Efficacy and safety of bazedoxifene for postmenopausal osteoporosis

Bazedoxifene, a novel selective estrogen receptor modulator, has been developed to have favorable effects on bone and the lipid profile while minimizing stimulation of uterine or breast tissues. Two large Phase III clinical trials showed that bazedoxifene, as well as raloxifene, increased bone mineral density, decreased levels of bone turnover markers, and significantly reduced the risk of new vertebral fractures in postmenopausal women compared with placebo. Although the incidence of nonvertebral fractures with bazedoxifene or raloxifene did not differ significantly from that with placebo, a post hoc analysis of a subgroup of women at higher fracture risk revealed that bazedoxifene significantly reduced the nonvertebral fracture risk relative to placebo and raloxifene. Bazedoxifene also improved the lipid profile by reducing the serum concentrations of total cholesterol and low-density lipoprotein cholesterol, with an increase in the serum level of high-density lipoprotein cholesterol. The incidences of vasodilatation (hot flushes), leg cramps, and venous thromboembolic events were significantly higher with bazedoxifene and raloxifene compared with placebo. There was no evidence of endometrial and breast stimulation with bazedoxifene. Taking advantage of the favorable effects of bazedoxifene on the breast and endometrium, the pairing of bazedoxifene with conjugated estrogens is under investigation for the treatment of menopausal symptoms and prevention of postmenopausal osteoporosis. A Phase III trial showed that combination therapy of bazedoxifene and conjugated estrogens significantly increased bone mineral density and decreased bone turnover markers, with relief of hot flushes and improvement of vaginal atrophy. This article reviews the clinical efficacy and safety of bazedoxifene in the treatment of postmenopausal osteoporosis

Alendronate improves QOL of postmenopausal women with osteoporosis

Hisaya Kawate1, Keizo Ohnaka2, Masahiro Adachi1, Suminori Kono3, Hideyuki Ikematsu4, Hisashi Matsuo5, Kazumi Higuchi6, Takehiko Takayama7, Ryoichi Takayanagi11Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; 2Department of Geriatric Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; 3Department of Preventive Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan; 4Internal Medicine, Haradoi Hospital, Fukuoka, Japan; 5Matsuo Naika Hospital, Fukuoka, Japan; 6Fukuoka Teishin Hospital, Fukuoka, Japan; 7Takayama Icho-ka and Naika Clinic, Fukuoka, JapanPurpose: Postmenopausal osteoporosis causes bone fracture as well as pain, physical, psychological and socially adverse effects, which affects a patient’s quality of life (QOL). The effect of alendronate on QOL was investigated compared with that of alfacalcidol in postmenopausal osteoporotic women.Patients and methods: A total of 44 postmenopausal osteoporotic women (mean age 69.8 years) with back or joint pain, although capable of walking, were randomly assigned to two groups; group A (n = 25) received 5 mg/day of alendronate, and group B (n = 19) received 0.5 μg/day of alfacalcidol, for the first 4 months. For the following 2 months, the group A received 0.5 μg/day of alfacalcidol and the group B received 5 mg/day of alendronate in a crossover design. The patient’s QOL was evaluated by score of Japanese Osteoporosis Quality of Life Questionnaire (JOQOL), and pain intensity using a visual analog scale (VAS). Bone metabolism was measured by bone mineral density (BMD) and a biomarker for bone resorption, urinary crosslinked N-terminal telopeptide of type I collagen (NTX).Results: With 4-month treatment, alendronate, but not alfacalcidol, improved pain-related QOL, reduced joint pain by VAS, and increased bone mineral density. Both treatments significantly reduced bone resorption, the inhibition was significantly higher with alendronate (−56.5%) compared with alfacalcidol (−18.1%). After crossover, the patients in group A received alfacalcidol and had a reduced total and daily living activity-related QOL scores, and increased upper back pain by VAS. The group B received alendronate had significantly reduced bone resorption after the 2 months.Conclusion: Alendronate improves the QOL of Japanese postmenopausal women with osteoporosis by reducing pain intensity as well as increasing bone mineral density. Keywords: osteoporosis, bisphosphonates, quality of life, pain, vitamin

Nuclear Compartmentalization of N-CoR and Its Interactions with Steroid Receptors

The repression mechanisms by the nuclear receptor corepressor (N-CoR) of steroid hormone receptor (SHR)-mediated transactivation were examined. Yellow fluorescent protein (YFP)-N-CoR was distributed as intranuclear discrete dots, while coexpression of androgen receptor (AR), glucocorticoid receptor α, and estrogen receptor α ligand-dependently triggered redistribution of YFP-N-CoR. In fluorescence recovery after photobleaching analysis, mobility of the N-CoR was reduced by 5α-dihydrotestosterone (DHT)-bound AR. The middle region of N-CoR mostly contributed to the interaction with agonist-bound SHRs and the suppression of their transactivation function. N-CoR impaired the DHT-induced N-C interaction of AR, and the impaired interaction was dose-dependently recovered by coexpression of SRC-1 and CBP. N-CoR also impaired the intranuclear complete (distinct) focus formation of SHRs. Coexpression of SRC-1 or CBP released YFP-N-CoR or endogenous N-CoR from incomplete foci and simultaneously recovered complete foci of AR-green fluorescent protein. These results indicate that the relative ratio of coactivators and corepressors determines the conformational equilibrium between transcriptionally active and inactive SHRs in the presence of agonists. The intranuclear foci formed by agonist-bound SHRs were completely destroyed by actinomycin D and α-amanitin, indicating that the focus formation does not precede the transcriptional activation. The focus formation may reflect the accumulation of SHR/coactivator complexes released from the transcriptionally active sites and thus be a mirror of transcriptionally active complex formation