Bisphosphonate (BP), with potent anti-resorptive; RANKL

在骨细胞样 MLO-Y4 细胞中，唑来膦酸一水合物（0.1–1 µM；48 小时）可增强硬化素和核因子 kB 配体受体激活剂 (RANKL) mRNA 的表达[2]。唑来膦酸一水合物可增加 MLO-Y4 细胞破骨细胞生成支持因子的表达[2]。在 MLO-Y4 细胞中，唑来膦酸一水合物通过 IL-6/JAK2/STAT3 途径增加 RANKL 的产生 [2]。一水唑来膦酸通过调节 JNK 和 NF-κB 信号通路抑制破骨细胞的发育和功能[3]。在 MC3T3-E1 细胞中，唑来膦酸一水合物（10-100 µM；1-7 天）显着降低活力[4]。在 MC3T3-E1 细胞中，唑来膦酸一水合物（10-100 µM；1-7 天）会导致细胞凋亡[4]。由于唑来膦酸一水合物（10–100 µM；4 天）会诱导细胞凋亡，因此会降低细胞活力[4]。当浓度低于 1 µM 时，唑来膦酸一水合物会抑制 MC3T3-E1 细胞的分化和成熟[4]。

连续三周，唑来膦酸一水合物（0.05 mg/kg；腹腔注射；每周）可增强骨矿物质的密度和含量[5]。唑来膦酸一水合物（0.5-1 mg/kg；腹腔注射；每周；持续 3 周）会抑制体内骨重塑以及破骨细胞和成骨细胞功能，从而干扰骨的机械特性[5]。

细胞活力测定[4]
细胞类型： MC3T3-E1 细胞
测试浓度： 0.02 µM、0.1 µM、1 µM、10 µM、100 µM
孵育时间：1天、3天、5天、7天
实验结果：10 µM和100 µM时细胞活力降低。

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细胞凋亡分析[4]
细胞类型： MC3T3-E1 细胞
测试浓度： 0.02 µM、0.1 µM、1 µM、 10 µM、100 µM
孵育时间：1 天、4 天、7 天
实验结果：增加早期凋亡细胞和晚期凋亡细胞的数量坏死细胞呈剂量依赖性和时间依赖性（高浓度）。

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蛋白质印迹分析[4]
细胞类型： MC3T3-E1 细胞
测试浓度： 0.02 µM、0.1 µM、1 µM , 10 µM, 100 µM
孵育时间： 4 天
实验结果： 下调非活性 caspase-3 的蛋白水平并上调浓度为 10 和 100 µM 的活性 caspase-3 的蛋白质水平。

Animal/Disease Models: Fiveweeks old C57BL6 mice[5]
Doses: 0.05 mg/kg, 0.5 mg/kg, 1 mg/kg
Route of Administration: intraperitoneal (ip)injection, weekly, for 3 weeks
Experimental Results: Inhibited both osteoclast and osteoblasts function and bone remodeling at 0.5 mg/kg and 1 mg/kg.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because no information is available on the use of zoledronic acid during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. However, absorption of zoledronic acid by a breastfed infant is unlikely.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

[1]. Various pathways of zoledronic acid against osteoclasts and bone cancer metastasis: a brief review. BMC Cancer. 2020; 20: 1059.

[2]. Zoledronate Enhances Osteocyte-Mediated Osteoclast Differentiation by IL-6/RANKL Axis. Int J Mol Sci. 2019 Mar; 20(6): 1467.

[3]. Zoledronic acid inhibits osteoclast differentiation and function through the regulation of NF-κB and JNK signalling pathways. Int J Mol Med. 2019 Aug;44(2):582-592.

[4]. Dose-dependent inhibitory effects of zoledronic acid on osteoblast viability and function in vitro. Mol Med Rep. 2016 Jan; 13(1): 613-622.

[5]. High-dose zoledronic acid impacts bone remodeling with effects on osteoblastic lineage and bone mechanical properties. Clin Cancer Res. 2009 Sep 15;15(18):5829-39.

[6]. Oral Zoledronic acid bisphosphonate for the treatment of chronic low back pain with associated Modic changes: A pilot randomized controlled trial. J Orthop Res. 2022 Feb 23.

Zoledronic Acid is a synthetic imidazole bisphosphonate analog of pyrophosphate with anti-bone-resorption activity. A third-generation bisphosphonate, zoledronic acid binds to hydroxyapatite crystals in the bone matrix, slowing their dissolution and inhibiting the formation and aggregation of these crystals. This agent also inhibits farnesyl pyrophosphate synthase, an enzyme involved in terpenoid biosynthesis. Inhibition of this enzyme prevents the biosynthesis of isoprenoid lipids, donor substrates of farnesylation and geranylgeranylation during the post-translational modification of small GTPase signalling proteins, which are important in the process of osteoclast turnover. Decreased bone turnover and stabilization of the bone matrix contribute to the analgesic effect of zoledronic acid with respect to painful osteoblastic lesions. The agent also reduces serum calcium concentrations associated with hypercalcemia.
An imidobisphosphonate inhibitor of BONE RESORPTION that is used for the treatment of malignancy-related HYPERCALCEMIA; OSTEITIS DEFORMANS; and OSTEOPOROSIS.

