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Home , Ospemifene, Promestriene, Toremifene, Triphenylethylene, Vaginal estrogen

Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences 2016; 20: 3934-3944 : a safe treatment of vaginal atrophy

L. DEL PUP

Gynecological Oncology, Centro di Riferimento Oncologico, IRCCS - National Cancer Institute, Aviano (PN), Italy

Abstract. – OBJECTIVE : Vaginal atrophy is a Vaginal atrophy impairs quality of life in most chronic, progressive medical condition that af - menopausal women 4, but the management of fects fifty percent of postmenopausal women, vaginal dryness is particularly frequent e difficult causing symptoms like , vaginal 5 dryness, and vaginal irritation. Until recently, the in sensitive cancer patients . only prescription options were systemic and While there are effective, placebo -controlled, therapies that might be limited non -hormonal treatments for hot flushes 6, vaginal by concerns about long-term safety and moisturizes have been till now the only treatment cancer risk. The objective is to analyze the litera - which is considered safe. Unfortunately , they are ture about ospemifene, a tissue-selective estro - not satisfying if used alone with no proper estro - gen (SERM) recently ap - 7 proved for the treatment of vulvovaginal atrophy genic stimulation of . and dyspareunia and to compare its effects with A new class of drugs like selective estrogen re - those of the other SERMs to assess its safety. ceptor modulators (SERMs) can now offer a safe MATERIALS AND METHODS: Review. Medline and effective treatment of vaginal atrophy bypass - search. ing those problems. They are synthetic non- RESULTS: Ospemifene treats vaginal atrophy, steroidal agents that exhibit tissue-specific estro - and, if compared with other SERMS, it has no or 8 not significant effects on endometrium and gens’ receptor (ER) or antagonist activity . thromboembolism. Experimental and animal Each SERM has the ability to induce distinct models suggest an inhibitory effect on the structural changes in the receptor that influence growth of malignant breast tissue. The available the interaction with coactivators (CoA) or co re - clinical data support ospemifene breast safety. pressors (CoR ), which are involved in the regula - CONCLUSIONS: Ospemifene relieves moder - ate to severe symptoms of vulvovaginal atrophy, tion of target gene transcription. The resulting bi - like dryness, irritation and soreness around the ologic action can vary according to the specific genital area, and painful sexual intercourse, in type of ER, co -factors , responses and ligands menopausal women. It is well tolerated, and it leading to tissue -specific agonist and antagonist has neutral effects on endometrium and coagu - activity. Different ligands can induce distinct re - lation. Clinical trials and even long-term studies ceptor conformations in ER and ER , leading to on effects support ospemifene β overall safety. structures that are different than those seen with an unliganded receptor. Key Words: SERMs can exert a wide range of physiologi - Ospemifene, , , , cal effects related to both pathological and ther - SERM, Vaginal atrophy, , Breast cancer, density, Thromboembolism . apeutic processes, with unique and often dis - tinctly different patterns of ER subtype expres - sion seen in different tissues. They are used for various indications, including treatment of vagi - Introduction nal atrophy, breast cancer, osteoporosis , and ovulation induction . Vaginal atrophy has been treated for decades Based on their efficacy and long-term safety, with local . Some of them have demon - SERMs are being increasingly prescribed . Os - strated a very low local absorption 1,2 but still pemifene is a novel SERM, a some concern exists mostly for breast cancer pa - derivative , that is structurally similar to tamox - tients which have a precocious and strong atroph - ifen, but without the 2-(dimethylamino)ethoxy ic symptoms 3. region, making it safe for the endometrium, ef -

