国产唑来膦酸治疗肿瘤高钙血症多中心Ⅱ期临床观察

Objective： To evaluate the effect and safety of clinical use of zoledronic acid in the treatment of malignant hypercalcemia. Methods： A multi-center, open phase II clinical trial was conducted in 15 cases with malignant hypercalcemia who received zoledronic acid intravenously for 15 min. The level of blood calcium and side effects were recorded regularly within 28 days after injection. Results： One case was dropped out due to bad compliance. The complete response rate （the corrected serum calcium was reduced to normal level） was 100.00% （14/14）. The medium time of complete response rate was 5.07 days. The medium maintain time was 22.30 days. Slight, or moderate fever was observed. Conclusion： Zoledronic acid can effectively reduce the malignant hypercalcemia. The use of zoledronic acid appears to be safety and convenient.     

新一代二膦酸盐类药物唑来膦酸的药理及临床

唑来膦酸是异环型第三代双膦酸盐类药物,它能抑制骨吸收而减少骨基质生长因子的释放,抑制癌细胞黏附于骨基质,降低癌症患者的骨转移发生率.临床上用于辅助治疗发生骨转移的癌症患者,以减少发生高钙血症、骨痛和骨折的危险;还可用于预防恶性肿瘤引起的骨骼相关疾病,延缓骨转移的发生,短期用药,长期显效.现综述唑来膦酸的药理作用、药动学和临床评价.     

Nitrogen‐containing bisphosphonate therapy: assessment of the alveolar bone structure in rats – a blind randomized controlled trial

This study aimed to assess the effect of zoledronic acid exposure on structures of the alveolar bone of rats. The sample was composed of 42 male Wistar rats. Animals in the T1 and T2 groups received weekly doses of 0.2 mg/kg intraperitoneal zoledronic acid for 3 weeks, while animals in the T3 group received the same treatment for 8 weeks. The control groups C1, C2 and C3 received equivalent doses of saline. The first upper molars of Wistar rats in the C2, T2, C3 and T3 groups were extracted. Cone‐beam computerized tomography scans were performed, and the image density was analysed by grey levels. The presence and type of inflammatory infiltrate, vascularization and bone necrosis were assigned by histological qualitative scores. Histomorphometric analysis of bone density was performed in the groups without extraction. No significant differences were found in the bone grey density estimated by grey‐level value and histomorphometric analysis between the C1 and T1 groups (P > 0.05). The grey levels in the T3 group were lower (P < 0.05) than in the C3 group, corresponding to the bone defect. Histological assessments showed the presence of bone necrosis in the T3 group and lower levels of bone remodelling in the test groups (T2 and T3) compared to the control groups (C2 and C3). The results of qualitative analyses did not differ significantly between the groups (P > 0.05). Zoledronic acid‐exposed animals showed maxillary changes including reduced grey levels, the presence of bone necrosis and a higher prevalence of inflammatory signs.     

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.     

Osteoporosis in children and young adults

Osteoporosis is a major public health problem with serious long-term complications. In children, the definition of osteoporosis is not only based on densitometric criteria but also takes into account vertebral and long bone fragility fractures. Several factors, such as long-term high-dose steroids, chronic inflammation, malnutrition, immobility, lack of sex steroids, and medication can reduce bone density and increase the risk for fragility fractures when left untreated. Also, genetic conditions can predispose to primary bone fragility disorders, with osteogenesis imperfecta being the most common. Furthermore, since the growing skeleton is at an increased rate of bone remodeling, the ability to heal long bone fractures and reshape vertebral fractures differentiates children from adults. The scope of this chapter is to review the risk factors of osteoporosis and fragility fractures and describe the commonest causes of primary and secondary osteoporosis and their management in children and young adults.     

低浓度唑来膦酸对成骨细胞和破骨细胞影响的体外实验

目的：观察低浓度(10-6 mol/L)唑来膦酸(zoledronate acid,ZA)对体外大鼠破骨细胞及成骨细胞的影响。方法体外分别培养大鼠来源的成骨细胞和破骨细胞,将两种细胞各分为两组：空白对照组及低浓度(10-6 mol/L)ZA组。应用抗酒石酸酸性磷酸酶染色、图像分析计算骨吸收陷窝面积,检测破骨细胞形态及骨吸收情况。碱性磷酸酶(alkaline phosphatase, ALP)染色、四甲基偶氮唑盐比色法了解成骨细胞的形态及增殖情况。结果培养1周后破骨细胞具有典型的形态特征,并在骨片上形成了吸收陷窝;ZA组与对照组相比,破骨细胞数量及生成吸收陷窝的数目和面积减少,差异有统计学意义(P＜0.05)。成骨细胞有典型的梭形、ALP染色阳性特征,培养至第7天ZA组成骨细胞光吸收值(3.37±0.11)高于对照组(2.87±0.12),差异有统计学意义(P＜0.05)。结论低浓度(10-6 mol/L)的ZA能够抑制破骨细胞的增殖和活性,促进成骨细胞的增殖,选择恰当给药方式和剂量能够在抑制破骨的同时促进成骨。     

Zoledronic acid suppresses mineralization through direct cytotoxicity and osteoblast differentiation inhibition

J Oral Pathol Med (2012) 41 : 713–720 Background: Zoledronic acid (ZA) is prescribed to treat various metabolic bone diseases. Despite its efficacy in preventing bone loss, ZA has been linked to osteonecrosis of the jaw in several reports. However, a mechanism underlying this occurrence is still unclear. Objective: This study was to investigate causative roles of ZA on osseous cellular activities of pre‐osteoblastic cell line MC3T3‐E1 (MC3T3) and mesenchymal stem cell (MSC). Methods: Morphological analysis, RT‐PCR, annexin V/PI staining, together with mineralization, cell viability, and alkaline phosphatase (ALP) activity assays were performed. Results: Zoledronic acid treatment decreased bone nodule formation at all concentrations tested (0.01–100 μM). Cell morphologies of both cell types were altered from their normal appearances after the addition of ZA (≥5 μM), and cell viability was significantly inhibited at concentrations ≥0.1 μM for MC3T3 and at concentrations ≥10 μM for MSC. ZA (100 μM) induced apoptosis in MC3T3 and MSC. Furthermore, ALP activity from both cells was strongly reduced when exposed to ZA (≥1 μM for MC3T3 and ≥5 μM for MSC). ZA also down‐regulated Runx 2 and Col I mRNA expressions. Conclusion: With this in vitro study, ZA mediated defective bone mineralization by directly disrupting osteoblast/osteoprogenitor cellular activities at several levels, that is, cell proliferation, osteoblast differentiation, and osteoblast function of both pre‐osteoblastic cells and MSC.     

The effect of systemically administrated zoledronic acid on the osseointegration of dental implants

Oral Diseases (2012) 18 , 802–808 Objective: The aim of conducting this study was to evaluate the effect of zoledronic acid (ZA) on the new bone formation (NBF) after the insertion of a titanium dental implant, which is very popular treatment in dentistry. Study Design: Twelve New Zealand white rabbits were used in this study. The rabbits were divided in two groups. ZA was systemically administered to the study group. Titanium implants were placed to the left and right tibias of the rabbits. Results: The data from the ZA group revealed a statistically significant increase in the bone mineral content and the bone mineral density. A non‐decalcified histomorphometric examination conducted on the study group revealed a significant increase of NBF and bone‐implant contact (BIC) at 2 and 4 weeks. Conclusion: A single dose of systemic ZA administration increases the rate of NBF and augments the quality of the bone.     

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。