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- Osteonecrosis of the jaw in a patient on raloxifene: A case report. [JOURNAL ARTICLE]
- Quintessence Int 2014 Oct 16.
Osteonecrosis of jaws (ONJ) is a chronic disease characterized by necrotic bone from any number of causes. ONJ can also occur due to several systemic and local factors which compromise blood flow within the bone. Among anti-resorptive medications, a very low risk of ONJ development is associated with oral bisphosphonates used for the management of osteopenia, osteoporosis, and Paget's disease. Raloxifene is a nonsteroidal benzothiophene which is classified as a selective estrogen receptor modulator (SERM). It is commonly used for the prevention and the treatment of osteoporosis in postmenopausal women and was recently approved to reduce the risk of breast cancer. Raloxifene is regarded as a safe alternative in the management of osteoporosis in terms of ONJ development. This report presents a case of ONJ in a patient receiving raloxifene, who presented with existing comorbidities and a history of discontinued oral bisphosphonates use. The clinical report is followed by a discussion aimed to clarify how the general practitioner should consider similar cases.
- Selective estrogen-receptor modulators suppress microglial activation and neuronal cell death via an estrogen receptor-dependent pathway. [JOURNAL ARTICLE]
- J Steroid Biochem Mol Biol 2014 Oct 8.
Growing evidence shows that steroid hormones, especially 17β-estradiol (E2), protect neuronal cells by attenuating excess activation of microglia. However, the use of E2 in the clinic is controversial because of its peripheral actions in reproductive organs and its potential to increase risk for endometrial cancer and breast cancer. Selective estrogen-receptor modulators (SERMs) bind to estrogen receptors (ERs), but their effects as ER agonists or antagonists are dependent on the target tissue. SERMs pose very little cancer risk as a result of their anti-estrogen action in reproductive organs, but their action in the brain is not well understood. In this study, we investigated the effects of SERMs tamoxifen (Tam) and raloxifene (Rlx) on microglial activation and subsequent neuronal injury. Tam and Rlx suppressed the increases in proinflammatory cytokines and chemokine expression that were induced by lipopolysaccharide (LPS) in rat primary microglia cultures. The microglial-conditioned media pretreated with Tam or Rlx significantly attenuated cellular injury in SH-SY5Y cells elicited by microglial-conditioned media treated with LPS alone. Rat primary microglia expressed ERα and ERβ primarily in the nucleus, and thus we examined the involvement of ERs in the suppressive action of Tam and Rlx on microglial activation using a pure ER antagonist, ICI182,780. Pretreatment with ICI182,780 abolished the suppressive effects of SERMs on microglial activation, as well as their protective action on SH-SY5Y cells. A luciferase assay using a vector with three estrogen response elements (EREs) revealed that Tam and Rlx activated ERE-mediated transcription in rat primary microglia. Taken together, these results suggest that Tam and Rlx suppress microglial activation and subsequent neuronal cell death via an ER-mediated transcription pathway. SERMs could represent a novel therapeutic strategy for disorders of the central nervous system based on their ability to suppress neuroinflammation.
- Quality of life in Japanese women with postmenopausal osteoporosis treated with raloxifene and vitamin D: post hoc analysis of a postmarketing study. [JOURNAL ARTICLE]
- Curr Med Res Opin 2014 Oct 9.:1-33.
Abstract Objectives: To assess the effect of active vitamin D3 on quality of life (QOL) and pain in raloxifene-treated Japanese women with postmenopausal osteoporosis. Research design and methods: This is a post hoc analysis of a previous prospective postmarketing observational study conducted without a comparator group. This study was conducted in 60 Japanese hospitals from September 2007 to February 2009. We compared changes from baseline in QOL and pain in patients receiving raloxifene plus active vitamin D3 with those in patients receiving raloxifene monotherapy at 8 and 24 weeks after treatment. Clinical trial registration: Japan Pharmaceutical Information Center (JapicCTI-070465) Main outcome measures: QOL and pain were assessed using Short Form-8 (SF-8), European Quality of Life Instrument 5-Dimensions (EQ-5D), Japanese Osteoporosis Quality of Life Questionnaire (JOQOL), visual analogue pain scales (VAS-pain), and pain frequency scores. Results: A total of 506 patients were included in the post hoc analysis. Both raloxifene monotherapy (RLX, n =354) and active vitamin D3 cotreatment (COMBI, n = 152) significantly improved QOL and reduced pain from the baseline at Week 8 and Week 24. The COMBI group had significantly greater improvements in JOQOL total score and activity of daily living (total) domain at Week 24 and last observation carried forward (LOCF) than the RLX group. The COMBI group also had significantly greater improvements in SF-8 domains of general health (at Week 8, Week 24, and LOCF), role physical (at Week 24 and LOCF), and mental health (at LOCF) than the RLX group. The COMBI group also had significantly greater reduction in VAS-pain at LOCF than the RLX group (mean [SD]: RLX = -0.99 [2.72], COMBI = -1.54 [2.21], P = 0.042). Conclusions: Active vitamin D3 supplementation to raloxifene treatment for 24 weeks may have additional benefits in improving QOL and relieving pain in Japanese women with postmenopausal osteoporosis.
