- Efficacy of Osteoporosis Therapies in Diabetic Patients. [REVIEW, JOURNAL ARTICLE]
- Calcif Tissue Int 2016 Jul 26.
Diabetes is characterized by increased fracture risk and by reduced bone strength for a given density. Contributing factors may include lower bone turnover and accumulation of advanced glycation endproducts. There are concerns that the pharmacological therapies for osteoporosis, particularly anti-resorptive therapies that suppress bone turnover, may not be as effective in the setting of diabetes. This review considers clinical trials and observational studies that have assessed the efficacy of anti-resorptive and anabolic therapies in diabetic patients. Post hoc analyses of randomized trials indicate that raloxifene has similar efficacy for prevention of vertebral fractures in diabetic compared with non-diabetic patients. Evidence from randomized clinical trials is lacking for anti-fracture efficacy of other osteoporosis therapies in diabetes. However, observational studies suggest that bisphosphonates are effective in preventing fractures in diabetic patients. The great majority of diabetic patients in studies to date have been type 2, and efficacy of osteoporosis therapies in type 1 diabetic patients remains to be addressed. Further evaluation of the efficacy of osteoporosis therapies in the setting of diabetes is needed to provide optimal fracture prevention for this population.
- Effect of antiresorptive drugs in the alveolar bone healing. A histometric and immunohistochemical study in ovariectomized rats. [JOURNAL ARTICLE]
- Clin Oral Investig 2016 Jul 27.
The aim of this study is to evaluate the alendronate and raloxifene influence in the alveolar healing process of osteoporotic rats.Sixty-four female rats were divided in four groups: sham rats (SHAM), ovariectomized rats and no medical treatment (OVX NT), ovariectomized rats and submitted to alendronate treatment (OVX ALE), and ovariectomized and submitted to raloxifene treatment (OVX RAL). The histomorphometrical and immunohistochemical analysis was performed. The quantitative data were analyzed through Kruskal-Wallis and Dunn tests (α = 0.05).In the longest period, SHAM and OVX RAL groups showed the better bone formation responses (P < 0.05). The worst bone formation response was observed in the group OVX NT. OVX RAL group showed the better response at 42 days. OVX ALE group showed a favorable response at 14 days, in comparison with OVX RAL group, but a reduced response at 42 days. It was possible to observe a mature bone in SHAM group at 14 days and an immature bone in the OVX NT group. An intermediate quality bone was observed in the groups OVX ALE and OVX RAL.Alendronate and raloxifene treatment improved the alveolar healing process in osteoporotic rats, but not enough to achieve the histometrical and protein expression values that were observed in the SHAM group.Alendronate is largely used as a potent antiresorptive agent. Otherwise, considering the undesirable effects in relation to the alveolar healing, other antiosteoporosis medications should be studied. Raloxifene seems to be a good candidate once its action mechanism involves the activation of osteoblasts.
- Estrogens and Coronary Artery Disease: New Clinical Perspectives. [Journal Article]
- Adv Pharmacol 2016.:307-60.
In premenopausal women, endogenous estrogens are associated with reduced prevalence of arterial hypertension, coronary artery disease, myocardial infarction, and stroke. Clinical trials conducted in the 1990s such as HERS, WHI, and WISDOM have shown that postmenopausal treatment with horse hormone mixtures (so-called conjugated equine estrogens) and synthetic progestins adversely affects female cardiovascular health. Our understanding of rapid (nongenomic) and chronic (genomic) estrogen signaling has since advanced considerably, including identification of a new G protein-coupled estrogen receptor (GPER), which like the "classical" receptors ERα and ERβ is highly abundant in the cardiovascular system. Here, we discuss the role of estrogen receptors in the pathogenesis of coronary artery disease and review natural and synthetic ligands of estrogen receptors as well as their effects in physiology, on cardiovascular risk factors, and atherosclerotic vascular disease. Data from preclinical and clinical studies using nonselective compounds activating GPER, which include selective estrogen receptor modulators such as tamoxifen or raloxifene, selective estrogen receptor downregulators such as Faslodex™ (fulvestrant/ICI 182,780), vitamin B3 (niacin), green tea catechins, and soy flavonoids such as genistein or resveratrol, strongly suggest that activation of GPER may afford therapeutic benefit for primary and secondary prevention in patients with or at risk for coronary artery disease. Evidence from preclinical studies suggest similar efficacy profiles for selective small molecule GPER agonists such as G-1 which are devoid of uterotrophic activity. Further clinical research in this area is warranted to provide opportunities for future cardiovascular drug development.
- Effect of Adjunctive Raloxifene Therapy on Severity of Refractory Schizophrenia in Women: A Randomized Clinical Trial. [JOURNAL ARTICLE]
- JAMA Psychiatry 2016 Jul 20.
