The Combination Sorafenib-raloxifene-loratadine as a Novel Potential Therapeutic Approach Against Human Liver Cancer.

BACKGROUND/AIM: Liver cancer is one of the malignancies with the highest mortality-to-incidence ratio worldwide. Therefore, novel therapeutic approaches are urgently needed. Combination therapy and drug repurposing can improve the response of the patients to therapy in several cancers. The aim of the present study was to merge these two strategies and evaluate whether the two-drug- or three-drug- combination of sorafenib, raloxifene, and loratadine improves the antineoplastic effect on human liver cancer cells in comparison to the single-drug effect. MATERIALS AND METHODS: The human liver cancer cell lines HepG2 and HuH7 were studied. The effect of sorafenib, raloxifene, and loratadine on the metabolic activity was determined using the MTT assay. The inhibitory concentrations (IC20 and IC50) were calculated from these results and used in the drug-combination experiments. Apoptosis and cell survival were studied by flow cytometry and using the colony formation assay, respectively. RESULTS: In both cell lines, sorafenib, raloxifene, and loratadine in two-drug and three-drug combinations significantly reduced metabolic activity and significantly increased the percentage of apoptotic cells compared to the single-drug effect. In addition, all the combinations significantly reduced the colony-forming capacity in the HepG2 cell line. Surprisingly, the effect of raloxifene on apoptosis was similar to that observed using the combinations. CONCLUSION: The triple combination sorafenib-raloxifene-loratadine may be a novel promising approach in the treatment of liver cancer patients.

Treating osteoporosis: risks and management.

Osteoporosis, osteopenia and minimal trauma fractures are becoming increasingly common in the ageing population. Fractures cause increases in morbidity and mortality and have a significant financial impact on the healthcare system and society Addressing risk factors for osteoporosis early may prevent or delay the onset of fractures and use of drugs. Calcium and vitamin D supplementation may benefit people with a high risk of deficiency (e.g. institutionalised older people) but may not be required in people without risk factors. Impact and resistance exercises and physical activity can increase bone density and prevent falls Antiresorptive drugs such as bisphosphonates and denosumab remain first-line treatment options for osteoporosis. The ongoing need for bisphosphonates should be assessed after five years and treatment may then be interrupted in some patients. Progressive bone loss will recur slowly. Denosumab therapy should not be interrupted without switching to another therapy, as post-treatment bone loss can progress rapidly. All patients will need ongoing monitoring and most will require some long-term therapy once started Raloxifene may be considered in women who do not tolerate first-line antiresorptive drugs. Romosozumab is a new anabolic treatment for osteoporosis and, together with teriparatide, is subsidised as second-line therapy for individuals with severe disease and multiple fractures. Specialist referral should be considered for patients who sustain fractures while undergoing osteoporosis therapy.

Pros and Cons of Skeletal Medications in the COVID-19 Era.

Purpose of Review: This review provides an overview regarding osteoporosis therapies during the COVID-19 pandemic. Recent Findings: The COVID-19 pandemic has disrupted treatments for osteoporosis and resulted in decreased adherence particularly for parenteral regimens. Osteoporosis medications are safe and effective during the pandemic and should be continued whenever possible. Bisphosphonates have long-lasting effects on bone turnover such that delays in their administration are unlikely to be harmful to skeletal health. In contrast, interruption of denosumab treatment is strongly discouraged because of rapid loss of bone mass and an associated increased risk for rebound vertebral fractures. When osteoanabolic treatments cannot be continued during the pandemic, change to an oral bisphosphonate is advised. Preclinical data suggest possible beneficial effects of some therapies against COVID-19, but require validation in clinical studies. Vitamin D deficiency is associated with a more severe COVID-19 clinical course but data supporting improvements in outcomes with vitamin D supplementation are lacking. Summary: The impact of the COVID-19 pandemic on long-term bone health remains unknown but focused interventions to ensure osteoporosis treatment initiation/maintenance should be implemented. Future studies are needed to determine whether osteoporosis medications have an impact on SARS-CoV-2 pathophysiology and COVID-19 clinical outcomes.

Turning scientific serendipity into discoveries in breast cancer research and treatment: a tale of PhD students and a 50-year roaming tamoxifen team.

