第3代双膦酸盐类药物--唑来膦酸

介绍唑来膦酸在药效学、药代动力学和临床应用等方面的研究进展.唑来膦酸可抑制破骨细胞调节的骨吸收,降低血清钙水平,抑制肿瘤细胞的生长,能有效治疗恶性肿瘤所致高钙血症、晚期肿瘤骨转移和变形性骨炎,还有望用于骨质疏松症的治疗.     

唑来膦酸治疗恶性肿瘤骨转移骨痛的效果观察

目的 探讨唑来膦酸治疗恶性肿瘤骨转移骨痛的临床效果.方法 回顾性分析本院收治的90例恶性肿瘤骨转移骨痛患者的临床资料,根据治疗方法不同分为治疗组和对照组各45例,对照组患者给予帕米膦酸二钠治疗,治疗组患者给予唑来膦酸治疗,比较两组患者的临床疗效.结果 治疗后治疗组患者的总有效率为91.11%,显著高于对照组患者的总有效率77.78%,P＜0.05.结论 唑来膦酸治疗恶性肿瘤骨转移骨痛临床效果显著.     

唑来膦酸治疗骨转移瘤疼痛效果观察

恶性肿瘤患者晚期20%～70%易出现骨转移,往往伴有疼痛,高钙血症,甚至是病理性骨折等临床症状.唑来膦酸(xoledronicacid)是由国外开发的高选择性新一代双膦酸类药物,目前已在包括美国、欧盟在内的40多个国家和地区上市.主要用于治疗癌症引起的高钙血症和多发性骨髓瘤及实体瘤的骨转移.我院用唑来膦酸治疗骨转移瘤15例,取得良好效果,报告如下.     

唑来膦酸治疗恶性肿瘤骨转移37例的疗效观察

骨组织是恶性肿瘤转移的第三好发器官。临床上癌症患者一旦确诊为骨转移，则失去了手术治疗原发灶的最佳时机。对于骨转移尤其是伴有剧烈疼痛的患者，控制骨痛及改善病人余生的生存质量则成为临床医生面临的主要问题。作为最新一代抑制肿瘤骨转移新药——唑来膦酸因其具有有效治疗、预防恶性肿瘤骨转移引起的骨骼相关事件及高钙血症的作用已较广泛的应用于临床。我科近3年使用唑来膦酸治疗恶性肿瘤骨转移，结果令人比较满意。现将其缓解骨痛及降低血钙水平两个方面的效果报道如下。     

唑来膦酸抗肿瘤作用的临床研究进展

唑来膦酸是第三代双膦酸盐类药物,主要通过抑制破骨细胞的活性和诱导破骨细胞凋亡来抑制骨吸收,目前用于治疗恶性高钙血症、控制恶性肿瘤骨转移等。多个临床前研究显示唑来膦酸具有明确的抗肿瘤作用。近年来,随着多项临床试验的开展,唑来膦酸潜在的抗肿瘤作用也越来越受到关注。多个临床研究结果表明,唑来膦酸能改善多发性骨髓瘤,乳腺癌、前列腺癌、肺癌等恶性肿瘤治疗的疗效,包括延长患者的总生存时间和无病生存期等。然而,对于唑来膦酸与其他抗肿瘤治疗合用的最佳方案和剂量、持续时间还需要进一步的研究。在此,本文就唑来膦酸抗肿瘤作用的临床研究进展作一综述。     

唑来膦酸治疗乳腺癌骨转移的临床观察

目的观察唑来膦酸治疗乳腺癌骨转移的临床疗效和不良反应。方法唑来膦酸4 mg加入0.9%氯化钠液100 m L静脉滴注15 min,每4周给药1次。对患者的骨痛、骨相关事件、生存质量及药物的不良反应进行评估。结果唑来膦酸治疗乳腺癌骨转移患者中重度骨痛、骨转移病灶、生活活动能力的有效率分别为77.4%、69.1%、77.4%;不良反应为发热29例(35.8%),感冒样症状23例(28.4%),低钙血症4例(4.9%),经对症治疗后消失。结论唑来膦酸在治疗乳腺癌骨转移癌性骨痛时起到积极作用,可预防骨相关事件发生,不良反应发生率低。     

