WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H200790
CAS#: 88416-50-6 (hydrate)
Description: Clodronic acid or clodronate disodium is a bisphosphonate and a bone resorption inhibitor and antihypercalcemic agent. It is used in experimental medicine to selectively deplete for macrophages. Clodronate binds to calcium and inhibits osteoclastic bone resorption and hydroxyapatite crystal formation and dissolution, resulting in a reduction of bone turnover. This agent may control malignancy-associated hypercalcemia, inhibit osteolytic bone metastasis and decrease pain.
Hodoodo Cat#: H200790
Name: Clodronate sodium hydrate
CAS#: 88416-50-6 (hydrate)
Chemical Formula: CH10Cl2Na2O10P2
Exact Mass: 0.00
Molecular Weight: 360.910
Elemental Analysis: C, 3.33; H, 2.79; Cl, 19.64; Na, 12.74; O, 44.33; P, 17.16
Related CAS #: 22560-50-5 (sodium ) 10596-23-3 (free acid) 88416-50-6 (hydrate)
Synonym: Clodronate sodium; clodronic acid disodium salt; disodium dichloromethylene diphosphonate; Dichloromethylenediphosphonic acid disodium salt. Foreign brand names: Bonefos; Clasteon; Difosfonal; Loron; Mebonat; Ossiten. Code name: CL2MDP; DMDP.
IUPAC/Chemical Name: sodium (dichloromethylene)bis(hydrogenphosphonate) tetrahydrate
InChi Key: UKPMBBKGFONQFO-UHFFFAOYSA-L
InChi Code: InChI=1S/CH4Cl2O6P2.2Na.4H2O/c2-1(3,8-10(4)5)9-11(6)7;;;;;;/h10-11H,(H,4,5)(H,6,7);;;4*1H2/q;2*+1;;;;/p-2
SMILES Code: ClC(OP([O-])=O)(OP([O-])=O)Cl.[H]O[H].[H]O[H].[H]O[H].[H]O[H].[Na+].[Na+]
Appearance: white solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in water
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
More Info: Two early observations about the first generation bisphosphonate, clodronate, suggested that it would likely have clinical utility; specifically, it was a more potent anti-resorptive but a less potent inhibitor of mineralisation than its predecessor etidronate. The known mechanism of action differs from that of the later nitrogen-containing bisphosphonates, as clodronate is metabolised intracellularly to a toxic analog of adenosine triphosphate, AppCCl2p, which causes mitochondrial dysfunction, impaired cellular energy metabolism and osteoclast apoptosis. For pre-clinical studies in a variety of disease models, liposomal clodronate has become the agent of choice for macrophage depletion, for example in a recent study to enhance haematopoietic chimerism and donor-specific skin allograft tolerance in a mouse model. For clinical use, clodronate was developed in oral and injectable formulations; while poorly absorbed from the gastro-intestinal tract, its absorption at 1-3% of the administered dose is approximately three-fold higher than for nitrogen-containing bisphosphonates. Following an early setback due to an erroneous association with toxic adverse events, a number of successful clinical studies have established clodronate, predominantly in its oral formulations, as a highly successful treatment in Paget's disease, hypercalcaemia (benign and malignant), multiple myeloma, and early or metastatic breast cancer. Novel uses in other disease areas, including veterinary use, continue to be explored. (copied from https://pubmed.ncbi.nlm.nih.gov/33127577/)
| Biological target: | Clodronic acid (Clodronate) disodium salt, a first-generation bisphosphonate, is an osteoclastic bone resorption inhibitor. |