PURPOSE: This retrospective, about a single "mobile" laboratory in six locations on two continents, is intended as a case study in discovery for trainees and junior faculty in the medical sciences. Your knowledge of your topic is necessary to expect the unexpected. HISTORICAL METHOD: In 1972, there was no tamoxifen, only ICI 46, 474, a non-steroidal anti-estrogen with little chance of clinical development. No one would ever be foolish enough to predict that the medicine, 20 years later, would achieve legendary status as the first targeted treatment for breast cancer, and millions of women would benefit from long-term adjuvant tamoxifen therapy. The secret of tamoxifen's success was a translational research strategy proposed in the mid 1970's. This strategy was to treat only patients with estrogen receptor (ER)-positive breast cancer and deploy 5 or more years of adjuvant tamoxifen therapy to prevent recurrence. Additionally, tamoxifen prevented mammary cancer in animals. Could the medicine prevent breast cancer in women? RESULTS: Tamoxifen and the failed breast cancer drug raloxifene became the first selective estrogen receptor modulators (SERMs): a new drug group, discovered at the University of Wisconsin, Comprehensive Cancer Center. Serendipity can play a fundamental role in discovery, but there must be a rigorous preparation for the investigator to appreciate the possibility of a pending discovery. This article follows the unanticipated discoveries when PhD students "get the wrong answer." The secret of success of my six Tamoxifen Teams was their technical excellence to create models, to decipher mechanisms, that drove the development of new medicines. Discoveries are listed that either changed women's health or allowed an understanding of originally opaque mechanisms of action of potential therapies. These advances in women's health were supported entirely by government-sponsored peer-reviewed funding and major philanthropy from the Lynn Sage Breast Cancer Foundation, the Avon Foundation, and the Susan G. Komen Breast Cancer Foundation. The resulting lives saved or extended, families aided in a time of crisis and the injection of billions of dollars into national economies by drug development, is proof of the value of Federal or philanthropic investment into unencumbered research aimed at saving millions of lives.

Raloxifene, identified as a novel LSD1 inhibitor, suppresses the migration of renal cell carcinoma.

Aim: As an important epigenetic modulator, histone lysine-specific demethylase 1 (LSD1) has been proved to be associated with the progression of renal cell carcinoma (RCC). Discovering novel LSD1 inhibitors offers therapeutic potential for RCC treatment. Methods & Results: We identified raloxifene as a novel LSD1 inhibitor (IC50 = 2.08 µM) through small compound library screening. Molecular docking indicated raloxifene might bind LSD1 in the flavin adenine dinucleotide (FAD) binding cavity in a reversible manner. Cell viability and migration assays showed raloxifene could suppress the proliferation and migration of RCC cells bearing overexpressed LSD1. Conclusion: Our findings indicated that LSD1 might be a promising therapeutic target for RCC and that raloxifene could serve as a lead compound for further anti-RCC metastasis drug discovery.

Evaluation of inhibitors of intestinal UDP-glucuronosyltransferases 1A8 and 1A10 using raloxifene as a substrate in Caco-2 cells: Studies with four flavonoids of Scutellaria baicalensis.

UDP glucuronosyltransferases (UGTs) of the gastrointestinal tract play a crucial role in protection against the toxic effects of xenobiotics in the environment. UGTs such as UGT1A8 and UGT1A10 are predominantly expressed in gastrointestinal tissues. In this study, we examined the phase II metabolism of raloxifene in differentiated Caco-2 monolayers by inducing UGT1A8 and UGT1A10 expression in these cells. The present study evaluated the following four flavonoids of Scutellaria baicalensis as model herbal compounds: scutellarein, salvigenin, baicalein, and wogonin. All test compounds, endpoint substrates, and their metabolites were quantified using liquid chromatography and high-resolution mass spectrometry. The transepithelial electrical resistance values for the individual compounds were comparable regardless of whether they were measured individually. Salvigenin significantly inhibited UGT1A8 and UGT1A10 activities in a concentration-dependent manner. All individual compounds except scutellarein inhibited UGT1A8 and UGT1A10 activity at a concentration of 100 µM. In addition, all individual flavonoids at 100 µM, except wogonin, significantly increased the amount of raloxifene in the basolateral chambers. The positive control, canagliflozin, significantly inhibited both UGT1A8 and UGT1A10 activities. These findings suggest that the Caco-2 assay can be utilized for identifying UGT1A8 and UGT1A10 inhibitors and indicate the potential of salvigenin for enhancing the pharmacological effects of UGT substrate drugs.

