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Zoledronic acid hydrate (Zoledronate; CGP 42446; CGP42446A; ZOL 446) is potent and semisynthetic bisphosphonate with anti-bone-resorption activity. It induces apoptosis in osteoclasts by inhibiting enzymes of the mevalonate pathway and preventing the isoprenylation of small GTP-binding proteins such as Ras and Rho. Zoledronic acid is a synthetic imidazole bisphosphonate analog of pyrophosphate with anti-bone-resorption activity. As 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.
| Targets |
Bisphosphonate (BP), with potent anti-resorptive; RANKL
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|---|---|
| ln Vitro |
In osteocyte-like MLO-Y4 cells, zoledronic acid monohydrate (0.1–1 µM; 48 hours) enhances the expression of sclerostin and receptor activator of nuclear factor kB ligand (RANKL) mRNA[2]. The expression of osteoclastogenesis supporting factor from MLO-Y4 cells is increased by zoledronic acid monohydrate[2]. In MLO-Y4 cells, zoledronic acid monohydrate increases the production of RANKL through the IL-6/JAK2/STAT3 pathway[2]. Monohydrate zoledronic acid suppresses osteoclast development and function by modulating the JNK and NF-κB signaling pathways[3]. In MC3T3-E1 cells, zoledronic acid monohydrate (10-100 µM; 1-7 days) significantly lowers viability[4]. In MC3T3-E1 cells, zoledronic acid monohydrate (10-100 µM; 1-7 days) causes apoptosis[4]. Because it induces apoptosis, zoledronic acid monohydrate (10–100 µM; 4 days) reduces cell viability[4]. At concentrations less than 1 µM, zoledronic acid monohydrate inhibits the differentiation and maturation of MC3T3-E1 cells[4].
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| ln Vivo |
For three weeks, zoledronic acid monohydrate (0.05 mg/kg; intraperitoneally; weekly) enhances the density and content of bone mineral[5]. In vivo bone remodeling and osteoclast and osteoblast function are inhibited by zoledronic acid monohydrate (0.5–1 mg/kg; i.p.; weekly; for 3 weeks), which interferes with the mechanical characteristics of bone[5].
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| Cell Assay |
Cell Viability Assay[4]
Cell Types: MC3T3-E1 cells Tested Concentrations: 0.02 µM, 0.1 µM, 1 µM, 10 µM, 100 µM Incubation Duration: 1 day, 3 days, 5 days, 7 days Experimental Results: decreased cells viability at 10 µM and 100 µM. Apoptosis Analysis[4] Cell Types: MC3T3-E1 cells Tested Concentrations: 0.02 µM, 0.1 µM, 1 µM, 10 µM, 100 µM Incubation Duration: 1 days, 4 days, 7 days Experimental Results: Increased the number of early apoptotic cells and late apoptotic or necrotic cells at dose-dependent and time-dependent (high concentrations). Western Blot Analysis[4] Cell Types: MC3T3-E1 cells Tested Concentrations: 0.02 µM, 0.1 µM, 1 µM, 10 µM, 100 µM Incubation Duration: 4 days Experimental Results: Down-regulated the protein level of inactive caspase-3 and up-regulated the protein level of active caspase-3 at the concentrations of 10 and 100 µM. |
| Animal Protocol |
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. |
| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation Since there is currently no information regarding the use of zoledronic acid during lactation, alternative medications are recommended, especially for breastfed newborns or premature infants. However, breastfed infants are unlikely to absorb zoledronic acid. ◉ Effects on Breastfed Infants As of the revision date, no relevant published information was found. ◉ Effects on Lactation and Breast Milk As of the revision date, no relevant published information was found. |
| References |
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| Additional Infomation |
Zoledronic acid is a synthetic imidazole bisphosphonate analogue, a pyrophosphate analogue with anti-bone resorption activity. As 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. The drug also inhibits farnesyl pyrophosphate synthase, an enzyme involved in the biosynthesis of terpenoids. Inhibition of this enzyme prevents the biosynthesis of isoprene lipids, which are donor substrates for farnesylation and geranylation during the post-translational modification of small GTPase signaling proteins, modifications that play an important role in osteoclast turnover. The reduction in bone turnover and the stabilization of the bone matrix contribute to the analgesic effect of zoledronic acid on painful osteoblastic lesions. The drug also reduces serum calcium concentrations associated with hypercalcemia.
