唑来膦酸钠对绝经后乳腺癌患者骨代谢影响结果分析

目的:通过观察唑来膦酸钠对绝经后乳腺癌患者骨代谢影响,探讨唑来膦酸钠在早期预防乳腺癌患者发生骨代谢障碍及抑制骨转移中的作用。方法:85例绝经后乳腺癌患者均手术治疗,且术后常规行6个疗程的化疗,无骨转移病例。对照组:28例化疗后接受中药治疗;来曲唑组:30例化疗后继续服用来曲唑2.5mg/d;来曲唑+唑来膦酸钠组:27例患者化疗后除服用来曲唑2.5mg/d外,使用唑来膦酸钠注射液4mg+生理盐水100ml,静脉滴注15min,每4周为1个疗程。6个月后应用双能X线骨密度仪对三组乳癌患者腰椎、股骨近端骨密度(BMD)进行测定,用SPETCT行全身核素骨显像检查,使用全自动生化仪器测定血清碱性磷酸酶(ALP)、血钙(Ca)、血磷(P)等生化指标,用免疫组化方法测定雌激素(E2),对三组患者治疗前后各项指标分析比较。结果:治疗后来曲唑组与对照组病人的BMD、E2、血清Ca、P指标比较,均明显降低(P<0.05)、ALP明显上高(P<0.05);来曲唑+唑来膦酸钠组与来曲唑组比较,BMD、血清Ca、P指标明显升高(P<0.05),ALP降低(P<0.05)、E2未见明显变化(P>0.05);来曲唑+唑来膦酸钠与对照组比较,ALP、E2指标明显降低(P<0.05),BMD明显升高(P<0.05),血清Ca、P未见明显变化(P>0.05)。与对照组比较唑来膦酸钠组的骨转移发生率明显降低(P<0.05)。结论:唑来膦酸钠对接受来曲唑治疗引起的骨代谢障碍早期防治疗效明显,且对骨转移发生有明显抑制作用。     

来曲唑联合唑来膦酸治疗绝经后乳腺癌骨转移疗效观察

目的:观察来曲唑联合唑来膦酸治疗绝经后乳腺癌骨转移的临床效果及不良反应.方法:42例绝经后乳腺癌骨转移患者给予来曲唑片口服 2.5mg/d,唑来膦酸4mg加入生理盐水100ml静滴,每4周1周期,两药连用3个周期后评价疗效.结果:治疗后止痛、体力状况的改善及骨转移病灶的有效率分别为85.71%、69.05%、45.24%,主要不良反应为发热.结论:来曲唑联合唑来膦酸治疗绝经后乳腺癌骨转移有较好的疗效,不良反应少,患者容易接受.     

唑来膦酸及依班膦酸钠治疗恶性肿瘤骨转移疼痛的临床疗效观察

目的 评价唑来膦酸及依班膦酸钠治疗恶性肿瘤引起骨疼痛的有效性和安全性.方法 入选恶性肿瘤骨转移疼痛60例,随机分为两组,一组给予唑来膦酸注射液4 mg,静脉滴注15 min;另一组给予依班膦酸钠注射液4 mg,静脉滴注3 h.采用平行对照研究方法,每组用药3～6个周期.观察止痛起效时间、临床获益及毒副反应.结果 唑来膦酸组和依班膦酸组用药后止痛有效率分别为75.02%和72.10%,差异无统计学意义(P>0.05);用药后冲位起效时间分别为第5天和第7天,差异无统计学意义(P>0.05);两组用药后7 d,ECOG评分改善,差异无统计学意义(P>0.05).结论 唑来膦酸及依班膦酸钠均能改善恶性肿瘤患者骨转移疼痛,显著改善生活质量,且毒副反应均可耐受.     