- Potential role of network meta-analysis in value-based insurance design. [Journal Article]
- Am J Manag Care 2014 Aug; 20(8):641-8.
Objectives Value-based insurance design (V-BID) has emerged as an approach to improve health outcomes and contain healthcare costs by encouraging use of high-value care. We estimated the impact of a V-BID for osteoporosis treatments using comparative effectiveness evidence and real-world data from a California health insurance plan to estimate the benefits of the design's implementation. Methods This study consisted of 4 steps. First, we reviewed randomized clinical trials including osteoporosis treatments-alendronate, ibandronate, risedronate, raloxifene, and teriparatide-reported in a recent Agency for Health Research Quality systematic review. Second, we performed a network meta-analysis to synthesize data from the clinical trials and estimate the comparative effectiveness of included treatments. Third, we implemented a V-BID by removing co-payments for the most effective treatments. Fourth, using a Monte Carlo simulation, we estimated the impact of the V-BID in terms of fracture reduction and cost-savings. Results Thirty-two randomized controlled trials were included in the network meta-analysis. We estimated that alendronate, risedronate, and teriparatide have the highest probability of being most effective across each fracture type-vertebral, hip, and nonvertebral/ nonhip. After eliminating co-payments, (ie, reducing them to zero), for these treatments, we estimated the health plan would experience a 7% (n = 287) decrease in fractures and an 8% ($6.8 million) decrease in costs. Conclusions Our study illustrates the benefits of comparative effectiveness evidence in V-BID development. We show that where clinical trials are lacking, network meta-analysis can provide valuable insights into the potential clinical and economic benefits of V-BID.
- Selenium analogues of raloxifene as promising antiproliferative agents in treatment of breast cancer. [JOURNAL ARTICLE]
- Eur J Med Chem 2014 Sep 30.:471-483.
Synthetic protocols for the preparation of selenium analogues of raloxifene were elaborated. General aim of the current research is to improve the positive impact of selenium atom introduction in drug design. Antiproliferative activity on CCL-8 (mouse sarcoma), MDA-MB-435s (human melanoma), MES-SA (human uterus sarcoma), MCF-7 (human breast adenocarcinoma), HT-1080 (human fibrosarcoma), MG-22A (mouse hepatoma) tumor cell lines, and normal cell line NIH 3T3 (mouse fibroblasts) was studied. Influence of aminoethoxy "tail" and benzoyl group position on SAR was discussed. Results of in vivo studies on BALB/c female mice with 4T1 cell induced breast cancer model showed that selenium analogue of raloxifene is able to suppress estrogen-depending tumor growth.
- Role of Nociceptor Estrogen Receptor GPR30 in a Rat Model of Endometriosis Pain. [JOURNAL ARTICLE]
- Pain 2014 Sep 30.
Endometriosis, the most common cause of chronic pelvic pain, is an estrogen-dependent disease in which classic estrogen receptors (ERα, ERβ) play an important role. While recent evidence suggests that the novel G protein-coupled estrogen receptor (GPR30) also plays a key role in the progression of endometriosis, whether it is also involved in endometriosis pain is still unknown. Here we tested the hypothesis that GPR30 expressed by nociceptors contributes to endometriosis pain. Intramuscular injection of the GPR30 agonists raloxifene or 17β-estradiol produced a fast-onset, persistent, mechanical hyperalgesia at the site of the injection. Intrathecal antisense (AS) oligodeoxynucleotides (ODN), but not mismatch (MM) ODN, targeting mRNA for GPR30 markedly inhibited its protein expression in nociceptors and attenuated the mechanical hyperalgesia induced by local raloxifene or 17β-estradiol. Pre-treatment with the GPR30 antagonist G-36 also inhibited the hyperalgesia induced by raloxifene or 17β-estradiol, in naïve control rats. Surgical implant of autologous uterine tissue onto the gastrocnemius muscle, which induces endometriosis-like lesions, produced local mechanical hyperalgesia. Intrathecal AS, but not MM, ODN targeting GPR30 mRNA reversibly inhibited the mechanical hyperalgesia at the site of endometriotic lesions. Finally, intralesional injection of the GPR30 antagonist G-36 also inhibited the mechanical hyperalgesia at the site of ectopic uterine tissue. We conclude that local GPR30 agonists produce persistent mechanical hyperalgesia in naïve female rats, whereas local GPR30 antagonists inhibit mechanical hyperalgesia in a model of endometriosis pain. Thus, GPR30 expressed by nociceptors innervating ectopic uterine lesions might play a major role in endometriosis pain.
