Raloxifene Treatment Research Articles

Update on Raloxifene

Raloxifene is the only selective estrogen receptor modulator approved for long-term treatment in the prevention of osteoporotic fractures and for the reduction of invasive breast cancer risk in post-menopausal women. The demonstrated beneficial effects on bone and mammalian tissue led clinical and molecular research to focus mainly on these organs, giving less attention to all other systemic effects. The aim of this review was to evaluate all described systemic effects of raloxifene, investigating its molecular and tissutal mechanism of action. A literature research was carried out in electronic databases MEDLINE, EMBASE, ScienceDirect, and the Cochrane Library in interval time between 2000 and 2012. Outcomes were considered in relation to positive/adverse effects concerning bone metabolism, lipid metabolism, coagulation pattern, menopausal symptoms, breast cancer onset, and endometrial cancer onset. Raloxifene acts as an estrogen agonist or antagonist depending on the tissue. This feature is related to specific actions on at least 2 distinct estrogen receptors, whose proportions vary according to tissue type. Raloxifene is a drug for the treatment of osteoporosis and for the prevention of estrogen receptor-positive breast cancer because it guarantees a safety profile on the endometrium. Raloxifene is furthermore an effective therapy in women with increased levels of plasma cholesterol. Raloxifene treatment shifts the coagulation pattern toward prothrombosis, and the patients should be exhaustively informed about the risks associated with therapy. Raloxifene does not show to affect memory and cognition. Finally, it is noteworthy that quality-of-life studies demonstrated some favorable effects of raloxifene.

Adherence to raloxifene therapy: assessment methods and relationship with efficacy

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. 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. 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. 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). 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.

Investigator-initiated pilot study of bicalutamide and raloxifene in hormone-resistant prostate cancer.

e16065 Background: Estrogens, in addition to androgen may contribute to the progression of prostate cancer.The combination of bicalutamide, a non-steroidal anti-androgen, and raloxifene, a selective estrogen receptor modulator, has a synergistic effect on cell death of prostate cancer cell lines such as DU145 and PC3. We investigated the safety of combined treatment of bicalutamide and raloxifene on quality of life in patients affected by hormone-resistant prostate cancer. Methods: Eligibility requirements included metastatic hormone-resistant prostate cancer, Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received the combination of bicalutamide, 50 mg, and raloxifene, 60 mg, daily in 28 day cycles for a maximum of 6 cycles. The primary endpoint was to describe the adverse event profile of combined treatment with bicalutamide and raloxifene. The secondary endpoint was to describe the quality of life of patients receiving the combination. Adverse events were graded by the investigator using the NCI Common Terminology Criteria for Adverse Events version 4.0 and the quality of life was assessed by the patient using aLinear Analog Scale Assessment (scale of 0-100). Serum levels of estradiol and testosterone were monitored during treatment. Results: Eighteen evaluable patients were included in the statistical analysis after an initial run-in safety cohort of six patients. Two patients completed 6 cycles per protocol, the remaining sixteen patients were taken off protocol after disease progression. Patients completed a median of 2 cycles. There were no grade 4 events and grade 3 adverse events consisted of hypertension (5.6%) and back pain (5.6%). Erectile dysfunction (grade 1) was the most common adverse event (77.8%). Patient assessment of quality of life (mental, physical, social, emotional, spiritual) did not reveal any statistically different changes after 2 cycles of treatment. An analysis of testosterone and estradiol levels will be reported. Conclusions: We conclude that combination of bicalutamide and raloxifene is well-tolerated. The combination of androgen and estrogen receptor blockade warrants further study for efficacy in hormone-resistant prostate cancer. Clinical trial information: NCT01050842.