An iminobisphosphonate bone resorption inhibitor used to treat malignant tumor-associated hypercalcemia, osteitis deformans, and osteoporosis. Drug Indications Prevention of skeletal-related events (pathological fracture, spinal cord compression, bone radiation or surgery, or tumor-induced hypercalcemia) in adult patients with advanced bone malignancies. Treatment of hypercalcemia caused by tumors in adults. Treatment of osteoporosis: postmenopausal women; men; those at increased risk of fracture, including those with recent low-energy hip fractures. Treatment of osteoporosis associated with long-term systemic glucocorticoid therapy in postmenopausal women and men at increased fracture risk. Treatment of Paget's disease. Prevention of skeletal-related events (pathological fracture, spinal cord compression, bone radiation or surgery, or tumor-induced hypercalcemia) in adult patients with advanced bone malignancies. Treatment of hypercalcemia caused by tumors (TIH) in adults. 4 mg/5 ml and 4 mg/100 ml: Prevention of skeletal-related events (pathological fracture, spinal cord compression, bone radiation or surgery, or tumor-induced hypercalcemia) in adult patients with advanced bone malignancies. Treatment of hypercalcemia caused by tumors (TIH) in adults. 5 mg/100 ml: Treatment of osteoporosis: Suitable for postmenopausal women; men; those at increased risk of fracture, including those with recent low-energy hip fractures. Treatment of osteoporosis associated with long-term systemic glucocorticoid therapy: Suitable for postmenopausal women; men; those at increased risk of fracture. Treatment of Paget's disease in adults. Prevention of skeletal-related events and treatment of hypercalcemia caused by tumors. Prevention of skeletal-related events (pathological fractures, spinal cord compression, bone radiation or surgery, or hypercalcemia caused by tumors) in adult patients with advanced bone malignancies. Treatment of hypercalcemia (TIH) caused by tumors in adults. Treatment of osteoporosis: Postmenopausal women; men; those at increased risk of fracture, including those with recent low-energy hip fractures. Treatment of osteoporosis associated with long-term systemic glucocorticoid therapy: Postmenopausal women; men; those at increased risk of fracture. Treatment of Paget's disease in adults. Treatment of osteoporosis in postmenopausal women increases the risk of fractures in adult men, including those with recent low-energy hip fractures. Treatment of osteoporosis in postmenopausal women associated with long-term systemic glucocorticoid therapy increases the risk of fractures in adult men. Treatment of Paget's disease in adults. Prevention of skeletal-related events in patients with advanced bone malignancies. |
| Molecular Formula |
C5H12N2O8P2
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|---|---|
| Molecular Weight |
290.1
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| Exact Mass |
290.006
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| Elemental Analysis |
C, 22.07; H, 3.70; N, 10.30; O, 41.16; P, 22.77
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| CAS # |
165800-06-6
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| Related CAS # |
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);
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| PubChem CID |
121586
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| Appearance |
White to off-white solid powder
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| Boiling Point |
764ºC at 760 mmHg
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| Melting Point |
245 °C(dec.)
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| Flash Point |
415.8ºC
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| Vapour Pressure |
1.53E-24mmHg at 25°C
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| LogP |
-2.3
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| Hydrogen Bond Donor Count |
6
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
17
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| Complexity |
327
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C(N1C=CN=C1)C(P(=O)(O)O)(P(=O)(O)O)O.O
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| InChi Key |
FUXFIVRTGHOMSO-UHFFFAOYSA-N
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| InChi Code |
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
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| Chemical Name |
(1-hydroxy-2-(1H-imidazol-1-yl)ethane-1,1-diyl)diphosphonic acid hydrate
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| Synonyms |
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.
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
H2O : ~14.29 mg/mL (~49.26 mM)
DMSO :< 1 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 3.33 mg/mL (11.48 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication (<60°C).
(Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.4471 mL | 17.2354 mL | 34.4709 mL | |
| 5 mM | 0.6894 mL | 3.4471 mL | 6.8942 mL | |
| 10 mM | 0.3447 mL | 1.7235 mL | 3.4471 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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