Multivariate Analysis of Solubility Parameters for Drug-Polymer Miscibility Assessment in Preparing Raloxifene Hydrochloride Amorphous Solid Dispersions.

The success of obtaining solid dispersions for solubility improvement invariably depends on the miscibility of the drug and polymeric carriers. This study aimed to categorize and select polymeric carriers via the classical group contribution method using the multivariate analysis of the calculated solubility parameter of RX-HCl. The total, partial, and derivate parameters for RX-HCl were calculated. The data were compared with the results of excipients (N = 36), and a hierarchical clustering analysis was further performed. Solid dispersions of selected polymers in different drug loads were produced using solvent casting and characterized via X-ray diffraction, infrared spectroscopy and scanning electron microscopy. RX-HCl presented a Hansen solubility parameter (HSP) of 23.52 MPa1/2. The exploratory analysis of HSP and relative energy difference (RED) elicited a classification for miscible (n = 11), partially miscible (n = 15), and immiscible (n = 10) combinations. The experimental validation followed by a principal component regression exhibited a significant correlation between the crystallinity reduction and calculated parameters, whereas the spectroscopic evaluation highlighted the hydrogen-bonding contribution towards amorphization. The systematic approach presented a high discrimination ability, contributing to optimal excipient selection for the obtention of solid solutions of RX-HCl.

Quality by design-steered development and validation of analytical and bioanalytical methods for raloxifene: Application of Monte Carlo simulations and variance inflation factor.

A sensitive, rapid, reproducible, and economical HPLC method is reported for the quantification of raloxifene hydrochloride employing Quality by Design (QbD) principles. Factor screening studies, employing Taguchi design, indicated buffer volume percentage and isocratic flow rate as the critical method parameters (CMPs), which significantly influence the chosen critical analytical attributes, that is, tailing factor and theoretical plate number. Method conditions were subsequently optimized using face-centered cubic design with magnitude of variance inflation factor for assessing multicollinearity among CMPs. Method operable design region (MODR) was earmarked and liquid chromatographic separation optimized using 0.05 M citrate buffer, acetonitrile, and methanol (57:40:3 v/v/v) as ggmobile phase at 0.9 mL min-1 flow rate, λmax of 280 nm, and column temperature of 40°C. Validation of the developed analytical method was accomplished as per International Council on Harmonization (ICH) guidelines confirming high levels of linearity, precision, accuracy, robustness, and sensitivity. Application of Monte Carlo simulations enabled the attainment of best plausible chromatographic resolution and corroboration of the demarcated MODR. Establishment and validation of the bioanalytical method using rat plasma samples, along with forced degradation and stability studies, corroborated the aptness of developed HPLC methods for drug quantification in the biological fluids, as well as in bulk and marketed dosage forms.

The contribution of larval zebrafish transcriptomics to chemical risk assessment.

In Canada, the Canadian Environmental Protection Act (1999) requires human health and environmental risk assessments be conducted for new substances prior to their manufacture or import. While this toxicity data is historically obtained using rodents, in response to the international effort to eliminate animal testing, Health Canada is collaborating with the National Research Council (NRC) of Canada to develop a New Approach Method by refining existing NRC zebrafish models. The embryo/larval zebrafish model evaluates systemic (whole body) general toxicity which is currently unachievable with cell-based testing. The model is strengthened using behavioral, toxicokinetic and transcriptomic responses to assess non-visible indicators of toxicity following chemical exposure at sub-phenotypic concentrations. In this paper, the predictive power of zebrafish transcriptomics is demonstrated using two chemicals; Raloxifene and Resorcinol. Raloxifene exposure produced darkening of the liver and malformation of the nose/mandible, while Resorcinol exposure produced increased locomotor activity. Transcriptomic analysis correlated differentially expressed genes with the phenotypic effects and benchmark dose calculations determined that the transcriptomic Point of Departure (POD) occurred at subphenotypic concentrations. Correlating gene expression with apical (phenotypic) effects strengthens confidence in evaluation of chemical toxicity, thereby demonstrating the significant advancement that the larval zebrafish transcriptomics model represents in chemical risk assessment.

Are noscapine and raloxifene ligands of the bradykinin B2 receptor? An assessment based on the human umbilical vein contractility assay.

The centrally acting antitussive opiate derivative, noscapine, has been claimed to be a non-competitive bradykinin B2 receptor antagonist. Raloxifene, a selective estrogen receptor modulator, was predicted to bind the bradykinin B2 receptor and to exert a partial agonist activity. These intriguing claims suggest that new molecular scaffolds ("chemotypes") may be identified for small molecule ligands of kinin receptors and that some off-target effects of noscapine or raloxifene may be mediated by bradykinin B2 receptors. An established contractile bioassay for ligands of the bradykinin B2 receptor, the isolated human umbilical vein, was exploited to characterize the inhibitory effect of noscapine and raloxifene on the B2 receptor-mediated contractile response to bradykinin. Observed effects were compared with those of the peptide antagonist icatibant, a potent, selective and competitive B2 receptor antagonist. Our results indicate that neither noscapine (2.5 µM) nor raloxifene (20 µM) behave as B2 receptor antagonists in concentrations that vastly exceeded an effective concentration of the control antagonist, icatibant; further, none of these drugs had direct contractile effects. It is suggested that the previously reported B2 receptor inhibitory effect of noscapine, a putative sigma-receptor agonist, might result from an indirect physiological antagonism, while raloxifene did not appear to have any significant affinity for the B2 receptors.

