Effect of raloxifene combined with monofluorophosphate as compared with monofluorophosphate alone in postmenopausal women with low bone mass: a randomized,controlled trial

Raloxifene effectively reduces the incidence of vertebral fractures in patients with postmenopausal osteoporosis. Recent data suggest that low-dose monofluorophosphate (MFP) plus calcium reduces the vertebral fracture rate in postmenopausal women with moderate osteoporosis. The objective of this study was to evaluate the combination of raloxifene and MFP in the treatment of postmenopausal women with osteopenia, osteoporosis and severe osteoporosis. A total of 596 postmenopausal women with osteopenia, osteoporosis and severe osteoporosis (mean femoral neck T-score of –2.87 SD) were randomized to treatment with 60 mg/day raloxifene HCl and 20 mg/day fluoride ions (as MFP) or 20 mg/day fluoride and placebo for 18 months. All patients received calcium (1000 mg/day) and vitamin D (500 IU/day) supplements. Changes in bone mineral density (BMD), as primary endpoint, and the rate of osteoporotic fractures and biochemical markers, as secondary endpoints, were assessed. As compared with MFP, raloxifene plus MFP was associated with significantly greater mean increases in the BMD of the femoral neck (1.37% versus 0.33%; P=0.004), total hip (0.89% versus –0.42%; P<0.001) and lumbar spine (8.80% versus 5.47% P<0.001). In the raloxifene plus MFP group, 16 patients sustained 17 osteoporotic fractures, as compared with 22 patients sustaining 34 incident osteoporotic fractures in the MFP group (P=0.313). One patient in the raloxifene plus MFP group sustained multiple osteoporotic fractures, as compared with eight patients in the MFP group (P=0.020). MFP alone significantly increased the serum bone alkaline phosphatase (bone ALP) and the urinary C-terminal crosslinking telopeptide of type I collagene (U-CTX). The addition of raloxifene in the combination arm blunted the rise in bone ALP, which remained nevertheless significant, and abolished the increase in U-CTX. The combination of raloxifene with MFP was generally well tolerated. This study demonstrates that, in postmenopausal women with osteopenia, osteoporosis and severe osteoporosis, the combination therapy of raloxifene plus MFP favorably influences the BMD and the bone formation and resorption balance, and may reduce the risk of multiple osteoporotic fractures compared to MFP alone.     

Role of nociceptor estrogen receptor GPR30 in a rat model of endometriosis pain

Endometriosis, the most common cause of chronic pelvic pain, is an estrogen-dependent disease in which classic estrogen receptors (ERα, ERβ) play an important role. Although recent evidence suggests that the novel G protein–coupled estrogen receptor (GPR30) also plays a key role in the progression of endometriosis, whether it is also involved in endometriosis pain is still unknown. Here we tested the hypothesis that GPR30 expressed by nociceptors contributes to endometriosis pain. Intramuscular injection of the GPR30 agonists raloxifene or 17β-estradiol produced a fast-onset, persistent, mechanical hyperalgesia at the site of the injection. Intrathecal antisense (AS) oligodeoxynucleotides (ODN), but not mismatch (MM) ODN, targeting mRNA for GPR30 markedly inhibited its protein expression in nociceptors and attenuated the mechanical hyperalgesia induced by local raloxifene or 17β-estradiol. Pretreatment with the GPR30 antagonist G-36 also inhibited the hyperalgesia induced by raloxifene or 17β-estradiol in naive control rats. Surgical implant of autologous uterine tissue onto the gastrocnemius muscle, which induces endometriosis-like lesions, produced local mechanical hyperalgesia. Intrathecal AS, but not MM, ODN targeting GPR30 mRNA reversibly inhibited the mechanical hyperalgesia at the site of endometriotic lesions. Finally, intralesional injection of the GPR30 antagonist G-36 also inhibited the mechanical hyperalgesia at the site of ectopic uterine tissue. We conclude that local GPR30 agonists produce persistent mechanical hyperalgesia in naive female rats, whereas local GPR30 antagonists inhibit mechanical hyperalgesia in a model of endometriosis pain. Thus, GPR30 expressed by nociceptors innervating ectopic uterine lesions might play a major role in endometriosis pain.     

