Serms in the Prevention and Treatment of Postmenopausal Osteoporosis: an Update

review

SERMs in the prevention and treatment of postmenopausal osteoporosis: an update

SERMs na prevenção e no tratamento da osteoporose pós-menopausa: uma atualização

Jaime Kulak Júnior1, Carolina Aguiar Moreira Kulak2, Hugh S. Taylor3

SUMMARY 1 Serviço de Tocoginecologia, Selective estrogen receptor modulators (SERMs) have the ability to bind the estrogen receptor Hospital de Clínicas, Universidade Federal do Paraná (UFPR), (ER) and are known to confer ER agonist or antagonist effects depending on the target tissue. Curitiba, PR, Brasil A number of newer SERMs, including bazedoxifene, lasofoxifene and ospemifene, are currently 2 Serviço de Endocrinologia e under clinical development for the prevention and treatment of postmenopausal osteoporosis Metabologia (SEMPR), Hospital de Clínicas, UFPR, Curitiba, PR, Brasil and for other indications. Although the possibility of developing a single agent that has all of 3 Departamento de Obstetrícia, the desired characteristics of an ideal SERM seems to be unlikely, progress in the clinical deve- Ginecologia e Ciências de lopment of SERMs targeted to the ER suggests that these newer compounds may have attribu- Reprodução, Yale University School of Medicine, New tes that represent an improvement relative to existing SERMs. A new approach to menopausal Haven, CT, United States therapy is the tissue selective estrogen complex or the pairing of a selective estrogen receptor modulator with estrogens. Further investigation will help to clarify relative benefits/risks of novel SERMs in development within specific indications.Arq Bras Endocrinol Metab. 2010;54(2):200-5 Keywords Selective estrogen receptor modulator (SERM); menopause; estrogens; osteoporosis; tissue selective estrogen complex (TSEC)

SUMÁRIO Correspondence to: Moduladores seletivos do receptor do estrogênio (SERMs) têm a habilidade de se ligar ao re- Jaime Kulak Júnior Rua General Carneiro, 180, ceptor de estrogênio (ER) e são conhecidos por conferir um efeito agonista ou antagonista 6º andar sobre o tecido-alvo. Um número de novos SERMs, incluindo bazedoxifeno, lasofoxifeno e os- 80060-150 − Curitiba, PR, Brasil [email protected] pemifeno, está atualmente em desenvolvimento clínico para prevenção e tratamento da osteoporose pós-menopausa e para outras indicações. Embora a possibilidade de desenvolver um simples agente que tenha todas as características desejadas de um SERM ideal parece ser Received on Nov/30/2009 Accepted on Feb/9/2010 pouco provável, esses novos SERMs apresentam propriedades que indicam uma melhora em relação aos SERMs existentes. Uma nova opção terapêutica é o uso do complexo estrogênico do tecido seletivo ou a associação do SERM com estrogênios. Novos estudos ajudarão a ras- trear os riscos e benefícios dos novos SERMs em desenvolvimento dentro das suas indicações específicas.Arq Bras Endocrinol Metab. 2010;54(2):200-5 Descritores Moduladores específicos dos receptores de estrogênio (SERM); menopausa; estrogênio; osteoporose; complexo estrogênico do tecido seletivo (TSEC)

INTRODUCTION agents for the management of postmenopausal osteo- ostmenopausal osteoporosis is an asymptomatic porosis may not be appropriate for all women. Selective Pskeletal disease that is often underdiagnosed and estrogen receptor modulator (SERM) refers to a struc- undertreated. Adequate intake of calcium and vitamin D turally diverse group of compounds that bind to the es- ABE&M todos os direitos reservados. os direitos ABE&M todos © is recommended as baseline therapy for osteoporosis trogen receptor (ER) and confer mixed functional ER

