不同双膦酸盐类药物抑制破骨细胞特征曲线的意义

目的比较双膦酸盐类药物唑来膦酸、伊班膦酸和帕米膦酸对体外培育破骨细胞的具体抑制作用,绘制特征性曲线并指导临床治疗。方法通过体外培育小鼠骨髓细胞,分化获得破骨细胞并将其分为唑来膦酸组、伊班膦酸组、帕米膦酸组、对照组。其中,唑来膦酸组培养液中加入唑来膦酸,药物的阶梯浓度为:10-3、10-2、10-1、1、10、102、103μmol/L。同时,伊班膦酸组与帕米膦酸组加入相应药物的阶梯浓度相同,对照组加入磷酸盐缓冲液。观察双膦酸盐类药物对破骨细胞形成、迁移、粘附、骨破坏的抑制作用特征并进行比较,绘制特征性曲线。结果随着药物浓度逐级增大,多核细胞数量随浓度增加而减少。唑来膦酸、伊班膦酸和帕米膦酸的最低有效抑制浓度分别为1、10、102μmol/L。三者50%有效浓度分别为0.66、5.58、51.9μmol/L。结论临床治疗骨质疏松症时建议参考破骨细胞抑制特征曲线,为唑来膦酸、伊班膦酸和帕米膦酸的静脉应用提供科学依据。     

Optimizing dosing frequencies for bisphosphonates in the management of postmenopausal osteoporosis: patient considerations

Postmenopausal osteoporosis is common and underrecognized among elderly women. Osteoporotic fractures cause disability and disfigurement and threaten patients’ mobility, independence, and survival. Care for incident fractures in this age group must go beyond orthopedic repair, to assessment and treatment of the underlying bone fragility. Fracture risk can be reduced by vitamin D and calcium supplementation along with antiresorptive drug treatment. First-line osteoporosis pharmacotherapy employs nitrogen-containing bisphosphonates. The inconvenience of daily oral treatment has motivated development of weekly, monthly, and intermittent oral regimens, as well as quarterly and yearly intravenous (iv) regimens. Ibandronate is the first bisphosphonate to have shown direct anti-fracture efficacy with a non-daily regimen; it was approved for once-monthly oral dosing in 2005 and for quarterly iv dosing in 2006. Intermittent oral risedronate and yearly iv zoledronic acid were approved in 2007. Newly available regimens with extended dosing intervals reduce the inconvenience of bisphosphonate therapy and provide patients with a range of options from which to select a maximally sustainable course of treatment. This review discusses the development, efficacy, safety, and tolerability of extended-interval bisphosphonate regimens and examines their potential to improve patient acceptance and long-term success of osteoporosis treatment.     

Pamidronate is superior to ibandronate in decreasing bone resorption,interleukin-6 and beta 2-microglobulin in multiple myeloma

OBJECTIVES: Bisphosphonates have been found to reduce skeletal events in patients with multiple myeloma (MM). This is the first randomised trial to compare the efficacy of pamidronate and ibandronate, a third-generation aminobisphosphonate, in bone turnover and disease activity in MM patients. METHODS: Patients with MM, stage II or III, were randomly assigned to receive either pamidronate 90 mg (group I: 23 patients) or ibandronate 4 mg (group II: 21 patients) as a monthly intravenous infusion in addition to conventional chemotherapy. Skeletal events, such as pathologic fractures, hypercalcaemia, and bone radiotherapy were analysed. Bone resorption markers [N-terminal cross-linking telopeptide of type-I collagen (NTX) and tartrate-resistant acid phosphatase type 5b (TRACP-5b)], bone formation markers (bone alkaline phosphatase and osteocalcin), markers of disease activity (paraprotein, CRP, beta 2-microglobulin), and interleukin-6 (IL-6) were also studied. RESULTS: In both groups, the combination of chemotherapy with either pamidronate or ibandronate produced a reduction in bone resorption and tumour burden as measured by NTX, IL-6, paraprotein, CRP, and beta 2-microglobulin from the second month of treatment, having no effect on bone formation. TRACP-5b also had a significant reduction in the pamidronate group from the second month of treatment and in the ibandronate group from the sixth month. However, there was a greater reduction of NTX, IL-6, and beta 2-microglobulin in group I than in group II, starting at the second month of treatment (P = 0.002, 0.001, and 0.004, respectively) and of TRACP-5b, starting at the fourth month (P = 0.014), that being continued throughout the 10-month follow-up of this study. There was no difference in skeletal events during this period. A significant correlation was observed between changes of NTX and changes of TRACP-5b, IL-6, and beta 2-microglobulin from the second month for patients of both groups. CONCLUSIONS: These results suggest that a monthly dose of 90 mg of pamidronate is more effective than 4 mg of ibandronate in reducing osteoclast activity, bone resorption, IL-6, and possibly tumour burden in MM. TRACP-5b has also proved to be a useful new marker for monitoring bisphosphonates treatment in MM.     