3934 Corresponding Author: Lino Del Pup, MD; e-mail: [email protected] Ospemifene: a safe treatment of vaginal atrophy fective for alleviating vaginal atrophy symptoms cancer. SERMs , considered as and according to the available data still protec - second-generation SERMs , include raloxifene tive, or at least neutral, for the breast and with no which is approved for the prevention of breast effect on . The present review aims at cancer and the prevention and treatment of osteo - helping clinicians understanding the role and porosis. Third-generation SERMs include baze - safety of ospemifene comparing it with the other doxifene and ospemifene , which also have antag - SERMS . onistic-antiestrogenic effects on the breast 9. Bazedoxifene is approved in combination with conjugated equine estrogens to treat vasomotor Materials and Methods symptoms and preventing osteoporosis. Os - pemifene is approved for the treatment of moder - A Medline search has been performed till Au - ate to severe symptoms of vulvovaginal atrophy gust 2016 using this strategy : ( “Ospemifene” (dryness, irritation and soreness around the geni - [Supplementary Concept] OR ospemifene[ti]) tal area, and painful sexual intercourse) in AND atrophy[mh]) OR ((Tamoxifen/adverse ef - menopausal women (check EMEA approval) . fects[Majr] OR Tamoxifen/toxicity[majr] OR Ta - Breast and endometrial cancer safety , and moxifen/therapeutic use[majr] OR Tamoxifen/ thromboembolic effects are key differentiators [majr] OR /adverse ef - among SERMs in clinical practice. For example, fects[Majr] OR Toremifene/TOXICITY[Majr] tamoxifen exhibits ER agonist activity in the OR Toremifene/therapeutic use[Majr] OR , resulting in an increased risk of endome - Toremifene/pharmacology[Majr]) AND Breast trial hyperplasia and malignancy, whereas os - [MAJR]) OR ((Raloxifene Hy - pemifene, raloxifene and bazedoxifene have neu - drochloride/adverse effects[majr] OR Raloxifene tral effects on the uterus 10 . Hydrochloride/TOXICITY[majr] OR Raloxifene SERMs as a class appear to have an increased Hydrochloride/therapeutic use[majr]) AND Os - risk of venous thromboembolism (VTE) similar teoporosis[Mh]) OR (Bazedoxifene/ADVERSE to estrogens , although available data on os - EFFECTS[majr] OR Bazedoxifene/therapeutic pemifene are reassuring 11 . use[majr]) OR (Selective Until large randomized controlled trials Modulators/adverse effects[Majr] OR Selective (RCTs) with cardiovascular primary endpoints Estrogen Receptor Modulators/contraindica - are performed, potential cardioprotective benefits tions[Majr] OR Selective Estrogen Receptor of SERMs will remain unclear . Central nervous Modulators/therapeutic use[Majr] OR Selective system effects are variable and not well defined. Estrogen Receptor Modulators/toxicity[Majr] )) There is some evidence of decreased effect on AND (ita[la] OR eng[la]) AND (review[pt] OR pro -inflammatory markers in women at neurode - systematic[sb] OR “”[Mesh] OR generative risk. SERMs as a class have shown an thrombos*[tiab] OR thrombot*[ti] OR “En - estrogen antagonist effect with a mild increase in dometrium/drug effects”[Mesh] OR “Uterine hot flashes, generally not enough significant to Diseases/chemically induced”[Mesh] OR discontinue therapy “Ovary/drug effects”[Mesh] OR “Ovarian Dis - Tamoxifen, raloxifene and bazedoxefine have eases/chemically induced”[Mesh]) ) NOT no direct positive effects on the , while os - (male[ti] OR men[ti]) . Other literature has been pemifene has them as the main beneficial effect 12 . collected using the following keywords: os - Most of the data on SERMs -relative estrogen pemifene, tamoxifen , raloxifene, bazedoxifene , receptors antagonistic or agonistic effects can be SERM, vaginal atrophy, endometrial cancer, species -dependent and come from preclinical da - breast cancer, , thromboembolism. ta ; therefore , any interpretation and comparison of preclinical vs . human findings must be made with caution. The strength of the antagonist and Results and Discussion agonist effect of ospemifene compared with oth - er SERMS in (A) Bone (B) endometrium and (C) SERMs show mixed agonist and antagonist breast are represented in Figure 1. activities depending on the target tissue. Triph - An overview of the comparative effects of the enylethylene SERMs, considered as first genera - most used SERMS and their main indications are tion SERMs, include tamoxifen and toremifene summarized in Table I and described in detail in which are approved to prevent and treat breast the following paragraphs.

3935 L. Del Pup

Figure 1. Strenght of the antagonist and agonist effect of ospemifene compared with other SERMS in (A) Breast (B) En - dometrium and (C) Bone. (Modified from Komm BS, Mirkin SJ. An overview of current and emerging SERMs. Biochem Mol Biol 2014; 143: 207-222).

OSPEMIFEN: Vaginal Atrophy lar to tamoxifen, but without the 2-(dimethy - Ospemifene is , as a SERM, an estrogen-recep - lamino)ethoxy region. Removal of this region has tor agonist/antagonist approved for the treatment been associated with reduced agonistic activity in of moderate-to-severe dyspareunia, a symptom of the uterus, and no effects on agonist activity in vulvovaginal atrophy, caused by . It is the cardiovascular system , explaining its putative a triphenylethylene derivative, structurally simi - neutral thromboembolic effect .

