ospemifene and Osteoporosis--Postmenopausal

Ospemifene is a selective estrogen-receptor modulator approved for treating menopause-related moderate to severe dyspareunia and vaginal dryness, symptoms of vulvovaginal atrophy (VVA), in the United States, and for treating menopause-related, symptomatic VVA in women not appropriate for local estrogen therapy in Europe. This review summarizes the effects of ospemifene on bone, including bone biomarker data from a phase 3 vaginal dryness study. Early-phase studies of postmenopausal women showed that ospemifene dose-dependently decreased bone turnover markers versus placebo, similar to raloxifene. A 12-week, phase 3 study of ospemifene 60 mg/day in postmenopausal women showed improvements in all VVA parameters and significantly greater decreases in seven of nine bone biomarkers versus placebo. Lower bone resorption markers with ospemifene were observed regardless of time since menopause (≤5 years or >5 years) or baseline bone mineral density (BMD) (normal [

Topics: Administration, Oral; Atrophy; Bone Density; Female; Humans; Osteoporosis, Postmenopausal; Randomized Controlled Trials as Topic; Selective Estrogen Receptor Modulators; Tamoxifen; Vagina; Vulva

Selective estrogen receptor modulators (SERMs) are synthetic non-steroidal agents which have varying estrogen agonist and antagonist activities in different tissues, most likely due to the receptor conformation changes associated with that SERM's binding and the subsequent effect on transcription. Clinical trials aim to differentiate amongst SERMs on selected target tissues for use in postmenopausal women including effects on breast, bone, cardiovascular venous thrombosis risk, endometrium, vagina, vasomotor symptoms, and brain. This paper describes differences in clinical effects on selected target tissues of SERMs that are approved, discontinued or in development. FDA approved SERMs include tamoxifen and toremifene used for prevention and treatment of breast cancer, raloxifene approved for prevention and treatment of osteoporosis and prevention of invasive breast cancer, and ospemifene approved for treatment of dyspareunia from menopausal vaginal atrophy. The FDA approved first tissue selective estrogen complex (TSEC) a pairing of conjugated equine estrogens with the SERM, bazedoxifene. This pairing reduces the risk of endometrial hyperplasia that can occur with the estrogenic component of the TSEC without the need for a progestogen in women with a uterus. It also allows for the estrogenic benefits on relief of hot flashes and prevention of bone loss without stimulating the breast or the endometrium. In clinical practice, the tissue-selective actions of SERMs, alone or paired with estrogens, allow for individualization in meeting the treatment needs of postmenopausal women by providing targeted tissue effects. This article is part of a Special Issue entitled 'Menopause'.

Topics: Breast Neoplasms; Clinical Trials as Topic; Dyspareunia; Estrogens, Conjugated (USP); Female; Hot Flashes; Humans; Indoles; Osteoporosis; Osteoporosis, Postmenopausal; Postmenopause; Pyrrolidines; Raloxifene Hydrochloride; Receptors, Estrogen; Selective Estrogen Receptor Modulators; Tamoxifen; Tetrahydronaphthalenes; Toremifene

Several selective estrogen receptor modulators are in clinical development for postmenopausal osteoporosis. Bazedoxifene has shown significant reductions in vertebral and non-vertebral (in higher-risk women) fracture risk, with no evidence of breast or endometrial stimulation. Lasofoxifene has demonstrated significant reductions in vertebral and non-vertebral fracture risk, but has been associated with endometrial/uterine effects. Both selective estrogen receptor modulators were generally safe and well tolerated but have been associated with some "class effects" (e.g., hot flushes, venous thromboembolic events). A tissue selective estrogen complex partnering bazedoxifene with conjugated estrogens is under clinical investigation for the treatment of menopausal symptoms and osteoporosis prevention. Future directions in selective estrogen receptor modulator research include ospemifene and RAD 1901.

