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Climacteric : the Journal of the... Dec 2012Selective estrogen receptor modulators (SERMs), which exhibit estrogen receptor agonist or antagonist activity based on the target tissue, have evolved through multiple... (Review)
Review
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.
Topics: Aged; Aged, 80 and over; Bone Density; Bone Density Conservation Agents; Breast Neoplasms; Endometrial Neoplasms; Female; Fractures, Bone; Hot Flashes; Humans; Indoles; Middle Aged; Osteoporosis, Postmenopausal; Pyrrolidines; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Spinal Fractures; Tetrahydronaphthalenes
PubMed: 22853318
DOI: 10.3109/13697137.2012.688079 -
Connective Tissue Research Jan 2022Raloxifene (RAL) is a selective estrogen receptor modulator (SERM) that has previously been shown to cause acellular benefits to bone tissue. Due to these improvements,...
Raloxifene (RAL) is a selective estrogen receptor modulator (SERM) that has previously been shown to cause acellular benefits to bone tissue. Due to these improvements, RAL was combined with targeted tibial loading to assess if RAL treatment during periods of active bone formation would allow for further mechanical enhancements. Structural, mechanical, and microstructural effects were assessed in bone from C57BL/6 mice that were treated with RAL (0.5 mg/kg), tibial loading, or both for 6 weeks, beginning at 10 weeks of age. microcomputed tomography (CT) images indicated RAL and loading work together to improve bone mass and architecture, especially within the cancellous region of males. Increases in cancellous bone volume fraction were heavily driven by increases in trabecular thickness, though there were some effects on trabecular spacing and number. In the cortical regions, RAL and loading both increased cross-sectional area, cortical area, and cortical thickness. Whole-bone mechanical testing primarily indicated the effects of loading. Further characterization through Raman spectroscopy and nanoindentation showed load-based changes in mineralization and micromechanics, while both loading and RAL caused changes in the secondary collagen structure. In contrast to males, in females, there were large load-based effects in the cancellous and cortical regions, resulting in increased whole-bone mechanical properties. RAL had less of an effect on cancellous and cortical architecture, though some effects were still present. RAL and loading work together to impact bone architecture and mechanical integrity, leading to greater improvements than either treatment individually.
Topics: Animals; Bone Density; Female; Male; Mice; Mice, Inbred C57BL; Raloxifene Hydrochloride; Tibia; X-Ray Microtomography
PubMed: 33427519
DOI: 10.1080/03008207.2020.1865938 -
Annals of Internal Medicine Mar 1999To review clinical data on raloxifene hydrochloride, a selective estrogen receptor modulator that was recently approved for the prevention of osteoporosis in... (Comparative Study)
Comparative Study Review
PURPOSE
To review clinical data on raloxifene hydrochloride, a selective estrogen receptor modulator that was recently approved for the prevention of osteoporosis in postmenopausal women.
DATA SOURCES
English-language articles published from 1980 to May 1998 were identified through MEDLINE searches. Bibliographies, book chapters, and meeting abstracts were reviewed for additional relevant publications.
STUDY SELECTION
Publications that contained information on the background of development, structure, mechanism of action, tissue-selective effects, and adverse effects of raloxifene hydrochloride were included.
DATA EXTRACTION
Data in selected articles were reviewed, and relevant clinical information was extracted.