A substantial proportion of women with schizophrenia experience debilitating treatment-refractory symptoms. The efficacy of estrogen in modulating brain function in schizophrenia has to be balanced against excess exposure of peripheral tissue. Raloxifene hydrochloride is a selective estrogen receptor modulator (mixed estrogen agonist/antagonist) with potential psychoprotective effects and fewer estrogenic adverse effects.To determine whether adjunctive raloxifene therapy reduces illness severity in women with refractory schizophrenia.This 12-week, double-blind, placebo-controlled, randomized clinical trial with fortnightly assessments was performed at an urban tertiary referral center and a regional center from January 1, 2006, to December 31, 2014. Participants included 56 women with schizophrenia or schizoaffective disorder and marked symptom severity despite substantial and stable antipsychotic doses. Data were analyzed using intention to treat as the basis.Adjunctive raloxifene hydrochloride, 120 mg/d, or placebo for 12 weeks.The primary outcome was the change in the Positive and Negative Syndrome Scale (PANSS) total score. Clinical response (defined as a ≥20% decrease in PANSS total score from baseline) and change in PANSS subscale scores, mood, cognition, reproductive hormone levels, and adverse events were also assessed.Of the 56 participants (mean [SD] age, 53 [7.7] years; age range, 40-70 years; mean [SD] duration of psychotic illness, 24  years), 26 were randomized to raloxifene and 30 were randomized to placebo. Raloxifene produced a greater reduction in the PANSS total score relative to placebo (β = -6.37; 95% CI, -11.64 to -1.10; P = .02) and resulted in an increased probability of a clinical response (hazard ratio, 5.79; 95% CI, 1.46 to 22.97; P = .01). A significant reduction was found in the PANSS general symptom scores for the raloxifene compared with the placebo (β = -3.72; 95% CI, -6.83 to -0.61; P = .02) groups. For patients who completed the full 12-week trial, there was not a statistically significant treatment effect on PANSS positive symptom scores (β for change in raloxifene vs placebo, -1.92; 95% CI, -3.83 to 0.00; P = .05). Change in mood, cognition, and reproductive hormone levels and the rate of adverse events did not differ between groups.Raloxifene hydrochloride, 120 mg/d, reduces illness severity and increases the probability of a clinical response in women with refractory schizophrenia. This large trial of raloxifene in this patient population offers a promising, well-tolerated agent that has potential application in clinical practice.clinicaltrials.gov Identifier: NCT00361543.
- Anti-Estrogen Withdrawal Effect With Raloxifene? A Case Report. [JOURNAL ARTICLE]
- Integr Cancer Ther 2016 Jul 13.
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.
- Relationship of ZNF423 and CTSO with breast cancer risk in two randomised tamoxifen prevention trials. [Journal Article]
- Breast Cancer Res Treat 2016 Aug; 158(3):591-6.
A case-control study from two randomised breast cancer prevention trials of tamoxifen and raloxifene (P-1 and P-2) identified single-nucleotide polymorphisms (SNPs) in or near genes ZNF423 and CTSO as factors which predict which women will derive most anti-cancer benefit from selective oestrogen receptor modulator (SERM) therapy. In this article, we further examine this question using blood samples from two randomised tamoxifen prevention trials: the International Breast Cancer Intervention Study I (IBIS-I) and the Royal Marsden trial (Marsden). A nested case-control study was designed with 2:1 matching in IBIS-I and 1:1 matching in Marsden. The OncoArray was used for genotyping and included two SNPs previously identified (rs8060157 in ZNF423 and rs10030044 near CTSO), and 102 further SNPs within the same regions. Overall, there were 369 cases and 662 controls, with 148 cases and 268 controls from the tamoxifen arms. Odds ratios were estimated by conditional logistic regression, with Wald 95 % confidence intervals. In the tamoxifen arms, the per-allele odds ratio for rs8060157 was 0.99 (95 %CI 0.73-1.34) and 1.00 (95 %CI 0.76-1.33) for rs10030044. In the placebo arm, the odds ratio was 1.10 (95 %CI 0.87-1.40) for rs8060157 and 1.01 (95 %CI 0.79-1.29) for rs10030044. There was no evidence to suggest that other SNPs in the surrounding regions of these SNPs might predict response to tamoxifen. Results from these two prevention trials do not support the earlier findings. rs8060157 in ZNF423 and rs10030044 near CTSO do not appear to predict response to tamoxifen.
- Clinician-Reported Barriers to Implementing Breast Cancer Chemoprevention in the UK: A Qualitative Investigation. [JOURNAL ARTICLE]
- Public Health Genomics 2016 Jul 12.