阿仑膦酸钠预防来曲唑引起的绝经后早期乳腺癌患者骨量丢失的疗效

目的探讨阿仑膦酸钠预防来曲唑引起的绝经后早期乳腺癌患者骨量丢失的疗效。方法选择服用来曲唑的绝经后乳腺癌患者82例,随机分为2组。A组42例服用来曲唑,B组40例服用来曲唑的同时给予阿仑膦酸钠治疗。分别在服用来曲唑前及服药后6、12个月采用双能X线骨密度仪对82例绝经后乳腺癌患者进行骨密度(BMD)检测。结果 2组患者接受来曲唑治疗后6、12个月,BMD均出现下降;来曲唑治疗后12个月,A组较B组BMD下降更明显(P均<0.05)。结论来曲唑可加剧绝经后乳腺癌患者骨量丢失;应用阿仑膦酸钠可有效减轻患者的骨量丢失。     

伊班膦酸钠与唑来膦酸对骨肿瘤患者的疗效比较

目的探讨唑来膦酸与伊班膦酸钠对骨肿瘤患者的疗效影响。方法选取2015年8月至2016年8月间山东单县海吉亚医院收治的104例骨肿瘤患者,采用随机数字表法分为观察组与对照组,每组52例。观察组采用伊班膦酸钠治疗,对照组采用唑来膦酸治疗,比较两组患者的疼痛治疗效果、不良反应和生活质量。结果治疗后观察组患者视觉模拟评分为(4.3±1.5)分,显著低于对照组的(6.0±1.6)分;观察组患者不良反应发生率为9.6%,低于对照组的26.9%;观察组患者Kamofsky评分为(58.5±8.5)分,显著高于对照组的(48.5±7.5)分;观察组患者药物治疗费用为(2025.5±70.5)元,显著低于对照组的(4052.5±80.5)元,以上两组比较,差异均有统计学意义(均P<0.05)。结论相比唑来膦酸,伊班膦酸钠可有效降低骨肿瘤患者的疼痛阈值,提高生活质量,不良反应少,治疗费用低。     

唑来膦酸钠联合89SrCl2治疗骨转移瘤的临床疗效

目的:评估89SrCl2联合唑来膦酸钠在恶性肿瘤骨转移治疗中的临床疗效。方法:95例恶性肿瘤骨转移患者随机分为三组,实验组32例应用89SrCl2联合唑来膦酸钠治疗,另外两组设为对照组,分别单纯给以89SrCl2或唑来膦酸钠治疗。随访观察6个月,根据治疗后疼痛缓解和全身骨扫描结果判断疗效。结果:实验组疼痛缓解总有效率为87.50%(28/32),对照组分别为77.42%(24/31)、75.00%(24/32)。实验组和对照组疼痛缓解改善比较差异有统计学意义(P<0.05)。实验组骨转移病灶好转或消退总有效率为34.38%（11/32）,对照组分别为32.26%（10/31）、31.25%（10/32）,实验组和对照组病灶改善比较差异无统计学差异(P>0.05)。实验组观察唑来膦酸钠的给药时间,一周内和一月后给药骨痛缓解总有效率分别为64.71%（11/17）,66.67%（10/15）,疼痛改善比较无统计学差异(P>0.05)。结论:89SrCl2联合唑来膦酸钠治疗恶性骨转移癌缓解骨痛优于单独给药。89SrCl2和唑来膦酸钠联合给药不存在拮抗和竞争,可以同时联合使用。     

唑来膦酸治疗乳腺癌及其骨转移的研究进展

唑来膦酸是第三代含氮双膦酸盐类药物的典型代表,在已上市的双膦酸盐类药物中其综合疗效最好,不仅可以通过抑制甲羟戊酸途径直接作用于破骨细胞,也可直接或间接对肿瘤细胞产生抑制作用.乳腺癌属于易发生骨转移的一类恶性肿瘤,大量研究表明唑来膦酸对乳腺癌骨转移具有一定的疗效,可缓解骨痛,目前其已被纳入乳腺癌骨转移的临床常规治疗中,同时唑来膦酸在辅助性内分泌治疗乳腺癌时亦发挥重要的作用.本文就唑来膦酸对乳腺癌骨转移治疗方面的相关研究进展做一综述.     