DATA SYNTHESIS
Raloxifene hydrochloride was developed in an effort to find a treatment for breast cancer and osteoporosis. It binds to the estrogen receptor and shows tissue-selective effects; thus, it belongs to a class of drugs recently described as selective estrogen receptor modulators. Tissue selectivity of raloxifene may be achieved through several mechanisms: the ligand structure, interaction of the ligand with different estrogen receptor subtypes in various tissues, and intracellular events after ligand binding. Raloxifene has estrogen-agonistic effects on bone and lipids and estrogen-antagonistic effects on the breast and uterus. An increase in bone mineral density at the spine, total hip, and total body has been reported with raloxifene but seems to be less than that seen with estrogen or alendronate therapy. Raloxifene has been shown to produce a reduction in total and low-density lipoprotein cholesterol concentrations similar to that produced by estrogen therapy, but high-density lipoprotein cholesterol and triglyceride concentrations do not increase during raloxifene therapy. In the uterus, raloxifene does not stimulate the endometrium. Long-term data on the effects of raloxifene in reduction of risk for fracture; prevention of cardiovascular events; cognitive function; and the incidence of breast, ovarian, and uterine cancer are not available. The most common adverse effect of raloxifene is hot flashes.
CONCLUSIONS
Raloxifene has been shown to have beneficial effects in selected organs in postmenopausal women. Although estrogen remains the drug of choice for hormonal therapy in most postmenopausal women, raloxifene may be an alternative in certain groups of women at risk for osteoporosis.
Topics: Animals; Estrogen Antagonists; Estrogens; Female; Humans; Molecular Structure; Osteoporosis, Postmenopausal; Piperidines; Raloxifene Hydrochloride; Receptors, Estrogen
PubMed: 10068418
DOI: 10.7326/0003-4819-130-5-199903020-00015 -
Expert Opinion on Pharmacotherapy May 2013Osteoporosis is a common disease characterized by the occurrence of fragility fractures. Major osteoporotic fractures are associated with decreased quality of life and... (Review)
Review
INTRODUCTION
Osteoporosis is a common disease characterized by the occurrence of fragility fractures. Major osteoporotic fractures are associated with decreased quality of life and high costs.
AREAS COVERED
This review summarizes clinical data on raloxifene (RLX), a second generation selective estrogen-receptor modulator (SERM), currently approved for the treatment of postmenopausal osteoporosis. RLX has estrogen effects on bone and lipid profile, whereas it has anti-estrogen effects on uterus and breast cells. Its main side effects are hot flushes and venous thromboembolism. Literature searches were conducted to retrieve articles reporting RLX clinical trial data. For comparison of safety and efficacy, post-marketing studies on RLX were included.
EXPERT OPINION
RLX is effective in reducing vertebral fracture risk in osteoporotic women, it is safe and its ability to prevent breast cancer has to be considered in the analyses of cost/effect and of the ideal candidate to this treatment. RLX has to be avoided in patients with previous history of venous thromboembolism.
Topics: Bone Density Conservation Agents; Breast Neoplasms; Clinical Trials as Topic; Cost-Benefit Analysis; Female; Humans; Osteoporosis, Postmenopausal; Osteoporotic Fractures; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Spinal Fractures
PubMed: 23521229
DOI: 10.1517/14656566.2013.782002 -
European Spine Journal : Official... Dec 2012Raloxifene is the first selective estrogen receptor modulator that has been approved for the treatment and prevention of osteoporosis in postmenopausal women in Europe... (Review)
Review
BACKGROUND/AIM
Raloxifene is the first selective estrogen receptor modulator that has been approved for the treatment and prevention of osteoporosis in postmenopausal women in Europe and in the US. Although raloxifene reduces the risk of invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk for invasive breast cancer, it is approved in that indication in the US but not in the EU. The aim was to characterize the clinical profiles of postmenopausal women expected to benefit most from therapy with raloxifene based on published scientific evidence to date.
METHODS
Key individual patient characteristics relevant to the prescription of raloxifene in daily practice were defined by a board of Swiss experts in the fields of menopause and metabolic bone diseases and linked to published scientific evidence. Consensus was reached about translating these insights into daily practice.