Raloxifene is a Female-specific Proteostasis Therapeutic in the Spinal Cord.

Several neurodegenerative disorders are characterized by proteasome dysfunctions leading to protein aggregations and pathogenesis. Since we showed that estrogen receptor alpha (ERα) activates the proteasome, drugs able to stimulate ERα in the central nervous system (CNS) could hold potential for therapeutic intervention. However, the transcriptional effects of selective estrogen receptor modulators (SERMs), such as tamoxifen and raloxifene, can be tissue specific. A direct comparison of the effects of different SERMs on gene transcription in the CNS has never been performed. Here, we report an RNA-seq analysis of the spinal cord treated with estrogen, tamoxifen, or raloxifene. We find stark SERM and sex-specific differences in gene expression profiles in the spinal cord. Notably, raloxifene, but not estrogen or tamoxifen, modulates numerous deubiquitinating enzymes, proteasome subunits and assembly factors, and these effects translate into decreased protein aggregates. In the SOD1-G93A mouse model of amyotrophic lateral sclerosis, we found that even a low dose of raloxifene causes a significant decrease in mutant SOD1 aggregates in the spinal cord, accompanied by a delay in the decline of muscle strength in females, but not in males. These results strongly indicate SERM-selective as well as sex-specific effects, and emphasize the importance of sex as a biological variable to be considered for the careful selection of specific SERM for use in clinical trials for neurodegenerative diseases.

Spray-dried raloxifene submicron particles for pulmonary delivery: Development and in vivo pharmacokinetic evaluation in rats.

Raloxifene hydrochloride (RH) is a selective oestrogen receptor modulator used for the treatment of osteoporosis. Even though 60% of an oral dose is quickly absorbed via the gastrointestinal tract, the absolute bioavailability of RH is only 2-3% in humans due to extensive first-pass metabolism. Various approaches to improve RH bioavailability have been reported over the past few years; however, none have focused on the development of products for pulmonary administration. Therefore, in this study, submicron particles containing RH were produced for pulmonary administration with the aim to limit first-pass metabolism. Powders were produced by vibrational atomisation spray drying with a high process yield (>80%). The drug content was between 440 and 890 mg·g-1, and powders had a high encapsulation efficiency (>95%), mean particle size of 400-700 nm, low residual moisture (<2%) and spherical shape. These powders showed an improved drug dissolution rate compared to the raw RH material. Moreover, they presented high dose uniformity (95-100%), a high in vitro respirable fraction (>55%) and adequate mass median aerodynamic diameter for pulmonary delivery (<5 µm). The pharmacokinetic study in male Wistar rats demonstrated an absolute bioavailability of 47.20% after pulmonary administration of the particles. Therefore, these submicron-sized powders are promising for pulmonary RH delivery as a dry powder medicine.

In-situ forming chitosan implant-loaded with raloxifene hydrochloride and bioactive glass nanoparticles for treatment of bone injuries: Formulation and biological evaluation in animal model.

In-situ forming implants receive great attention for repairing serious bone injuries. The aim of the present study was to prepare novel chitosan in-situ forming implants (CIFI) loaded with bioactive glass nanoparticles and/or raloxifene hydrochloride (RLX). Incorporating raloxifene hydrochloride (RLX) as a selective estrogen receptor modulator was essential to make use of its anti-resorptive properties. The prepared formulae were tested for their in-vitro gelation time, drug release, injectability, rheological properties, erosion rate and morphological properties. Results revealed that the formulation composed of 1% (w/v) chitosan with 2% (w/v) NaHCO3 and 1% (w/v) bioactive glass nanoparticles (CIFI-BG) possessed the most sustained drug release profile which extended over four months with low burst release effect compared to the same formulation lacking bioactive glass nanoparticles (CIFI). Selected formulations were tested for their ability to enhance bone regeneration in induced puncture in rate tibia. Results declared that these formulations were able to enhance bone regeneration after 12 weeks in comparison to the untreated tibial punctures and that containing bioactive glass could be considered as novel approach for treatment of serious bone injuries which require long term treatment and internal mechanical bone support during healing.