唑来膦酸治疗肺癌骨转移患者首次骨相关事件的临床分析

目的 探讨唑来膦酸对肺癌骨转移患者首次骨相关事件(SRE)的作用.方法 回顾性分析2007年1月至2010年6月期间106例肺癌骨转移患者的临床资料.A组为未使用唑来膦酸病例67例(63.2％);B组为骨转移后使用唑来膦酸治疗病例39例(36.8％),比较2组首次SRE的发生情况.结果 106例患者中50例(47.2％)患者发生首次SRE,A组的首次SRE发生率为56.7％ (38/67),明显高于B组[30.8％ (12/39)],2组比较差异有统计学意义(P＜0.05).其中,A组的骨放疗事件发生率明显高于B组[40.3％ (29/67)比20.5％ (8/39)],2组比较有统计学差异(P＜0.05).2组患者的中位无SRE生存时间分别为7.4和8.4个月.2组比较差异无统计学意义(P＞0.05).结论 唑来膦酸能减少肺癌骨转移患者的首次SRE发生率,尤其减少骨放疗事件的发生.     

唑来膦酸注射液致急性肾损伤1例并文献复习

唑来膦酸注射液属含氮双膦酸化合物,通过抑制破骨细胞而抑制骨吸收,临床上主要用于治疗骨质疏松症、恶性肿瘤引起的骨转移及高钙血症,应用广泛,因此临床医师必须考虑其长期用药安全性。唑来膦酸注射液对肾脏的不良影响临床病例较少,因此易造成忽视。现报道1例因注射唑来膦酸注射液致急性肾损伤后经人工肾替代治疗恢复的病例,分析其诊断特征、病理机制、危险因素及防治策略,并复习相关文献,旨在提高临床医师对唑来膦酸注射液肾毒性的认识与了解,评估具有高危因素的患者,并对其采用防护措施。     

唑来膦酸的临床应用

目的为临床应用唑来膦酸提供参考。方法综述唑来膦酸的药理作用及临床应用。结果唑来膦酸临床用于治疗恶性高钙血症,控制恶性肿瘤骨转移,并能改善多发性骨髓瘤,前列腺癌、乳腺癌、肺癌等恶性肿瘤治疗的疗效。结论唑来膦酸可提高肿瘤患者的生活质量和延长患者的生存期。     

唑来膦酸在恶性肿瘤骨转移中的临床应用

摘 要骨转移是恶性肿瘤常见并发症之一,在乳腺癌、肺癌、前列腺癌等发病率高达30% 85%。骨转移导致的持续疼痛及爆发痛,严重影响患者的生活质量。唑来膦酸是第三代双膦酸盐类药物,主要通过抑制破骨细胞的活性和诱导破骨细胞凋亡来抑制骨吸收。唑来膦酸治疗恶性肿瘤骨转移也越来越受到关注,并有良好的应用前景。在此,本文就唑来膦酸治疗恶性肿瘤骨转移的临床研究进展作一综述。     

A comprehensive review of denosumab for bone metastasis in patients with solid tumors

Background:

Denosumab is fully human monoclonal antibody that specifically binds and inactivates receptor activator of NF-kB ligand (RANKL), an important ligand that regulates bone remodeling. In this review, we aimed to show the clinical data about denosumab treatment and discuss its advantages for the management of patients with solid tumors and bone metastasis.

Scope:

Denosumab showed positive results in clinical studies of solid tumors with bone metastasis. PubMed database and ASCO Symposium Meeting abstracts were searched until August 2015 by using the terms ‘denosumab’, ‘RANKL inhibitor’ and ‘bone metastasis’. The last search was on 21 August 2015. All resulting studies were retrieved and were also checked for related publications. Clinical trials in this review fulfilled the following criterion: inclusion of sufficient data to allow estimation of the efficacy and safety of denosumab.

Findings:

The effects of denosumab on skeletal-related events (SREs) were investigated in three large randomized trials: one in patients with breast cancer, one in patients with prostate cancer, and one in patients with multiple myeloma or solid tumors other than breast or prostate cancer. In the breast cancer and prostate cancer studies denosumab was non-inferior and also superior to zoledronic acid in terms of the primary outcome time to first on-study SRE. In the third study denosumab was non-inferior to zoledronic acid but was not superior to zoledronic acid in solid tumors excluding breast and prostate cancer with bone metastases. In the three studies median overall survival and disease progression rates were similar between zoledronic acid and denosumab. Denosumab has also been studied in bone loss associated with hormonal therapy in both breast and prostate cancer. Adjuvant denosumab significantly reduced the risk of clinical fracture risk by 50% in breast cancer patients and by 62% in non-metastatic prostate cancer patients treated with adjuvant aromatase inhibitors or androgen deprivation therapy. In addition, biochemical markers of bone turnover and fractures were significantly reduced in patients under denosumab treatment.