雷洛昔芬对去卵巢大鼠纤维蛋白原的影响

目的探讨选择性雌激素受体调节剂雷洛昔芬对去卵巢大鼠血浆纤维蛋白原的影响。方法40只12周龄雌性SD大鼠随机分为5组，每组8只。（1）去卵巢组（Ovariectomy，OVX）：切除大鼠双侧卵巢建立绝经后模型，给予等量生理盐水灌胃；（2）假手术对照组（Control，C）：只打开腹腔未切除双侧卵巢，给予等量生理盐水灌胃；（3）雌激素组（Ovariectomy＋Estrogen，E）：切除大鼠双侧卵巢，给予雌激素（倍美力，1mg／kg·d）灌胃治疗；（4）小剂量雷洛昔芬（Ovariectomy＋Raloxifene，Rs）：切除大鼠双侧卵巢，给予雷洛昔芬（易维特，1mg／kg·d）灌胃治疗；（5）大剂量雷洛昔芬组（Ovariectomy＋Raloxifene，Rl）：切除大鼠双侧卵巢，给予雷洛昔芬（易维特，3mg／（kg·d）灌胃治疗。治疗3个月后，测量治疗后各组血浆纤维蛋白原的变化。结果去卵巢组血清雌二醇水平明显下降，显著低于假手术对照组。雌激素或雷洛昔芬治疗后血清雌二醇水平都上升，接近假手术对照组（OVX：36．69±6．91比C：248．32±32．51比E：240．89±29．44比Rs：239．56±25．73比Rl：243．48±27．62pg／mL,P〈0．01）。去卵巢组的血浆纤维蛋白原浓度显著高于假手术对照组和雷洛昔芬组。雌激素组纤维蛋白原的浓度也升高，与假手术对照组比较有统计学意义。雷洛昔芬治疗后纤维蛋白原下降，低于去卵巢组和雌激素组（OVX：4．25±0．43比C：1．76±0．20比E：3．46±0．31比Rs：1．63±0．19比Rl：1．41±0．16g／L，P〈0．05）。结论雌性SD大鼠双侧卵巢切除后，纤维蛋白原水平升高。雌激素治疗不能降低纤维蛋白原水平反而升高其水平，而雷洛昔芬能降低纤维蛋白原水平。     

甲状旁腺素1-34对骨质疏松大鼠治疗作用的实验研究

目的探讨甲状旁腺素134(hPTH134)对骨质疏松的治疗作用以及与血钙、磷、维生素D代谢和生长因子的关系。方法用摘除大鼠双侧卵巢的方式制备骨质疏松模型(OVX),实验动物分为4个组:模型对照组(OVX组,摘除大鼠双侧卵巢不作任何处理);hPTH134治疗组(PTH组,摘除大鼠双侧卵巢12w后用hPTH134治疗8w);盐酸雷洛昔芬治疗组(摘除大鼠双侧卵巢12w后用雷洛昔芬治疗8w);假手术组(Sham组,仅切除卵巢周围的脂肪组织约3g,术后12w纳入实验)。应用HOLOGIC第4代双能X线4500W骨密度仪测大鼠腰椎、股骨上段骨密度值(BMD);以骨形态计量学测股骨骨小梁面积、矿化沉积率;用ELISA法测定血清IGF1水平和血清25OHVitD浓度以及血淋巴细胞VitD受体(VDR)含量。结果hPTH134治疗组、盐酸雷洛昔芬治疗组均较OVX组腰椎、股骨上段骨密度增高,组间比较差异有显著性(P<0.01)。hPTH134治疗组较盐酸雷洛昔芬治疗组股骨上段骨密度增高,两组之间差异有显著性(P<0.01)。hPTH134治疗组骨小梁面积明显增加、矿化沉积率增高。hPTH134治疗组、盐酸雷洛昔芬治疗组血清IGF1浓度值、血清25OHVitD浓度值升高,与OVX组比较差异有显著性(P<0.01)。各组血淋巴细胞VDR含量无明显变化,与OVX组比较差异无显著性(P>0.05)。结论hPTH134能够预防腰椎、股骨上段骨密度丢失,使骨小梁面积明显增加、矿化沉积率增高并且血清IGF1及血清25OHVitD浓度值升高,但对VDR含量无明显作用。     

