebral fracture risk was not significant either [odds ratio for fracture, 0.67 (0.45-0.98) for smokers and 0.56 (0.47-0.68) for nonsmokers; P = 0.44]. These results were not modified after stratification by tertiles of body mass index or when comparing heavy smokers vs. light smokers. We conclude that smoking does not influence the antiosteoporotic effect of raloxifene. This may represent an advantage over estrogen replacement therapy.
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Ultrasound measurement of endometrial thickness on day 11 of both the pretreatment and treatment cycles, surgeon satisfaction (0 to 10, visual analogue scale), and side effects.
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It is well-known that osteoporosis treatment should be discussed from the view point of bone quality, however, in vivo assessment of bone quality is limited only for bone geometry and trabecular microstructure. Hip structure analysis (HSA) is a program to evaluate geometry and biomechanical property using two-dimensional DXA data of proximal femur. In vivo assessment of trabecular microstructure has been realized by the benefit of recent developments of imaging technique and technology, such as high resolution clinical CT and MR. These imaging techniques are going to be applied to assess risk of fracture and efficacy of anti-osteoporotic agents, although their spatial resolution is lower than real trabecular structure.
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Plasma homocysteine levels were not altered in the placebo group. After 12 months, a significant reduction versus baseline in the mean plasma homocysteine level (-16%) was found only in the raloxifene 150-mg group. The mean change in plasma homocysteine levels within this group also was significantly different from the changes versus baseline found in the placebo group (+2%) and the raloxifene 60-mg group (-2%), but not different from those found in the CEE group (-8%). After 24 months, plasma homocysteine levels were decreased significantly in the raloxifene 150-mg and CEE groups compared with both baseline (-13% and -10%, respectively) and placebo values (-15% and -11%, respectively). No significant change in plasma homocysteine levels was observed in the raloxifene 60-mg group.
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Selective estrogen receptor modulators (SERMs) mimic estrogen action in certain tissues while opposing it in others. The therapeutic effectiveness of SERMs such as tamoxifen and raloxifene in breast cancer depends on their antiestrogenic activity. In the uterus, however, tamoxifen is estrogenic. Here, we show that both tamoxifen and raloxifene induce the recruitment of corepressors to target gene promoters in mammary cells. In endometrial cells, tamoxifen, but not raloxifene, acts like estrogen by stimulating the recruitment of coactivators to a subset of genes. The estrogen-like activity of tamoxifen in the uterus requires a high level of steroid receptor coactivator 1 (SRC-1) expression. Thus cell type- and promoter-specific differences in coregulator recruitment determine the cellular response to SERMs.
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There may be an association between raloxifene and the development of malignant mixed mesodermal tumor. Special attention should be paid when attempting to sample the endometrium in patients with mullerian abnormalities.
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Raloxifene, a selective estrogen receptor modulator, improves cardiovascular risk factors, but its effect on cardiovascular events is unknown.
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Forty-two postmenopausal women with osteoporosis on raloxifene were randomized to raloxifene alone or 1-34PTH daily for 12 months (continuing raloxifene). Women were then followed for 12 months on raloxifene alone. Bone turnover markers and BMD were measured at baseline and at 3, 6, 12, 18 and 24 months.
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We retrieved thirteen electronic databases, read the titles and abstracts to exclude ineligible articles, and then read the full text and references to form a basis for decisions using the inclusion criteria. If full text was not available, we asked the author for a copy of the article. After the data were extracted and recorded, the research quality was evaluated by two authors using the Jadad score and Cochrane handbook.
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The modulatory effects of E(2) and R at therapeutic doses on GH action are different. R during GH therapy exerts a greater inhibitory effect on lipid oxidation and protein anabolism compared to E(2).
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In recent years, the question of whether breast cancer can be prevented has been examined in a number of large clinical trials, employing either selective estrogen receptor modifiers such as tamoxifen and raloxifene or aromatase inhibitors. In this paper, we review the most prominent studies, all of which are either under way or in follow-up.
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Co-administration of apigenin with raloxifene in a 1:2 ratio by weight resulted in a 55% and 37% increase in the C(max) and AUC of intact raloxifene, respectively. When equal proportions of raloxifene and apigenin (1:1) were administered, the C(max) and AUC of intact raloxifene were increased by 173% and 97% respectively. This increase in intact raloxifene was not associated with an increase in total raloxifene (intact plus conjugated raloxifene) because AUC and C(max) of total raloxifene when administered alone or in combination with apigenin were found to be similar. The results indicated that apigenin inhibited the glucuronidation and sulfation of raloxifene in the intestine bringing about an increased bioavailability of the drug.