Long lasting in-situ forming implant loaded with raloxifene HCl: An injectable delivery system for treatment of bone injuries.

Bone injury is very serious in elder people or osteoporotic patients. In-situ forming implants (IFI) for bone rebuilding are usually poly-lactic-co-glycolic acid (PLGA)-based, which have a burst release effect. This study aimed to prepare novel liquid lipid-based PLGA-IFI loaded with raloxifene hydrochloride for prolonged non-surgical treatment of bone injuries by applying solvent-induced phase inversion technique. Labrasol® and Maisine® were added to the selected IFI forming long lasting lipid-based IFI (LLL-IFI). The formulations were characterized by analysing their in-vitro drug release, solidification time, injectability, rheological properties, and DSC in addition to their morphological properties. Results revealed that the LLL-IFI composed of 10%w/v PLGA with a lactide to glycolide ratio of 75:25 with ester terminal and 10% Maisine® possessed the most sustained drug release and lowest burst effect, as well as delayed pore formation compared to its counterpart lacking Maisine®. The selected LLL-IFI and PLGA-IFI formulations were tested for their capability to enhance bone regeneration in bone injuries induced in rats. Both formulations succeeded in healing the bones completely with the superiority of LLL-IFI in the formation of well-organized bone structures lacking fibrous tissues. The results suggest that LLL-IFI and PLGA-IFI are innovative approaches for treating critical and non-critical sized bone injuries.

Combined administration on You-Gui Yin and low-dose Raloxifene partially attenuates the bone loss in ovariectomized mice through the proliferation and osteogenic differentiation of bone marrow stromal cells.

BACKGROUND: Osteoporosis is a systemic skeletal disease of fragility fractures due to the loss of mass and deterioration of the microarchitecture of bone. PURPOSE: The aim of the study was to assess the osteogenic effects and the underlying mechanisms of the combined administration of You-Gui Yin (YGY) and Raloxifene hydrochloride (RLX) in ovariectomized (OVX) mice. METHODS: First, a classic animal model was used to mimic postmenopausal osteoporosis through the removal of the ovary of mice. Second, the OVX mice were administered YGY, RLX, and YGY + RLX for 12 weeks. Next, the bone microtomographic histomorphometry and bone mineral density (BMD) were assessed by micro-CT, and the biochemical markers of procollagen type I N-terminal propeptide (P1NP) and beta-isomerized C-telopeptide (ß-CTX) in serum were assessed. Finally, primary bone marrow stromal cells (BMSCs) were isolated from the tibia and cultured to evaluate cell proliferation and osteogenic differentiation. RESULTS: The results showed that BMD on the YGY + RLX group was higher than that on the RLX group (p < 0.05) and did not have a significant difference when compared with the sham group. Notably, the YGY + RLX group had a dramatically increased trabecular number (Tb.N) compared with that of the YGY group (p < 0.05). Moreover, the BV/TV (bone volume/total volume) and Tb.N in the YGY + RLX group were higher than that in the RLX group (p < 0.05), and the Tb.Sp (trabecular separation) was lower than that in the RLX group (p < 0.05). Moreover, the serum level of P1NP from the YGY + RLX group dramatically increased when compared with that from the YGY and RLX groups (YGY group: p < 0.05; RLX groups: p < 0.01). Notably, there was no significant difference between the YGY and YGY + RLX groups. In addition, cell proliferation from the co-administration of YGY and RLX was clearly higher than a single use of YGY and RLX (p < 0.01, respectively). The ALP/BCA (alkaline phosphatase/bicinchoninic acid) in the YGY + RLX group was higher than that in the RLX group (p < 0.01). CONCLUSION: Overall, co-administered YGY and RLX could partially attenuate bone loss and were more effective than individually using either one; this outcome might be associated with the proliferation and osteogenic differentiation of BMSCs.

Pharmacotherapy for schizophrenia in postmenopausal women.