RETRACTED ARTICLE: Extranuclear ERα is associated with regression of T47D PKCα-overexpressing, tamoxifen-resistant breast cancer

BackgroundPrior to the introduction of tamoxifen, high dose estradiol was used to treat breast cancer patients with similar efficacy as tamoxifen, albeit with some undesirable side effects. There is renewed interest to utilize estradiol to treat endocrine resistant breast cancers, especially since findings from several preclinical models and clinical trials indicate that estradiol may be a rational second-line therapy in patients exhibiting resistance to tamoxifen and/or aromatase inhibitors. We and others reported that breast cancer patients bearing protein kinase C alpha (PKCα)- expressing tumors exhibit endocrine resistance and tumor aggressiveness. Our T47D:A18/PKCα preclinical model is tamoxifen-resistant, hormone-independent, yet is inhibited by 17β-estradiol (E2) in vivo. We previously reported that E2-induced T47D:A18/PKCα tumor regression requires extranuclear ERα and interaction with the extracellular matrix.MethodsT47D:A18/PKCα cells were grown in vitro using two-dimensional (2D) cell culture, three-dimensional (3D) Matrigel and in vivo by establishing xenografts in athymic mice. Immunofluoresence confocal microscopy and co-localization were applied to determine estrogen receptor alpha (ERα) subcellular localization. Co-immunoprecipitation and western blot were used to examine interaction of ERα with caveolin-1.ResultsWe report that although T47D:A18/PKCα cells are cross-resistant to raloxifene in cell culture and in Matrigel, raloxifene induces regression of tamoxifen-resistant tumors. ERα rapidly translocates to extranuclear sites during T47D:A18/PKCα tumor regression in response to both raloxifene and E2, whereas ERα is primarily localized in the nucleus in proliferating tumors. E2 treatment induced complete tumor regression whereas cessation of raloxifene treatment resulted in tumor regrowth accompanied by re-localization of ERα to the nucleus. T47D:A18/neo tumors that do not overexpress PKCα maintain ERα in the nucleus during tamoxifen-mediated regression. An association between ERα and caveolin-1 increases in tumors regressing in response to E2.ConclusionsExtranuclear ERα plays a role in the regression of PKCα-overexpressing tamoxifen-resistant tumors. These studies underline the unique role of extranuclear ERα in E2- and raloxifene-induced tumor regression that may have implications for treatment of endocrine-resistant PKCα-expressing tumors encountered in the clinic.

The SERM raloxifene improves diaphyseal fracture healing in mice

Although several studies reported that raloxifene treatment improves postmenopausal osteoporotic bone structure and reduces fracture risk, only a few animal and no human studies have examined its effects on the fracture healing process. Thus the aim of the present study was to determine, whether systemic application of the selective estrogen receptor modulator raloxifene promotes fracture healing compared to untreated control-, estrogen-deficient-, as well as estrogen-treated mice using a standardized femoral osteotomy model (n=60 mice). Ten days after surgery, contact radiography and undecalcified histomorphometric analysis revealed that raloxifene administration significantly improved the early stage of fracture healing compared to all other groups. At day 20, raloxifene and estrogen treatment led to a significant increase in callus mineralization and trabecular thickness compared to control mice. μCT analyses revealed no evidence of complete bony bridging of the fracture site in any control-, nor estrogen-deficient mouse after 20days, while all femoral fractures in the raloxifene and estrogen group already healed adequately at this time. These data indicate that raloxifene treatment significantly improves all phases of fracture healing at least in mice. Therefore, raloxifene could be a possible pharmaceutical to enhance fracture healing in women, without the known side effects of estrogen.

The effect of smoking on the response to raloxifene treatment in postmenopausal osteoporosis

Amac: Bu calismada amacimiz, postmenopozal osteoporoz tedavisinde raloksifen kullanan kadin-larda, sigara iciminin tedavinin etkinligine olan etkisini incelemektir. Gerec ve yontem: Bu kesitsel calismada, postmenopozal doneminde olan ve osteoporoz saptanan 88 (sigara icmeyen n= 54, sigara icen n= 34) olguya Raloksifen HCl (60 mg/gun) + 600 mg iyonize kalsiyum/gun + 400 IU vit D/gun tadavisi verildi. Tedavinin 1.yili sonunda 63 olguda (Sigara icmeyen grup n= 39, Sigara icen grup n= 24) DEXA yontemi kullanilarak L1-4 arasi lomber vertebra, femur trokanter, femur boynu ve total kalca (hip) bolgelerinde kemik mineral yogunluklari (gr/cm2) olculdu ve T skorlari hesaplandi. Iki grup arasinda tedavi sonuclari karsilastirildi. Sonuclar: Raloksifen tedavisine baslanmadan once her iki grubun ortalama yas (55,8 ±3,3\'e karsi 53,0 ±1,3 yil), menopoz yaslari (49,3 ±2,9\'a karsi 48,1 ±2,1 yil) menopoz suresi (5,0 ±1,3\'e karsi 7,0 ±1,4 yil), vucut kutle indeksleri (27,2 ±3,7\'e karsi 23,4 ±0,2 kg/m2) ve estradiol duzeyleri (26,0 ±3,7\'e karsi vs 23,4 ±0,2) arasinda anlamli farklilik saptanmadi (p> 0,05). Tedavinin baslangicinda BMD degerleri tum olcum bolgelerinde iki grup arasinda farkli degildi (p> 0,05). Raloksifenin BMD uzerine etkisi sigara icen ve icmeyen gruplara gore karsilastirildiginda sigara icmeyen grupta tum olcum bolgelerinde BMD degerlerinde belirgin duzelme saptanirken (p 0,05). Sonuc: Sigara icmek raloksifenin BMD uzerine olan tedavi etkinligini olumsuz yonde etkilemektedir.