Denosumabe e teriparatida para o tratamento indivíduos com osteoporose grave e falha terapêutica aos medicamentos disponíveis no Sistema Único de Saúde / Denosumab and teriparatide for the treatment of individuals with severe osteoporosis and therapeutic failure to the drugs available in the Unified Health System

INTRODUÇÃO: A osteoporose, doença que aumenta da fragilidade óssea e suscetibilidade à fratura, afeta cerca de 200 milhões de pessoas no mundo. No geral, a prevalência de osteoporose em estudos brasileiros varia de 6% a 33% dependendo da população e outras variáveis avaliadas. Entre os indivíduos com osteoporose, aqueles que apresentaram fratura osteoporótica têm duas vezes o risco para nova fratura. Para evitar novas fraturas, o tratamento preconizado deve incluir estratégias medicamentosas e não medicamentosas. Entre as medicamentosas, suplementação de cálcio e colecalciferol, alendronato, risedronato, pamidronato, raloxifeno, calcitonina e estrógenos conjugados são opções disponíveis no Protocolo Clínico de Diretrizes Terapêuticas (PCDT) de Osteoporose do Sistema Único de Saúde (SUS). Apesar da disponibilidade de tratamentos, estima-se que 25% dos pacientes continuam a apresentar falha terapêutica aos tratamentos disponíveis. Nesse contexto, as diretrizes clínicas nacionais e internacionais de sociedade médicas, recomendam o uso de denosumabe ou teriparatida a pacientes com osteoporose grave e falha terapêutica aos medicamentos disponíveis no SUS (alendronato, pamidronato, raloxifeno e risedronato). Entretanto, há incerteza se os benefícios identificados para população em tratamento de primeira linha, principal população incluída nos estudos, são sustentados em população com osteoporose grave e falha terapêutica em vigência de tratamento; e se a escolha, por estas opções terapêuticas, pode valer a pena e ser viável economicamente para o SUS. Assim, o objetivo do presente relatório é analisar as evidências científicas sobre eficácia, efetividade, segurança, bem como evidências econômicas do denosumabe e da teriparatida para o tratamento de pacientes com osteoporose grave com falha terapêutica aos medicamentos disponíveis no SUS (alendronato, pamidronato, raloxifeno e risedronato). TECNOLOGIAS: Denosumabe (Prolia®) e teriparatida (Fortéo®). PERGUNTA: Os medicamentos denosumabe e

Eficácia e segurança da Teriparatida comparada aos bifosfonados orais e Raloxifeno para prevenção de fraturas em osteoporose: revisão rápida de evidências / Effectiveness, safety and cost-effectiveness of Teriparatide compared to oral biposphonates or Raloxifene for osteoporotic fracture prevention: rapid review of evidence

Tecnologia: Teriparatida, comparada a bifosfonados orais ou Raloxifeno. Indicação: prevenção de fraturas em pessoas com osteoporose. Pergunta: A Teriparatida é mais eficaz e segura que os bifosfonados orais ou o Raloxifeno para tratamento da osteoporose e prevenção de fraturas secundárias à osteoporose? Métodos: Levantamento bibliográfico foi realizado na base de dados PUBMED, seguindo estratégias de buscas predefinidas. Foi feita avaliação da qualidade metodológica das revisões sistemáticas com a ferramenta Assessing the Methodological Quality of Systematic Reviews version 2 (AMSTAR-2). Resultados: Foram selecionadas 2 revisões sistemáticas, que atendiam aos critérios de inclusão. Conclusão: Para a população em geral com osteoporose, a Teriparatida evita mais fraturas vertebrais que o Alendronato de sódio ou Risedronato de sódio, mas efeito similar para fraturas não vertebrais. Teriparatida previne mais fraturas vertebrais e não vertebrais que Raloxifeno. Teriparatida tem maior efeito sobre a massa óssea corporal que o Risedronato de sódio e o Raloxifeno, mas tem efeito similar ao Alendronato de sódio. Na população masculina com osteoporose, a terapia com bifosfonados orais é mais eficaz que suplementação nutricional ou placebo para prevenir fraturas. Já o tratamento com Teriparatida não é mais eficaz que a suplementação nutricional ou placebo

Teriparatide compared to oral bisphosphonates or Raloxifene. Indication: prevention of fractures in people with osteoporosis. Question: Is Teriparatide more effective and safer than oral bisphosphonates or Raloxifene for treating osteoporosis and preventing fractures secondary to osteoporosis? Methods: Bibliographic survey was carried out in the PUBMED database, following predefined search strategies. Evaluation of the methodological quality of systematic reviews was carried out using the tool Assessing the Methodological Quality of Systematic Reviews version 2 (AMSTAR-2). Results: Two systematic reviews were selected, which met the inclusion criteria. Conclusion: For the general population with osteoporosis, Teriparatide prevents more vertebral fractures than Alendronate or Risedronate sodium, but has similar effect for non-vertebral fractures. Teriparatide prevents more vertebral and non-vertebral fractures than Raloxifene. Teriparatide has a greater effect on body bone mass than Risedronate sodium and Raloxifene, but it has a similar effect to Alendronate sodium. In the male population with osteoporosis, oral bisphosphonates is more effective than nutritional supplementation or placebo to prevent fractures. Treatment with teriparatide is no more effective than nutritional supplementation or placebo

Denosumab, raloxifene, romosozumab and teriparatide to prevent osteoporotic fragility fractures: a systematic review and economic evaluation.