200 Arq Bras Endocrinol Metab. 2010;54/2 Arq Bras Metab. Endocrinol 2010;54/2 ER throughregulated are genes of sets different (4). Microarray gene expression analysis has shown that typecellgiven a onSERM a of effect determinetheto interact microenvironment cellular the and regulators co ER of balance the thatsuggests evidencealthough understood, totally not are actions tissue-specific their exert SERMswhich mechanismsby exact The (3). sue agonistsER antagonistsor depending theontarget tis as act differentially to abilitytheir in lies SERMs of ise prom The (2). events transcriptional mediate to affinity and high with ERs to bind to known are SERMs THE PROMISEOFSERMs term the “SERM” will be used throughout review, the article. this in however, drug”; antagonist tly replaced the term “SERM” with “estrogen agonist/ recen (FDA) Administration Drug and Food US the that noted be should It osteoporosis. postmenopausal treatmentthe evaluate on of to theirsafetyefficacy and SERMs on literature recent most the describes update withestrogen deficiency, particularly osteoporosis. This associated conditions postmenopausal of management the for investigation clinical undergoing currently are specifi within balance benefit-risk favorable a demonstrated have Ms SER of number a date, to SERM ideal an of lack the ly stimulate (e.g., breast and endometrium) (1). Despite activity in tissues estrogens have been shown to adverse antagonistorneutral ER systems),and nervous central desirable(e.g.,skeletal,estrogensis cardiovascular, and agonist activity in tissues ER where mimicking the action have of would SERM ideal an Conceptually, tissue. disease, stroke, or deep vein thrombosis (Table 1) (5). heart coronary of risk the increase not and symptoms; tion); provide relief of hot flushes and other menopausal and endometrial cancer (and limit endometrial prolifera prevent bone loss and fractures; reduce the risk of breast shoul SERM ideal An potential.clinical its determines that properties pharmacologic unique has SERM each because individually evaluated be must SERMs result, a As structure. chemical common a than rather ways path signalingER-regulated on effects pharmacologic proteins (1). SERMs are characterized by their complex ER/ligan the of binding and expression and ligand, ER the of binding after mation expressionby tissues,differenttheinofER conforER mediated be to seem SERMs of effects wide-ranging sus ER β in response to estradiol and SERMs (2). The (2). SERMs and estradiol to response in teaetc niain. ee SERMs Newer indications. therapeutic c d complex to coregulator to complex d α

ver ------symptoms, and sometimes stroke (9,10). symptoms, andsometimesstroke vasomotor events, thromboembolic venous of cidence in- increased an with associated is Tamoxifen cancer. breast with population postmenopausal the in use its limit concerns safety endometrial however, (7,8); fits bene- cardioprotective and skeletal provide to shown been also has Tamoxifencancer. breast ER-positive of recognized as agent a for highly the effective treatment breast and estrogen-like activity in the uterus (6), and is Tamoxifen has a well known antiestrogen activity in the Tamoxifen CURRENTLY AVAILABLE SERMs Table 1.EffectsofSERMs ing Outcomes Relevant to Evista trial (16) have shown Continu- the entered who those and (15) trial the MORE in enrolled women of subgroups of analyses hoc Post (12,14). fracture nonvertebral of risk on overall the effect significant no shown has it reduction, ture frac - vertebral in efficacy demonstrated has raloxifene ducing the risk of invasive breast cancer (13). Although oxifene was shown to be as as tamoxifen effective in - re Raloxifene trial of than more 19,000 postmenopausal women, ral- and Tamoxifen the In (12). osteoporosis with women postmenopausal in respectively, placebo, and 50% 0.5-0.8) (relative risk, 0.5; CI, 95% CI, 0.4-0.7) compared 95% with 0.7; risk, (relative 30% by risk fracture vertebral reduced significantly years 3 for day mg/ 120 and 60 raloxifene with treatment that found tiple Outcomes of Raloxifene Evaluation (MORE) trial by 2.4% relative to placebo (P < 0.001) (11). The Mul- BMD spine lumbar increase to shown was mg 60 fene raloxi- with treatment (BMD), density mineral bone women. In postmenopausal women with low or normal postmenopausal in cancer breast of prevention the for indicated also is it and fractures vertebral and porosis the prevention and treatment of postmenopausal osteo- for worldwide approved SERM only the is Raloxifene Raloxifene SERM Lasofoxifene Raloxifene Tamoxifen Ospemifene Bazedoxifene Endometrial stimulation Yes Yes Yes Yes No SERMs andosteoporosis anupdate maturation Vaginal Yes Yes No No No Hot flushes ↑ ↑ ↑ ↑ - 201

Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. SERMs andosteoporosis anupdate 202 and symptoms ofvaginalatrophy, signs including dyspareunia. es improv lasofoxifene with treatment that clinicaldatahavealsoshown placebo (23).Preliminary with compared cholesterol lipoprotein low-density and markers turnover of bone levels reduced significantly raloxifene and lasofoxifene Both hip. total for parable com- were responses the although (1.7%), mg raloxi- 60 fene with compared mg/day respectively) 1.0 3.9%, and and (3.6% 0.25 lasofoxifene with 0.05) < (P toplacebowassignificantlygreater spine BMDrelative lumbar in change mean the 410), = (N women pausal a postmeno- In of study double-blind women. randomized, 2-year, postmenopausal in atrophy vaginal of treatment the for and osteoporosis of treatment and prevention the for investigated been has Lasofoxifene Lasofoxifene described inthefollowingsections. (21,22). thickness in Progress the clinical development of novel SERMs is endometrial increased including was discontinued, in part, because of osteoporosis adverse uterine effects, postmenopausal for vormeloxifene le- and idoxifene of development clinical the instance, For profiles. tolerability and/or safety unacceptable of because discontinued were some but years, recent in development clinical entered have SERMs new Several NEW SERMsINDEVELOPMENT 20.6% and 23.6% increase, therapy; respectively) (20). estrogen/progestogen or therapy (estrogen therapyhormoneincrease)placeboor (6.3% relativeto in the incidence of hot flushes (P < 0.05) with raloxifene statisticallysignificant increasea showed trials domized ran eight of analysis An (18,19). women menopausal post in symptoms vasomotorexacerbate or induce to CI, 1.5-6.2). Like tamoxifen, raloxifene has been shown womenofwhoreceived placebo (relative risk,3.1; 95% of women who received raloxifene, compared with 0.3% (17).Venous thromboembolic1.0% eventsin occurred endometrialcancer of risk the in increase no was there vs. 0.01withplacebopared< years (+0.27(P aftermm)3 com raloxifene with seen was mm) (+0.01 thickness fractures. baseline vertebral and lower leg) in raloxifene-treated women with severe hip, pelvis, wrist, humerus, (clavicle, sites common six at risk fracture nonvertebral in reduction significant a lcb) f hrp i te OE ra, although trial, MORE the in therapy of placebo) A statistically significant increase in endometrial in increase significant statistically A - - -

treatment of vaginal atrophy 2006. in January the for FDA US the by approved not was lasofoxifene preventiveosteoporosis.therapyfora Moreover, as use the need for additional data on safety and benefits on its cited which 2005,September in FDA US the from ter The (23). manufacturer cancer of lasofoxifene received or a nonapproval let hyperplasia endometrial of risk bo, although there has been no evidence of an increased place with compared thickness endometrial increased cause may treatment lasofoxifene that suggests dence shown to be more common with lasofoxifene (23). Evi been have eventsadverse of becausecontinuationrates dis althoughraloxifene, of that to similar be to seems increased endometrial thickness and uterine volume (27). associatedwithospemifenebesuggests dence thatmay and ospemifene in the incidence of hot flushes (26). Evi haveshownsignificantno difference between raloxifene postmenopausalHowever,(25).womenstudiesfurther that ospemifene does not induce vasomotor symptoms in (P < 0.05) at most doses (24,25). A phase 2 study placebo found with compared baseline from changes greater significantly and raloxifene with compared formation bone and resorption bone of markers most on effect similar astudies, ospemifenehad2 phase evaluated. In bone turnover in postmenopausal of markers biochemicalwomen have onalso ospemifene been of effects The Ospemifene et in ments - improve and events cardiovascular and fractures bral - non-verte in reduction of endpoints secondary meet in cancer postmenopausal women. However, arzoxifene failed to breast and fractures vertebral in reduction of endpoints primary its met arzoxifene that showed study clinical five-year a from results preliminary August 2009 in However, (29). mass bone low to normal with women postmenopausal including trial controlled placebo- randomized, a in studied further were overall safety and safety, uterine fractures, density, mineral bone on mg/d 20 arzoxifene of effects The (28). sion le- the of resection before weeks 6 to 2 treated noma - carci breast in indices proliferation decrease to shown was arzoxifene as evaluations, clinical early in observed and prevention of breast cancer. Promising results were treatment the for investigated initially was Arzoxifene Arzoxifene The safety and tolerability profile of lasofoxifene of profile tolerability and safety The cognitive function. Based on these results, results, these on Based function. cognitive Arq Bras Metab. Endocrinol 2010;54/2 - - - - -