Table I. Overview of the comparative effects of the most used SERMS and their main indications.

Vagina Endometrium Breast Bone Venous thromboembolism Main indication

Ospemifene +++ = -- ++ = Vaginal Atrophy Tamoxifen = ++ --- ++ ++ Breast cancer Prevention Raloxifene ==-- +++ + Osteoporosis Bazedoxifene = =/- -- ++ + Menopause (+ Conjugated Equine Estrogens)

+: agonistic/stimulatory effect; -: antagonistic/inhibitory effect; =: neutral.

3936 Ospemifene: a safe treatment of vaginal atrophy

The binding affinity of ospemifene for ER cial cells (p < 0.0001), has decreased the percent - and ER β has been evaluated in a competitive age of parabasal cells (p < 0.0001), and has de - binding assay . Ospemifene has displaced labeled creased vaginal pH (p < 0.0001). 17 β-estradiol in a concentration-dependent man - Ospemifene has received its first marketing ner, with relative binding affinities of 0.8% and approval for the treatment of dyspareunia in post - 13 0.6% for ER and ER β, respectively and it is menopausal women in February 2013 by the comparable to 4-OH tamoxifen with a better FDA 22 and then in November 2014 by the EMEA safety profile because ospemifene does not have with the indication to treat moderate to severe an endometrial stimulatory effect 14 . symptoms of vulvovaginal atrophy (dryness, irri - tation and soreness around the genital area, and Vagina painful sexual intercourse) in women who have The most distinguishing effect of ospemifene been through menopause. It is used in women is its significant estrogenic effect on vaginal ep - who cannot use locally applied estrogen therapy. ithelium 15 . This is evidenced by an increase in in - termediate and superficial cells in repeated Pap Endometrium smears 16 . Ospemifene has no clinically significant en - Ospemifene estrogenic effect on the vaginal dometrial effects based on transvaginal ultra - epithelium , improves vaginal maturation index sonography and biopsies , in comparison to ralox - (VMI ), vaginal pH, dryness and dyspareunia 17 . ifene (thought to be neutral on the endometrium) The estrogenic effect on the vaginal epitheli - and tamoxifen (known to stimulate endometrial um of the treatment with ospemifene 30-90 mg tissue). for 3 months has been also demonstrated in a In a phase III study of postmenopausal women study on 119 patients with the disappearance of receiving ospemifene 30 or 60 mg or placebo for parabasal cells and the appearance of intermedi - up to 12 weeks, the mean change from baseline ate and superficial cells, in contrast to the ralox - for endometrial thickness has been 0.42, 0.72, ifene treatment, which has been resulting in no and −0.02 mm for ospemifene 30 mg, os - changes. There has been no associated endome - pemifene 60 mg, and placebo, respectively 20 . trial stimulation. In a randomized, double-blind, placebo-con - Also , the Kupperman index of climacteric trolled, parallel group study, women aged 40 to symptoms and visual analog scale scores for va - 80 years with VVA and an intact uterus , have somotor symptoms have been decreasing in this been randomized 6:1 to receive ospemifene 60 study 18 but not in another 19 . mg/day or placebo. The primary objective was 826 women have been randomized to receive 12-month safety, particularly endometrial 23 . ospemifene 30 mg, 60 mg, or placebo once dai - Safety assessments included endometrial his - ly in a 12-week study 20 . Ospemifene 30 or 60 tology and thickness, breast and gynecological mg significantly increased the percentage of su - examinations. Efficacy evaluations included perficial cells , significantly decreased the per - changes from baseline to week 12 in the percent - centage of parabasal cells and decreased vaginal age of superficial and parabasal cells and vaginal pH (p < 0.001 for each group relative to place - pH. Of the 426 randomized subjects, 81.9% com - bo) . By week 4 of treatment, a significant im - pleted the study, being adverse events as the most provement in the maturation index has been ob - common reason for discontinuation (ospemifene served for both ospemifene groups compared 9.5%; placebo 3.9%). Most (88%) treatment- with placebo (p < 0.001). The use of os - emergent adverse events in the ospemifene arm pemifene 60 mg significantly reduced dyspareu - were considered mild or moderate. Three cases nia by 12 weeks, also ospemifene 30 or 60 mg (1.0%) of active proliferation were observed in significantly decreased vaginal dryness in the the ospemifene group. For one, active prolifera - same period. tion was seen at the end of study (week 52), and , In another 12-week phase III trial, 605 post - on a follow-up biopsy 3 months after the last menopausal women with vulvovaginal atrophy dose, was diagnosed as a simple hyperplasia have been randomized to ospemifene 60 mg or without atypia. This subsequently resolved with placebo once daily 21 . treatment and dilatation and curet - Compared with placebo, ospemifene treatment tage. In six subjects (5 ospemifene [1.4%] and 1 has significantly reduced dyspareunia (p = placebo [1.6%]) endometrial polyps have been 0.0001), has increased the percentage of superfi - found (histopathology); however, only one (in

