唑来膦酸与伊班膦酸对破骨细胞抑制作用比较

目的:探讨唑来膦酸和伊班膦酸抑制破骨细胞分化及骨吸收功能特征。方法:诱导C57小鼠骨髓单核细胞向破骨细胞分化。依据双膦酸盐种类不同分为3组,对照组采用α-MEM培养基常规孵育,加入磷酸盐缓冲液;唑来膦酸组培养基中分别加入浓度为1×10 -8、1×10 -7、1×10 -6、1×10 ...     

唑来膦酸治疗骨质疏松症对心电影响的研究

目的观察使用唑来膦酸治疗骨质疏松是否对患者的心电产生影响。方法采用前瞻性自身治疗前后的对照研究,观察90例原发性骨质疏松患者,年龄52～92岁,平均(68.3±9.7)岁,其中男性6例,女性84例。使用唑来膦酸前行血清生化学及常规心电图检查,静滴唑来膦酸(5 mg/100 mL)后再查常规心电图。比较使用唑来膦酸前后的心电参数,记录有意义心电图报告的改变。结果受试者心脏的房率、室率在使用唑来膦酸后显著增快(P0.05);QT间期使用唑来膦酸后显著缩短(P0.05);P波时限、P-R间期、QRS波时限、QRS电轴、RV5+SV1、QTc使用唑来膦酸后的改变均没有统计学意义(P0.05)。由心律失常转变为无心律失常的良性变化病例2例(2.2%);心电图提示不良变化8例(8.8%),其中房颤1例(1.1%)。结论使用唑来膦酸治疗骨质疏松时发生严重心律失常如房颤的概率相对较小,总体来说在心电方面的安全性较高。     

唑来膦酸在骨质疏松患者中的应用及疗效

目的观察唑来膦酸(5mg/100ml)在原发性骨质疏松症及糖尿病合并骨质疏松症患者中的疗效及安全性。方法收集我院住院的骨质疏松症患者46例,分为原发性骨质疏松症组25例及糖尿病合并骨质疏松症组21例,体格检查计算体质指数(BMI),葡萄糖氧化酶法检测血糖,双能X线骨密度仪测定腰椎(L2-L4)及左股骨颈BMD,所有患者均静脉给予唑来膦酸5mg治疗,观察不良反应。1年后再次复查骨密度,观察唑来膦酸治疗后骨密度变化。结果治疗前两组间年龄、体质指数、腰椎及股骨颈骨密度无明显差异(P0.05),给予唑来膦酸治疗后,两组均出现不同程度的发热、乏力、头痛、关节痛、恶心等反应,糖尿病组有7例出现血糖一过性升高,但3天后均症状消失、血糖回复正常。使用唑来膦酸1年后复查骨密度,原发性骨质疏松组腰椎骨密度升高4.27%,股骨颈升高4.11%,糖尿病合并骨质疏松组骨密度分别升高3.42%、3.26%。两组骨密度较用药前均有升高(P0.05),但两组间骨密度比较无差异(P0.05)。结论唑来膦酸可以提高骨质疏松症患者骨密度,在原发性骨质疏松症及糖尿病合并骨质疏松症患者中均有较好疗效。     

唑来膦酸治疗恶性肿瘤骨转移临床疗效评价

唑来膦酸（卓莱）为第3代双膦酸盐类药物,在预防和治疗晚期恶性肿瘤骨转移引起的骨骼并发症及各种原因引起的高钙血症方面均有显著疗效。较第1代、第2代双磷酸盐具有更高的疗效、更低的不良反应和更快捷给药时间等优点,是目前最安全、有效、方便的双膦酸盐药物。2008-12～2010-12,我院使用卓莱治疗晚期肿瘤骨转移患者58例,疗效满意,报告如下。     

唑来膦酸预防乳腺癌骨转移的疗效研究

目的 探讨唑来膦酸预防乳腺癌骨转移的疗效。方法 回顾性收集2006年1月至2009年12月期间新疆医科大学第一附属医院确诊的418例浸润性乳腺导管癌患者,根据患者用药情况将其分为2组：预防组216例,接受唑来膦酸预防治疗;对照组202例,未接受唑来膦酸预防治疗。比较2组患者的骨转移及复发情况。结果 预防组患者发生骨转移37例（17.13%）,对照组发生骨转移73例（36.14%）,预防组的骨转移发生率较低（χ 2=19.45,P＜0.05）;不同分子分型乳腺癌患者中,均是预防组的骨转移发生率低于对照组（P＜0.05）。2组患者的肺转移、肝转移、其他部位转移和多脏器转移发生率,以及复发率比较差异均无统计学意义（P＞0.05）。结论 乳腺癌术后化疗后给予唑来膦酸预防治疗具有显著的临床获益,可减少乳腺癌骨转移的发生。     

