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 no- vel 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 os- teoporose 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 Copyright prevention and treatment. Available pharmacological agonist or antagonist activity depending on the target 200 Arq Bras Endocrinol Metab. 2010;54/2 SERMs and osteoporosis an update tissue. Conceptually, an ideal SERM would have ER Table 1. Effects of SERMs Endometrial Vaginal agonist activity in tissues where mimicking the action of SERM Hot flushes estrogens is desirable (e.g., skeletal, cardiovascular, and stimulation maturation central nervous systems), and ER neutral or antagonist Tamoxifen Yes No ↑ activity in tissues estrogens have been shown to adverse- Raloxifene Yes No ↑ ly stimulate (e.g., breast and endometrium) (1). Despite Lasofoxifene Yes Yes ↑ the lack of an ideal SERM to date, a number of SER- Ospemifene Yes Yes - Ms have demonstrated a favorable benefit-risk balance Bazedoxifene No No ↑ within specific therapeutic indications. Newer SERMs are currently undergoing clinical investigation for the CURRENTLY AVAILABLE SERMS management of postmenopausal conditions associated with estrogen deficiency, particularly osteoporosis. This Tamoxifen update describes the most recent literature on SERMs Tamoxifen has a well known antiestrogen activity in the to evaluate their safety and efficacy on the treatment of breast and estrogen-like activity in the uterus (6), and is postmenopausal osteoporosis. It should be noted that recognized as a highly effective agent for the treatment the US Food and Drug Administration (FDA) recen- of ER-positive breast cancer. Tamoxifen has also been tly replaced the term “SERM” with “estrogen agonist/ shown to provide skeletal and cardioprotective bene- antagonist drug”; however, in this review, the term fits (7,8); however, endometrial safety concerns limit “SERM” will be used throughout the article. its use in the postmenopausal population with breast cancer. Tamoxifen is associated with an increased in- THE PROMISE OF SERMS cidence of venous thromboembolic events, vasomotor symptoms, and sometimes stroke (9,10). SERMs are known to bind to ERs with high affinity and to mediate transcriptional events (2). The prom- Raloxifene ise of SERMs lies in their ability to differentially act as ER agonists or antagonists depending on the target tis- Raloxifene is the only SERM approved worldwide for sue (3). The exact mechanisms by which SERMs exert the prevention and treatment of postmenopausal osteo- their tissue-specific actions are not totally understood, porosis and vertebral fractures and it is also indicated although evidence suggests that the balance of ER co- for the prevention of breast cancer in postmenopausal regulators and the cellular microenvironment interact women. In postmenopausal women with low or normal to determine the effect of a SERM on a given cell type bone mineral density (BMD), treatment with raloxi- (4). Microarray gene expression analysis has shown that fene 60 mg was shown to increase lumbar spine BMD different sets of genes are regulated through ERα ver- by 2.4% relative to placebo (P < 0.001) (11). The Mul- sus ERβ in response to estradiol and SERMs (2). The tiple Outcomes of Raloxifene Evaluation (MORE) trial wide-ranging effects of SERMs seem to be mediated found that treatment with raloxifene 60 and 120 mg/ by expression of the ER in different tissues, ER confor- day for 3 years significantly reduced vertebral fracture mation after binding of the ER ligand, and expression risk by 30% (relative risk, 0.7; 95% CI, 0.5-0.8) and and binding of the ER/ligand complex to coregulator 50% (relative risk, 0.5; 95% CI, 0.4-0.7) compared with proteins (1). SERMs are characterized by their complex placebo, respectively, in postmenopausal women with pharmacologic effects on ER-regulated signaling path- osteoporosis (12). In the Tamoxifen and Raloxifene ways rather than a common chemical structure. As a trial of more than 19,000 postmenopausal women, ral- result, SERMs must be evaluated individually because oxifene was shown to be as effective as tamoxifen in re- each SERM has unique pharmacologic properties that ducing the risk of invasive breast cancer (13). Although determines its clinical potential. An ideal SERM shoul raloxifene has demonstrated efficacy in vertebral frac- prevent bone loss and fractures; reduce the risk of breast ture reduction, it has shown no significant effect on and endometrial cancer (and limit endometrial prolifera- the overall risk of nonvertebral fracture (12,14). Post tion); provide relief of hot flushes and other menopausal hoc analyses of subgroups of women enrolled in the ABE&M todos os direitos reservados. os direitos ABE&M todos symptoms; and not increase the risk of coronary heart MORE trial (15) and those who entered the Continu- © disease, stroke, or deep vein thrombosis (Table 1) (5). ing Outcomes Relevant to Evista trial (16) have shown Copyright Arq Bras Endocrinol Metab. 2010;54/2 201 SERMs and osteoporosis an update a significant reduction in nonvertebral fracture risk at The safety and tolerability profile of lasofoxifene six common sites (clavicle, humerus, wrist, pelvis, hip, seems to be similar to that of raloxifene, although dis- and lower leg) in raloxifene-treated women with severe continuation rates because of adverse events have been baseline vertebral fractures. shown to be more common with lasofoxifene (23). Evi- A statistically significant increase in endometrial dence suggests that lasofoxifene treatment may cause thickness (+0.01 mm) was seen with raloxifene com- increased endometrial thickness compared with place- pared with placebo (+0.27 mm) after 3 years (P < 0.01 bo, although there has been no evidence of an increased vs. placebo) of therapy in the MORE trial, although risk of endometrial hyperplasia or cancer (23). The there was no increase in the risk of endometrial cancer manufacturer of lasofoxifene received a nonapproval let- (17). Venous thromboembolic events occurred in 1.0% ter from the US FDA in September 2005, which cited of women who received raloxifene, compared