BACKGROUND: Fragility fractures are fractures that result from mechanical forces that would not ordinarily result in fracture. OBJECTIVES: The objectives were to evaluate the clinical effectiveness, safety and cost-effectiveness of non-bisphosphonates {denosumab [Prolia®; Amgen Inc., Thousand Oaks, CA, USA], raloxifene [Evista®; Daiichi Sankyo Company, Ltd, Tokyo, Japan], romosozumab [Evenity®; Union Chimique Belge (UCB) S.A. (Brussels, Belgium) and Amgen Inc.] and teriparatide [Forsteo®; Eli Lilly and Company, Indianapolis, IN, USA]}, compared with each other, bisphosphonates or no treatment, for the prevention of fragility fracture. DATA SOURCES: For the clinical effectiveness review, nine electronic databases (including MEDLINE, EMBASE and the World Health Organization International Clinical Trials Registry Platform) were searched up to July 2018. REVIEW METHODS: A systematic review and network meta-analysis of fracture and femoral neck bone mineral density were conducted. A review of published economic analyses was undertaken and a model previously used to evaluate bisphosphonates was adapted. Discrete event simulation was used to estimate lifetime costs and quality-adjusted life-years for a simulated cohort of patients with heterogeneous characteristics. This was done for each non-bisphosphonate treatment, a strategy of no treatment, and the five bisphosphonate treatments previously evaluated. The model was populated with effectiveness evidence from the systematic review and network meta-analysis. All other parameters were estimated from published sources. An NHS and Personal Social Services perspective was taken, and costs and benefits were discounted at 3.5% per annum. Fracture risk was estimated from patient characteristics using the QFracture® (QFracture-2012 open source revision 38, Clinrisk Ltd, Leeds, UK) and FRAX® (web version 3.9, University of Sheffield, Sheffield, UK) tools. The relationship between fracture risk and incremental net monetary benefit was estimated using non-parametric regression. A probabilistic sensitivity analysis and scenario analyses were used to assess uncertainty. RESULTS: Fifty-two randomised controlled trials of non-bisphosphonates were included in the clinical effectiveness systematic review and an additional 51 randomised controlled trials of bisphosphonates were included in the network meta-analysis. All treatments had beneficial effects compared with placebo for vertebral, non-vertebral and hip fractures, with hazard ratios varying from 0.23 to 0.94, depending on treatment and fracture type. The effects on vertebral fractures and the percentage change in bone mineral density were statistically significant for all treatments. The rate of serious adverse events varied across trials (0-33%), with most between-group differences not being statistically significant for comparisons with placebo/no active treatment, non-bisphosphonates or bisphosphonates. The incremental cost-effectiveness ratios were > £20,000 per quality-adjusted life-year for all non-bisphosphonate interventions compared with no treatment across the range of QFracture and FRAX scores expected in the population eligible for fracture risk assessment. The incremental cost-effectiveness ratio for denosumab may fall below £30,000 per quality-adjusted life-year at very high levels of risk or for high-risk patients with specific characteristics. Raloxifene was dominated by no treatment (resulted in fewer quality-adjusted life-years) in most risk categories. LIMITATIONS: The incremental cost-effectiveness ratios are uncertain for very high-risk patients. CONCLUSIONS: Non-bisphosphonates are effective in preventing fragility fractures, but the incremental cost-effectiveness ratios are generally greater than the commonly applied threshold of £20,000-30,000 per quality-adjusted life-year. STUDY REGISTRATION: This study is registered as PROSPERO CRD42018107651. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 29. See the NIHR Journals Library website for further project information.