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Tamoxifen was approved for breast cancer prevention in October 1998. Thus, for the first time, we as gynecologists are being asked to prescribe this drug to healthy women. In the past each one of us has cared for women with breast cancer who have been treated with tamoxifen by oncologists or breast surgeons for the malignancy. Effects of tamoxifen on the uterus resulting in carcinomas, hyperplasia, and polyps are well known. Furthermore, tamoxifen has estrogenic properties in the venous system, increasing the incidence of deep vein thrombosis and pulmonary emboli. A new SERM (selective estrogen receptor modulator), raloxifene, has been approved for prevention and treatment of osteoporosis in postmenopausal women. It does not have stimulatory effects on the endometrium; however, it is estrogenic in the venous system. Preclinical data, as well as the breast cancer incidence reported in studies of the skeleton, seem to indicate that its effects in the breast are similar to those of tamoxifen. This article reviews tamoxifen and the new SERM, raloxifene, in an attempt to help gynecologists better understand each compound and what data are currently known, what we hope to learn from future studies, and what currently makes sense for clinical practice.
Recent studies have shown that the antiestrogens tamoxifen and raloxifene may protect against breast cancer, presumably because of a blockade of estrogen receptor (ER)-mediated transcription. Another possible explanation is that antiestrogen-liganded ER transcriptionally induces genes that are protective against cancer. We previously reported that antiestrogen-liganded ERbeta transcriptionally activates the major detoxifying enzyme quinone reductase (QR) [NAD(P)H:quinone oxidoreductase]. It has been established that metabolites of estrogen, termed catecholestrogens, can form DNA adducts and cause oxidative DNA damage. We hypothesize that QR inhibits estrogen-induced DNA damage by detoxification of reactive catecholestrogens. We report here that physiological concentrations of 17beta-estradiol cause oxidative DNA damage, as measured by levels of 8- hydroxydeoxyguanine, in ER-positive MCF7 breast cancer cells, MDA-MB-231 breast cancer cells (ERalpha negative/ERbeta positive) and nontumorigenic MCF10A breast epithelial cells (very low ER), which is dependent on estrogen metabolism. Estrogen-induced 8-hydroxydeoxyguanine was inversely correlated to QR and ERbeta levels and was followed by downstream induction of the DNA repair enzyme XPA. Trans-hydroxytamoxifen, raloxifene, and the pure antiestrogen ICI-182,780 protected against estradiol-mediated damage in breast cancer cells containing ERbeta. This is most likely due to the ability of these antiestrogens to activate expression of QR via ERbeta. We conclude that up-regulation of QR, either by overexpression or induction by tamoxifen, can protect breast cells against oxidative DNA damage caused by estrogen metabolites, representing a possible novel mechanism of tamoxifen prevention against breast cancer.
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Selective estrogen receptor modulators (SERMs) are small molecules that, depending on the end point measured, may either function as estrogen receptor (ER) agonists or antagonize estrogens' agonist activity. A key feature of SERMs is the inhibition of ER agonist action on the uterus and mammary gland, but the degree of antagonism varies among compounds and end points. Bazedoxifene is a SERM that is being clinically evaluated both as a monotherapy for the prevention and treatment of osteoporosis and in combination with conjugated estrogens (CEs) for the treatment of menopausal symptoms and prevention of osteoporosis. The studies reported here compare the relative ER agonist and antagonist effects of three pharmacologically distinct SERMs (bazedoxifene, raloxifene, and lasofoxifene) on the ovariectomized mouse when administered alone or as a tissue-selective estrogen complex, a term used to describe the partnering of a SERM and one or more estrogens. At the minimum dose required to maximally reduce CE-stimulated uterine wet weight increase for each SERM, the degree of inhibition varied among the SERMs, with a rank order of bazedoxifene approximately raloxifene > lasofoxifene, in which only bazedoxifene was statistically similar to vehicle. In the mammary gland, in which amphiregulin mRNA and morphological effects were measured, bazedoxifene generally exhibited less agonist activity and was a more effective antagonist of CE than raloxifene or lasofoxifene. In summary, in an animal model evaluating estrogen-modulated uterine effects and mammary gland development, bazedoxifene exhibited less ER agonist activity than raloxifene or lasofoxifene, and, as a tissue-selective estrogen complex, bazedoxifene/CE demonstrated less mammary gland stimulation than raloxifene/CE and lasofoxifene/CE.
