DRUG EVALUATION Bazedoxifene: a new selective estrogen-receptor modulator for postmenopausal osteoporosis Bazedoxifene acetate (WAY-140424; TSE-424) is an oral, nonsteroidal, indole-based selective estrogen- receptor modulator that is being clinically evaluated as a monotherapy for the prevention and treatment of osteoporosis and in combination with conjugated estrogens for the treatment of menopausal symptoms and prevention of osteoporosis. Developed by Wyeth (now Pfizer) Pharmaceuticals (NJ, USA), it is undergoing regulatory review for clinical use under the trade name Viviant™ by the US FDA. Bazedoxifene is currently marketed in Switzerland, Spain, Italy, Germany, Ireland and Japan. Its brand names in the EU and Japan are Conbriza® and Viviant™, respectively. In the EU, Conbriza is indicated for the treatment of postmenopausal osteoporosis in women at increased risk of fracture. Bazedoxifene reduces vertebral fractures in postmenopausal osteoporotic women, and nonvertebral fractures in a subgroup of postmenopausal osteoporotic women at higher risk. This review describes the mechanism of action and summarizes the clinical experience with bazedoxifene. Current evidence indicates that bazedoxifene is effective and safe for the treatment of postmenopausal osteoporosis. KEYW ORDS: bazedoxifene n fracture n osteoporosis n sSERM Annie Kung Department of Medicine, University of Hong Kong, China [email protected] Osteoporosis is a global public health problem estrogen–progestin therapy, namely hormone that is estimated to affect more than 200 mil- replacement therapy, has been used extensively in lion people worldwide. The disease affects one post menopausal women for both prevention and in three postmenopausal women and one in treatment of osteoporosis. However, the signifi- five men aged above 65 years. According to the cant increase in incidences of breast cancer, stroke, WHO, osteoporosis is the cause of over 8.9 mil- heart attack and venous thromboembolism with lion fractures globally each year [1] . The com- estrogen–progestin therapy and the significant bined lifetime risk for hip, spine and forearm increase in the incidence of stroke with estrogen fracture has been estimated to be approximately therapy outweighed the benefit of fracture risk 40%, similar to that for coronary artery disease. reduction in older postmenopausal women [2]. By 2050, the cost of treating hip fracture alone Although other treatments for osteoporosis are in the USA is projected to be US$130 billion. available (bisphosphonates, RANKL inhibitor, In addition to this major burden on the health parathyroid hormone, calcitonin and strontium economy, hip fracture is associated with a mor- ranelate), the development of agents that can tality rate of 20–50% within the first year of mimic the action of estrogens in decreasing the occurrence. Although the age-adjusted fracture rate of bone turnover and preserve or increase rates have leveled off in North America and bone mass without the side effects of h ormone Europe, there is a rising trend in most parts of replacement therapy would be preferable. Asia. Rapid aging and changing lifestyle habits Selective estrogen-receptor modulators of the population mean that most fractures in (SERMs) are nonsteroidal estrogen-like molecules Asia are expected to occur in 50 years’ time. In that bind to the estrogen receptor (ER) a and b. view of the major consequence of osteoporotic Each SERM presents diverse clinical effects in fractures, early prevention and treatment of response to the conformational changes follow- individuals at risk remains an important goal ing formation of a distinct ER–SERM ligand throughout the world in the management of complex. They demonstrate variable agonist osteoporosis. and antagonist activity that is dependent on the genes being regulated and occurs on a tissue-by- Overview of the market tissue basis (i.e., a tissue-selective response). An Bone loss in postmenopausal women occurs as ideal SERM would possess agonistic ER action a result of lost estrogenic inhibition of osteo- on bone with an associated reduced fracture risk clastic bone resorption. Estrogen therapy or and beneficial effects on lipoprotein cholesterols 10.2217/IJR.12.47 © 2012 Future Medicine Ltd Int. J. Clin. Rheumatol. (2012) 7(6), 583–590 ISSN 1758-4272 583 DRUG EVALUATION Kung Bazedoxifene & postmenopausal osteoporosis DRUG EVALUATION with decreased cardiovascular risks. It would have bioavailability of both tablet and capsule formula- no stimulatory action on uterine endometrium tions is the same at approximately 6.2%, threefold or breast tissue. Positive effects in the CNS and higher than that of raloxifene [4]. To determine vagina, with fewer hot flushes and the mainte- the pharmacokinetics, multiple