唑来膦酸在早期乳腺癌中的抗肿瘤研究进展

早期乳腺癌在接受辅助治疗（化疗和内分泌治疗）时均会对患者骨密度造成不良影响,加速骨丢失。第三代双磷酸盐—唑来膦酸其作用机制是抑制破骨细胞介导的骨质重吸收,主要用于恶性肿瘤骨转移引起的高钙血症。唑来膦酸-弗隆辅助协同试验（ZO-FAST）显示唑来膦酸在早期乳腺癌辅助内分泌治疗同时使用不仅可有效防止骨质丢失,还具有明显降低肿瘤复发的作用。奥地利乳腺癌和结直肠癌研究小组-12（ABCSG-12）试验结果同样表明唑来膦酸在联合内分泌治疗时可显著降低患者的疾病进展风险和死亡风险。除此之外,临床前实验和临床试验也证实唑来膦酸联合化疗也具有协同的抗肿瘤作用。唑来膦酸联合新辅助化疗降低复发（AZURE试验）,对于绝经5年以上和年龄>60岁的人群,辅助化疗加唑来膦酸显著减低疾病进展和死亡风险。在ABCSG-12试验中同样发现对于年龄>40岁的患者,唑来膦酸可明显降低复发风险,而年龄≤40岁患者却未在唑来膦酸的治疗中获益。这些结果表明唑来膦酸在雌激素低水平（自然的或治疗后结果）的早期乳腺癌患者中易于发挥抗肿瘤作用。目前对于唑来膦酸的最佳剂量和持续时间尚有待于进一步的研究确认,相信随着相关临床试验结果的公布可以提供更充足的证据来支持唑来膦酸在早期乳腺癌的使用。      

唑来膦酸治疗绝经后乳腺癌患者骨质疏松的临床疗效和安全性

目的 采用唑来膦酸治疗绝经后乳腺癌患者骨质疏松,分析其疗效及安全性.方法 选择绝经后乳腺癌患者作为研究对象,实验组采用唑来膦酸联合来曲唑,对照组仅用来曲唑,测量2组患者治疗前后骨密度,进行VAS疼痛评分,观察并比较2组患者的并发症发生率.结果 治疗后实验组患者LI-L4、Ward's三角、股骨颈的骨密度高于对照组,差异有统计学意义(P＜0.05);治疗后2组患者静息痛、前屈后伸痛、翻身痛的VAS评分较治疗前降低,且实验组低于对照组,差异有统计学意义(P＜0.05);实验组患者发生发热2例,骨痛1例,总发生率15％,对照组发生率为10％,2组无明显差异,且均经对症治疗后缓解,无不良影响.结论 绝经后乳腺癌患者出现骨质疏松,采用唑来膦酸治疗,能够提高骨密度,缓解关节疼痛程度,且不良反应轻微,安全有效.     

唑来膦酸钠静脉注射导致低钙血症一例

患者男,42岁,2008年2月行根治性远端胃大部切除术,病理诊断为胃中-低分化腺癌、部分为印戒细胞癌,T1N2M0,II期,术后行6个疗程化疗。2009年4月骨扫描证实全身多发骨转移,B超（BUS）提示可疑颈淋巴结转移。既往史、家族史无特殊。X线片示肋骨、锁骨、胸腰椎、双肩关节和骨盆未见明显骨破坏。颈椎MRI示椎体信号稍欠均匀,     

Retrospective analysis of antitumor effects of zoledronic acid in breast cancer patients with bone-only metastases

BACKGROUND:

Bisphosphonates have been used successfully in the treatment of hypercalcemia and to reduce skeletal complications of bone metastasis, but have not been shown to prevent bone metastasis or to prolong survival time in metastatic breast cancer patients. The aim of this study was to determine whether the progression‐free survival (PFS) and overall survival (OS) of patients with bone‐only breast cancer metastasis differed based on whether patients received zoledronic acid, pamidronate, or no bisphosphonate upon diagnosis of their metastases.

PATIENTS AND METHODS:

We retrospectively identified 314 patients diagnosed with bone‐only metastasis at the time of initial staging or who developed bone metastasis as the first recurrence site during follow‐up from January 1, 1997 to December 31, 2008, at The MD Anderson Cancer Center. Univariate and multivariate Cox hazards models were used to assess the effects of each treatment on PFS and OS.