INTRODUCTION: Reduced estrogen levels at menopause mean a loss of the neuroprotection that is conferred, from puberty until menopause, on women with schizophrenia. The postmenopausal stage of schizophrenia requires therapeutic attention because women with this diagnosis almost invariably experience increased symptoms and increased side effects at this time. So far, few targeted therapies have been successfully developed. AREAS COVERED: This non-systematic, narrative review is based on the relevant published literature indexed in PubMed. A digital search was combined with a manual check of references from studies in the field of gender differences, menopause and schizophrenia. Aside from the inclusion of a few early classic papers, the review focuses on 21st century basic, psychopharmacologic, and clinical literature on the treatment of women with schizophrenia after menopause. EXPERT OPINION: Beyond a relatively low dose threshold, all antipsychotic medications have adverse effects, which become more prominent for women at the time of menopause. Estrogen modulators may not help all symptoms of schizophrenia but are, nevertheless, relatively safe and, when used as adjuncts, help to keep antipsychotic doses low, thus reducing the side effect burden. The field is currently moving towards precision medicine and individual genetic profiles will help to determine the efficacy of available treatments in the future.

Poly(methyl vinyl ether-co-maleic acid) for enhancement of solubility, oral bioavailability and anti-osteoporotic effects of raloxifene hydrochloride.

Raloxifene HCl (RH) has poor water solubility and due to its extensive first pass metabolism; its bioavailability is only 2%. The purpose of the present study was to enhance the aqueous solubility, oral bioavailability and anti-osteoporotic effects of RH by electro-sprayed nanoparticles (NPs) in ovariectomized rats. NPs containing RH and different ratio of poly(methyl vinyl ether-co-maleic acid) (PMVEMA) were electrosprayed. The voltage, distance of needle to the collector, flow rate of the solution and polymeric percentage were optimized according to the size of NPs and drug solubility. The optimized formulation was characterized by SEM, XRD, DSC, and FTIR. The pharmacokinetic parameters were studies by oral administration of a single dose of 15mg/kg in Wistar rats. The anti-osteoporotic effects were studied in female ovariectomized rats. Animals were treated with 6mg/kg/day for 2months then serum calcium, phosphorous and alkaline phosphatase levels were measured. RH loaded electrosprayed NPs showed 10-fold enhanced solubility compared to the free drug. Moreover, the XRD and SEM tests displayed an amorphous state of drug in the NPs. FTIR and DSC tests revealed no interaction between the polymer and the drug. Serum calcium, phosphorous and alkaline phosphatase levels were significantly decreased in ovariectomized rats receiving oral RH NPs (P<0.05). No significant difference was detected between RH NPs and estradiol groups (P>0.05). Oral bioavailability of NPs showed 7.5-fold increase compared to the pure drug. The electrosprayed PMVEMA nanoparticles can enhance solubility, bioavailability and antiosteoporotic effects of RH.

Design, characterization and in vitro evaluation of novel amphiphilic block sunflower oil-based polyol nanocarrier as a potential delivery system: Raloxifene-hydrochloride as a model.

Presently, modern pharmaceuticals, are almost exclusively derived from the arduous refining of petroleum whose supply is inherently unsustainable. In order to address this issue bio-based materials are increasingly being used for chemical synthesis, particularly in drug delivery systems. Biodegradable and biocompatible hyper-branched polyol (an alcohol containing three or more hydroxyl groups) was synthesized via a facile method through the ring-opening and thiol-ene click reactions at room temperature. Due to the bio-based content of the polyol backbone, the synthesized polyol had both excellent biodegradability and low cytotoxicity. Raloxifene hydrochloride, an oral selective estrogen receptor modulator, was used as a hydrophobic drug model to test the potential of polyol as a drug delivery system carrier. Polyol showed an amphiphilic character and could be prepared as a nanoparticle for the sustained delivery of raloxifene hydrochloride, a drug with poor bioavailability in aqueous solution. Raloxifene hydrochloride was readily encapsulated in the lipophilic core of polyol whose branched hydroxyls were on the external part of the prepared nanoparticles. The diameter of the nanoparticles was 94±0.43nm, their drug entrapment efficiency was 93±0.5% and they showed a sustained release profile (17±1.5% after 4weeks). The 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay showed low toxicity towards human osteoblast MG-63 cells. Based on its good biodegradability and low cytotoxicity, polyol provides a bio-based source for the design new drug delivery systems.

Effects of raloxifene and alendronate on non-enzymatic collagen cross-links and bone strength in ovariectomized rabbits in sequential treatments after daily human parathyroid hormone (1-34) administration.