BACKGROUND: Fragility fractures are fractures that result from mechanical forces that would not ordinarily result in fracture, known as low-level (or 'low-energy') trauma. Some people are at particularly high risk of fragility fractures. The first treatment used is often a bisphosphonate, but non-bisphosphonate treatments are alternatives. AIMS: We aimed to determine how effective non-bisphosphonates {denosumab [Prolia®; Amgen Inc., Thousand Oaks, CA, USA], raloxifene [Evista®; Daiichi Sankyo Company, Ltd, Tokyo, Japan], romosozumab [Evenity®; Union Chimique Belge (UCB) S.A. (Brussels, Belgium) and Amgen Inc.] and teriparatide [Forsteo®; Eli Lilly and Company, Indianapolis, IN, USA]} are at preventing fractures, whether or not treatment has any risks for patients and whether or not the clinical benefits are achieved at a reasonable cost. METHODS: We have systematically identified and examined trials that assessed the clinical effects of non-bisphosphonates. For each clinical outcome, we have combined data from multiple trials to estimate the clinical effectiveness of each non-bisphosphonate treatment. We combined data from published sources in an economic model to estimate lifetime costs and clinical benefits for each non-bisphosphonate and compared these with the estimated costs and clinical outcomes for untreated patients and patients treated with bisphosphonates. RESULTS: All non-bisphosphonates reduced the risk of vertebral fractures compared with no treatment. For fractures at the hip or at any non-vertebral site, all of the non-bisphosphonates reduced the average number of fractures, but, for some non-bisphosphonates, we could not exclude the possibility that this was a chance finding. The chance of patients experiencing serious side effects was generally similar regardless of whether patients took non-bisphosphonates, bisphosphonates or placebo (a dummy pill). Blood clots were more common in patients taking raloxifene than in those taking placebo, but these were still a rare outcome (fewer than 1 in 100). The benefits of denosumab, teriparatide and romosozumab are few compared with their costs. For raloxifene, the risks generally outweigh the benefits. Treatment with bisphosphonates is likely to represent better value for money than treatment with non-bisphosphonates.

Breast Cancer Characteristics and Survival among Users versus Nonusers of Raloxifene.

Raloxifene reduces breast cancer incidence. However, it is unclear whether it also reduces mortality from breast cancer. For raloxifene to reduce incidence but not mortality, breast cancer survival would have to be worse for raloxifene users than nonusers. Surveillance Epidemiology and End Results-Medicare was used to identify women with invasive breast cancer diagnosed from 2007 to 2015 at ages 65-89 who had prior Medicare Part D (prescription drug) enrollment; breast cancer characteristics and survival were assessed among raloxifene regular users (≥180 days in past year) versus nonusers. Logistic regression was used to assess cancer characteristics. Two methods utilizing proportional hazards models were employed to assess breast cancer-specific survival. In method 1, survival was assessed adjusting for demographics, mammography use, and chronic conditions in the subset with Medicare fee-for-service enrollment. In method 2, predicted survival as a function of breast cancer characteristics was modeled in nonusers and the model applied to users to predict survival. A total of 116,317 raloxifene nonusers and 1,223 regular users were identified. Users were significantly more likely to have hormone receptor (HR)-negative cancers, but less likely to have T2+, N1+, and metastatic disease. There were 10,869 and 101 breast cancer-related deaths in nonusers and regular users, respectively. The HR (users vs. nonusers) for breast cancer-specific survival in method 1 was 0.94 (95% confidence interval, 0.73-1.22). In method 2, predicted survival was higher in users than nonusers (8-year survival 84.9% vs. 83.4%). Breast cancer-specific survival in raloxifene users was not worse than in nonusers, providing indirect evidence that raloxifene reduces breast cancer-related mortality.

Debería usarse Denosumab para la prevención y tratamiento de fracturas osteoporóticas en la mujer postmenopáusica? / Should Denosumab be used for the prevention and treatment of osteoporotic fractures in postmenopausal women?

CONTEXTO: La osteoporosis es un trastorno esquelético caracterizado por resistencia óssea comprometida, predisposición pacientes a un mayor riesgo de fractura. La prevalência aumenta del 6% de las mujeres de edad 50 a 59 años a más del 40% de las mujeres de edad 80 años y mayores.1 Consecuencias de mantener una fractura puede ser grave e incluir un aumento riesgo de fracturas posteriores, hospitalización o institucionalización, disminución de la calidad de vida, y mortalidad prematura, con una carga relacionada com el sistema de salud. DESCRIPCIÓN DE LA TECNOLOGÍA: El denosumab es un anticuerpo monoclonal que inhibe la resorción ósea producida por los osteoclastos. Fue comercializado en 2010 para el tratamiento de la osteoporosis. En estos años se han identificado varios efectos adversos potencialmente graves: predisposición a infecciones, cáncer, reacciones de hipersensibilidad, transtornos autoinmunes, e incremento de la incidencia de múltiples fracturas vertebrales espontáneas al suspender el tratamiento. En este número revisamos estas novedades. TECNOLOGÍAS ALTERNATIVAS: Los agentes antirresortivos como los bifosfonatos orales son el estándar tratamiento para la osteoporosis posmenopáusica, en conjunto con medidas no farmacológicas y sobre todo el énfasis en la prevención de las caídas. Otras opciones de tratamiento incluyen un bisfosfonatos intravenoso (ácido zoledrónico), un agente formador de hueso (teriparatida) y un modulador selectivo del receptor de estrógeno (raloxifeno). MÉTODOS: Se realizó una búsqueda bibliográfica utilizando las siguientes bases de datos bibliográficas: MEDLINE, EMBASE, The Cochrane Library, y PubMed. Aplicaron filtros metodológicos para evaluaciones de tecnología sanitaria, estudios económicos, revisiones sistemáticas, metanálisis, y ensayos controlados aleatorios (ECA). La búsqueda también se limitó a Idioma en Inglés y humanos. Se excluyeron los resúmenes de congresos en los resultados de búsqueda. Se identificó la literatura gris (literatura que no se publica comercialmente) fue identificado mediante la búsqueda de secciones relevantes de la Lista de verificación de Grey Matters (http://www.cadth.ca/en/resources/grey-matters). Google y otros motores de búsqueda de internet fueron se utiliza para buscar en la web adicional materiales Estas búsquedas se complementaron con revisar las bibliografías de documentos clave y a través de contactos con expertos apropiados. ESTRATEGIA DE BÚSQUEDA: Se realizó una búsqueda con última fecha 26/08/2019 en diversas bases de datos, incluidas PubMed y Embase, así como la biblioteca Cochrane, ClinicalTrials.gov y bases de datos de revisiones sistematicas Epistemonikos. La búsqueda sólo incluyó documentos escrito en ingles y espanol. RESULTADOS: Denosumab comparado con placebo para pacientes con osteoporosis. El riesgo en el grupo de intervención (y su intervalo de confianza del 95%) se basa en el riesgo asumido en el grupo de comparación y en el efecto relativo de la intervención (y su intervalo de confianza del 95%). Eficacia frente a bifosfonatos: comparaciones directas. Se evalúa el perfil de evidencia GRADE donde se evidencia el metaanálisis entre cuatro ECA 5-8 que comprendieron 2071 participantes con un rango de seguimiento de 12 a 24 meses y compararon el uso de Denosumab con bifosfonatos orales (Alendronato,Etidronato). Existe incertidumbre en el efecto de denosumab sobre el riesgo de fracturas en comparación con bifosfonatos. La certeza em la evidencia va desde BAJA A MUY BAJA considerando la presencia de imprecisión muy seria y el potencial riesgo de sesgo de publicación. Eficacia frente a bifosfonatos: comparaciones indirectas. No se han encontrado en la literatura comparaciones directas entre Denosumab y otros fármacos distintos. Esta recomendación de cobertura otorga más peso a la incertidumbre en la eficacia comparada con bifosfonatos, al potencial impacto presupuestario de su uso y la potencial reducción de la equidad; que a la preferencia de los pacientes respecto de la forma de administración de las drogas para osteoporosis.