Arq Bras Metab. Endocrinol 2010;54/2 statistically a showed mg/day 20 bazedoxifene line), base- at fractures vertebral mild 2 ≥ or moderate 1 ≥ known on skeletal risk factors based (femoral neck T-score fracture ≤ -3.0 for and/or risk higher at 1,772) = intheoverallpopulation. amonggroups bral fractures There were no in differences the incidence of - nonverte (34) comparisons) all for 0.05 < (P placebo to relative and 40 mg/day and raloxifene 60 mg/day, respectively, 20 bazedoxifene with 0.89) < 0.38 CI, 95% 0.58; risk, tive risk, 0.63; 95% CI, 0.42 < 0.96), and 42% (relative - (rela 37% 0.89), < 0.38 CI, 95% 0.58; risk, (relative new fracture was vertebral significantlyreduced by pausal women with osteoporosis showed that the risk of cholesterol). high-densitylipoprotein cholesterol, lipoprotein low-density cholesterol, (total parameters lipid on effects favorable had and comparisons) all for baseline(P<0.001vs.placebo from 32%, respectively) and 22%, 24%, (25%, C-telopeptide and respectively) 27%, and 22%, 22%, (21%, osteocalcin reduced of levels serum significantly mg/day 60 raloxifene and day for all comparisons). Bazedoxifene 10, 20, and 0.001 40 mg/ < P respectively; 1.7%, and 1.6%, 1.8%, (1.3%, (1.1%, 1.4%, spine 1.5%, and 1.5%, respectively) and the lumbar total hip at BMD increased significantly day mg/ 60 raloxifene and mg/day 40 and 20, bazedoxi- 10, fene placebo, to Relative (33). sites skeletal at all BMD of loss experienced women placebo-treated whereas loss, bone prevent to shown was zedoxifene ba- with treatment BMD, low or normal with women postmenopausal 1,583 of study 2-year a In completed. been have treatment and prevention osteoporosis for metrial stimulation(32).Phase3trialsofbazedoxifene endo- of evidence or pain breast of incidence the ing - increas without remodeling bone of markers in tions reduc- significant statistically demonstrated treatment bazedoxifene women, postmenopausal healthy of ies stud- 2 phase In (31). profile safety breast and uterine favorable a with metabolism, lipid and bone on fects ef- positive including criteria, selection preclinical gent strin- using developed was Bazedoxifene teoporosis. os- postmenopausal of treatment and prevention the for development clinical late-stage in is Bazedoxifene Bazedoxifene (30). approval regulatory seek not would and drug the of development further discontinuing are they announced company drug the In a post hoc analysis of a subgroup of women (n women of subgroup a of analysis hoc post a In postmeno- 7,492 of study 3-year a recently, Most 42%

breast cancer were not different compared with placebo. bazedoxifene treatment, and the rates of breast pain and incidenceendometrialof hyperplasiacarcinoma with or increasedan evidenceof no wasplacebo.There or line throughout both studies, with no differences from base Endometrial thickness with bazedoxifene studies.remained 3 phaseboth stable raloxifenein andplacebo of that to similar profile safetybreast endometrialandvorable 0.05)(34).Bazedoxifene< (P associatedwasfa awith with placebo (0.1%) in the osteoporosis treatment study compared higher and and 0.5%) bazedoxifene < 0.4% (range, raloxifene with similar was thrombosis vein with previous reports of SERMs. The incidence of deep consistent is and 6.3%) study:treatment 14.2%; range, study: (prevention placebo with that than higher was that 13.0%) < 12.0% study: treatment 24.1%; < 18.6% range, study: (prevention flushes hot of incidence simi lar a showed raloxifene and these bazedoxifene In studies, (33,34). placebo with those from different studies,adverseoverallwithphase3eventsratesof not tive risk,0.56;95%CI,0.31<1.01;P=0.05)(34). - (rela mg 60 raloxifene and 0.02) = P 0.90; < 0.28 CI, 95% 0.50; risk, (relative placebo both to relative tures significantreduction in the risk of all frac- nonvertebral nvl prah emd h tsu-eetv estrogen tissue-selective the termed approach novel a n pia menopausal optimal an possible to achieve optimal results raloxifene, the percent increase in lumbar spine BMD spine lumbar in increase percent the raloxifene, with Compared hip. the at measured also was density bone mineral density of the lumbar spine; bone mineral The primary outcome for both substudies was change in placeboadministeredormg),was(60 daily raloxifenemg),0.45(0.625 or CEwith mg) 40 or 20, respectively.Substudies,(10, II BZA and I Prevention years postmenopause were enrolled in the Osteoporosis 1-5 and years 5 than more women 3,397 prevention, estrogens (BZA/CE), for postmenopausal osteoporosis bazedoxifene/conjugated complex, estrogen selective tissue- the (35,36).of Tobothefficacy onevaluate the results positiveshowing atrophy) vaginal vulvar and es flush (hotsymptoms menopausal of treatment the for investigationclinical under currently is (CE) estrogens complex. Bazedoxifene in combination with conjugated balance ideal an achieve to able been has alone SERM no date, To Tissue SelectiveEstrogenComplex (TSEC) iseslcie ciiis f SR and SERM a of activities tissue-selective aeoiee a sf ad el oeae i both in tolerated well and safe was Bazedoxifene

