Economic evaluation of chemoprevention of breast cancer with tamoxifen and raloxifene among high-risk women in Japan

Raloxifene was approved for chemoprevention against breast cancer among high-risk women in addition to tamoxifen by the US Food and Drug Administration. This study aims to evaluate cost-effectiveness of these agents under Japan''s health system. A cost-effectiveness analysis with Markov model consisting of eight health states such as healthy, invasive breast cancer, and endometrial cancer is carried out. The model incorporated the findings of National Surgical Adjuvant Breast and Bowel Project P-1 and P-2 trial, and key costs obtained from health insurance claim reviews. Favourable results, that is cost saving or cost-effective, are found by both tamoxifen and raloxifene for the introduction of chemoprevention among extremely high-risk women such as having a history of atypical hyperplasia, a history of lobular carcinoma in situ or a 5-year predicted breast cancer risk of ⩾5.01% starting at younger age, whereas unfavourable results, that is ‘cost more and gain less'' or cost-ineffective, are found for women with a 5-year predicted breast cancer risk of ⩽5.00%. Therapeutic policy switch from tamoxifen to raloxifene among postmenopausal women are implied cost-effective. Findings suggest that introduction of chemoprevention targeting extremely high-risk women in Japan can be justifiable as an efficient use of finite health-care resources, possibly contributing to cost containment.     

苯并二氢吡喃衍生物的合成及其对骨和血管的初步生物活性

绝经后骨质疏松症的主要治疗手段是雌激素替代疗法 (ＨＲＴ) ,但长期用雌激素可引起子宫内膜和乳腺增生 ,增加发生子宫内膜癌和乳腺癌的危险性[1,2 ] 。异丙氧基异黄酮 (ｉｐｒｉｆｌａｖｏｎｅ)和 1998年初美国上市的选择性雌激素受体调节剂 (ＳＥＲＭｓ)雷洛昔芬 (ｒａｌｏｘｉｆｅｎｅ)可降低雌性激素样活性和致癌危险性 ,实现了雌激素的药理作用分离[3] 。异丙氧基异黄酮有很强的心血管保护作用 ,但其对绝经后骨质疏松症的防治效力不及雷洛昔芬[4 ,5] 。分析对比两种药物结构 :异丙氧基异黄酮较雷洛昔芬的结构简单 ,两者均含有苯并杂环 …     

雷诺昔酚对去势后大鼠骨密度、血生化指标的影响

目的:研究选择性雌激素受体调节剂(SERM)雷诺昔酚(RAL)对去势后雌性大鼠血生化及骨密度(BMD)的影响.方法:将5 mo龄未经产雌性二级SD大鼠24只,随机分为假手术(Sham)组、去势(OVX)组、去势 RAL(OVX RAL)组.OVX RAL组大鼠术后7 d开始给药.术后16wk处死各组大鼠,对各组大鼠血生化指标、BMD进行检测,并进行骨组织形态学观察.结果:OVX组与Sham组相比较,血钙(Ca2 )明显增高[(3.02±0.38)mmol/Lvs(2.24±0.30)mmol/L,P＜0.01],血碱性磷酸酶(ALP)升高[(2.336±0.032)μkat/Lvs(1.832±0.028)μkat/L,P＜0.05],血磷(P)无明显差异.OVX RAL治疗组与OVX组相比,血清Ca ,ALP均降低[(2.38±0.39)mmol/Lvs(3.02±0.38)mmol/L,(1.952±0.023)μkat/Lvs(2.336±0.032)μkat/L,P＜0.05],血P无明显差异.与Sham组相比,OVX组股骨近端[(0.181±0.021)g/cm2vs(0.287±0.025)g/cm2]、股骨干[(0.157±0.034)g/cm2vs(0.260±0.039)g/cm2]及腰椎BMD明显降低(P＜0.01);OVX RAL治疗组各部位BMD高于OVX组(P＜0.05),但未达到Sham组水平(P＞0.05).结论:去势后16 wk大鼠松质骨、皮质骨骨量、骨组织形态计量学指标均明显下降.经RAL治疗后的去势大鼠松质骨、皮质骨密度、骨组织形态计量学指标得到较好维持.     

苯并二氢吡喃腙衍生物的合成及其初步药理活性

为进一步筛选活性更强、副作用更小的抗绝经后骨质疏松症药物 ,在综合考察雷洛昔芬和异丙氧基异黄酮的基础上 ,设计合成一系列苯并二氢吡喃腙化合物 .化合物的结构均经波谱鉴定 ,并通过研究其对幼年小鼠子宫增重和血碱性磷酸酶活性的影响 ,初步考察化合物的药理活性 .结果表明 ,XY990 2具有较弱的雌激素受体激动作用和一定的雌激素受体拮抗作用 ,并有助于成骨细胞增殖 ,对治疗骨质疏松症是有利的 .     

Effects of raloxifene on fracture risk in postmenopausal women: the Raloxifene Use for the Heart Trial.