Conclusion:

The promising outcomes in the initial trials with denosumab have shown clinical activity and a favorable safety profile in patients with solid tumors and bone metastasis. Denosumab significantly reduced treatment-related osteoporosis associated with breast and prostate cancer and was superior to zoledronic acid in prevention or delaying of SRE.     

乳腺癌临床分期与骨转移之间的关系

目的：探讨乳腺癌临床分期与骨转移之间的关系。方法：对76例经病理证实为乳腺癌的女性患者行全身骨显像。结果：检出骨转移41例,统计显示不同临床分期转移率之间差异具显著意义（P＜0．05）。结论：说明随临床分期I到Ⅳ期骨转移率逐渐增加;且病灶转移以中轴骨为主（81．4％）,四肢及颅骨转移则较少（18．6％）。     

唑来膦酸单药治疗肺癌合并骨转移的临床研究

目的探讨唑来膦酸单药治疗肺癌合并骨转移的临床疗效。方法将56例肺癌合并骨转移的患者随机分为两组,分别使用唑来膦酸和帕米膦酸单药静脉滴注治疗,治疗3个月后,比较两组患者的疼痛治疗效果、生活质量评分(QOL)、一般状况评分(KPS)及不良反应的发生情况。结果两组的疼痛治疗有效率、不良反应的发生率比较,差异均无统计学意义(P>0.05)。两组患者治疗后的QOL和KPS评分与治疗前比较,差异有统计学意义(P<0.05),但两组之间QOL和KPS评分比较,差异无统计学意义(P<0.05)。结论唑来膦酸可有效缓解肺癌并骨转移患者的疼痛,综合疗效与帕米膦酸相当。     

肺癌骨转移105例预后分析

目的探讨肺癌骨转移患者的临床特征及其与预后的关系，筛选影响预后的独立因素。方法对天津市胸科医院2006年1月至2010年12月诊治的105例肺癌骨转移患者的临床特征及预后进行回顾性分析。应用生存曲线法估计全组患者确诊肺癌和确诊骨转移后的生存率；以对数秩检验Log—rank法和考克斯比例风险模型COX法分别进行单因素和多因素分析，筛选影响患者预后的独立因素。结果自确诊肺癌起，患者的中位生存期为19．0个月，1、2年生存率分别为82．9％、29．5％。自确诊骨转移起，患者的中位生存期为10.3个月，1年生存率为38．1％，2年生存率为12．4％。单因素方差分析显示．确诊肺癌时的临床分期、肺癌原发灶手术、确诊骨转移时体力状态（PS）评分、骨转移后的化疗、酪氨酸激酶抑制剂治疗、双磷酸盐治疗与预后相关（P〈0．05）。多因素方差分析显示，确诊肺癌时的临床分期、确诊骨转移时的PS评分、骨转移后的化疗是影响预后的独立因素。结论肺癌骨转移患者的总体预后差，确诊肺癌时临床分期较早、确诊骨转移时PS评分为0～1分、骨转移后接受化疗的患者可能预后相对较好。     

Betulinic acid,a bioactive pentacyclic triterpenoid,inhibits skeletal-related events induced by breast cancer bone metastases and treatment

Many breast cancer patients experience bone metastases and suffer skeletal complications. The present study provides evidence on the protective and therapeutic potential of betulinic acid on cancer-associated bone diseases. Betulinic acid is a naturally occurring triterpenoid with the beneficial activity to limit the progression and severity of cancer, diabetes, cardiovascular diseases, atherosclerosis, and obesity. We first investigated its effect on breast cancer cells, osteoblastic cells, and osteoclasts in the vicious cycle of osteolytic bone metastasis. Betulinic acid reduced cell viability and the production of parathyroid hormone-related protein (PTHrP), a major osteolytic factor, in MDA-MB-231 human metastatic breast cancer cells stimulated with or without tumor growth factor-β. Betulinic acid blocked an increase in the receptor activator of nuclear factor-kappa B ligand (RANKL)/osteoprotegerin ratio by downregulating RANKL protein expression in PTHrP-treated human osteoblastic cells. In addition, betulinic acid inhibited RANKL-induced osteoclastogenesis in murine bone marrow macrophages and decreased the production of resorbed area in plates with a bone biomimetic synthetic surface by suppressing the secretion of matrix metalloproteinase (MMP)-2, MMP-9, and cathepsin K in RANKL-induced osteoclasts. Furthermore, oral administration of betulinic acid inhibited bone loss in mice intra-tibially inoculated with breast cancer cells and in ovariectomized mice causing estrogen deprivation, as supported by the restored bone morphometric parameters and serum bone turnover markers. Taken together, these findings suggest that betulinic acid may have the potential to prevent bone loss in patients with bone metastases and cancer treatment-induced estrogen deficiency.     