伊班膦酸钠干预骨关节炎模型大鼠丝裂原活化蛋白激酶信号通路的变化

背景:丝裂原活化蛋白激酶信号通路参与成骨细胞与破骨细胞的分化,与软骨下骨重建过程密切相关,在骨关节炎的发生发展中起重要作用。双膦酸盐作为骨吸收抑制剂,主要用于骨质疏松的治疗。目的:探讨伊班膦酸钠对大鼠骨关节炎的治疗效果,以及其对丝裂原活化蛋白激酶信号通路的影响。方法:实验方案经南华大学附属第一医院动物实验伦理委员会批准。30只雌性SD大鼠随机分为假手术组、模型组、治疗组。模型组和治疗组行双侧去卵巢及前交叉韧带切断术,假手术组大鼠只切除卵巢周围与卵巢大小相仿的脂肪组织,切开双侧膝关节腔,但不切断前交叉韧带。术后1周,治疗组予以腹腔注射伊班膦酸钠10μg/kg,模型组予以腹腔注射等量生理盐水,假手术组不作干预。12周以后,处死实验动物,进行关节软骨的组织形态学观察及Mankin评分,软骨下骨的Micro-CT扫描及骨组织显微结构定量分析,检测丝裂原活化蛋白激酶信号通路中细胞外信号调节蛋白激酶(ERK1)和c-Jun氨基酸末端激酶(JNK)的mRNA表达量及蛋白表达水平。结果与结论:①模型组软骨结构明显破坏,Mankin评分较假手术组明显增高,而治疗组的Mankin评分较模型组显著降低(P<0.01);②与假手术组比较,模型组中的骨密度、骨体积分数、骨小梁数量降低,骨小梁分离度显著增高(P<0.01);与模型组相比,治疗组的骨密度、骨体积分数、骨小梁数量增加,骨小梁分离度明显下降(P<0.01);③模型组中的ERK1、JNK mRNA表达和蛋白表达较假手术组明显增加(P<0.05,P<0.01);与模型组相比,治疗组中的ERK1、JNK mRNA表达和蛋白表达显著降低(P<0.05);④结果说明,伊班膦酸钠可能通过抑制ERK1、JNK丝裂原活化蛋白激酶信号通路的表达改善膝骨关节炎大鼠的软骨下骨的微结构,抑制软骨的退变。     

Oral ibandronate is as active as intravenous zoledronic acid for reducing bone turnover markers in women with breast cancer and bone metastases.

BACKGROUND: Phase III study comparing the effect of oral ibandronate and intravenous zoledronic acid on bone markers. PATIENTS AND METHODS: Breast cancer patients with bone metastases received ibandronate 50 mg/day (n = 137) or zoledronic acid 4 mg every 4 weeks (n = 138) for 12 weeks. The primary end point was mean percentage change in serum levels of cross-linked C-terminal telopeptide of type I collagen (S-CTX) at week 12. Urinary CTX (U-CTX), bone alkaline phosphatase (ALP), amino-terminal procollagen propeptide of type I collagen (PINP) and osteocalcin (OC) were also measured and bone pain and safety assessed. RESULTS: Both bisphosphonates significantly reduced S-CTX (mean ibandronate 76% +/- 29 (SD) versus mean zoledronic acid 73% +/- 47; P < 0.001 for both versus baseline) and U-CTX (ibandronate 78% +/- 50 versus zoledronic acid 86% +/- 17; P < 0.001). The difference in S-CTX between treatments was 0.6% (confidence interval -1.7% to 3.0%), which was within the prespecified noninferiority margin. Bone ALP, PINP and OC decreased by 26%-47% compared with baseline with both bisphosphonates. Compared with zoledronic acid, ibandronate patients reported fewer adverse events overall (65.0% versus 75.9%), and on days 1-3 (8.0% versus 47.5%), including less pyrexia (overall incidence 0% versus 16.8%) and bone pain (5.8% versus 12.4%). CONCLUSIONS: Oral ibandronate was well tolerated and statistically noninferior to zoledronic acid for percentage change in the bone resorption marker, S-CTX.     