唑来膦酸联合泰索帝治疗乳腺癌骨转移效果观察

目的评价唑来膦酸联合泰索帝治疗激素受体阴性乳腺癌多发骨转移的效果及安全性。方法 36例乳腺癌骨转移患者随机分为唑来膦酸联合泰索帝组(A组)及单用唑来膦酸组(B组),分别对两组进行治疗并比较和分析其效果。结果两组骨痛缓解率、生活质量改善及毒副作用无统计学差异。A组转移灶修复率66.7%(12/18),B组11.1%(2/18),两组比较,差异有统计学意义(P0.05)。结论唑来膦酸联合泰索帝对乳腺癌多发骨转移较单用唑来膦酸有较好的治疗作用。     

唑来膦酸应用于乳腺癌辅助治疗的研究

唑来膦酸(zoledronic acid,ZOL)是第三代双膦酸盐(bisphosphonates,BPs)药物,通过抑制破骨细胞介导的骨重吸收作用,降低骨相关事件,预防肿瘤治疗相关骨流失,提高骨密度,是目前乳腺癌骨转移的标准治疗之一。越来越多临床前研究及临床研究结果表明,ZOL这种骨改良药物,不仅仅是一种骨保护剂,还具有直接和间接的抗肿瘤活性,可降低肿瘤复发、转移,改善预后。ZOL早期应用于乳腺癌辅助治疗的应用地位得以提高,尤其是对于低雌激素水平(自然或治疗相关性)的早期乳腺癌患者。     

聚甲基丙烯酸甲酯骨水泥混合唑来膦酸对乳腺癌细胞的细胞毒性研究

目的观察唑来膦酸混入聚甲基丙烯酸甲酯（PMMA）骨水泥中的释放效果,并观察缓释液对乳腺癌细胞的抑制效果。方法制作骨水泥混合唑来膦酸的试件,提取骨水泥试件的缓释液,用高效液相色谱仪检测药物释放,用MTT分析法观察缓释液对乳腺癌细胞的抑制作用。结果唑来膦酸均在前24 h释放剂量最大,之后释放量明显递减,2周后释放处于极其微量状态。MTT实验显示,唑来膦酸缓释液对乳腺癌细胞抑制效果明显,抑制率和唑来膦酸浓度总体呈正相关。结论唑来膦酸可从PMMA骨水泥中有效释放,其缓释液对乳腺癌细胞抑制效果明显。     

唑来膦酸治疗35例原发性骨质疏松症的疗效及观察

目的观察唑来膦酸治疗原发性骨质疏松症的临床疗效及安全性。方法应用唑来膦酸注射液治疗35例57～85岁原发性骨质疏松症患者,分别观察治疗前后患者骨痛的缓解情况、血钙、磷、碱性磷酸酶、骨钙素、尿DPD/Cr变化情况。采用双能X线骨密度仪测定患者治疗前后骨密度。观察患者治疗后不良反应的发生情况。结果全部患者骨痛症状明显改善,总优良率达100%。血钙、磷、碱性磷酸酶、骨钙素无显著变化,尿DPD/Cr较治疗前显著降低(P<0.01)。骨密度较治疗前显著增加(P<0.01),35例患者均无明显不良反应发生。结论唑来膦酸是治疗原发性骨质疏松症的安全有效性药物。     