唑来膦酸在乳腺癌中抗肿瘤差别化效应的研究进展

乳腺癌是女性发病率和死亡率较高的恶性肿瘤。 肿瘤复发和远处转移是导致死亡的主要原因。 唑来膦酸（ZOL）具有潜在抑制破骨细胞介导的骨吸收的特性, 既可抑制肿瘤细胞增殖和启动肿瘤细胞凋亡, 又可干扰肿瘤细胞与骨基质的黏附, 从而抑制肿瘤细胞的迁移和侵袭。 一些临床前研究已经证实 ZOL 具有直接抗肿瘤作用, 且在对绝经前和绝经后乳腺癌患者的治疗效果上有差异。 本文就 ZOL 在乳腺癌中抗肿瘤差别化效应的基础及临床研究进展作一综述。     

肺癌骨转移的相关因素研究

目的研究肺癌骨转移的相关临床因素。方法选取笔者所在医院收治的67例肺癌骨转移患者,回顾性研究其临床资料,分析骨转移情况及性别、年龄、病理分型、原发灶部位、转移类型及接受治疗方法与骨转移之间的关系。骨转移率采用Kaplan-Meier法计算。单因素分析采用Log-rank法,多因素分析采用Cox回归模型。结果本组患者显示70%以上的骨转移是在肺癌确诊后18个月内发生的,单因素和多因素分析均显示肺癌骨转移与病理分型及原发病灶手术治疗相关(P<0.05),肺小细胞癌和肺腺癌骨转移的风险大,肺鳞癌骨转移风险小,肺癌原发病灶手术治疗可显著降低骨转移风险。单因素分析还显示肺癌骨转移伴随其他脏器转移率明显较大(P<0.05)。结论肺癌骨转移与病理分型及原发灶手术治疗明显相关,临床上应密切观察和积极随访,及早诊断并争取手术治疗,预防骨转移发生。     

Anticancer activity of bisphosphonates in breast cancer

Despite progress in surgical and adjuvant therapy, a subset of patients with early stage breast cancer experience disease recurrence and/or distant metastases. Disseminated tumor cells (DTCs) in the bone marrow are believed to be the source of late relapses in bone and other tissues. Bone is the most common site of breast cancer metastasis, and agents that modify the bone microenvironment could therefore affect the disease course. Bisphosphonates are an effective bone-targeted therapeutic option for preventing cancer treatment- induced bone loss (CTIBL) in pre- and postmenopausal women with breast cancer. Bisphosphonates inhibit osteoclast-mediated bone resorption, thereby inhibiting the release of growth factors necessary to promote cancer cell growth, differentiation, and tumor formation in bone. Preclinical and clinical data also suggest anticancer synergy between cytotoxic chemotherapy agents and bisphosphonates. Recent trials of zoledronic acid in the adjuvant setting in breast cancer have demonstrated reduced disease recurrence in bone and other sites. Currently, several ongoing clinical trials are evaluating whether antiresorptives can inhibit disease recurrence and the development of bone metastases from breast cancer. Based on recent data, the role of bisphosphonates in the breast cancer setting is expected to expand in the future. With recent changes to treatment guidelines, routine use of bisphosphonates to prevent bone loss during adjuvant therapy is likely to become standard practice, especially for patients receiving endocrine therapy. Furthermore, the use of zoledronic acid to reduce the risk of recurrence is emerging based on ongoing clinical research.     

对1例乳腺癌患者使用唑来膦酸的药学监护

1例65岁女性患者,因“左乳癌根治术后3年,多发转移19月余”入院。给予口服卡培他滨和拉帕替尼进行化疗,化疗期间加用唑来膦酸抗骨转移治疗。临床药师针对化疗过程中唑来膦酸可能出现的不良反应的预防和药物的合理性应用作为药学监护点,建议医生调整唑来膦酸的给药时间以提高抑制骨转移的疗效,从而使患者能顺利完成化疗。