RESULTS:

Patients who had more than 1 bone metastasis and Eastern Cooperative Oncology Group (ECOG) performance status of 2 and 3 were more likely to receive zoledronic acid in this analysis. Compared with no bisphosphonate use, the use of zoledronic acid was not significantly associated with longer PFS (hazard ratio [HR] = 0.72, P = .058 in univariate analysis, and HR = 0.80, P = .235 in multivariate analysis) nor with longer OS (HR = 1.04, P = .863 in univariate analysis and HR = 1.34, P = .192 in multivariate analysis).

CONCLUSION:

Our study demonstrates that for patients with bone‐only metastases, zoledronic acid did not prolong PFS or OS. In patients with bone‐only metastasis, we could not demonstrate antitumor effects of zoledronic acid. Cancer 2012. © 2011 American Cancer Society.     

唑来膦酸治疗恶性肿瘤骨转移研究进展

骨骼是恶性肿瘤常见的转移部位之一,并可带来一系列的并发症,如骨痛、病理性骨折、脊髓压迫症和高钙血症等.二膦酸盐是治疗骨转移最常见的药物,唑来膦酸作为新一代含氮二磷酸盐类药物,是至今已发现的药物中抗骨吸收能力最强的.本文综述了唑来膦酸治疗恶性肿瘤骨转移的研究进展.     

Final 5-year results of Z-FAST trial: adjuvant zoledronic acid maintains bone mass in postmenopausal breast cancer patients receiving letrozole

BACKGROUND:

Postmenopausal breast cancer (BC) patients receiving adjuvant aromatase inhibitor therapy are at risk of progressive bone loss and fractures. Zoledronic acid inhibits osteoclastic bone resorption, is effective in maintaining bone health, and may therefore be beneficial in this setting.

METHODS:

Overall, 602 postmenopausal women with early, hormone receptor‐positive BC receiving adjuvant letrozole were randomized (301 each group) to receive upfront or delayed‐start zoledronic acid (4 mg intravenously every 6 months) for 5 years. The primary endpoint was the change in lumbar spine (LS) bone mineral density (BMD) at month 12. Secondary endpoints included changes in LS BMD, total hip BMD, and bone turnover markers at 2, 3, and 5 years; fracture incidence at 3 years; and time to disease recurrence.

RESULTS:

At month 61, the adjusted mean difference in LS and total hip BMDs between the upfront and delayed groups was 8.9% and 6.7%, respectively (P < .0001, for both). Approximately 25% of delayed patients received zoledronic acid by month 61. Only 1 patient experienced grade 4 renal dysfunction; no confirmed cases of osteonecrosis of the jaw were reported. Fracture rates (upfront, 28 [9.3%]; delayed, 33 [11%]; P = .3803) and Kaplan‐Meier disease recurrence rates (upfront, 9.8 [95% confidence interval (CI), 6.0‐10.3]; delayed, 10.5 [95% CI, 6.6‐14.4]; P = .6283) were similar at month 61.

CONCLUSIONS:

Upfront zoledronic acid seems to be the preferred treatment strategy versus delayed administration, as it significantly and progressively increases BMD in postmenopausal women with early BC receiving letrozole for 5 years, and long‐term coadministration of letrozole and zoledronic acid is well tolerated. Cancer 2012. © 2011 American Cancer Society.     

Clinical efficacy and safety of zoledronic acid in prostate and breast cancer

The anti-estrogen treatment for hormone-sensitive breast cancer and the androgen deprivation therapy for prostate cancer can lead to the development of osteoporosis and bone fractures. Metastases associated with prostate and breast cancer can also occur in bone. Bisphosphonates are used in these types of bone dysfunction. Zoledronic acid is the most potent bisphosphonate. In osteoporosis, zoledronic acid inhibits bone reabsorption and increases bone mineral density for at least a year after intravenous administration. The efficacy and safety of zoledronic acid in osteoporosis secondary to hormone-sensitive cancers (prostate and breast), and in the bone metastases associated with these cancers are reviewed.     