Raloxifene and Bevacizumab for severe complications of hereditary haemorrhagic telangiectasia in a haemodialysis patient.

Hereditary haemorrhagic telangiectasia (HHT), or Osler–Weber–Rendu syndrome, is inherited in an autosomal-dominant fashion. There are two different forms of HHT: HHT type 1, caused by mutations in the endoglin gene, located in chromosome 9 (which encodes endoglin), and HHT type 2, caused by mutations in the gene encoding activin A receptor type II-like 1 (ALK1) on chromosome 12. Mucocutaneous telangiectasias, arteriovenous malformations, epistaxis, gastrointestinal bleeding and iron-deficiency anaemia are the commonest clinical manifestations of HHT [1]. Hepatic involvement, characterized by different arteriovenous malformations within the liver parenchyma, occurs in up to 74% of patients with HHT [2]. As far as we know, no information has been published on therapeutic alternatives for haemodialysis patients suffering from severe complications of HHT. We report on a 59-year-old woman with chronic renal failure secondary to bilateral renal hypoplasia and undergoing haemodialysis, who received the diagnosis of HHT. She had presented relapsing epistaxis during the last year, with severe anaemia and hypotension. Due to the need for weekly transfusions and the poor tolerance to haemodialysis sessions, we consider treatment with raloxifene (60 mg/day), a selective estradiol receptor modulator. Raloxifene increases the expression of endoglin and ALK1, whose synthesis is defective in HHT patients, at the surface of endothelial cells [3]. A remarkable improvement of HHT symptoms along with a significant decrease in the number and severity of epistaxis was observed after raloxifene treatment. However, 6 months after the onset of raloxifene treatment, the patient presented with signs and symptoms of high-output cardiac failure, with severe ascites and a left pleural effusion. Increase of haemodialysis ultrafiltration along with large-volume paracentesis were started, but the patient showed a poor tolerance to these measures, owing to the presence of anaemia, hypotension and chronic liver disease. Serum biochemistry demonstrated a progressive cholestasis. A computed tomography (CT) scan showed liver cirrhosis with splenomegaly and massive arteriovenous malformations (Figure 1). Prompted by the progressive clinical deterioration of the patient, we decided to start treatment with bevacizumab, a humanized recombinant monoclonal antibody against the vascular endothelial growth factor (VEFG). The VEGF is a key regulator of angiogenesis and is upregulated in a variety of diseases. On the other hand, endoglin and ALK1 are involved in the transforming growth factor-β signalling pathway, which is a potent stimulator of VEFG production. Bevacizumab has been shown to be effective in diseases of abnormal angiogenesis, improving survival and symptomatology [4, 5]. Bevacizumab has been also used for the treatment of liver complications of HHT, inducing a clear improvement [6]. After obtaining the patient's informed consent, six courses of bevacizumab (5 mg/kg) were administered during a 3-month period and raloxifene was maintained without changes. A further reduction in the frequency of epistaxis was observed besides a remarkable improvement of ascites and liver enzymes. As shown in Figure 1, serial CT scans demonstrated a clear diminution of hepatic vascularity and a smooth contour of the liver. Fig. 1. CT scan of the liver with intravenous contrast before and 6 months after bevacizumab treatment, showing a dramatic reduction of vascularity and improvement of liver surface. Many different therapies have been proposed for epistaxis and hepatic involvement in HHT, but none of them have shown conclusive results. Hormonal therapy with estradiol for epistaxis and gastrointestinal management of HHT has shown a variable degree of efficacy depending on the patient. According to our experience, both raloxifene and bevacizumab are very effective alternatives for the treatment of severe HHT in haemodialysis patients.