| In vitro activity: | Clodronate effects, in vitro, were studied in cultured MSCs. SOX9 expression was surveyed in order to evaluate chondrogenic differentiation. All results were reported as normalized values compared to their expression at the end of the differentiation process (in specific mediums) without IL1β and/or clodronate addition to cultures. The in vitro experiments confirmed IL1β inhibition of chondrogenic maturation. This pro-inflammatory cytokine halved MSCs ability to differentiate. On the other hand, clodronate increased MSCs’ potential to undergo chondrogenic differentiation in a dose dependent way. Two different combinations of IL1β + clodronate (50 nM and 100 nM) were then added to the cultures. At the lower dose, the drug inhibited cytokine pro-inflammatory action only partially; but at the higher dose, clodronate action exceeded IL1β inhibition, stimulating MSCs maturation (Figure 2A). In order to improve the therapeutic effect against OA, customized nanoparticles produced with molecules which are employed in cartilage tissue engineering, as chitosan and hyaluronic acid were tested. Nanoparticles embedded-clodronate exhibited a stronger effect in counteracting IL1β inhibition of SOX9 (Figure 2B) and COL2A1 (Figure 2C) expression. Notably, MSCs cultured with chondrogenic differentiation medium in the presence of clodronate alone or embedded in nanoparticles, exhibited a strong positive staining with alcian-blue indicating the production of glycosaminoglycan (GAG) and therefore the chondrogenic maturation (Figure 3). Clodronate may therefore be considered a good therapeutic tool against OA. Reference: Int J Mol Sci. 2017 Dec; 18(12): 2696. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5751297 |
| In vivo activity: | The effects of clodronate on tumor growth were first examined using a syngeneic mouse model of ovarian cancer. In the ID8-VEGF model, mice treated with clodronate had an 80.2% decrease in tumor weight (P < 0.001) relative to the control liposome group (Fig. 1A). To determine whether similar effects would be noted in another model, the SKOV3ip1 model was next used. In this model, there was a 69.9% decrease in tumor weight (P = 0.008) and a 69.3% decrease in the number of tumor nodules (P = 0.03) in the clodronate treatment group compared with the controls (Fig. 1A and B). Mouse body weights did not differ significantly between the clodronate treatment group and controls, suggesting no obvious adverse effects of clodronate. Next, potential effects of treatment on the tumor microenvironment were examined. Tumor sections from the clodronate treatment groups showed 52.9% (ID8-VEGF model) and 52.4% (SKOV3ip1 model) decrease in macrophage density (P = 0.001 and P < 0.001, respectively) relative to controls (Fig. 1C). On inspection of the tumor sections, the control groups had many macrophages within the tumor islands, while the clodronate treatment groups had predominantly extratumoral macrophages between the tumor islands. Additionally, clodronate treatment resulted in a 70.2% decrease in microvessel density (P < 0.001) relative to controls (Fig. 1D). These results suggest that clodronate treatment alters tumor size, the number of tumor nodules, macrophage density, and capillary density within the microenvironment. Reference: Cancer Biol Ther. 2014 Aug 1; 15(8): 1061–1067. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4119073/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| H2O | 72.0 | 249.25 |