Using data from a randomized placebo-controlled trial of 10,101 postmenopausal women not selected on the basis of osteoporosis, we examined whether the effect of raloxifene treatment on fractures was consistent across categories of fracture risk. Treatment with raloxifene for 5 yr reduced the risk of clinical vertebral fractures, but not nonvertebral fractures, irrespective of the presence or absence of risk factors for fracture. INTRODUCTION: In The Raloxifene Use for The Heart (RUTH) trial, women assigned to raloxifene had a lower risk of clinical vertebral fractures but not nonvertebral fractures. However, it is uncertain whether the effect of raloxifene on fractures in this population not selected for low BMD differs according to risk factors for fractures. MATERIALS AND METHODS: We randomly assigned 10,101 postmenopausal women >or=55 yr of age with documented coronary heart disease or at high risk for coronary events to 60 mg raloxifene daily or placebo and followed them for a median of 5.6 yr. Fractures (nonvertebral and clinical vertebral) were prespecified secondary endpoints that were reported at semiannual visits. Fractures were adjudicated and confirmed using X-ray reports or medical records. RESULTS: There was no difference between raloxifene and placebo groups in risk of nonvertebral fractures (428 versus 438 events; hazard ratio [HR], 0.96; 95% CI, 0.84-1.10), including hip/femur (89 versus 103 events; HR, 0.85; 95% CI, 0.64-1.13) and wrist (107 versus 111 events; HR, 0.95; 95% CI, 0.73-1.24) fractures. Women treated with raloxifene had a lower risk of clinical vertebral fractures (64 versus 97 events; HR, 0.65; 95% CI, 0.47-0.89). The effect of treatment with raloxifene on risk of nonvertebral and clinical vertebral fractures was consistent across fracture risk categories defined at baseline by age, smoking status, physical activity level, prior history of fracture, family history of hip fracture, diabetes mellitus, previous use of hormone therapy, thyroid hormone use, statin use, weight loss, body mass index, or fracture specific summary risk score. CONCLUSIONS: In older women with or at high risk of coronary heart disease not selected on the basis of osteoporosis or increased fracture risk, treatment with raloxifene for 5 yr reduced the risk of clinical vertebral fractures, but not nonvertebral fractures, irrespective of presence or absence of risk factors for fracture.     

坤泰胶囊辅助治疗对绝经后骨质疏松症妇女骨密度、骨代谢和激素水平的影响

目的探讨坤泰胶囊辅助治疗对绝经后骨质疏松症患者骨密度、激素水平和骨代谢的影响。方法 150例绝经后骨质疏松症患者被随机分为治疗组、联合治疗组和对照组,每组50例。治疗组给予雷洛昔芬,联合治疗组给予雷洛昔芬加坤泰胶囊治疗,治疗12个月。检测治疗后两组患者髋部及腰椎的骨密度(bone mineral density,BMD)改变,同时测定血清雌二醇(estradiol,E2)、黄体生成素(luteinizing hormone,LH)、促卵泡剌激素(follicle stimulating hormone,FSH)、骨钙素(OC)和I型胶原交联C-末端肽(CTX-1)的水平,并记录治疗期间出现的药物不良反应。结果对照组的腰椎和髋部BMD在1年后较基线时有不同程度降低,比较差异有统计学意义(P0. 05);治疗1年后,治疗组和联合治疗组髋部及腰椎BMD都有不同程度的升高,且组间比较差异有明显的统计学意义(P0. 05);同时治疗组和联合治疗组血清CTX-1水平均降低,OC水平均升高,两组比较有明显的统计学意义(P0. 05);各组血清FSH和LH水平均降低,E2水平升高,两组比较有明显的统计学意义(P0. 05)。两组患者治疗时均未发现明显药物不良反应。结论坤泰胶囊辅助治疗有助于降低骨转换率,改善性激素水平,改善绝经后女性骨质疏松患者髋部及腰部的骨密度。     

Raloxifene for older women: a review of the literature

Raloxifene is a non-steroidal selective estrogen-receptor modulator (SERM) which is used for prevention and treatment of postmenopausal osteoporosis. Raloxifene decreases the incidence of vertebral fractures by 30%–50% in postmenopausal women with osteoporosis but has not been shown to decrease the incidence of hip fractures or other non-vertebral fractures. At the present time, estrogen-replacement therapy and bisphosphonate treatment are the only medical treatments that are proven to prevent hip fractures with the exception of vitamin D and calcium replacement, which has been shown to prevent hip fractures in elderly individuals and nursing home residents. Raloxifene has been shown to have additive effects on bone turnover and bone mineral density (BMD) when used along with alendronate and teriparatide. Raloxifene could have a role in renal failure as it has been shown to increase BMD of the vertebra over 1 year of therapy. Raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer. The increased incidence of venous thromboembolism is the main concern of raloxifene therapy and previous history of venous thromboembolism is a contraindication for use of raloxifene. Raloxifene has a role in treatment of vertebral osteoporosis in older women. The decision to use raloxifene should be based on evaluation of fracture risk and on potential other benefits than fracture reduction along with consideration of side effects.     