3937 L. Del Pup the ospemifene group ) has been confirmed as a Ospemifene has delayed the development of true polyp during the additional expert review. breast tumors, and average tumor volumes were Endometrial histology showed no evidence of smaller 31 . carcinoma. Statistically significant improvements Ospemifene has been found to be toxic to with ospemifene vs . placebo have been seen for MCF-7 cell lines and not on MDA-MB-231 cell all primary and secondary efficacy measures and lines so new structural analogs of ospemifene are have been sustained through week 52. screened for their activity against MCF-7 (ER- Ospemifene showed no endometrial stimula - positive) and MDA-MB-231 (ER-negative) hu - tion effect in a previous study too 18 . man breast cancer cell lines. The compounds There has been also no effect of ospemifene containing more polar groups like amine and on the appearance of proliferation marker Ki-67 amide are more potent than ospemifene against in the endometrium as compared with placebo, MCF-7 cells and are better even in the case of and endometrial thickness increased only by non-estrogen dependent MDA-MB-231 cells. mean 0.4 to 0.6 mm (p = 0.05), perhaps as a re - High in the case of amines and amides sult of increased uterine blood flow 16, 24 . could be due to their improved hydrogen bonding abilities 32 . Breast Ospemifene and tamoxifen are anti-breast can - Ospemifene has shown inhibiting effects on cer agents’ precursors of other analogs against breast tissue in both experimental, animal and ER-positive (MCF-7) and ER-negative (MDA- preliminary human clinical data . MB-231) human breast cancer cell lines that are Animal models with ospemifene suggest an in development 33 . inhibitory effect on the growth of malignant If compared with the other SERMs, it has been breast tissue, and clinical trials, including three reported that the presence of chlorine group in long-term studies assessing the overall safety of ospemifene reduces the antiestrogenic activity ospemifene, supporting that ospemifene is usual - and the introduction of azide group in some or - ly well tolerated, with neutral effects on the ganic molecules enhances the anticancer activi - breast, no significant effects on the endometrium ty 34 . and beneficial effects on the vagina 9. Breast Safety Data on Humans Breast Safety Experimental and The overall long -term breast safety of os - Animal Studies pemifene has been assessed also in humans 35,36 . Experimental in vitro and animal studies con - An initial 12-week study has been evaluating cordantly support the breast safety of the efficacy and of ospemifene 30 ospemifene 25-27 . mg/d and 60 mg/d in 826 women (ospemifene 30 In rat and human mammary cells in vitro , os - mg, n 282; ospemifene 60 mg, n 276; placebo, n pemifene evokes a dose-dependent inhibition on 268) 20 . After completing the initial study, women estrogen-induced cell responses and cell prolifer - with a uterus were eligible to continue a blinded ation, supporting an antiestrogenic effect in the treatment for a total of 52 weeks (12 weeks in the breast 28 . initial study plus 40 weeks in the safety exten - The expression of pS2, an estrogen marker , is sion [N180]). Safety assessments of the breast in - suppressed and the tumor growth is inhibited in a cluded mammograms and palpation on a physical dose-dependent manner by ospemifene (12%, examination performed at week 52 or at study 59%, and 79%-88% in the 1-, 10-, and 50- mg/kg discontinuation 37 . groups, respectively) 13 . The majority of breast palpations at week 52 The growth of ER-dependent MCF-7 cells had normal results, and the findings were similar with no effect on ER-independent MDA-MB-231 for all the study groups (normal results: 100% for cells is inhibited by ospemifene 29 . placebo, 100% for ospemifene 30 mg/d, and Ospemifene significantly reduces 7,12-Di - 98.3% for ospemifene 60 mg/d). Furthermore, re - methylbenz[a]anthracene (DMBA) -induced sults of mammograms performed at week 52 mammary carcinomas, similarly to tamoxifen 30. were normal for all the subjects in all study The growth of transplanted cells and occur - groups, with the exception of one subject in the rence of tumors have been significantly reduced ospemifene 60-mg/d group who had an abnormal in mice treated with either ospemifene or tamox - mammogram finding that subsequently resolved ifen compared with untreated mice 26 . during follow-up after completion of the study.