Divergent responsiveness of the dentary and vertebral bone to a selective estrogen-receptor modulator (SERM) in the teleost Sparus auratus

In teleosts the regulation of skeletal homeostasis and turnover by estrogen is poorly understood. For this reason raloxifene, a selective estrogen-receptor modulator (SERM), was administered to sea bream (Sparus auratus) and its effect on plasma calcium balance and transcript expression in dentary (dermal bone) and vertebra (perichondral bone) was studied. The concentration of total calcium or phosphorus in plasma was unchanged by raloxifene treatment for 6days. The activity of alkaline phosphatase (ALP) in dentary bone of raloxifene treated fish was significantly (p<0.05) higher than control fish but it was not changed in vertebral bone. Transcripts for estrogen receptor (ER) α were in very low abundance in the sea bream dentary and vertebra and were unchanged by raloxifene treatment. In contrast, raloxifene caused significant (p<0.05) up-regulation of the duplicate ERβ transcripts in the dentary but did not affect specific transcripts for osteoclast (TRAP), osteoblast (ALP, Runx2, osteonectin) or cartilage (IGF1, CILP2, FN1a). In the vertebra ERβb was not changed by raloxifene but ERβa was significantly (p<0.05) down-regulated as was the skeletal specific transcripts, TRAP, ALP, CILP2, FN1a. In summary, ERβs regulate estrogen sensitivity of the skeleton in sea bream, which responds in a non uniform manner. In common with mammals raloxifene appears to have an anti-resorptive role (in sea bream vertebra), but also an osteoblast stimulatory role, inducing ALP activity in the dentary of sea bream. Overall, the results indicate bone specific responsiveness to raloxifene in the sea bream. Further work will be required to understand the basis of bone responsiveness and the role of E2 and ERs in teleost bone homeostasis.

Raloxifene Inhibits Growth of RT4 Urothelial Carcinoma Cells via Estrogen Receptor-Dependent Induction of Apoptosis and Inhibition of Proliferation

Bladder cancer is the fifth most common type of cancer in the USA, with over 70,000 new cases diagnosed each year. Treatment often involves invasive surgical therapies, as chemotherapy alone is often ineffective and associated with high recurrence rates. Identification of estrogen receptor-β (ERβ) in up to 75 % of urinary tumors raises the question of whether this receptor could be targeted to effectively treat bladder cancer. In this study, a panel of five bladder cancer cell lines representing a variety of disease stage and grades were treated with the antiestrogens 4-hydroxytamoxifen, raloxifene, or the pure antagonist ICI 182,780. All cell lines were ERβ positive while only a few expressed estrogen receptor-α (ERα). Notably, all but the TCCSUP cell line were growth inhibited 20-100 % by at least two antiestrogens. Using RT4 cells, we demonstrate that growth inhibition by raloxifene is ER dependent and either ERα or ERβ can mediate this response. Activation of caspase-3 and its effector poly-ADP ribose polymerase (PARP) demonstrate that raloxifene-induced growth inhibition is in part the result of increased apoptosis; this PARP cleavage was ER dependent. Moreover, changes in the expression of cell cycle genes indicate that cell proliferation is also affected. Specifically, raloxifene treatment results in the stabilization of p27 protein, likely via the downregulation of S-phase kinase-associated protein (SKP2). Expression of the negative cell cycle regulator B-cell translocation gene (BTG2) is also increased, while cyclin D1 transcription is reduced. These results indicate that antiestrogens may be useful therapeutics in the treatment of bladder cancer by targeting ER and inhibiting growth via multiple mechanisms.