雷洛昔芬对慢性低氧大鼠肺动脉血管重构的作用

目的 探讨雷洛昔芬对慢性低氧大鼠肺动脉结构重构的调节作用。方法 选取体质量180~200 g的健康SD大鼠40只,♂,随机分为常氧组、低氧组、低氧+17β-雌二醇组、常氧+雷洛昔芬组、低氧+雷洛昔芬组;原代培养大鼠肺动脉平滑肌细胞(pulmonary arterial smooth muscle cells,PASMC)分组同上。采用间断常压低氧法建立慢性低氧大鼠和细胞模型,采用免疫组织化学法检测肺动脉平滑肌的增殖情况,以蛋白免疫印迹法检测PASMC小窝蛋白(Caveolin-1,Cav-1)的表达,采用荧光探针法检测PASMC活性氧(ROS)的含量。结果 与常氧组相比,低氧组大鼠肺小动脉平滑肌增殖、中膜厚度及肌化程度明显增加(P<0.01),雷洛昔芬可显著抑制低氧诱导的肺动脉改变(P<0.05)。低氧组大鼠PASMC中ROS浓度增加(P<0.01),给予低氧组大鼠雷洛昔芬治疗,可下调ROS浓度(P<0.05)。低氧组大鼠PASMC中Cav-1表达显著降低(P<0.01),雷洛昔芬可改善其低表达(P<0.05)。雷洛昔芬的缓解肺动脉重构、上调Cav-1的表达、减少ROS的产生、抑制PASMC增殖的效果类似于17β-雌二醇。结论 雷洛昔芬可上调PASMC中Cav-1的表达,减少ROS的产生,抑制PASMC增殖,在缓解慢性低氧大鼠的肺动脉重构中发挥重要作用。     

Comparison of raloxifene and bisphosphonates based on adherence and treatment satisfaction in postmenopausal Asian women

We evaluated adherence with raloxifene therapy compared with daily bisphosphonate in Asian postmenopausal women at increased risk of osteoporotic fractures. In this 12-month observational study conducted in Asia (Hong Kong, Malaysia, Pakistan, Philippines, Singapore, Taiwan), 984 postmenopausal women (aged 55 years or older) were treated with raloxifene 60 mg/day (n = 707; 72%) or daily bisphosphonate (alendronate 10 mg/day; n = 206; 21%, or risedronate 5 mg/day; n = 71; 7%) during their normal course of care. Patients were assessed at baseline, 6, and 12 months. Baseline characteristics (including age, race, education, menopausal status, and baseline fractures) were comparable between the raloxifene and bisphosphonate groups. More women on raloxifene completed the study compared with those on bisphosphonate (50.2% versus 37.5%; P < 0.001). Patients also took raloxifene for a longer period than bisphosphonate (median, 356 versus 348 days; P = 0.011). Compared with those taking bisphosphonate, significantly fewer patients taking raloxifene discontinued the study because of stopping treatment (5.7% versus 10.1%, P = 0.017) or changing treatment (2.8% versus 9.7%, P < 0.001). Inconvenient dosing was reported as a primary reason for discontinuation due to stopping or changing treatment in 19 (6.9%) bisphosphonate patients compared with 0 raloxifene patients. The percentage of patients who had consumed 80% or more of their study medication was similar for raloxifene patients (48–56 weeks; 95.2%) and bisphosphonate patients (48–56 weeks; 93.3%). More raloxifene patients responded that they were satisfied with their medication than bisphosphonate patients at 48–56 weeks (P = 0.002). We concluded that Asian postmenopausal women at increased risk of osteoporotic fractures showed a greater propensity to remain on raloxifene compared with bisphosphonate. The women on raloxifene exhibited lower discontinuation rates and higher treatment satisfaction.     

Three-month changes in bone turnover markers and bone mineral density response to raloxifene in Japanese postmenopausal women with osteoporosis

It has been well established that raloxifene (RLX) improves bone turnover, increases bone mineral density (BMD), and reduces the risk of fractures. However, it remains obscure how to monitor the therapeutic effects of RLX, while numerous clinical trials for other antiresorptive agents have suggested that greater short-term reductions of bone turnover markers (BTMs) can predict greater increases in BMD and greater reduction in risk of future fractures. The purpose of this study was to investigate associations between short-term reductions of BTMs and subsequent changes of BMD after 1-year treatment with RLX. Seventy-three Japanese postmenopausal women with untreated osteoporosis were selected for this study. Reductions in BTMs [bone-specific alkaline phosphatase (BAP) or serum N-terminal telopeptide of type I collagen (NTx)] after 3 months did not correlate with increases of BMD at any major sites (lumbar spine, femoral neck, total neck, and distal 1/3 radius) either after 6 months or after 12 months. Our results suggest that short-term reductions or 3-month reductions of BTMs with RLX treatment cannot be used to predict increases of BMD. However, this does not directly mean that short-term reductions or 3-month reductions of BTMs with RLX treatment cannot be used to predict risk reduction of future fractures or the ultimate effects of RLX on bone. Further studies with fracture endpoints in longer observation and larger number of patients are warranted to establish how to monitor the therapeutic effects of RLX or early identification of responders or nonresponders to RLX treatment.