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Drug Indication
Prevention of skeletal-related events (pathological fractures, spinal compression, radiation or surgery to bone, or tumour-induced hypercalcaemia) in adult patients with advanced malignancies involving bone. Treatment of adult patients with tumour-induced hypercalcaemia.
Treatment of osteoporosis: , , , in post-menopausal women; , in men; , , , at increased risk of fracture, including those with a recent low-trauma hip fracture. , , Treatment of osteoporosis associated with long-term systemic glucocorticoid therapy in post-menopausal women and in men at increased risk of fracture. , , Treatment of Paget's disease of the bone. ,
Prevention of skeletal related events (pathological fractures, spinal compression, radiation or surgery to bone, or tumour-induced hypercalcaemia) in adult patients with advanced malignancies involving bone. Treatment of adult patients with tumour-induced hypercalcaemia (TIH).
4 mg / 5 ml and 4 mg / 100 ml: Prevention of skeletal-related events (pathological fractures, spinal compression, radiation or surgery to bone, or tumour-induced hypercalcaemia) in adult patients with advanced malignancies involving bone. Treatment of adult patients with tumour-induced hypercalcaemia (TIH). 5 mg / 100 ml: Treatment of osteoporosis: in post-menopausal women; in men; at increased risk of fracture, including those with a recent low-trauma hip fracture. Treatment of osteoporosis associated with long-term systemic glucocorticoid therapy: in post-menopausal women; in men; at increased risk of fracture. Treatment of Paget's disease of the bone in adults.
Prevention of skeletal-related events and treatment of tumour-induced hypercalcaemia.
Prevention of skeletal related events (pathological fractures, spinal compression, radiation or surgery to bone, or tumour-induced hypercalcaemia) in adult patients with advanced malignancies involving bone. Treatment of adult patients with tumour-induced hypercalcaemia (TIH).
Treatment of osteoporosis: , , , in post-menopausal women; , in men; , , , at increased risk of fracture including those with a recent low-trauma hip fracture. , , Treatment of osteoporosis associated with long-term systemic glucocorticoid therapy: , , , in post-menopausal women; , in men; , , , at increased risk of fracture. , , Treatment of Paget's disease of the bone in adults. ,
Treatment of osteoporosisin post-menopausal womenin adult menat increased risk of fracture, including those with recent low-trauma hip fracture. Treatment of osteoporosis associated with long-term systemic glucocorticoid therapyin post-menopausal womenin adult menat increased risk of fracture. Treatment of Paget's disease of the bone in adults.
Prevention of skeletal related events in patients with advanced malignancies involving bone

C5H12N2O8P2

290.1

290.006

C, 22.07; H, 3.70; N, 10.30; O, 41.16; P, 22.77

165800-06-6

Zoledronic Acid;118072-93-8;Zoledronic acid disodium tetrahydrate;165800-07-7; 165800-06-6 (free acid hydrate); 131654-46-1 (disodium); 165800-08-8 (trisodium hydrate); 827573-11-5 (trisodium); 165800-07-7 (disodium hydrate);

121586

White to off-white solid powder

764ºC at 760 mmHg

245 °C(dec.)

415.8ºC

1.53E-24mmHg at 25°C

-2.3

181.96

6

9

4

17

327

0

C(N1C=CN=C1)C(P(=O)(O)O)(P(=O)(O)O)O.O

FUXFIVRTGHOMSO-UHFFFAOYSA-N

InChI=1S/C5H10N2O7P2.H2O/c8-5(15(9,10)11,16(12,13)14)3-7-2-1-6-4-7;/h1-2,4,8H,3H2,(H2,9,10,11)(H2,12,13,14);1H2

(1-hydroxy-2-(1H-imidazol-1-yl)ethane-1,1-diyl)diphosphonic acid hydrate

CGP42446; CGP42446A; ZOL446; CGP-42446; CGP-42446A; ZOL-446; CGP 42446; CGP 42446A; ZOL 446; Zoledronate, trade names: Zometa; Zoledronic acid monohydrate; Zoledronic acid (monohydrate); Zometa; Zoledronate monohydrate; (1-Hydroxy-2-(1H-imidazol-1-yl)ethane-1,1-diyl)diphosphonic acid hydrate; Zoledronate hydrate; Reclast.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~14.29 mg/mL (~49.26 mM)
DMSO :< 1 mg/mL

配方 1 中的溶解度: 3.33 mg/mL (11.48 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶。 (<60°C).

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。