3种方案治疗绝经后骨质疏松疗效观察

目的:探讨3种不同方案治疗绝经后妇女骨质疏松的临床疗效。方法:将绝经后伴骨量减少妇女110例,随机分成3组。A组36例,钙尔奇D 1 200 mg/d+骨化三醇0.25μg/bid;B组39例,钙尔奇D 1 200 mg/d+骨化三醇0.25μg/bid+替勃龙1.25 mg/d;C组35例,钙尔奇D 1200 mg/d+骨化三醇0.25μg/bid+盐酸雷洛昔芬60 mg/d。3组妇女连续治疗1年。治疗前后测定腰椎第1~4节(L1~4)及股骨骨密度(BMD);同时检测血清骨碱性磷酸酶(BALP)及血清Ⅰ型前胶原肽(CTX)评价骨代谢指标。结果:①骨痛症状改善。3组妇女治疗1年后骨痛症状均得到改善,A、B、C组改善率分别为83%、92%、95%。②骨密度升高。3组妇女治疗后骨密度明显升高,分别与治疗前比较,差异均有统计学意义(P<0.05);治疗后1年B、C组妇女BMD均较A组显著升高,差异有统计学意义(P<0.01),但B、C两组间比较,差异无统计学意义(P>0.05)。③骨代谢指标。3组妇女治疗后BALP及CTX水平均较治疗前降低,差异有统计学意义(P<0.05);3组间比较,治疗1年后血清CTX水平,B组较C组显著下降,差异有统计学意义(P<0.01),B组较A组下降更为显著,差异有统计学意义(P<0.000 1)。结论:3种方案均可用于骨质疏松的治疗,降低骨转换、增加BMD、减少骨吸收。     

雷罗昔芬治疗卵巢切除大鼠的实验研究

为探讨选择性雌激素受体调节剂雷罗昔芬(Raloxifene)对卵巢切除大鼠的骨密度、骨代谢、血脂代谢的影响，观测了Raloxifene治疗的卵巢切除大鼠腰椎和股骨骨密度、血清BGP、尿PYD、血清CHOL、TG、HDL、LDL、雌二醇(E2)、动脉钙磷含量等指标。结果表明，Raloxifene治疗卵巢切除大鼠后其E2增高，股骨和腰椎骨密度增高，骨转换降低，血清胆固醇和低密度脂蛋白胆固醇降低，而血清甘油三脂和高密度脂蛋白胆固醇无明显变化。结果提示，Raloxifene能提高卵巢切除大鼠骨密度，降低骨转换，保护脂代谢，提高雌激素水平，可能与其拟雌激素样作用有关。     

Effect of raloxifene on bone mineral density and biochemical markers of bone turnover in Japanese postmenopausal women with osteoporosis: results from a randomized placebo-controlled trial

The safety and efficacy of raloxifene, a selective estrogen receptor modulator (SERM), has been studied extensively in large, global clinical trials. However, the effect of raloxifene on bone mineral density (BMD) and on biochemical markers of bone turnover in Japanese postmenopausal women with osteoporosis has not been rigorously evaluated. This study was designed to assess the safety and efficacy of raloxifene in Japanese postmenopausal women with osteoporosis following 1 year of therapy. Participants in this multicenter trial were randomly assigned to receive placebo, raloxifene 60 mg/day (RLX60), or raloxifene 120 mg/day (RLX120). Lumbar spine BMD was measured at baseline, 24, 40, and 52 weeks, and biochemical markers of bone turnover were assessed at baseline, 12, 24, and 52 weeks. Serum lipids were assessed at baseline, 12, 24, 40, and 52 weeks, and breast examinations and transvaginal ultrasound of the endometrium were performed at enrollment and 52 weeks. Compared with baseline, women taking RLX60 had significant increases in lumbar spine (L2-L4) BMD at 24 weeks (+3.3%, p<0.001) through 52 weeks (+3.5%, p<0.001) of therapy, and similar results were observed in the RLX120 group. Markers of bone turnover and total cholesterol and LDL-C were significantly reduced, and no significant treatment-group difference was observed for patients reporting at least one adverse event following randomization. In addition, there were no reported venous thromboembolic events (VTE) in any treatment group. The results of this study demonstrate that raloxifene is associated with early increases in lumbar spine BMD, has favorable effects on biochemical markers of bone turnover and lipid profile, and is well tolerated in postmenopausal Japanese women.The named authors wrote this article on behalf of the Japan Clinical Trial Research Group.