Correlation between a Bone Resorption Marker and Structural Geometry of the Proximal Femur in Osteoporotic Women Treated with Raloxifene

To assess correlations between a bone resorption marker and the structural geometry of the proximal femur in raloxifene-treated postmenopausal women with osteoporosis. 45 postmenopausal, osteoporotic women aged 57 to 79 (mean, 67) years underwent raloxifene treatment (60 mg/day) for 12 months. Serum type-I collagen crosslinked N-telopeptide (sNTX) as the bone resorption marker was measured at baseline and 6 months, whereas hip structure analysis (HSA) parameters of the femur (neck, intertrochanter, and shaft) were measured at baseline and 12 months using dual energy X-ray absorptiometry. The HSA parameters included areal bone mineral density (BMD), inner diameter, mean cortical thickness, cross-sectional area, section modulus, and buckling ratio. Correlations between sNTX and HSA parameters were analysed using Pearson's R. At baseline, sNTX correlated inversely with BMD, cross-sectional area, mean cortical thickness, and section modulus, and positively with buckling ratio in the intertrochanter and shaft (but not the neck). These correlations were significant both crude and adjusted for age. After 12 months of raloxifene treatment, HSA parameters improved significantly for the intertrochanter and shaft only. Of the 3 femoral sites, only the change in sNTX at month 6 correlated positively with changes in the inner diameter at the intertrochanter at month 12 (r=0.303, p=0.045 adjusted for age). Changes in sNTX did not correlate with changes in any other parameters. The surrogate markers for hip fracture including sNTX, BMD, and HSA parameters correlated significantly with each other. Improvement (decrease) of sNTX indicated reduction in bone resorption.

Safety and effectiveness profile of raloxifene in long-term, prospective, postmarketing surveillance

This large-scale postmarketing surveillance of raloxifene (60mg/day) was conducted to assess the safety and effectiveness of raloxifene for long-term use in postmenopausal Japanese women with osteoporosis. The baseline examination included 6,967 women (mean age, 70.4years). Participants completed observation after 6, 12, 24, and 36months of therapy. Adverse drug reactions (ADR) were reported in 776 participants (11.14%), with a total of 87 serious ADR cases occurring in 76 participants (1.09%). The most frequently reported ADRs were edema peripheral (45/6,967, 0.65%) and venous thromboembolism (11/6,967, 0.16%). Of the 6,967 participants, 2,784 were included in the effectiveness analysis. Lumbar spine bone mineral density (BMD) increased significantly (p<0.001, paired t test) compared with baseline at 6, 12, 24, and 36 months (2.51%, 2.85%, 4.76%, and 3.51%, respectively). Significant decreases in serum and urinary cross-linked amino-terminal telopeptide of type I collagen (NTX) and urinary deoxypyridinoline levels from baseline were observed at 3months, followed by a significant decrease of serum bone alkaline phosphatase at 6months [p<0.001 for all comparisons except serum NTX (p=0.011), Wilcoxon signed-rank test]. Early reductions in the biochemical markers of bone turnover (BTM) observed at 3months with raloxifene treatment correlated negatively with subsequent increases in lumbar spine BMD at 1year (r=-0.347, p=0.008). The incidence of any new clinical fractures within 3years was 1.18% (82/6,967 participants). In summary, no new signals in safety were observed in the daily use of raloxifene. Moreover, the effectiveness profile of raloxifene was confirmed in practical use by this large-scale, long-term, postmarketing surveillance.

Hypocalcemia Induced by Raloxifene

Raloxifene is an anti-resorptive agent used in postmenopausal osteoporosis. This is the first report of the occurrence of clinically significant hypocalcemia following raloxifene treatment in a patient with occult vitamin D deficiency. Since vitamin D deficiency is widely prevalent in the community, screening for vitamin D deficiency and its correction is advisable before the initiation of anti-resorptive therapy.

Effect of osteoporosis in postmenopausal breast cancer patients randomized to adjuvant exemestane or anastrozole: NCIC CTG MA.27.