Topics: Bone Density Conservation Agents; Breast; Endometrium; Female; Fractures, Bone; Humans; Indoles; Osteoporosis, Postmenopausal; Piperidines; Pyrrolidines; Selective Estrogen Receptor Modulators; Tamoxifen; Tetrahydronaphthalenes; Thiophenes

Postmenopausal osteoporosis is an asymptomatic skeletal disease that is often underdiagnosed and undertreated. Osteoporotic fractures are associated with substantial morbidity and mortality and impaired quality of life-socially, emotionally, and financially. Considering the growing burden of osteoporotic fractures worldwide, there remains an ongoing need for progress in the diagnosis of osteoporosis, identification of individuals at high fracture risk, and treatment to prevent fractures. Adequate intake of calcium and vitamin D is recommended as baseline therapy for osteoporosis prevention and treatment. Available pharmacological agents for the management of postmenopausal osteoporosis may not be appropriate for all women. Oral bisphosphonates are generally considered first-line therapy for patients with osteoporosis, but their use may be limited by gastrointestinal side effects. Other agents include hormone therapy, the selective estrogen receptor modulator (SERM) raloxifene, salmon calcitonin, teriparatide (human recombinant parathyroid hormone), and strontium ranelate (in some countries). Factors that may contribute to poor compliance and persistence with current osteoporosis therapies include drug intolerance, complexity of dosing regimens, and poor understanding of the relative benefit and risk with treatment. Emerging therapies for postmenopausal osteoporosis include novel SERMs (bazedoxifene, lasofoxifene, ospemifene, arzoxifene) and denosumab. Because SERMs can display mixed functional estrogen receptor agonist or antagonist activity depending on the target tissue, they may confer beneficial effects on bone with limited stimulation of other tissues (e.g., breast, endometrium). Clinical investigation of these promising new agents is ongoing to evaluate efficacy and safety, with the goal of developing effective strategies to maximize long-term tolerance, compliance, and persistence with therapy.

Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bone Density Conservation Agents; Denosumab; Drug Therapy, Combination; Female; Humans; Indoles; Middle Aged; Osteoporosis, Postmenopausal; Parathyroid Hormone; Piperidines; Postmenopause; Pyrrolidines; Raloxifene Hydrochloride; RANK Ligand; Selective Estrogen Receptor Modulators; Tamoxifen; Tetrahydronaphthalenes; Thiophenes; Vitamin D; Women's Health

Ospemifene is a novel selective estrogen receptor modulator (SERM) that is initially being developed for the treatment of vaginal atrophy in postmenopausal women. However, it also shows promise in the prevention and treatment of osteoporosis. As a part of a phase II trial, we compared the effects of ospemifene and raloxifene on bone turnover in postmenopausal women. The study was conducted as a randomized, double-blind study in which 118 healthy postmenopausal women received 30 (n = 29), 60 (n = 30), or 90 mg (n = 30) ospemifene or 60 mg (n = 29) raloxifene for 3 months. Bone resorption was assessed by measuring the urinary outputs of N- and C-terminal cross-linking telopeptides of type I collagen (NTX and CTX, respectively). Bone formation was assessed by measuring bone-specific alkaline phosphatase (bone ALP), osteocalcin (OC), procollagen type I N propeptide (PINP), and procollagen type I C propeptide (PICP) in serum. All markers were studied before and at 3 months and 2-4 weeks after cessation of the medication. Urine NTX outputs decreased in all study groups, and the only statistically significant difference in NTX was observed between raloxifene and 30 mg ospemifene, which was reduced more in the raloxifene group. The output of CTX decreased most clearly in 60- and 90-mg ospemifene groups, but no significant differences between study groups emerged. A significant difference was found between the 90-mg ospemifene group and raloxifene in PINP in favor of ospemifene. No other differences in bone formation markers emerged between ospemifene and raloxifene. The study confirms the bone-restoring activity of ospemifene, which is comparable to that of raloxifene.

Topics: Biomarkers; Bone Remodeling; Collagen; Double-Blind Method; Female; Finland; Humans; Osteoporosis, Postmenopausal; Postmenopause; Raloxifene Hydrochloride; Tamoxifen