Use of raloxifene and tamoxifen by breast cancer risk level in a Medicare-eligible cohort.

BACKGROUND: Raloxifene and tamoxifen are Food and Drug Administration-approved for breast cancer risk reduction; in 2013, the US Preventive Services Task Force recommended these drugs for breast cancer risk reduction in high-risk women. Information on the use of raloxifene and tamoxifen for breast cancer risk reduction in the general population indicates that the risk is believed to be low; however, there is little literature. OBJECTIVE: The purpose of this study was to assess the use of breast cancer risk reduction medications by breast cancer risk level in an older cohort of women. STUDY DESIGN: Women who were enrolled in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial were assessed for the use of raloxifene, tamoxifen, and other medications. The data sources for use of the drugs were a mailed medication use questionnaire in 2013 and linked Medicare Part D claims files from 2010-2014. Estimated breast cancer risk within 5 years was assessed with the use of the modified Gail model and self-reported breast cancer risk factors; comorbidities were assessed through a questionnaire. RESULTS: A total of 22,235 women completed the medication use questionnaire; of these, 13,640 women (61%) had linked Part D data. In 2013, 45% of the women were 65-74 years old, and 55% of the women were 75-84 years old. From the medication use questionnaire, raloxifene use (past month) was 1.8%, 2.5%, and 4.0% for women with breast cancer risk within 5 years of <1.66%, 1.66-3.0%, and ≥3%, respectively (probability value trend, <.0001). From Part D, for any use during the period among women with coverage, raloxifene rates were 3.3%, 4.0%, and 6.6% for the 3 categories for breast cancer risk within 5 years (probability value trend, <.0001); use was 7.4% and 3.3% in women with and without osteoporosis, respectively. Raloxifene use significantly decreased from 2010-2014, and specifically from 2012-2014, both for all women and for women with breast cancer risk within 5 years of ≥3%. Tamoxifen use from Part D was 0.36%, 0.45%, and 0.85% for the 3 categories for breast cancer risk within 5 years (probability value trend, .009). CONCLUSION: Raloxifene use was low overall but increased modestly with breast cancer risk, and usage decreased from 2010-2014. Tamoxifen use was very low.

Fracture risk and healthcare resource utilization and costs among osteoporosis patients with type 2 diabetes mellitus and without diabetes mellitus in Japan: retrospective analysis of a hospital claims database.