of ER agonist and antagonist activity for activity antagonist and agonist ER of

hrp. oee, t a be may it However, therapy. SERMs andosteoporosis anupdate

based on the blended

srgn in estrogens for 2 years.2 for 203 - - - -

Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. SERMs andosteoporosis anupdate 204 post- of treatment and prevention the for approved SERM only the currently is Raloxifene osteoporosis. by SERMs in development for postmenopausal offered protection bone the outweigh not may concerns safety endometrial However, cancer. breast with diagnosed been already have who women in risks associated the characteristics ofanidealSERMseemstobeunlikely. desired the of all has that molecule single a designing of possibility The osteoporosis. particularly deficiency, themanage- for ment of postmenopausal conditions related to estrogen agents therapeutic in the of progress identification significant to led has years recent in ER the to targeted SERMs novel of development The CONCLUSIONS symptomatic women with a uterus. without the need for a progestogen in postmenopausal, therapy hormone of benefits the provide to potential compared with placebo (37). Such combination has the pain breastincrease not didBZA/CE phlebitis,and or thrombosis, superficial thromboembolism,venousder, disor artery coronary infarction,myocardial for found were placebo and groups BZA/CE between ferences dif significant no that note to important is It 0.001). < placeboBZA/CEwithdosesthanall(Pgreaterwith significantly wereC-telopeptide and osteocalcin serum all time points, median percent changes from baseline in (20 mg)/CE (0.45 mg) at month 24. In substudy II, at fene for BZA (10 mg)/CE (0.625 or 0.45 mg), and BZA BMDwas significantly Totalbetterhip12. (P < month0.05) at than mg) with(0.45 raloxi mg)/CE (40 BZA for except BMD, neck femoral for doses BZA/CE all were as 24, and 12months placeboatwith than BMD hip total for 0.01) < (P significantly higher were doses substudyBZA/CEmg)/CEall(0.625(20Inmg).II, BZA and mg) 0.45 or (0.625mg)/CE (10 BZA with baseline month 24 nificantly0.05) from to < higher (P ifene, mean percent increases in total hip BMD were sig decreases observed with placebo. Compared with ralox comparedbaselinethe24withandmonthsfrom 12to significantly higher (P < 0.001) with all BZA/CE doses was BMD hip total I, substudy In mg). (40 BZA with BZA/CEalldoses,0.05)forexcept thoseoxifene< (P menopause, BMD significantly improvedrelative to ral post years 5 > women Among postmenopause. years 1-5 women for 0.05) < (P groupstreatmentBZA/CE from baseline to month 24 was significantly higher for all The benefits of tamoxifen use probably outweigh probably use tamoxifen of benefits The ------the benefit/riskbalanceofSERMsindevelopment. determine appropriately to needed is events) embolic fication of other safety concerns (i.e., venous- thrombo option for symptomatic postmenopausal asuitable women. Clari- mayindicate data safety overall and profile bleeding the as well as loss bone and symptoms pausal onmeno- BZA/CE of effects beneficial The profile. posed of BZA/CE has an acceptable endometrial safety com- TSEC a that indicate trials these from Findings protection. endometrial for estrogens to progestin a of metrial profile, suggesting an alternative to endo- the addition acceptable an had BZA/CE containing TSEC The raloxifene. and placebo both to relative fracture subgroup of more than 1,700 women at higher risk for a in risk fracture nonvertebral in reduction significant a showed bazedoxifene study, treatment osteoporosis active-controlled and placebo- global the In studies. 3 metrial or breast stimulation in large, prospective phase endo- of evidence without women postmenopausal in turnover, and decrease the risk of new vertebral fracture been shown to maintain or increase BMD, reduce bone Bazedoxifene clinical study has relevance. to determine further warrants and flushes hot of incidence increased an be to seems date to SERMs with associated event cancer. breast of prevention the for adverse common A and are also undergoing investigation as possible agents atrophy, vaginal as such menopause, of symptoms the SERMs. Other SERMs have shown promise in treating represent an improvement relative to currently available that attributes have may compounds these that dicate cancer. breast benefit ofpreventing added the with fractures, and loss bone preventing in menopausal osteoporosis, having demonstrated efficacy 4. 3. 2. 1. 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