3938 Ospemifene: a safe treatment of vaginal atrophy

Only two subjects experienced a serious treat - In ovariectomized rats, ospemifene 10 mg/kg ment-emergent adverse event breast-related : one prevented an ovariectomy-induced reduction in (2%) subject in the placebo group had breast can - total tibial weight, prevented the ovariectomy-in - cer in situ, and one (1.4%) subject in the os - duced loss of bone strength in the femoral neck pemifene 60-mg group had breast prosthesis im - and lumbar vertebrae , and normalized histomor - plantation surgery. Six subjects experienced a phometric parameters in the direction of the con - non -serious breast-related event : 2.0% in the trol values, with effects similar to those achieved 13 placebo group had a breast cyst; 3.2% in the os - with 17 β- 50 g/kg . pemifene 30-mg/d group had evidence of a breast Ospemifene in clinical setting decreased the mass; and 4.3% in the ospemifene 60-mg/d levels of bone resorption markers 40 . group had a breast mass, breast microcalcifica - Ospemifene has effects on bone turnover tion, or an abnormal mammogram (as noted pre - markers comparable with raloxifene 60 mg/day viously). All six non -serious breast-related events in a randomized , double -blind study on post - were mild in severity. menopausal women 41 . A randomized, double-blind, placebo -con - Ospemifene decreased bone resorption in a trolled study 38 has evaluated the safety and the dose-dependent manner, as demonstrated by the efficacy of ospemifene 60 mg over 52 weeks in decreases in the levels of urinary N-telopeptide 426 women with VVA and an intact uterus (os - (NTX; p < 0.05 for all doses vs . placebo) and a fall pemifene, n 363; placebo, n 63). in the level of urinary C-telopeptide (CTX) with Breast safety has been assessed by palpation at ospemifene 90 mg (p < 0.05 vs . placebo). A dose- screening, then at weeks 12, 26, 52, and at the dependent decrease in bone formation markers post -treatment follow-up visit (< 4 weeks after procollagen type INpropeptide (PINP; p < 0.05 treatment completion). Mammography has been and p < 0.01, respectively) and alkaline phos - conducted at screening and week 52 or end of phates (ALP; both p < 0.05 vs. placebo) have also treatment . No clinically significant changes from been seen with ospemifene 60 and 90 mg 40 . baseline to week 52 have been noted on breast examination or mammography for any study par - Venous Thromboembolism ticipant at any time. No cases of breast cancer Ospemifene seems neutral or partial agonistic have occurred during this study. on venous thromboembolism. Only one case of Similar breast safety results have been venous thromboembolism has been noted in achieved in a long -term, open-label safety exten - long-term safety studies. sion of the same initial 12-week study. In this as - Overall, the prevalence rates per thousand sessment of women without a uterus treated with women of thromboembolic events with os - ospemifene 60 mg/d for 52 weeks, no clinically pemifene 60 mg in clinical trials (duration of significant changes in overall breast safety have treatment of up to 15 months) have been 0.72 been observed at week 26 or week 52 (N ¼ 301; (thromboembolic ; 1 case), 1.45 (hemor - data on file). All breast-related TEAEs have been rhagic stroke; 2 cases), and 1.45 (deep vein considered mild or moderate in severity. One thrombosis [DVT]; 2 cases), whereas for placebo subject in the ospemifene group had a report of a these rates have been 1.04 (1 case), 0 (no cases), breast-related TEAE (breast mass), assessed as and 1.04 (1 case), respectively . The absolute mild and unlikely related to the study drug, and numbers are very small and comparable to place - still ongoing at the end of the study and at the 4- bo. Therefore, the warning of potential venous week follow-up visit. Subsequent mammograms thrombosis on ospemifene label can be consid - during routine care visits after study completion ered only a class effect 42 . have been reported to be normal.