BACKGROUND: Osteoporosis, osteoporosis-related fractures, and diabetes are considerable health burdens in Japan. Diabetes in patients with osteoporosis has been reported to be associated with increased fracture risk. This retrospective analysis of a Japanese hospital claims database investigated the real-world effect of type 2 diabetes mellitus (T2DM) on the incidence of clinical fractures, costs, and healthcare resource utilization in patients with osteoporosis and a subgroup of patients prescribed raloxifene. METHODS: Women aged ≥50 years diagnosed with osteoporosis who had a first prescription claim for osteoporosis treatment with a pre-index period ≥12 months and a post-index period of 30 months were selected from a database extract (April 2008-July 2013). Patients prescribed raloxifene were classed as a subgroup. Patients diagnosed with T2DM constituted the T2DM group; all other patients (excluding patients with type 1 diabetes mellitus) constituted the non-diabetes mellitus (non-DM) group. Groups were matched by exact matching, using selected baseline characteristics. Patient demographic and clinical characteristics were compared using chi-squared tests, t-tests, or Wilcoxon rank sum tests. Time to first fracture was examined using Kaplan-Meier survival analysis. RESULTS: Overall, the T2DM and non-DM groups had 7580 and 7979 patients, respectively; following matching, there were 3273 patients per group. In the raloxifene subgroup, the T2DM and non-DM groups had 668 and 699 patients, respectively; following matching, there were 239 patients per group. At baseline, the T2DM group (overall and raloxifene subgroup) had significantly higher healthcare resource utilization and comorbidities. During the post-index period, a similar pattern was observed in the overall group, even after matching; the T2DM group also had a higher incidence of fracture. In the raloxifene subgroup, after matching, there were no significant differences in fracture incidence or costs and fewer differences in healthcare resource utilization between the T2DM and non-DM groups. CONCLUSIONS: These findings suggest that comorbid T2DM increases fracture incidence in patients with osteoporosis, compared with patients without DM. Increases in fracture incidence were accompanied by greater costs and healthcare resource utilization, which are important considerations for clinical practice in Japan. Further research investigating the use of raloxifene for treatment of osteoporosis with comorbid T2DM may also be warranted.

Comparison of Calipers for Matching on the Disease Risk Score.

Previous studies have compared calipers for propensity score (PS) matching, but none have considered calipers for matching on the disease risk score (DRS). We used Medicare claims data to perform 3 cohort studies of medication initiators: a study of raloxifene versus alendronate in 1-year nonvertebral fracture risk, a study of cyclooxygenase 2 inhibitors versus nonselective nonsteroidal antiinflammatory medications in 6-month gastrointestinal bleeding, and a study of simvastatin + ezetimibe versus simvastatin alone in 6-month cardiovascular outcomes. The study periods for each cohort were 1998 through 2005, 1999 through 2002, and 2004 through 2005, respectively. In each cohort, we calculated 1) a DRS, 2) a prognostic PS which included the DRS as the independent variable in a PS model, and 3) the PS for each patient. We then nearest-neighbor matched on each score in a variable ratio and a fixed ratio within 8 calipers based on the standard deviation of the logit and the natural score scale. When variable ratio matching on the DRS, a caliper of 0.05 on the natural scale performed poorly when the outcome was rare. The prognostic PS did not appear to offer any consistent practical benefits over matching on the DRS directly. In general, logit-based calipers or calipers smaller than 0.05 on the natural scale performed well when DRS matching in all examples.

The selective estrogen receptor modulators in breast cancer prevention.

BACKGROUNDS: Persistently increased blood levels of estrogens are associated with an increased risk of breast cancer. Selective estrogen receptor modulators (SERMs) are a class of compounds that act on the estrogen receptor (ER). METHODS: Several clinical trials have demonstrated the effectiveness of its prophylactic administration. Incidence of invasive ER-positive breast cancer was reduced by SERMs treatment, especially for those women with high risk of developing breast cancer. In this study, we reviewed the clinical application of SERMs in breast cancer prevention. RESULTS: To date, four prospective randomized clinical trials had been performed to test the efficacy of tamoxifen for this purpose. Concerning on the benefit and cost of tamoxifen, various studies from different countries demonstrated that chemoprevention with tamoxifen seemed to be cost-effective for women with a high risk of invasive breast cancer. Based above, tamoxifen was approved for breast cancer prevention by the US Food and Drug Administration in 1998. Raloxifene was also approved for postmenopausal women in 2007 for breast cancer prevention which reduces the risk of invasive breast cancer with a lower risk of unwanted stimulation of endometrium. Thus, raloxifene is considered to have a better clinical possesses as prophylactic agent. Several other agents, such as arzoxifene and lasofoxifene, are currently being investigated in clinic. The American Society of Clinical Oncology and National Comprehensive Cancer Network had published guidelines on breast cancer chemoprevention by SERMs. However, use of tamoxifen and raloxifene for primary breast cancer prevention was still low. CONCLUSION: A broader educational effort is needed to alert women and primary care physicians that SERMs are available to reduce breast cancer risk.

Comparison of the prescribing pattern of bisphosphonate and raloxifene in Korean women with osteoporosis: from a national health insurance claims database.