501 Background: NCIC CTG MA.27 compared adjuvant steroidal [exemestane (E)] and non-steroidal [anastrozole (A)] aromatase inhibitors (AIs) and showed neither to be superior in breast cancer outcomes. AIs are known to increase the risk of osteoporosis. We examined the effects of baseline or subsequent self reported osteoporosis on disease outcomes. Methods: MA.27 enrolled 7,576 women. Event free survival (EFS) was the primary endpoint. Distant disease-free-survival (DDFS) was a secondary outcome. MA.27 permitted bisphosphonates to prevent or treat osteopenia or osteoporosis unless prohibited by enrollment to one of two cohorts in a bone substudy. Osteoporosis was considered present for this analysis if reported at baseline or prior to relapse or breast cancer death. Multivariate stratified Cox regression was used to examine the effects of trial therapy, osteoporosis, baseline patient and tumour characteristics on EFS; DDFS; bone only relapse; bone concurrent with other relapse; and non-bone recurrence. Bone marrow recurrence (N=8) was excluded. Results: Osteoporosis was reported at baseline by 654 of 7576 (8.6%) women, and prior to relapse by an additional 661 women. EFS events occurred in 693/7576 (9.15%). Osteoporosis was significantly associated with better EFS [HR 0.81 (95% CI 0.66-0.99), p=0.04] with no difference in multivariate HR of E vs A: 1.02, 95% CI 0.88-1.19, p=0.77. Women experienced 313 (4.1%) DDFS events. Osteoporosis was associated with better DDFS [HR 0.71 (95% CI 0.51-0.98), p=0.04], adjusted HR of E to A: 0.94 (95% CI of 0.75-1.17), p=0.56. Both EFS and DDFS interactions of osteoporosis with trial therapy were not significant (p&gt;0.05). Osteoporosis was not significantly associated with the site of relapse. Conclusions: Osteoporosis had a significant prognostic association with improved EFS and DDFS in women treated with AIs. We plan to investigate the use of bisphosphonates, raloxifene treatment prior to randomization, and markers of bone resorption with outcome.

The enhanced antiproliferative response to combined treatment of trichostatin A with raloxifene in MCF-7 breast cancer cells and its relevance to estrogen receptor β expression

Antiestrogen is one type of the endocrine therapeutic agents for estrogen receptor α (ERα)-positive breast cancer. Unfortunately, this treatment alone is insufficient. Here we reported a novel potential anticancer strategy by using histone deacetylase (HDAC) inhibitor to enhance the action of endocrine therapy in ERα-positive breast cancer cell. The well-described HDAC inhibitor, trichostatin A (TSA), and antiestrogen raloxifene were found to, respectively, inhibit E2-induced proliferation of MCF-7 breast cancer cell in a dose-responsive and time-dependent manner. TSA and raloxifene enhanced the antiproliferative activity of each other by promoting cell death via apoptosis and cell cycle arrest. Thus, they displayed better antiproliferative effects in combined treatment than that with either agent alone. The expression level of estrogen receptor β (ERβ) showed a marked increase after TSA or/and raloxifene treatment. Treatments with TSA or/and raloxifene resulting in the up-regulation of ERβ are in accordance with the antiproliferative effects of the two agents. Furthermore, the over-expression of ERβ by adenovirus delivery could inhibit the proliferation of MCF-7 tumor cells and drastically enhanced the antiproliferative effects of TSA and raloxifene. These results demonstrated that the interference of ERβ on the antiproliferative effects of HDAC inhibitor and antiestrogen constitutes a promising approach for breast cancer treatment.

A microarray study on the effect of four hormone therapy regimens on gene transcription in whole blood from healthy postmenopausal women

BackgroundPostmenopausal hormone therapy is associated with many diseases and conditions, e.g., cardiovascular diseases and asthma, but the underlying molecular mechanisms are incompletely understood. The aim of the current study was to investigate the effect of four different postmenopausal hormone therapy regimens on gene transcription. Materials and methodsTwenty-four healthy postmenopausal women (six women in four groups) were randomly allocated to conventional-dose 17β-estradiol/norethisterone acetate (NETA), low-dose 17β-estradiol/NETA, tibolone, or raloxifene hydrochloride. RNA was isolated from whole blood before and after 6weeks of treatment. The changes in mRNA were assessed with a microarray chip. ResultsThe genes FKBP5, IL13RA1, TPST1, and TLR2 were up-regulated and among the most significantly changed genes in the groups treated with conventional-dose 17β-estradiol/NETA and tibolone. Up-regulation of TPST1 was associated with reduction of tissue factor pathway inhibitor in plasma. Nine biological pathways were associated with conventional-dose 17β-estradiol/NETA, most significantly the pathways for asthma, toll-like receptor signaling, cell adhesion molecules, and MAPK signaling. Transcriptional changes with false discovery rate below 0.10 were found in 10 genes in the conventional-dose 17β-estradiol/NETA group, 7 genes in the tibolone group, and zero genes in the women on low-dose 17β-estradiol/NETA. No genes or pathways were associated with raloxifene treatment. ConclusionsThe difference between low-dose and conventional-dose17β-estradiol/NETA indicates an effect of dose on transcriptional response. Several genes and pathways related to cell adhesion molecules and immunity related cell surface receptors were influenced by conventional-dose 17β-estradiol/NETA.