雌二醇对唑来膦酸预防乳腺癌骨转移疗效的影响

目的探讨雌二醇（E2）对唑来膦酸预防骨转移疗效的影响。方法收集新疆医科大学第一附属医院2006年1月至2009年12月期间收治的乳腺浸润性导管或小叶癌行改良根治术、术后常规化疗后给予唑来膦酸预防骨转移的患者216例,根据2011年St．Gallen乳腺癌专家共识分型,其中luminalA型55例,luminalB型63例,HER-2阳性型50例,三阴型48例。根据血清E2水平分为2组：①E2低水平组,39例,化疗后均行药物卵巢去势;②E2正常组,177例,未行卵巢去势。2组均给予唑来膦酸预防骨转移,临床总观察时间为化疗后3～5年或直至病情进展（包括出现复发、骨转移或远处其他脏器转移等病情进展视为观察终点）。结果发生骨转移情况：E2低水平组共发生7例（17．95％）,E2正常组共发生105例（59．32％）,E2低水平组发生骨转移率明显低于E2正常组钟：21．91,P〈0．05）;其中luminalA型、luminalB型、HER-2阳性型及三阴型患者中E2低水平组骨转移发生率亦均明显低于E2正常组（1uminalA型：5．13％（2／39）比12．43％（22／177）,χ2=4．54,P〈0．05;luminalB型：7．69％（3／39）比13．56％（24／177）,χ2=6．04,P〈0．05;HER-2阳性型：2．56％（1／39）比15．25％（27／177）,χ2=3．95,P〈0．05;三阴型：2．56％（1／39）比18．08％（32／177）,P〈0．05]。E2低水平组各型乳腺癌患者骨转移发生率比较差异无统计学意义（χ2=0．55,P〉0．05）。结论从本组有限的数据初步总结,绝经前年轻乳腺癌患者去势后应用唑来膦酸预防骨转移有明显临床获益,并且这种获益在各型乳腺癌中无明显差异;未行去势且雌激素水平正常或升高的患者应用唑来膦酸临床获益不明显。     

Anticancer effects of zoledronic acid against human osteosarcoma cells.

Based on neoadjuvant chemotherapy, the prognosis of osteosarcoma patients has improved dramatically. However, due to therapy resistance in patient subgroups, the development of new treatment strategies is still of utmost importance. The aim of our study was to test the effects of the nitrogen-containing bisphosphonate zoledronic acid (ZOL) on osteosarcoma cell lines (N = 9). Exposure to ZOL at low micromolar concentrations induced a dose- and time-dependent block of DNA synthesis and cell cycle progression followed by microfilament breakdown and apoptosis induction. The ZOL-induced cell cycle accumulation in S phase was accompanied by significant changes in the expression of cyclins and cyclin-dependent kinase inhibitors with a prominent loss of cyclin E and D1. ZOL not only inhibited growth but also migration of osteosarcoma cells. The mevalonate pathway intermediary geranyl-geraniol (GGOH) but not farnesol (FOH) significantly inhibited the anticancer effects of ZOL against osteosarcoma cells. Correspondingly, ZOL sensitivity correlated with the blockade of protein geranylgeranylation indicated by unprenylated Rap1. Overexpression of even high levels of P-glycoprotein, as frequently present in therapy-resistant osteosarcomas, did not impair the anticancer activity of ZOL. Summarizing, our data suggest that ZOL, which selectively accumulates in the bone, represents a promising agent to improve osteosarcoma therapy.     

唑来膦酸治疗COPD患者骨质疏松症的疗效及对肺功能影响的分析

目的研究COPD患者骨质疏松症经唑来膦酸治疗的疗效及对肺功能影响。方法 COPD合并骨质疏松患者52例,给予唑来膦酸及基础药物治疗,疗程1年,测量治疗前后腰椎、髋部骨密度(BMD)、肺功能及血清中血钙、血磷、骨特异性碱性膦酸酶(BALP),血清骨钙素(BGP)和晨尿游离脱氧吡啶啉排泄率(Dpd/Cr)、VAS及活动能力评分。结果治疗1年后疼痛症状改善,FEV1、FEV1%有显著提高,腰椎、股骨颈BMD升高,差异有统计学意义。治疗前FEV1、治疗后FEVl变化值△FEV1与腰椎骨密度变化值正相关。治疗后BGP值升高,ALP、Dpd/Cr值均下降,而血磷、血钙均无变化。结论唑来膦酸可以增加骨密度,改善骨代谢,同时改善通气功能,可以应用在COPD骨质疏松症的治疗。     

Docetaxel and zoledronic acid in patients with metastatic hormone-refractory prostate cancer

OBJECTIVE

To evaluate the safety and efficacy of combined docetaxel‐zoledronic acid treatment in patients with metastatic hormone‐refractory prostate cancer (HRPC), as bisphosphonates are reported have a synergistic antitumoral effect when combined with taxanes.