The use of tamoxifen and raloxifene as preventive therapy for women at increased risk of breast cancer was approved by the National Institute for Health and Care Excellence (NICE) in 2013. We undertook a qualitative investigation to investigate the factors affecting the implementation of preventive therapy within the UK.We recruited general practitioners (GPs) (n = 10) and clinicians working in family history or clinical genetics settings (FHCG clinicians) (n = 15) to participate in semi-structured interviews. Data were coded thematically within the Consolidated Framework for Implementation Research.FHCG clinicians focussed on the perceived lack of benefit of preventive therapy and difficulties interpreting the NICE guidelines. FHCG clinicians felt poorly informed about preventive therapy, and this discouraged patient discussions on the topic. GPs were unfamiliar with the concept of preventive therapy, and were not aware that they may be asked to prescribe it for high-risk women. GPs were reluctant to initiate therapy because it is not licensed, but were willing to continue a prescription if it had been started in secondary or tertiary care.Barriers to implementing preventive therapy within routine clinical practice are common and could be addressed by engaging all stakeholders during the development of policy documents.
- Neonatal exposure to SERMs disrupts neuroendocrine development and postnatal reproductive function through alteration of hypothalamic kisspeptin neurons in female rats. [JOURNAL ARTICLE]
- Neurotoxicology 2016 Jul 6.:64-75.
Selective estrogen receptor modulators (SERMs) are a class of therapeutic chemicals which present tissue-specific estrogen receptor modulating activity. Neonatal exposure to SERMs has been reported to adversely affect central nervous system development, however, mechanism and involvement of hypothalamic kisspeptin neurone in this impairment remains undetermined. To clarify this uncertainty, neonates from female Donryu rats were subcutaneously injected with raloxifene (RLX) at 0.1, 1, and 10mg/kg or tamoxifen (TMX) at 10mg/kg on postnatal day 0, and then hypothalamic KiSS1 mRNA expression and gonadotropin levels were investigated during young adulthood and estrous cycling was monitored until middle age. Treatment with RLX or TMX at 10mg/kg significantly depressed luteinizing hormone surge levels and KiSS1 mRNA expression in the anteroventral periventricular nucleus (AVPV), the control center of estrous cyclicity. The 10mg/kg TMX group also showed decreased levels of follicle-stimulating hormone and KiSS1 mRNA expression in the arcuate nucleus (ARC). Early cessation of normal estrous cycling was observed in the 10mg/kg RLX group, while the estrous cycle in the 10mg/kg TMX group had ceased by the start of the analysis. The same dose of tamoxifen or raloxifene had either weak-estrogenic or anti-estrogenic activity on the uterus, respectively; however, treatment in adulthood with both SERMs did not affect KiSS1 mRNA expression in either the AVPV or ARC in the present study. These results indicate that neonatal exposure to SERMs could disrupt neuroendocrine development and postnatal reproductive function through the alteration of kisspeptin neurons.
- Effect of aerobic exercise and raloxifene combination therapy on senile osteoporosis. [Journal Article]
- J Phys Ther Sci 2016 Jun; 28(6):1791-4.
[Purpose] This study assessed the effects of combined application of raloxifene and aerobic exercise on senile osteoporosis. [Subjects and Methods] A total of 70 elderly patients with osteoporosis, who treated at our hospital between April 2013 and August 2014, were divided into equal-sized observation and control groups. The control group was administered raloxifene, whereas the observation group received raloxifene treatment plus aerobic exercise. [Results] Outpatient outcomes were considered dependent variables. After treatment, the two groups differed significantly in terms of lumbar spine (L2-L4) and proximal femoral bone mineral density. The urine pyridine/creatinine ratio decreased significantly and serum calcitonin level increased significantly in the observation group. These differences were statistically significant. [Conclusion] Raloxifene combined with aerobic exercise therapy significantly improves bone density and promotes bone formation in patients with senile osteoporosis.
- Alendronate- and risedronate-induced acute polyarthritis. [JOURNAL ARTICLE]
- Osteoporos Int 2016 Jul 4.
Bisphosphonates are the mainstay treatment for postmenopausal osteoporosis. Although bisphosphonates are safety drugs, they have numerous side-effects such as arthralgia, elevated erythrocyte sedimentation rate and C-reactive protein, gastrointestinal disturbances, and flu-like illness with symptoms of fatigue, fever, chills, malaise, and myalgia. We present a case of acute polyarthritis after administration of alendronate and risedronate in a 52-year-old woman. To the best of the author's knowledge, this is the first case of acute polyarthritis induced by per os administration of both alendronate and risedronate during weekly usage. This is a report of a 52-year-old woman admitted to our hospital every week in a month, within 48 h, after receiving three times alendronate and one time risedronate with diffuse arthralgias, miyalgias, and swelling with effusions in both wrists, both ankles, interphalangeal joints in both hands and feet, and in both knees. When we discontinued alendronate and risedronate, oral raloxifene (60 mg/day) with oral calcium (1 g/day), and vitamin D3 (800 IU/day) was initiated. The symptoms regressed in 1 week. During the 1 year follow-up period, no myalgia, arthritis, or synovitis was detected. The side-effects of bisphosphonates are rarely reported in the literature. We believe that the prevalance of these side-effects would increase by closer follow-up of patients receiving these medications. To our knowledge, this patient is the first reported case of acute polyarthritis induced by per os administration of both alendronate and risedronate during weekly usage.