Raloxifene in Hemodialysis Patients

Dear Editor, There is good news for the renal patients since more treatment options have been derived for Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD) apart from suppressing parathyroid hormone levels. The role of parathyroid hormone apparently seems to be clear. However, it is still unclear what ‘adynamic bone’ disease really means. Whether renal patients treated with supra-physiological parathyroid hormone would not suffer from adynamic bone disease? Or ‘adynamic bone disease’ is a specific form of osteoporosis in renal patients? The beneficial effect of raloxifene, an established osteoporosis treatment now has been shown on bone mineral density in both, diabetic and non-diabetic dialysis patients (1). Bone resorption was less, parathyroid hormone levels decreased and bone density was improved by raloxifene. Bone mineral density also improved while on raloxifene treatment in postmenopausal women with CKD before dialysis (2). Thus, ‘adynamic bone disease’ the presumed osteoporosis subtype of CKD-MBD could be seen as the metabolic consequence of sex hormone deficits. The next step might be a raloxifene trial even in men with CKD. At present it will be prudent, however, to use the lower dose of 60 mg per day since raloxifene exposure is higher in renal patients (3). In addition, such treatment should be restricted to 1 year because safety and cardiovascular risks after long-term use are still unknown in this population.

Significant Effect of Raloxifene on Bone in Hemodialysis Patients

Dear Editor, Attention should be drawn to the study by colleagues Saito O et al. published in the International journal of Endocrinology and Metabolism (1). The study suggests that raloxifene has a significant beneficial effect on bone in postmenopausal women with type 2 diabetes (2DM) undergoing hemodialysis (1). Hemodialysis patients are known to have a high risk of low bone mineral density and bone fractures (2). Furthermore, patients with 2DM are at high risk of bone fracture even if their BMD is normal or high, a phenomenon which might be explained by poor bone quality (3). Patients with 2DM and a need for hemodialysis at thus at specific risk, and it is thus highly relevant to search for new treatments that protect bone mass in this group of patients. Raloxifene is a selective estrogen receptor modulator (SERM) used in the prevention and treatment of postmenopausal osteoporosis (4). The present study by Saito O et al. is the first report of raloxifene for hemodialysis patients with 2DM using the same regimen as recommended for prevention and treatment of postmenopausal osteoporosis (3). The 1-year study included 60 postmenopausal women, 30 women with 2DM and 30 women without 2DM. The mean age was 66 years and the mean time since the start of hemodialysis was 5 years. The women were randomized to raloxifene 60 mg per day or no treatment securing a comparable number of patients in each of the 4 groups: plus minus raloxifene treatment, plus minus 2DM. Irrespective of whether the women had 2DM or not, the marker of bone resorption, N-terminal cross-linking telopeptide of type I collagen, NTx, a widely accepted marker of bone resorption (5), decreased by 13-20% whereas NTX increased by 2-3 % in the control groups receiving no raloxifene treatment. This corresponded to an increase of 0.5-1 % in heel speed of sound (SOS), a marker correlated with bone mineral density (BMD) (6), whereas SOS decreased by 0.8 % in the control group. The study thus indicates a uniform suppression of the increased bone resorption observed in hemodialysis patients (2). Although the study was only one year of duration the results are significant. The incidence of side effects was low, an aspect which is specifically important to this vulnerable group of patients. The effect of raloxifene was comparable to the effect seen in otherwise healthy postmenopausal women (3) suggesting a beneficial effect of raloxifene on bone regardless of the presence of 2DM or need for hemodialysis. Other studies have shown that a reduction in bone resorption and an increase in BMD are associated with a protection against fractures (5, 6). As the fracture rate was not obtained in this short-term study, this aspect, however, remains to be investigated in longer-term studies.