RESULTS
Through estrogen agonistic effects on bone, raloxifene reduces biochemical markers of bone turnover to premenopausal levels, increases bone mineral density (BMD) at the lumbar spine, proximal femur, and total body, and reduces vertebral fracture risk in women with osteopenia or osteoporosis with and without prevalent vertebral fracture. Through estrogen antagonistic effects on breast tissue, raloxifene reduces the risk of invasive estrogen-receptor positive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk for invasive breast cancer. Finally, raloxifene increases the incidence of hot flushes, the risk of venous thromboembolic events, and the risk of fatal stroke in postmenopausal women at increased risk for coronary heart disease. Postmenopausal women in whom the use of raloxifene is considered can be categorized in a 2 × 2 matrix reflecting their bone status (osteopenic or osteoporotic based on their BMD T-score by dual energy X-ray absorptiometry) and their breast cancer risk (low or high based on the modified Gail model). Women at high risk of breast cancer should be considered for treatment with raloxifene.
CONCLUSION
Postmenopausal women between 50 and 70 years of age without climacteric symptoms with either osteopenia or osteoporosis should be evaluated with regard to their breast cancer risk and considered for treatment with raloxifene within the framework of its contraindications and precautions.
Topics: Aged; Breast Neoplasms; Female; Humans; Middle Aged; Osteoporosis, Postmenopausal; Raloxifene Hydrochloride; Risk Factors; Selective Estrogen Receptor Modulators; Switzerland
PubMed: 22739699
DOI: 10.1007/s00586-012-2404-y -
Annals of Internal Medicine Apr 2013Medications to reduce risk for primary breast cancer are recommended for women at increased risk; however, use is low. (Review)
Review
BACKGROUND
Medications to reduce risk for primary breast cancer are recommended for women at increased risk; however, use is low.
PURPOSE
To update evidence about the effectiveness and adverse effects of medications to reduce breast cancer risk, patient use of such medications, and methods for identifying women at increased risk for breast cancer.
DATA SOURCES
MEDLINE and Cochrane databases (through 5 December 2012), Scopus, Web of Science, clinical trial registries, and reference lists.
STUDY SELECTION
English-language randomized trials of medication effectiveness and adverse effects, observational studies of adverse effects and patient use, and diagnostic accuracy studies of risk assessment.
DATA EXTRACTION
Investigators independently extracted data on participants, study design, analysis, follow-up, and results, and a second investigator confirmed key data. Investigators independently dual-rated study quality and applicability using established criteria.
DATA SYNTHESIS
Seven good- and fair-quality trials indicated that tamoxifen and raloxifene reduced incidence of invasive breast cancer by 7 to 9 cases in 1000 women over 5 years compared with placebo. New results from STAR (Study of Tamoxifen and Raloxifene) showed that tamoxifen reduced breast cancer incidence more than raloxifene by 5 cases in 1000 women. Neither reduced breast cancer-specific or all-cause mortality rates. Both reduced the incidence of fractures, but tamoxifen increased the incidence of thromboembolic events more than raloxifene by 4 cases in 1000 women. Tamoxifen increased the incidence of endometrial cancer and cataracts compared with placebo and raloxifene. Trials provided limited and heterogeneous data on medication adherence and persistence. Many women do not take tamoxifen because of associated harms. Thirteen risk-stratification models were modest predictors of breast cancer.
LIMITATION
Data on mortality and adherence measures and for women who are nonwhite, are premenopausal, or have comorbid conditions were lacking.
CONCLUSION
Medications reduced the incidence of invasive breast cancer and fractures and increased the incidence of thromboembolic events. Tamoxifen was more effective than raloxifene but also increased the incidence of endometrial cancer and cataracts. Use is limited by adverse effects and inaccurate methods to identify candidates.
PRIMARY FUNDING SOURCE
Agency for Healthcare Research and Quality.
Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Cataract; Endometrial Neoplasms; Female; Fractures, Bone; Humans; Medication Adherence; Patient Participation; Raloxifene Hydrochloride; Risk Assessment; Tamoxifen; Thromboembolism; Treatment Outcome
PubMed: 23588749
DOI: 10.7326/0003-4819-158-8-201304160-00005 -
Clinical Interventions in Aging 2014To systematically review the literature describing the efficacy, effectiveness, and safety of raloxifene for postmenopausal Japanese women with osteoporosis or low bone... (Review)
Review
PURPOSE
To systematically review the literature describing the efficacy, effectiveness, and safety of raloxifene for postmenopausal Japanese women with osteoporosis or low bone mass (osteopenia).
MATERIALS AND METHODS
Medline via PubMed and Embase was systematically searched using prespecified terms. Retrieved publications were screened and included if they described randomized controlled trials or observational studies of postmenopausal Japanese women with osteoporosis or osteopenia treated with raloxifene and reported one or more outcome measures (change in bone mineral density [BMD]; fracture incidence; change in bone-turnover markers, hip structural geometry, or blood-lipid profile; occurrence of adverse events; and change in quality of life or pain). Excluded publications were case studies, editorials, letters to the editor, narrative reviews, or publications from non-peer-reviewed journals; multidrug, multicountry, or multidisease studies with no drug-, country-, or disease-level analysis; or studies of participants on dialysis.
RESULTS
Of the 292 publications retrieved, 15 publications (seven randomized controlled trials, eight observational studies) were included for review. Overall findings were statistically significant increases in BMD of the lumbar spine (nine publications), but not the hip region (eight publications), a low incidence of vertebral fracture (three publications), decreases in markers of bone turnover (eleven publications), improved hip structural geometry (two publications), improved blood-lipid profiles (five publications), a low incidence of hot flushes, leg cramps, venous thromboembolism, and stroke (12 publications), and improved quality of life and pain relief (one publication).
CONCLUSION
Findings support raloxifene for reducing vertebral fracture risk by improving BMD and reducing bone turnover in postmenopausal Japanese women with osteoporosis or osteopenia. Careful consideration of fracture risk and the risk-benefit profile of antiosteoporosis medications is required when managing patients with osteoporosis.
Topics: Aged; Aged, 80 and over; Biomarkers; Bone Density; Bone Density Conservation Agents; Bone Diseases, Metabolic; Female; Fractures, Bone; Hip Joint; Humans; Lipids; Lumbar Vertebrae; Middle Aged; Osteoporosis, Postmenopausal; Quality of Life; Raloxifene Hydrochloride; Randomized Controlled Trials as Topic
PubMed: 25395843
DOI: 10.2147/CIA.S70307 -
BMJ Clinical Evidence May 2011The lifetime risk of fracture in white women is 20% for the spine, 15% for the wrist, and 18% for the hip, with an exponential increase in risk beyond the age of 50... (Review)
Review
INTRODUCTION
The lifetime risk of fracture in white women is 20% for the spine, 15% for the wrist, and 18% for the hip, with an exponential increase in risk beyond the age of 50 years.
METHODS AND OUTCOMES
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of bisphosphonates to prevent fractures in postmenopausal women? What are the effects of pharmacological treatments other than bisphosphonates to prevent fractures in postmenopausal women? What are the effects of non-pharmacological treatments to prevent fractures in postmenopausal women? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
RESULTS
We found 71 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
CONCLUSIONS
In this systematic review we present information relating to the effectiveness and safety of the following interventions: alendronate, calcitonin, calcium, calcium plus vitamin D, clodronate, denosumab, etidronate, exercise, hip protectors, hormone replacement therapy, ibandronate, multifactorial non-pharmacological interventions, pamidronate, parathyroid hormone, raloxifene, risedronate, strontium ranelate, vitamin D, vitamin D analogues, and zoledronate.
Topics: Administration, Oral; Alendronate; Bone Density Conservation Agents; Calcium, Dietary; Etidronic Acid; Evidence-Based Medicine; Female; Fractures, Bone; Humans; Incidence; Postmenopause; Raloxifene Hydrochloride
PubMed: 21542947
DOI: No ID Found -
Calcified Tissue International Mar 2023Thermoneutral housing and Raloxifene (RAL) treatment both have potential for improving mechanical and architectural properties of bone. Housing mice within a 30 to...