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Hormone replacement therapy (HRT) with estrogens (in non-hysterectomized women with estrogens and progestins) during the peri- and postmenopausal period has been widely applied for many years. On the basis of new data, HRT is currently being critically reviewed. HRT administered for up to 5 years to treat climacteric hot flashes, mood changes and sleep disturbances continues to be advocated and is largely safe. When HRT is used for longer periods, as required for the prevention of osteoporosis, a possible increase in the relative risk for breast cancer must be considered. Correctly applied in combination with an adequate dose of progestins, HRT can avoid an increase in the endometrial cancer risk. HRT is no longer recommended for secondary prevention of cardiovascular disease, and its use in primary prevention has not been convincingly demonstrated. The hoped-for efficacy of HRT in the prevention of Alzheimer's disease has not been confirmed by the data. Selective estrogen receptor modulators (e.g. Raloxifene) and biphosphonates are efficacious drugs for the prevention and treatment of osteoporosis. For women at risk of developing cardiovascular disease, changes in lifestyle, lipid-lowering drugs (statins), blood pressure control, use of acetylsalicylic acid, among others, have well-documented efficacy in primary and secondary prevention.
A comparison between the atheroprotective and osteoprotective effects of the selective estrogen receptor modulator (SERM) raloxifene and those of hormone replacement therapy (HRT) has not been made in elderly women.
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The acetylcholine-induced responses obtained in the OVX were lower than those obtained in the SHAM, and all treatments restored this response. l-NAME reduced and equalized the acetylcholine-induced response in all groups. The attenuation of the acetylcholine-induced responses by aminoguanidine was greater in the OVX. Endothelial dysfunction in OVX was associated with oxidative stress and an increase in iNOS and decrease in eNOS expression. Except for the production of reactive oxidative species (ROS) in the OVX+tamoxifen, treatments improved the nitric oxide component of the relaxation response and normalized both the oxidative stress and the expression of those signaling pathway enzymes. Serum levels of TNF-α and IL-6 were increased in OVX, and treatments normalized these levels.
There were no significant differences in the baseline characteristics between study groups. In comparison with raloxifene, follicle-stimulating hormone levels decreased significantly more in the 90-mg ospemifene group and sex hormone-binding globulin levels increased more in all ospemifene groups. Total cholesterol and low-density lipoprotein cholesterol levels decreased more in raloxifene than in ospemifene groups, although the difference in low-density lipoprotein cholesterol between 90-mg ospemifene and raloxifene was not significant. Endometrial thickness did not change in any study group and endometrial biopsies showed atrophy in the majority of subjects at 3 months. All ospemifene groups demonstrated a clear estrogenic effect on the vaginal epithelium, as seen in Pap smears. This was in sharp contrast to the raloxifene group, which had no effect on the vaginal epithelium. Kupperman index decreased in all study groups during treatment. The adverse events were mild, mainly single cases, and no clustering of events was observed. There were no clinically significant abnormal findings in laboratory safety parameters.
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While breast cancer risk can be calculated with a fair degree of accuracy, its impact on women's choices about chemoprevention is likely best assessed in tandem with women's feelings about developing breast cancer, whether within the context of a clinical trial or not.
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Postmenopausal women with prevalent vertebral fractures had greater prevalence of depressive symptoms and probable depression as assessed by the GDS than women without vertebral fracture with low BMD. The dual diagnosis of depression and osteoporosis may mean worse health outcomes. Patients with prevalent vertebral fractures may be considered not only for interventions that address fracture risk reduction, but also for psychosocial interventions that address depressive symptoms.
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Although an increased risk of femoral shaft and subtrochanteric fractures are seen with the use of several types of bisphosphonates, the increased risk before the start of the drugs may point at an effect of the underlying disease being treated. The increased risk may, thus, perhaps be due to confounding by indication.
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In elderly women with osteoporosis, raloxifene treatment with vitamin D supplementation improves vaginal maturation index and vaginal pH.