Bone TAMOXIFEN: Breast Cancer Prevention Ospemifene has bone protective effects, both in preclinical and in clinical studies 39 . It has an Tamoxifen is widely used for its antagonistic estrogenic effect on bone, as seen by improved effects on breast to prevent and treat invasive bone mineral density, strength, mass, and histo - breast cancer: reduction of invasive breast cancer morphometry in preclinical models, consistent in women with ductal carcinoma in situ (DCIS) with improvements in markers of bone resorption after surgery and radiation therapy; treatment of and formation in postmenopausal women. ; adjuvant treatment of

3939 L. Del Pup breast cancer; and reduction of breast cancer in - Bone cidence in high-risk women . For women who Tamoxifen has estrogen agonist effects on bone, have ER-positive breast cancer, tamoxifen has resulting in the preservation of bone mineral den - been shown to reduce the risk of recurrence and sity (BMD) in postmenopausal women. Lumbar death when used as adjuvant therapy in early BMD increases 0.61% per year with tamoxifen 10 stage disease or as palliation for those with mg/day vs . 1% decrease with placebo 48 . metastatic cancer 10 . The RR of hip fracture is 0.55; 95% CI, 0.25- Its agonistic further beneficial actions are: in - 1.15 with tamoxifen 20 mg/day vs . placebo 45 . creased bone mass density, decreased fracture rates improved , and decreased cardio - Venous Thromboembolism vascular morbidity . Unfortunately , it causes en - Tamoxifen increases both venous thromboem - dometrial stimulation, increasing the risk of en - bolic and risks . This is the dometrial carcinoma including the mixed meso - main limit to long -term continuation beyond 10 dermal type. Other limits are the venous throm - years, versus 5 years , of adjuvant tamoxifen ther - boembolic effect and the increased risk of pul - apy: the RR of pulmonary embolism is 1.87 monary embolism. (95% CI 1.13-3.07, p = 0 .01) 49 . Another triphenylethylene SERMs, considered A review of tamoxifen in large RCTs has sug - as the first generation , is toremifene approved to gested cardioprotective effects with improved prevent and to treat breast cancer . Toremifene has profiles in women, but cardiovascular out - similar effects but less endometrial stimulation comes are challenging to interpret 50,51 . than tamoxifen 43 .

Vagina RALOXIFENE: Osteoporosis Prevention Tamoxifen has a mixed effect on the vagina. Although estrogenic vaginal effects have been Raloxifene hydrochloride is a selective estro - noted with tamoxifen, adverse vaginal effects gen receptor modulator that has antiestrogenic during treatment have also been reported, includ - effects on breast and endometrial tissue and es - ing dyspareunia, leucorrhea, and vaginal dry - trogenic effects on bone, lipid , and ness 42 . blood clotting. Raloxifene increases the bone mass density, prevents vertebral fractures and im - Endometrium proves . Tamoxifen estrogenic activity on endometrial tissue results in an increased rate of endometrial Vagina hyperplasia and risk of endometrial cancer 44 . The Raloxifene has a neutral effect on vagina 52 . endometrial cancer risk with tamoxifen 20 mg/day vs . placebo is increased from relative risk Endometrium (RR ) 2.53 (95% CI, 1.35-4.97) 45 to as high as RR Raloxifene does not increase the risk of en - 7.5 [95% CI, 1.7-32.7] in women with breast dometrial cancer (RR, 0.8; 95% CI, 0.2-2.7) 53 . cancer 46 . While tamoxifen exhibits ER agonist activity Breast in the uterus, resulting in an increased risk of en - Raloxifene prevents invasive ER -positive dometrial hyperplasia and malignancy, os - breast cancer. This is demonstrated in CORE, pemifene, raloxifene and bazedoxifene demon - STAR and MORE 53 trial, where breast cancer RR strate none or minimal clinically meaningful ef - is 0.35; 95% CI, 0.21-0.58 with raloxifene 60 or fect on the uterus 47 . 120 mg vs . placebo .

Breast Bone Tamoxifen has an antiestrogenic effect in the Raloxifene has become the first SERM to re - breast . In rat models of induced mammary tu - ceive FDA regulatory approval for osteoporo - mors , it causes a delayed appearance of the dis - sis 54,55 . eases , reduces the total number of resulting tu - mors, and causes tumor regression. Clinically it Venous Thromboembolism reduces invasive breast cancer risk to 49% reduc - Raloxifene increases the risk of VTE and fatal tion with tamoxifen 20 mg/day vs . placebo 45 . stroke 56 .