This study aimed to evaluate the differences of prescribing pattern between bisphosphonate and raloxifene users among Korean women with osteoporosis, focusing on the underlying conditions, concurrent medications, nature of healthcare utilization, and regional disparity. We used the Health Insurance Review and Assessment Service National Patients Sample database of the year 2010. Study subjects were defined as female osteoporosis patients aged over 50 years with both the diagnosis of osteoporosis and prescriptions of bisphosphonate or raloxifene. The frequency and the proportion of bisphosphonate and raloxifene were compared using chi-square test and the trend of the proportion using the Cochran-Armitage test. Medications were quantified as defined daily doses per 1,000 patients per day. The prescription pattern was visualized by using the Quantum Geographic Information Systems program. Of the 1,367,367 people who utilized medical services in 2010, the final number of study subjects was 26,881--26,032 (96.8%) bisphosphonate and 849 (3.2%) raloxifene recipients. Raloxifene users were younger than bisphosphonate users and were more frequently patients with a lipid disorder (16.0% vs. 22.1%, p-value < 0.0001), rheumatic disease (4.0% vs. 6.1%, p-value = 0.0024), hot flash (1.8% vs. 6.1%, p <0.0001), and coronary artery disease (1.2% vs. 2.8%, p< 0.0001). The proportion of raloxifene users was higher in tertiary care institutions (21.6% vs. 44.7%, p-value < 0.0001). A regional distribution showed that raloxifene use was higher in the Seoul metropolitan area. These differences in demographic and clinical profiles of each recipient may influence prescription decisions.

Psychometric properties of the osteoporosis assessment questionnaire (OPAQ) 2.0: results from the multiple outcomes of raloxifene evaluation (MORE) study.

BACKGROUND: We explored psychometric properties of the Osteoporosis Assessment Questionnaire 2.0 in terms of reliability, validity, and responsiveness with generic, clinical, demographic, and preference-based data collected from a population of postmenopausal women with osteoporosis. METHODS: The Multiple Outcomes of Raloxifene Evaluation study was a randomized, placebo-controlled, multinational clinical trial evaluating efficacy and safety of raloxifene. The Osteoporosis Assessment Questionnaire 2.0, a generic quality of life measure (Nottingham Health Profile), and a preference-based measure (Health Utilities Index) were administered at baseline and annually. Psychometric properties of the 14 Osteoporosis Assessment Questionnaire 2.0 domains were evaluated by standard statistical techniques. RESULTS: This study included a subset of 1477 women from the Multiple Outcomes of Raloxifene Evaluation study population completing the questionnaires. Mean (standard deviation) age was 68.4 (6.8) years. Prevalent vertebral fractures were found in 70% (n =1038) of women. Internal consistency was >0.7 in 9 Osteoporosis Assessment Questionnaire 2.0 domains. Correlations were moderate and significant for similar Osteoporosis Assessment Questionnaire 2.0 domain scores, Nottingham Health Profile domains, and Health Utilities Index scores. All but 2 Osteoporosis Assessment Questionnaire 2.0 domains distinguished between patients with or without prevalent vertebral fractures and detected worsening with increased number of vertebral fractures. Women with ≥ 1 incident vertebral fracture generally had a greater worsening in Osteoporosis Assessment Questionnaire 2.0 scores (excluding social activity and support of family and friends) from baseline to study endpoint compared with women without incident vertebral fractures. CONCLUSIONS: Most domains in the Osteoporosis Assessment Questionnaire 2.0 demonstrated robust psychometric properties; however, several domains not showing these criteria may need to be reassessed and removed for a potentially shorter and validated version of the Osteoporosis Assessment Questionnaire.

Osteoporosis knowledge in patients with a first fragility fracture in Puerto Rico.

PURPOSE: To determine the level of knowledge about osteoporosis and factors associated with low level of knowledge in patients with a first osteoporotic fracture. METHODS: A cross-sectional study in adult patients with a first osteoporotic fracture admitted to the University Hospital of the Puerto Rico Medical Center, San Juan, Puerto Rico was performed. Socio-demographic parameters, clinical features, and pharmacologic treatment were examined. A validated questionnaire was used to assess subjects' level of knowledge about osteoporosis. Differences between study groups were evaluated using chi-square and Student's t tests, as appropriate. RESULTS: A total of 54 patients participated in the study. The mean (SD) age was 73.7 (10.7) years; 77.8% were females. Overall, 61.1% of the participants had a low level of knowledge about osteoporosis. Patients with low level of knowledge were more likely to have the Puerto Rico Government health insurance, lower level of education, and higher hip FRAX scores than those with mid/high level of knowledge. Also, they were less likely to receive osteoporosis counseling by their primary care physicians (PCP), have prior BMD measurement, receive bisphosphonates/raloxifene treatment, and to take calcium and vitamin D supplements. CONCLUSIONS: In this population of Hispanic patients with a first osteoporotic fracture, the majority had a low level of knowledge about osteoporosis. Low knowledge was associated with low socio-economic status, lack of counseling about osteoporosis by PCP, prior BMD measurement, and osteoporosis treatment. Better efforts should be undertaken to educate, identify, and manage patients at risk for osteoporotic fractures.

Substantial under-treatment among women diagnosed with osteoporosis in a US managed-care population: a retrospective analysis.