Effects of oral UFT combined with or without zoledronic acid on bone metastasis in the 4T1/luc mouse breast cancer

Bone metastasis is one of the major causes of increased morbidity and eventual mortality in breast cancer patients. Therefore, intervention of bone metastases is one of the important targets in the management of breast cancer. In the present study, we examined the effects of the orally administrable chemotherapeutic agent UFT (a combination of tegafur and uracil at a molar ratio of 1:4) on bone metastases using an animal model of the 4T1/luc mouse breast cancer. The 4T1/luc cells developed spontaneous metastases to bone following orthotopic cell inoculation. Oral daily administration of UFT (20 mg/kg/day) significantly reduced the orthotopic tumor burden; however, the lower dose (15 mg/kg/day) did not. In contrast, histologic examination showed that both doses of UFT significantly suppressed bone metastases in a dose-dependent manner. Since clinical studies have demonstrated that bisphosphonates (BPs), specific inhibitors of osteoclastic bone resorption, are beneficial for breast cancer patients with bone metastases, we next examined the effects of UFT combined with the BP zoledronic acid (ZOL) on established bone metastases. The combination of UFT (20 mg/kg/day) with ZOL (250 microg/kg) caused an enhanced reduction of bone metastases compared with UFT alone. In vitro studies showed that 5-fluorouracil (5-FU), an active metabolite of UFT, and ZOL increased apoptosis in 4T1/luc cells and inhibited osteoclast-like cell formation in an additive fashion. Our results suggest that oral UFT is an effective chemotherapeutic agent for advanced breast cancer accompanying bone metastases and that the combination with BP increases its benefits for bone metastases.     

Effective inhibition of aromatase inhibitor-associated bone loss by zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: ZO-FAST Study results

BACKGROUND: Letrozole is safe and effective in postmenopausal women with estrogen receptor-positive early breast cancer, but long-term aromatase inhibitor use may cause bone loss and increase fracture risk. This study evaluated an immediate or delayed strategy of bone protection therapy with zoledronic acid. METHODS: A total of 1065 patients who were receiving adjuvant letrozole were randomized to immediate-start or delayed-start zoledronic acid (4 mg intravenously biannually for 5 years). The delayed group received zoledronic acid if lumbar spine or total hip T-score decreased below -2.0 or when a nontraumatic fracture occurred. The primary endpoint was change in lumbar spine bone mineral density (BMD) at Month 12. Secondary endpoints included changes in total hip BMD, serum bone turnover markers, and safety at Month 12. RESULTS: Lumbar spine BMD increased from baseline in the immediate arm, while it decreased from baseline in delayed-arm patients. At Month 12, the differences between the groups in lumbar spine and total hip BMD were 5.7% (P < .0001; 95% confidence intervals [CI], 5.2% to 6.1%), and 3.6% (P < .0001; 95% CI, 3.3 to 4.0%), respectively. Both regimens were well tolerated with few serious adverse events. Bone pain was higher in the immediate group, as expected, because some patients experienced acute-phase reactions after zoledronic acid infusion. CONCLUSIONS: At 12 months, immediate zoledronic acid therapy prevented bone loss in postmenopausal women who were receiving adjuvant letrozole.     

Changes of bone turnover markers and serum PTH after night or morning administration of zoledronic acid in breast cancer patients with bone metastases

Persistent circadian rhythm of bone turnover in bone metastatic breast cancer suggests greater skeletal retention of bisphosphonates if administered in the night. We assessed differential effects of night vs morning administration of zoledronic acid (ZA) on bone turnover. Forty-four breast cancer patients with bone metastases were randomised to receive intravenous ZA (4 mg) at 1100 or 2300 hours every 28 days for four times. Urinary concentration N-telopeptide of type-I collagen (NTX) and deoxypyridinolines, and serum C-telopeptide of type-I collagen (CTX), bone alkaline phosphatase (ALP), osteocalcin and Parathyroid hormone (PTH) was measured in the morning at baseline and after 4, 7, 14, 28, 56 and 84 days. Urinary ZA concentration was also measured. Zoledronic acid caused significant decreases of NTX and CTX (P<0.001), without any difference in percent changes between night and morning arms. Bone ALP and osteocalcin were also significantly affected by ZA (P=0.001), without any difference between arms. Parathyroid hormone significantly increased in both the arms; PTH increase was lower in the night arm (P=0.001). From the second administration onwards, urinary ZA level was significantly higher in the night arm (P<0.01). Administration of ZA at two opposite phases of the circadian cycle causes similar changes of bone-turnover marker levels, but has differential effects on the level of serum PTH.