This study investigated the effects of raloxifene and alendronate to follow parathyroid hormone (PTH) on bone collagen and biomechanical properties in ovariectomized rabbits. Sequential treatments of raloxifene and alendronate after hPTH(1-34) treatment improved biomechanical properties with and without bone collagen improvement, respectively. INTRODUCTION: The standard sequential treatment to follow human parathyroid hormone (hPTH) (1-34) therapy for osteoporosis has yet to be determined. The objective of this study was to compare the effects of raloxifene and alendronate treatments to follow daily hPTH(1-34) treatment on non-enzymatic collagen cross-links, bone mass, and bone strength in ovariectomized (OVX) rabbits. METHODS: From 3 months after ovariectomy, seven month-old female New Zealand white rabbits were given either vehicle or hPTH(1-34) (8 µg/kg/day), once daily for 5 months. After hPTH(1-34) treatment, the hPTH(1-34)-treated animals were divided into two groups, and given raloxifene (10 mg/kg, daily) orally or alendronate (100 µg/kg, twice weekly) subcutaneously for 5 months. We evaluated bone mineral density (BMD), bone structural parameters, advanced glycation end product (AGE) content in collagen, and bone mechanical parameters including intrinsic parameters in the femur. RESULTS: Raloxifene (hPTH/RLX) and alendronate (hPTH/ALN) to follow hPTH(1-34) increased cortical thickness, maximum load, and maximum stress and decreased endocortical surface in the diaphysis, in addition to increasing total BMD in the distal metaphysis. Decreased trabecular AGE, pentosidine, and homocysteine contents and increased toughness and breaking energy were noted with hPTH/RLX treatment only. With hPTH/ALN treatment, no effects on non-enzymatic collagen cross-link AGEs were noted although increases in stiffness and elastic modulus were observed. CONCLUSION: These results suggest that sequential treatments with hPTH(1-34) and antiresorptive drugs (raloxifene and alendronate) have a beneficial effect on bone mass and biomechanical properties in OVX rabbits.

Anti-Estrogen Withdrawal Effect With Raloxifene? A Case Report.

A 66-year-old patient presented with acute recurrent metastatic estrogen and progesterone receptor-positive, Her-2/neu-negative breast cancer, bone lesions (lumbar spine, pelvis), pulmonary nodules, hepatic metastasis, elevated cancer antigen 15 and liver enzymes, dyspepsia, and diarrhea. The patient had been taking raloxifene for approximately 8 years. After discontinuation, clinical parameters and symptoms improved rapidly without oncological therapy or other forms of treatment. Three months after raloxifene discontinuation, capecitabine was initiated by the treating oncologist who deemed an anti-estrogen withdrawal effect (AEWE) implausible. However, the lasting regression was more indicative of a raloxifene rebound effect than chemotherapy or other interventions. Today, the patient is asymptomatic with a good performance status. Hepatic metastatic regression has been confirmed, without any oncological treatment administered in the past 16 months and approximately 23 months following the withdrawal of raloxifene. This case highlights the need to screen breast cancer patients for the possibility of an AEWE if they are using raloxifene and possibly similar selective estrogen receptor modulators (SERMs) which includes tamoxifen, when diagnosed with advanced breast cancer, especially in the recurrent disease setting.

Cost-effectiveness of Pharmaceutical Interventions to Prevent Osteoporotic Fractures in Postmenopausal Women with Osteopenia.

BACKGROUND: To assess the cost-effectiveness of drug therapy to prevent osteoporotic fractures in postmenopausal women with osteopenia in Korea. METHODS: A Markov cohort simulation was conducted for lifetime with a hypothetical cohort of postmenopausal women with osteopenia and without prior fractures. They were assumed to receive calcium/vitamin D supplements only or drug therapy (i.e., raloxifene or risedronate) along with calcium/vitamin D for 5 years. The Markov model includes fracture-specific and non-fracture specific health states (i.e. breast cancer and venous thromboembolism), and all-cause death. Published literature was used to determine the model parameters. Local data were used to estimate the baseline incidence rates of fracture in those with osteopenia and the costs associated with each health state. RESULTS: From a societal perspective, the estimated incremental cost-effectiveness ratios (ICERs) for the base cases that had T-scores between -2.0 and -2.4 and began drug therapy at the age of 55, 60, or 65 years were $16,472, $6,741, and -$13,982 per quality-adjusted life year (QALY) gained, respectively. Sensitivity analyses for medication compliance, risk of death following vertebral fracture, and relaxing definition of osteopenia resulted in ICERs reached to $24,227 per QALY gained. CONCLUSIONS: ICERs for the base case and sensitivity analyses remained within the World Health Organization's willingness-to-pay threshold, which is less than per-capita gross domestic product in Korea (about $25,700). Thus, we conclude that drug therapy for osteopenia would be a cost-effective intervention, and we recommend that the Korean National Health Insurance expand its coverage to include drug therapy for osteopenia.