PATIENTS AND METHODS

Between January 2001 and June 2003, 14 patients with HRPC were treated; their mean (range) age was 71 (57–86) years and mean prostate‐specific antigen (PSA) level 202 (6–489) ng/mL. Five patients had had previous chemotherapy (cyclophosphamide in two, mitoxantrone‐prednisolone in three). The response criteria were the Karnofsky performance status, a positive response in mean daily analgesic consumption (defined as a decrease by more than half), decreased serum PSA (by more than half) at 8 weeks, blood transfusion, bone scan at 6 months, skeletal‐related events and survival.

RESULTS

Patients received a mean (range) of 7.3 (6–10) cycles of therapy; there was no reported drug‐related toxicity and all patients stayed at home for their treatment. Only three patients required a blood transfusion and no bone fractures were reported. At 2 months, six patients requiring analgesic drugs decreased their consumption by more than half (anti‐inflammatory, paracetamol, narcotics) and eight had a reduction in PSA by more than half; of these eight with a PSA response at 2 months, six had biochemical progression with a mean delay of 6.2 (3–11) months. At 6 months, five patients had disease progression on bone scan. Nine patients had chemo‐naïve hormone‐refractory prostate cancer; three had biochemical progression at 2 months and two of these had progression on their bone scan. Two patients died at 7 and 15 months of follow‐up; the mean follow‐up was 10.2 (6–15) months. Using Kaplan‐Meier plots, biochemical progression‐free survivals were five of 14 at 6 months and two of 14 at 12 months; overall survival was 12 of 14 at 6 and 12 months.

CONCLUSION

Docetaxel‐zoledronic acid therapy is safe and decreased the serum PSA by more than half at 2 months in more than half the patients. Prospective randomized trials are needed to assess this new approach.

     

唑来膦酸连续2年治疗绝经后女性骨质疏松临床观察

目的：观察唑来膦酸连续2年治疗绝经后女性骨质疏松的疗效、急性发热反应情况及其相关因素分析。方法回顾性分析我科2010年7月至2013年7月连续2年静脉使用唑来膦酸5mg滴注治疗绝经后女性骨质疏松患者共46人。年龄60～74岁,平均年龄（66．87±6．77）岁。观察每次急性期发热出现比例及每例患者前后2次药物输注后发热出现情况。比较治疗第1年、第2年骨质疏松差异及甲状旁腺激素、血清钙差异。结果46例患者中第1次输注唑来膦酸共观察到20人发热,占43．4％,次年输注唑来膦酸仅1例出现发热,发热组治疗前甲状旁腺激素水平显著高于无发热组（ P＜0．05）。第2次输注前甲状旁腺激素、血清钙较第1年输注前均无显著差异（ P＞0．05）,第2次输注前骨密度监测腰椎及全髋T值较第1次有所改善（P＜0．05）。结论绝经后女性骨质疏松患者连续静脉用唑来膦酸治疗对骨密度有改善,首次治疗出现急性期发热反应并不少见,但均为一过性,次年均可耐受。治疗前PTH水平可能与发热反应相关。     

唑来膦酸治疗女性绝经后骨质疏松所致急性发热临床分析

目的分析静脉用唑来膦酸治疗女性绝经后骨质疏松患者引起的急性发热反应及其相关因 素。方法回顾性分析我科2010年6月至2012年4月使用静脉用唑来膦酸5皂早治疗的绝经后骨质 疏松患者共63人。观察急性期发热出现比例。按是否出现发热症状分为发热组与无发热组。比较 两组患者年龄、静脉用唑来膦酸治疗前骨质疏松严重程度、甲状旁腺激素、血清钙差异,及治疗前使用 抗骨质疏松药物差异。结果63例患者中共观察到21例发热,占33.3%_。71%( 15/21 )的患者治 疗当天出现发热,于患者均为次日出现发热。66.7% ( 14/21 )的患者发热持续1天,5例发热持续2 天,发热时平均体温（38.8依0.5 )益。发热组与无发热组比较,发热组治疗前甲状旁腺激素水平显著 高于无发热组（孕值<0.05 );骨质疏松严重程度、血清钙两组无显著差异。结论绝经后骨质疏松患 者静脉用唑来膦酸治疗时出现急性期发热反应并不少见,但均为一过性。治疗前PTH水平与发热相 关。     