Safety of Raloxifene in Hemodialysis Patients

Dear Editor, With interest I read the article from Saito and colleagues about “the effects of raloxifene on bone metabolism in hemodialysis patients with type 2 diabetes” (1). The article addresses the possibility of treatment with raloxifene for osteoporosis in these patients. Raloxifene, a selective estrogen receptor modulator could be a good option, because it has no known renal side effects like bisphosphonates. Additionally, bisphosphonate use in chronic kidney disease is associated with adynamic bone disease, compared with a low bone turnover (2). In another trial in a group of 17 postmenopausal hemodialysis patients raloxifene improved lumbar spine Bone Mineral Density (BMD) by 2.6% in 53% of the patients while 70% of the control group consisting of 10 aged-matched women showed a reduction in BMD by 4%. The effects of raloxifene on serum calcium and serum iPTH level suggest it improves bone resorption (3). Primary, in these patients treatment of secondary hyperparathyroidism should be performed as is recommended (4). However of concern is the safety of raloxifene treatment in this patient group with multimorbidity. Long term studies should be performed to determine the efficacy and safety of raloxifene in hemodialysis patients. Diabetes mellitus and chronic kidney disease both have a negative effect on bone metabolism and there is an increased risk of vascular complications. In the dialysis population the incidence of myocardial infarction and stroke is 5- to 15 fold higher (5) and cardiovascular mortality is 10- to 30-fold higher (6) than seen in the general population (7-9). In this hemodialysis population with or without diabetes mellitus I would expect an increased risk of fatal stroke with raloxifene therapy. Taking into account the data of the RUTH-trial in 10101 postmenopausal women with a mean age of 67 years, with a high Framingham Stroke Risk Score (FSRS) ( ≥ 13), a 75% increased risk of raloxifene–associated fatal stroke was found. (HR 1.75; 95% CI, 1.01-3.02) (10). The FSRS includes the classical risk factors for cardiovascular disease including age, sex, systolic blood pressure, total and high density lipoprotein cholesterol, diabetes mellitus, smoking and echocardiogram based left ventricular hypertrophy (11-13). This score was originally validated for people aged up to 75 years (14). The FSRS also seems to underestimate the vascular risk in hemodialysis patients. The prevalence of traditional cardiovascular disease risk factors is very high in this hemodialysisgroup, but seems not to explain all of the increased cardiovascular risk (15). I would recommend a longer term randomized, double-blind, placebo-controlled trial in hemodialysis patients (subgroup analysis with or without diabetes mellitus). Raloxifene versus placebo should be given for 3 years with attention to the change in BMD and monitoring fractures and vascular complications. First it should be shown that the number needed to treat to prevent fracture is clearly smaller than the number needed to harm in a clinical trial of the duration of the required raloxifene treatment before raloxifene can be safely recommended as common practice in the treatment of osteoporosis in hemodialysis patients. Saito et al. performed an important preliminary study that warrants the investment of such a trial to reach the quality standard of safe and evidence based therapy in this vulnerable patient group.

Effects of Raloxifene on Bone Metabolism in Hemodialysis Patients

Effects of Raloxifene on Bone Metabolism in Hemodialysis Patients

Effects of 3 Years of Treatment with a Selective Estrogen Receptor Modulator for Postmenopausal Osteoporosis on Markers of Bone Turnover and Bone Mineral Density

Aim: The aim of the present study was to assess the changes in bone mineral density and bone turnover markers in long-term SERM. Methods: The study was performed on 25 female outpatients with primary osteoporosis treated at the Osteoporosis Department of Showa University School of Medicine. All patients had been on raloxifene (60mg/day) for ≥ 3 years. The mean patient age was 67.1 years and the women were, on average, 18.4 years postmenopausal. Levels of bone turnover markers (urinary naltrexone [NTX] and bone-specific alkaline phosphatase [BAP]) and bone mineral density (BMD; front lumbar vertebrae, three proximal femur sites, and two distal radius sites) were determined before and then annually after starting raloxifene for a period of 3 years. Results: Over the 3-year treatment period, significant decreases were seen in both urinary NTX and BAP levels. Although BMD of the lumbar vertebrae and distal radius was increased over the 3 years after initiation of raloxifene treatment, the difference failed to reach statistical significance. The BMD of the femoral neck decreased, whereas that of the femoral trochanter and femoral intertrochanter area increased. Conclusions: The selective estrogen receptor modulator raloxifene is suitable for the treatment of osteoporosis in postmenopausal patients because it reduces bone turnover while maintaining adequate bone density.