3940 Ospemifene: a safe treatment of vaginal atrophy

BAZEDOXIFENE: Treatment of ness, burning, dyspareunia, discharge, urinary Menopausal Hot Flashes and Prevention frequency and urgency. Despite the high preva - of Bone Loss (if Combined With CEE) lence and the substantial effect on quality of life, vulvovaginal atrophy often remains underreport - Bazedoxifene (BZA) is a SERM which is not ed and undertreated 63 . used alone, but in a tissue-selective estrogen The main reason is the fear of the breast can - complex (TSEC), combined with conjugated cer effects of estrogens 64-66 . Cancer patients suf - (CEE), as a novel strategy of fer more from vaginal atrophy 67 , and they have menopausal without involving different questions and needs related to sexuality any progestin 57 . and fertility 68,69 . It also allows for the estrogenic benefits on re - The available clinical data for ospemifene, in - lief of hot flashes and prevention of bone loss cluding long -term safety evaluations in post - without stimulating the breast or the endometri - menopausal women with vulvovaginal atrophy, um. support a neutral effect on endometrium, breast and thromboembolism. In particular , investiga - Vagina tions in animal models suggest that ospemifene Bazedoxifene has a neutral effect on vagina 58 . may have an inhibitory effect on the growth of malignant breast tissue. The other SERMS have Endometrium not such a beneficial vaginal effect. All of them Bazedoxifene alone does not increase endome - are beneficial for the bone, as ospemifene, but ta - trial thickness or rates of moxifen increases endometrial cancer risk and, or cancer 59,60 . as raloxifene and bazedoxifene , it may increase The pairing with CEE reduces the risk of en - venous thrombotic risk. These data make os - dometrial hyperplasia that can occur with the es - pemifene a valuable tool for those women who trogenic component of the TSEC without the suffer from vaginal climacteric symptoms, and need for a progestogen in women with a uterus . are afraid of or cannot use local estrogens.

Breast –––––––––––––––– –-– –– The effect of bazedoxifene on the breast is Conflict of Interest neutral to antagonist 61 . The Authors declare that there are no conflicts of interest. It significantly lowers the incidence of fibro - 60 cystic breast disease (p ≤ 0.05) . The combined effect of bazedoxifene + CEE References seems neutral: no breast tenderness or changes in breast density. It warrants further studies for 1) DEL PUP L, P OSTRUZNIK D, C ORONA G. Effect of one- month treatment with vaginal on breast cancer effect. serum sulfate levels in cancer patients: a pilot study. Maturitas 2012; 72: 93-94. Bone 2) DEL PUP L, D I FRANCIA R, C AVALIERE C, F ACCHINI G, Bazedoxifene is associated with a reduced rate GIORDA G, D E PAOLI P, B ERRETTA M. Promestriene, a of vertebral fracture vs . placebo (p < 0.05) 59 specific topic estrogen. Review of 40 years of vaginal atrophy treatment: is it safe even in can - cer patients? Anticancer Drugs 2013; 24: 989- Venous Thromboembolism 998. Venous thromboembolic events (pulmonary 3) DEL PUP L, S ALVAGNO F, R EVELLI A, G UIDO M, C ASTELLO embolism, retinal vein thrombosis , deep vein C, B ORINI A, P ECCATORI F. Gonadotoxic effects of thrombosis , and thrombophlebitis) are rare, oc - breast cancer treatment and fertility protection curring in less than 1 per 1000 patients treated strategies: evidence based answers to the main with CEE + bazedoxifene 62 . questions the patients ask WCRJ 2014; 1: e409. 4) DONATI SARTI C, G RAZIOTTIN A, M INCIGRUCCI M, R ICCI E, CHIAFFARINO F, B ONACA S, B ECORPI A, C IPRIANI S, PARAZZINI F; G RUPPO DI STUDIO IPER AOGOI . Corre - Conclusions lates of sexual functioning in Italian menopausal women. Climacteric 2010; 13: 447-456. About fifty percent of menopausal women suf - 5) DEL PUP L. Management of vaginal dryness and fer from vaginal atrophy which symptoms in - dyspareunia in estrogen sensitive cancer patients. clude vaginal dryness, irritation, itching, sore - Gynecol Endocrinol 2012; 28: 740-745.

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