Influence of vitamin D and retinoids on the gammacarboxylation of osteocalcin in human osteosarcoma MG63 cells

Osteocalcin (OC) is a bone matrix protein, synthesized by osteoblasts, which contains three residues of gammacarboxyglutamic acid (GLA). A fraction of circulating OC, which is not fully carboxylated and does not bind to hydroxyapatite, is called undercarboxylated OC (ucOC). In elderly institutionalized women, we have shown an increase of circulating ucOC level which may result not only from vitamin K deficiency but also from vitamin D deficiency (Szulc et al., J Clin Invest 91: 1769; 1993). This intriguing finding prompted us to study the effect of vitamin D on the secretion of ucOC by osteoblastic cells in vitro in the presence of warfarin, an inhibitor of gammacarboxylation of GLA-containing proteins. The potential influence of retinoic acid (RA) was also studied, because its mechanism of action involves pathways that are similar to vitamin D. In the presence of warfarin (0.05 μg/mL), 1,25(OH)₂D (10⁻⁸-10⁻⁶ mol/L) decreased dose dependently ucOC secretion by human osteosarcoma MG63 cells (from 3.87 ± 0.96 to 2.12 ± 0.13 ng/10⁶ cells). When expressed as a fraction of total OC, secretion ucOC decreased from 47.4 ± 1.4% to 24.8 ± 3.2% in the MG63 cells. The secretion of total OC was stimulated by RA and by Ro 13-7410, which is a specific ligand of retinoic acid receptor (RAR), but not by 9-cis retinoic acid (9-cisRA), which is a physiologic ligand of retinoid X receptor (RXR). RA and Ro 13-7410 decreased ucOC secretion and ucOC% in warfarin-treated MG63 cells (RA: from 50.4 ± 13.3% to 13.5 ± 2.8%; Ro 13-7410: from 28.4 ± 8.2% to 11.3 ± 8.4%). 9-cisRA had no effect on OC gammacarboxylation. These results show that vitamin D, RA, and Ro 13-7410, but not 9-cisRA, may modify the gammacarboxylation of OC in human MG63 cells.     

唑来膦酸与阿仑膦酸钠治疗原发性骨质疏松疗效及安全性的Meta分析

目的系统评价唑来膦酸与阿仑膦酸钠治疗原发性骨质疏松的有效性与安全性。方法计算机检索PubMed、Embase、Cochrane Library、CNKI、CBM、万方数据库,检索时间均为建库至2018年12月,采用改良Jadad量表及Cochrane风险偏倚评估工具评价纳入研究的方法学质量。使用Rev Man5.3及Stata15.0软件进行Meta分析。结果共纳入12篇文献,1 344例患者。Meta分析结果表明:在疗效方面,腰椎骨密度(bone mineral density,BMD)在治疗12个月后[SMD=0.96,95%CI(0.03,1.90),P=0.04]、24个月后[SMD=1.70,95%CI(0.30,3.11),P=0.02],股骨颈BMD在治疗12个月后[SMD=0.34,95%CI(0.19,0.50),P0.000 1],VAS评分[MD=-0.76,95%CI(-0.93,-0.58),P0.000 01],Oswestry功能障碍指数(ODI)[MD=-10.48,95%CI(-11.38,-9.58),P0.000 01],差异具有统计学意义(P0.05),唑来膦酸治疗效果优于阿仑膦酸钠。在安全性方面,不良反应[RR=1.79,95%CI(1.41,2.28),P0.000 01]差异具有统计学意义,唑来膦酸安全性小于阿仑膦酸钠。结论与阿仑膦酸钠相比,唑来膦酸在治疗后期能明显提高患者腰椎、股骨颈BMD,有效降低VAS评分、Oswestry功能障碍指数,进而显著提升患者的生活质量,但不良反应相对较多。     

Effect of zoledronic acid on metastatic hormone-refractory prostate cancer resistant to taxane, estramustine, carboplatin, and dexamethasone

This case report demonstrates the effect of zoledronic acid (ZA) on a patient with bone metastatic hormone-refractory prostate cancer (HRPC) resistant to taxane, estramustine phosphate, carboplatin, and dexamethasone. The pathogenesis, diagnosis, and management of bone metastasis on HRPC are also reviewed.