伊班膦酸钠联合化疗治疗骨转移瘤的临床观察

目的观察伊班膦酸钠联合化疗治疗骨转移瘤的临床效果。方法80例患者分为2组，即联合治疗组（伊班膦酸钠＋化疗）和化疗组，伊班膦酸钠4mg＋生理盐水500ml静滴，至少2h以上，每4周重复1次，化疗每3-4周重复1个周期，治疗2个周期后评价治疗效果。结果联合治疗组止痛、活动能力的改善及骨转移病灶的有效率分别为82．5％、62．5％、45％，均优于单纯化疗组（P〈0．05）。结论伊班膦酸钠联合化疗治疗骨转移瘤疗效好，毒副作用可以耐受。     

伊班膦酸钠联合放疗治疗骨转移癌疼痛的临床疗效

目的观察伊班膦酸钠(艾本)联合放疗治疗骨转移癌患者疼痛的疗效。方法40例恶性肿瘤骨转移癌患者,艾本2mg~4mg溶于不含钙离子的0.9%生理盐水或5%葡萄液,缓慢静脉滴注(不少于2小时)。同时配合放疗,DT30Gy。结果治疗后完全缓解21例(52.5%),部分缓解13例(32.5%),疼痛总缓解率为85%,3例患者血钙均降至正常。结论艾本联合放疗治疗骨转移癌疼痛疗效确切,可降低高钙血症血钙浓度,预防病理性骨折的发生,提高了患者的生活质量,毒副反应轻,值得临床进一步观察。     

艾本治疗骨转移癌疼痛的临床疗效

目的　探讨艾本 (伊班膦酸钠 )治疗骨转移癌疼痛的临床疗效。方法　艾本 2～ 4mg溶于 5 0 0ml生理盐水中缓慢静脉滴注 (至少 4h)每月 1次 ,连续用 3次 ,于 3周期结束时评价疗效。结果　骨痛完全缓解 6 0 % ( 18/ 30 ) ,部分缓解 2 6 7% ( 8/ 30 ) ,总有效率为 86 7% ( 2 6 / 30 ) ;骨转移病灶完全缓解 13 3 % ( 4/30 ) ,部分缓解 5 0 % ( 15 / 30 ) ,总有效率为 6 3 3% ( 19/ 30 ) ;生活能力显效 2 6 7% ( 8/ 30 ) ,有效 43 3 % ( 13/30 ) ,总有效率 70 % ( 2 1/ 30 )。副作用为暂时性发热。结论　艾本治疗骨转移癌疼痛 ,止痛效果确切 ,而且骨转移灶明显受到控制 ,活动能力明显改善 ,副作用小 ,值得推广。     

Changes in bone structure after augmentation cystoplasty in chronic uraemic rats

OBJECTIVE: To investigate the effect of urinary diversion using several types of intestinal segments on cortical and cancellous bone structure of growing rats with renal insufficiency. MATERIAL AND METHODS: In all, 110 female Sprague-Dawley rats (8 weeks old) had either a two-stage subtotal nephrectomy by removing five-sixths of the renal mass, or a sham operation. Except for a uraemic control group, all uraemic rats then had an enterocystoplasty using stomach, ileum or colon (20 animals per group). An additional group with colic augmentation received the bisphosphonate ibandronate. After 12 weeks, the left tibia was assessed using peripheral quantitative computed tomography and bone histomorphometry. RESULTS: After subtotal nephrectomy all groups had approximately 30% less endogenous creatinine clearance. Renal failure alone or in association with gastric or colic augmentation induced only negligible changes in the mass and structure of cortical and cancellous tibial bone. In contrast, rats after ileal augmentation and renal failure had a significant reduction in cancellous bone mineral density (P < 0.05) whereas the reduction in trabecular bone area and volume was not statistically significant. Furthermore, ileocystoplasty caused a decrease in trabecular number and perimeter, increased trabecular separation and enlarged bone marrow space, whereas ileocystoplasty had no effect on cortical bone. The changes were not associated with alterations in serum pH. Ibandronate treatment in the colonic cystoplasty group increased trabecular bone mass and structural variables over the untreated colonic cystoplasty group. CONCLUSIONS: These results suggest that cystoplasty using an ileal segment causes a decrease in bone mass and architecture in growing rats with mild uraemia. It remains open to question whether the results obtained from experimental animals can be directly extrapolated to the clinical situation.