- Novel hydroxyapatite biomaterial covalently linked to raloxifene. [Letter, Research Support, Non-U.S. Gov't]
- Int J Immunopathol Pharmacol 2014 Jul-Sep; 27(3):437-44.
Since raloxifene, a drug used in osteoporosis therapy, inhibits osteoclast, but not osteoblast functions, it has been suggested to improve recovery during implant surgery. The present paper describes an effective method to link raloxifene, through a covalent bond, to a nano-Hydroxyapatite-based biomaterial by interfacing with (3-aminopropyl)-Triethoxysilane as assessed by Infra Red-Fourier Transformed (IR-FT) spectroscopy and Scanning Electron Microscope (SEM). To evaluate the safety of this modified new material, the vitality of osteoblast-like cells cultured with the new biomaterial was then investigated. Raloxifene-conjugated HAbiomaterial has been shown to be a safe material easy to obtain which could be an interesting starting point for the use of a new functional biomaterial suitable in bone regeneration procedures.
- Back pain in patients with severe osteoporosis on teriparatide or antiresorptives: a prospective observational study in a multiethnic population. [Journal Article]
- Singapore Med J 2014 Sep; 55(9):493-501.
We evaluated reduced back pain in a multiethnic population treated with teriparatide and/or antiresorptives in real-life clinical settings over 12 months.This prospective observational study comprised 562 men and postmenopausal women (mean age 68.8 years) receiving either teriparatide (n = 230), antiresorptives (raloxifene or bisphosphonates; n = 322), or both (n = 10) for severe osteoporosis. The primary endpoint was the relative risk of new/worsening back pain at six months.At baseline, a higher proportion of teriparatide-treated than antiresorptive-treated patients had severe back pain (30.9% vs. 17.7%), extreme pain/discomfort (25.3% vs. 16.8%), extreme anxiety/depression (16.6% vs. 7.8%) and were confined to bed (10.0% vs. 5.3%). Teriparatide-treated patients had higher visual analog scale (VAS) scores for pain (5.8 ± 2.42 vs. 5.1 ± 2.58) and lower mean European Quality of Life-5 Dimensions (EQ-5D) scores (37.7 ± 29.15 vs. 45.5 ± 31.42) than antiresorptive-treated patients. The incidence of new/worsening back pain at six months for patients on teriparatide and antiresorptives was 9.8% and 10.3% (relative risk 0.99, 95% confidence interval 0.80-1.23), respectively. The incidence of severe back pain at 12 months was 1.3% and 1.6% in the teriparatide and antiresorptive treatment groups, respectively. Teriparatide-treated patients had lower mean VAS (2.71 ± 2.21 vs. 3.30 ± 2.37) and EQ‑5D (46.1 ± 33.18 vs. 55.4 ± 32.65) scores at 12 months. More teriparatide-treated patients felt better (82.7% vs. 71.0%) and were very satisfied with treatment (49.4% vs. 36.8%) compared to antiresorptive-treated patients.Patients treated with either teriparatide or antiresorptives had similar risk of new/worsening back pain at six months.
- Effects of hormone therapy on blood pressure. [JOURNAL ARTICLE]
- Menopause 2014 Sep 29.
Although hormone therapy remains the most efficacious option for the management of vasomotor symptoms of menopause, its effects on blood pressure remain unclear. This review scrutinizes evidence of the mechanisms of action of hormone therapy on signaling pathways affecting blood pressure and evidence from clinical studies.Comprehensive Ovid MEDLINE searches were conducted for the terms "hypertension" and either of the following "hormone therapy and menopause" or "selective estrogen receptor modulator" from year 2000 to November 2013.In vitro and physiologic studies did not reveal a clear deleterious effect of hormone therapy on blood pressure. The effect of oral therapy was essentially neutral in large trials conducted in normotensive women with blood pressure as primary outcome. Results from all other trials had several limitations. Oral therapy had a neutral effect on blood pressure in hypertensive women. Transdermal estrogen and micronized progesterone had a beneficial effect on blood pressure in normotensive women and, at most, a neutral effect on hypertensive women. In general, tibolone and raloxifene had a neutral effect on blood pressure in both hypertensive and normotensive women.Large randomized trials are needed to assess the effect of oral hormone therapy on blood pressure as a primary outcome in hypertensive women and the effect of transdermal preparations on both normotensive and hypertensive women. Transdermal preparations would be the preferred mode of therapy for hypertensive women, in view of their favorable physiologic and clinical profiles. The decision regarding the use of hormone therapy should be individualized, and blood pressure should be monitored during the course of treatment.
- Proposal on Raloxifene use after prophylactic salpingo-oophorectomy in BRCA1-2: hypothesis and rationale. [Journal Article]
- Eur J Cancer Prev 2014 Nov; 23(6):514-5.