Thermoneutral housing and Raloxifene (RAL) treatment both have potential for improving mechanical and architectural properties of bone. Housing mice within a 30 to 32 °C range improves bone quality by reducing the consequences of cold stress, such as shivering and metabolic energy consumption (Chevalier et al. in Cell Metab 32(4):575-590.e7, 2020; Martin et al. in Endocr Connect 8(11):1455-1467, 2019; Hankenson et al. in Comp Med 68(6):425-438, 2018). Previous work suggests that Raloxifene can enhance bone strength and geometry (Ettinger et al. in Jama 282(7):637-645, 1999; Powell et al. in Bone Rep 12:100246, 2020). An earlier study in our lab utilized long bones to examine the effect of thermoneutral housing and Raloxifene treatment in mice, but no significant interactive effects were found. The lack of an impact is hypothesized to be connected to the short 6-week duration of the study and the type of bone analyzed. This study will examine the same question within the axial skeleton, which has a higher proportion of trabecular bone. After 6 weeks of treatment with RAL, vertebrae from female C57BL/6 J mice underwent microcomputed tomography (μCT), architectural analysis, and compression testing. Most of the tested geometric properties (bone volume/tissue volume percent, trabecular thickness, trabecular number, trabecular spacing) improved with both the housing and RAL treatment. The effect sizes suggested an additive effect when treating mice housed under thermoneutral conditions. While ultimate force was enhanced with the treatment and housing, force normalized by bone volume fraction was not significantly different between groups. For longer pre-clinical trials, it may be important to consider the impacts of temperature on mice to improve the accuracy of these models.
Topics: Mice; Female; Animals; Raloxifene Hydrochloride; Cancellous Bone; X-Ray Microtomography; Housing; Mice, Inbred C57BL; Bone Density
PubMed: 36371724
DOI: 10.1007/s00223-022-01038-z -
BioMed Research International 2013Raloxifene hydrochloride (RL-HCL) is an orally selective estrogen receptor modulator (SERM) with poor bioavailability of nearly 2% due to its poor aqueous solubility and...
Raloxifene hydrochloride (RL-HCL) is an orally selective estrogen receptor modulator (SERM) with poor bioavailability of nearly 2% due to its poor aqueous solubility and extensive first pass metabolism. In order to improve the oral bioavailability of raloxifene, raloxifene loaded solid lipid nanoparticles (SLN) have been developed using Compritol 888 ATO as lipid carrier and Pluronic F68 as surfactant. Raloxifene loaded SLN were prepared by solvent emulsification/evaporation method, and different concentrations of surfactant, and homogenization speed were taken as process variables for optimization. SLN were characterized for particle size, zeta potential, entrapment efficiency, surface morphology, and crystallinity of lipid and drug. In vitro drug release studies were performed in phosphate buffer of pH 6.8 using dialysis bag diffusion technique. Particle sizes of all the formulations were in the range of 250 to 1406 nm, and the entrapment efficiency ranges from 55 to 66%. FTIR and DSC studies indicated no interaction between drug and lipid, and the XRD spectrum showed that RL-HCL is in amorphous form in the formulation. In vitro release profiles were biphasic in nature and followed Higuchi model of release kinetics. Pharmacokinetics of raloxifene loaded solid lipid nanoparticles after oral administration to Wistar rats was studied. Bioavailability of RL-HCL loaded SLN was nearly five times than that of pure RL-HCL.
Topics: Animals; Biological Availability; Delayed-Action Preparations; Drug Evaluation, Preclinical; Estrogen Antagonists; Male; Nanoparticles; Raloxifene Hydrochloride; Rats; Rats, Wistar
PubMed: 24228255
DOI: 10.1155/2013/584549