Relationship Between Breast Density and Selective Estrogen-Receptor Modulators, Aromatase Inhibitors, Physical Activity, and Diet: A Systematic Review.

Background Lower breast density (BD) is associated with lower risk of breast cancer and may serve as a biomarker for the efficacy of chemopreventive strategies. This review explores parameters that are thought to be associated with lower BD. We conducted a systematic review of articles published to date using the PRISMA strategy. Articles that assessed change in BD with estrogen-receptor modulators (tamoxifene [TAM], raloxifene [RLX], and tibolone) and aromatase inhibitors (AIs), as well as cross-sectional and longitudinal studies (LSs) that assessed association between BD and physical activity (PA) or diet were reviewed. Results Ten studies assessed change in BD with TAM; all reported TAM-mediated BD decreases. Change in BD with RLX was assessed by 11 studies; 3 reported a reduction in BD. Effect of tibolone was assessed by 5 RCTs; only 1 reported change in BD. AI-mediated BD reduction was reported by 3 out of 10 studies. The association between PA and BD was assessed by 21 studies; 4 reported an inverse association. The relationship between diet and BD was assessed in 34 studies. All studies on calcium and vitamin D as well as vegetable intake reported an inverse association with BD in premenopausal women. Two RCTs demonstrated BD reduction with a low-fat, high-carbohydrate intervention. Conclusion TAM induces BD reduction; however, the effect of RLX, tibolone, and AIs on BD is unclear. Although data on association between diet and BD in adulthood are contradictory, intake of vegetables, vitamin D, and calcium appear to be associated with lower BD in premenopausal women.

Response of bone turnover markers to raloxifene treatment in postmenopausal women with osteopenia.

UNLABELLED: We used two methods of identifying women who reached the target for raloxifene treatment with bone turnover markers. Both approaches identified women that responded to treatment but did not fully agree and may be complementary. INTRODUCTION: The change in bone turnover markers (BTMs) in response to osteoporosis therapy can be assessed by a decrease beyond the least significant change (LSC) or below the mean of the reference interval (RI). We compared the performance of these two approaches in women treated with raloxifene. METHODS: Fifty postmenopausal osteopenic women (age 51-72 years) were randomised to raloxifene or no treatment for 2 years. Blood samples were collected for the measurement of BTM. The LSC for each marker was calculated from the untreated women and the RI obtained from healthy premenopausal women (age 35-40 years). Bone mineral density (BMD) was measured at the spine and hip. RESULTS: There was a decrease in BTM in response to raloxifene treatment, percentage change at 12 weeks: C terminal telopeptide of type I collagen (CTX) -39 % (95 % CI -48 to -28) and N terminal propeptide of type I procollagen (PINP) -32 % (95 % CI -40 to -23) P < 0.001. The proportion of women classified as responding to treatment using LSC at 12 weeks was as follows: CTX 38 % and PINP 52 % and at 48 weeks CTX 60 % and PINP 65 %. For the RI approach, the proportion of women classified as responding to treatment at 12 weeks was CTX and PINP 38 % and at 48 weeks CTX 40 % and PINP 45 %. There was a significant difference in the change in spine BMD in the raloxifene-treated group compared to the no-treatment group at week 48: difference 0.031 g/cm(2) (95 % CI 0.016 to 0.046, P < 0.001). CONCLUSIONS: The two approaches identified women that reached the target for treatment using BTM. Both LSC and RI criteria appear useful in identifying treatment response, but the two approaches do not fully overlap and may be complementary.