oral doses of 5, nance of vaginal secretion, would p rovide further 20 and 40 mg were administered to postmeno- benefits. pausal women in a crossover manner for 14 days. At present, two SERMs are available for clini- The maximum plasma concentration of bazedoxi- cal use: tamoxifen, a triphenylethylene approved fene was achieved 1–2 h following administra- for the treatment of breast cancer, and raloxifene, tion. The elimination half-life was 28 h without a benzothiophene approved for the prevention accumulation. More than 99% of the compound and treatment of postmenopausal osteoporosis was protein bound and a steady-state plasma con- and the prevention of breast cancer. centration was achieved by day 7 of oral admin- istration. When administration was extended to Introduction to the compound 30 days at various doses from 1 to 80 mg, plasma Bazedoxifene acetate (WAY-140424; TSE-424) concentration increased in a linear fashion with is an oral, nonsteroidal, indole-based SERM steady-state achieved by day 14 [5]. being developed for the prevention and treat- The metabolic disposition of bazedoxifene ment of osteoporosis. It is classified as a third- was evaluated in six healthy postmenopausal generation SERM and has the chemical name women by evaluation of blood, urine and feces 1H-indo-5-ol,1-[[4-[2(hexahydro-1H-azepin- following administration of a single 20-mg oral 1-yl)ethoxy]methyl]2-(-4-hydroxyphenyl)-3- dose of 14C-bazedoxifene [6]. Bazedoxifene was methyl] acetic acid [3]. The core binding domain mainly excreted in the feces (84.7%), with only consists of a 2-phenyl-3-methyl indole and a a minute amount excreted in the urine (0.81%). h examethylenamine ring at the side chain affecter Glucuronidation is the major metabolic path- region. way, as the major metabolite is bazedoxifene- Preclinical studies with bazedoxifene have 5-glucuronide. Little or no CYP450-mediated demonstrated estrogen agonist effects on the m etabolism was found. skeleton and lipid metabolism but not on breast and uterine endometrium. Phase III clinical stud- Preclinical data ies have shown favorable effects on the skeleton n Uterus without stimulation of endometrium and breast: E2 stimulates the uterine endometrium and causes bone loss in postmenopausal women without endometrial hyperplasia and cancer. The action of osteoporosis is prevented and vertebral fractures bazedoxifene on the uterus was evaluated with in women with postmenopausal osteoporosis an immature rat model by assessing uterine wet reduced. In women at high risk of fracture with weight [7,8]. At a dose of 0.5 mg/kg, bazedoxifene multiple risk factors, bazedoxifene reduces non- increased uterine wet weight by 35%; nonetheless, vertebral fracture risk in post hoc ana lysis. Clinical a dose of 5 mg/kg resulted in no significant differ- trials with bazedoxifene have shown beneficial ence in weight compared with placebo. Although effects on bone mineral density and bone turn- the 0.5 mg/kg dose of bazedoxifene increased uter- over markers with little or no stimulation of breast ine wet weight, which is consistent with that seen and endometrium. with raloxifene, no luminal epithelial cell hyper- trophy or hyperplasia, myometrial hypertrophy, or Pharmacodynamics, luminal distention was noted. These results show pharmacokinetics & metabolism that the increased uterine weight was not accom- Bazedoxifene binds to both ERa and ERb, with panied by hypertrophy or hyperplasia. Overall, a slightly higher affinity for ERa. The dissocia- bazedoxifene exhibits a small stimulatory effect tion constant for ERa is approximately equal to (at low doses) on rat uterine wet weight without 0.1 nM and for ERb is 0.3 nM. The IC50 (i.e., detectable histological changes. inhibitory concentration required to compete 50% of 17b -estradiol [E2] off the estrogen receptor) for nBreast bazedoxifene is 23 ± 15 and 85 ± 59 nM for ERa E2 stimulates the breast, exhibited by increased and ERb, respectively, compared with 4 ± 3 and ductal branching with minimal end-bud cell 43 ± 13 nM, respectively, for raloxifene [3]. proliferation, but has been associated with an The oral bioavailability of bazedoxifene has increased risk of breast cancer. Bazedoxifene has been evaluated in 18 healthy postmenopausal no stimulatory effect on MCF-7 human breast women under fasting conditions. The absolute tumor cell line proliferation [8,9]. In the presence 584 Int. J. Clin. Rheumatol. (2012) 7(6) future science group DRUG EVALUATION Kung Bazedoxifene & postmenopausal osteoporosis DRUG EVALUATION of E2, bazedoxifene dose-dependently inhibited the preclinical data indicate that bazedoxifene E2-induced MCF-7 cellular proliferation with may represent a promising new therapy for post- an IC50 value of 3.7 ± 1.6 nM [7]. In an in vivo