BACKGROUND: Multiple therapies are approved for the treatment of osteoporosis (OP), but many patients with osteoporosis may not initiate treatment upon osteoporosis diagnosis. OBJECTIVE: To characterize initiation of pharmacologic OP treatment among women within 1 year of OP diagnosis in a US managed care population. RESEARCH DESIGN AND METHODS: The retrospective cohort study included women aged ≥55 years with a claims-documented diagnosis of OP who were naïve to OP medications prior to OP diagnosis (index date) during 2001-2010. Continuous enrollment for 12 months before (baseline) and after (follow-up) the index date was required. Patients who received OP medications but did not have an OP diagnosis were excluded. Differences in baseline characteristics between the treated and untreated cohorts were compared using Wilcoxon rank-sum (continuous variables) and chi-square tests (categorical variables). MAIN OUTCOMES MEASURES: During the follow-up period, the percentages of patients treated with bisphosphonates (alendronate, ibandronate, risedronate, zoledronic acid) and non-bisphosphonates (calcitonin, raloxifene, teriparatide) were determined. RESULTS: A total of 65,344 patients, mean age 65.7 years, met study inclusion exclusion criteria. During the follow-up period, 42,033 patients (64.3%) received no OP medication and 23,311 patients (35.7%) received OP treatment. A total of 20,200 patients (30.9% of total study population) received bisphosphonates and 3111 (4.8% of total) patients received non-bisphosphonates as their index medication. At baseline, untreated patients were slightly older and had higher rates of hypertension, chronic inflammatory joint disease, diabetes mellitus, and gastrointestinal events (p ≤ 0.01) compared with treated patients. CONCLUSIONS: Among women aged ≥55 years in a US managed-care population, 64.3% received no pharmacologic treatment within 1 year after being diagnosed with OP. The authors were not able to determine if untreated patients did not receive or did not fill a prescription. Further research is needed to understand the barriers to OP treatment and reasons for non-treatment.

Comparative cost-effectiveness of bazedoxifene and raloxifene in the treatment of postmenopausal osteoporosis in Europe, using the FRAX algorithm.

UNLABELLED: Bazedoxifene and raloxifene were evaluated in the treatment of postmenopausal osteoporosis from health economic perspective in Europe. Based on a computer-based algorithm calculating efficacy of the treatments, bazedoxifene appears to be a cost-effective strategy compared to raloxifene, particularly in patients at high fracture risk. INTRODUCTION: The purpose of this study was to compare cost-effectiveness of bazedoxifene and raloxifene in eight European countries: Belgium, France, Germany, Ireland, Italy, Spain, Sweden, and the UK. METHODS: The Fracture Risk Assessment Tool, which is a computer-based algorithm to calculate fracture probability using clinical risk factors alone or with bone mineral density, was incorporated in a Markov Tunnel model to evaluate cost-effectiveness of bazedoxifene 20 or 40 mg vs. raloxifene 60 mg in postmenopausal osteoporotic women. The efficacy of bazedoxifene and raloxifene for vertebral and non-vertebral fractures was measured as a function of the 10-year probability of a major osteoporotic fracture. The model estimated the incremental cost-effectiveness ratio and net monetary benefit (NMB) from a healthcare perspective, given the willingness to pay 30,000. RESULTS: In postmenopausal osteoporotic women, bazedoxifene was a cost saving strategy compared to raloxifene in the countries studied. The median NMB of bazedoxifene compared to raloxifene increased monotonically with the 10-year fracture probability. In general, the median NMB became greater than 0 in women with 10-year probabilities of a major osteoporotic fracture between 5 and 10% or above. The impact on results by varying the assumptions in the model was examined in sensitivity analysis. CONCLUSION: Bazedoxifene appears to be a cost-effective strategy compared to raloxifene for the treatment of postmenopausal osteoporotic women in Europe, particularly in patients at high fracture risk.

Adherence to raloxifene therapy: assessment methods and relationship with efficacy.

UNLABELLED: Response to therapy depends on patient compliance but accurate assessment is difficult and adequate levels of adherence are uncertain. Adherence to raloxifene treatment may be assessed more accurately by electronic monitoring than by counting returned tablets. The level of adherence is positively associated with the degree of bone response. INTRODUCTION: Adherence to study medication is usually estimated by counting returned tablets. This method relies on subjects' honesty and may be inaccurate. We aimed to assess adherence more accurately, and examine its effect on measures of bone response, by using electronic monitoring. METHODS: Osteopenic women, ages 50 to 80, were prescribed daily raloxifene for 2 years. Electronic bottle caps (Medication Event Monitoring System (MEMS), Aardex) recorded the date and time on opening. Returned tablets were also counted. We measured bone mineral density (BMD) in duplicate at the spine and hip at baseline and 2 years. We also measured urinary N-terminal cross-linked telopeptide of type I collagen (NTX) at baseline, 1 and 2 years. We calculated the percentage changes in BMD and NTX from mean baseline to mean follow up measurements. Percentage adherence was assessed by both methods for 71 subjects that completed the study. RESULTS: The two methods correlated significantly (p <0.001, Spearman's rho = 0.73) but the tablet count showed a higher median adherence than the MEMS caps (95.7 vs. 85.0%, p <0.001), with greater divergence at lower adherence levels. MEMS adherence in 65 subjects with complete data correlated with NTX response (p <0.01, rho = -0.33) but with BMD response only at the femoral neck. However, adherence in the lowest quartile was associated with poorer BMD response at all sites (p <0.05). CONCLUSION: Tablet counts may give similar results overall but conceal substantial individual non-adherence. Monitoring caps may assess adherence more accurately than tablet counts and would be the preferred method in clinical trials. The degree of adherence is associated with both bone turnover and BMD responses to anti-resorptive therapy.