The following data is based on the product molecular weight 360.91 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| Formulation protocol: | 1. Valenti MT, Mottes M, Biotti A, Perduca M, Pisani A, Bovi M, Deiana M, Cheri S, Dalle Carbonare L. Clodronate as a Therapeutic Strategy against Osteoarthritis. Int J Mol Sci. 2017 Dec 13;18(12):2696. doi: 10.3390/ijms18122696. PMID: 29236045; PMCID: PMC5751297. 2. Reusser NM, Dalton HJ, Pradeep S, Gonzalez-Villasana V, Jennings NB, Vasquez HG, Wen Y, Rupaimoole R, Nagaraja AS, Gharpure K, Miyake T, Huang J, Hu W, Lopez-Berestein G, Sood AK. Clodronate inhibits tumor angiogenesis in mouse models of ovarian cancer. Cancer Biol Ther. 2014 Aug;15(8):1061-7. doi: 10.4161/cbt.29184. Epub 2014 May 19. PMID: 24841852; PMCID: PMC4119073. 3. Lee S, Kivimäe S, Szoka FC. Clodronate Improves Survival of Transplanted Hoxb8 Myeloid Progenitors with Constitutively Active GMCSFR in Immunocompetent Mice. Mol Ther Methods Clin Dev. 2017 Sep 7;7:60-73. doi: 10.1016/j.omtm.2017.08.007. PMID: 29034260; PMCID: PMC5633862. |
| In vitro protocol: | 1. Valenti MT, Mottes M, Biotti A, Perduca M, Pisani A, Bovi M, Deiana M, Cheri S, Dalle Carbonare L. Clodronate as a Therapeutic Strategy against Osteoarthritis. Int J Mol Sci. 2017 Dec 13;18(12):2696. doi: 10.3390/ijms18122696. PMID: 29236045; PMCID: PMC5751297. 2. Reusser NM, Dalton HJ, Pradeep S, Gonzalez-Villasana V, Jennings NB, Vasquez HG, Wen Y, Rupaimoole R, Nagaraja AS, Gharpure K, Miyake T, Huang J, Hu W, Lopez-Berestein G, Sood AK. Clodronate inhibits tumor angiogenesis in mouse models of ovarian cancer. Cancer Biol Ther. 2014 Aug;15(8):1061-7. doi: 10.4161/cbt.29184. Epub 2014 May 19. PMID: 24841852; PMCID: PMC4119073. |
| In vivo protocol: | 1. Reusser NM, Dalton HJ, Pradeep S, Gonzalez-Villasana V, Jennings NB, Vasquez HG, Wen Y, Rupaimoole R, Nagaraja AS, Gharpure K, Miyake T, Huang J, Hu W, Lopez-Berestein G, Sood AK. Clodronate inhibits tumor angiogenesis in mouse models of ovarian cancer. Cancer Biol Ther. 2014 Aug;15(8):1061-7. doi: 10.4161/cbt.29184. Epub 2014 May 19. PMID: 24841852; PMCID: PMC4119073. 2. Lee S, Kivimäe S, Szoka FC. Clodronate Improves Survival of Transplanted Hoxb8 Myeloid Progenitors with Constitutively Active GMCSFR in Immunocompetent Mice. Mol Ther Methods Clin Dev. 2017 Sep 7;7:60-73. doi: 10.1016/j.omtm.2017.08.007. PMID: 29034260; PMCID: PMC5633862. |
1: McCloskey E, Paterson AH, Powles T, Kanis JA. Clodronate. Bone. 2021 Feb;143:115715. doi: 10.1016/j.bone.2020.115715. Epub 2020 Oct 27. PMID: 33127577.
2: Culemann S, Knab K, Euler M, Wegner A, Garibagaoglu H, Ackermann J, Fischer K, Kienhöfer D, Crainiciuc G, Hahn J, Grüneboom A, Nimmerjahn F, Uderhardt S, Hidalgo A, Schett G, Hoffmann MH, Krönke G. Stunning of neutrophils accounts for the anti-inflammatory effects of clodronate liposomes. J Exp Med. 2023 Jun 5;220(6):e20220525. doi: 10.1084/jem.20220525. Epub 2023 Mar 28. PMID: 36976180; PMCID: PMC10067541.
3: Moriyama Y, Nomura M. Clodronate: A Vesicular ATP Release Blocker. Trends Pharmacol Sci. 2018 Jan;39(1):13-23. doi: 10.1016/j.tips.2017.10.007. Epub 2017 Nov 13. PMID: 29146440.
4: Franzosi MG, Devoto MA. Clodronato [Clodronate]. Medicina (Firenze). 1988 Jan-Mar;8(1):105-9. Italian. PMID: 2976107.
5: Saviola G, Abdi-Ali L, Comini L, Dalle-Carbonare LG. Use of clodronate in the management of osteoarthritis: an update. J Biol Regul Homeost Agents. 2019 September-October,;33(5):1315-1320. doi: 10.23812/19-58-A. PMID: 31591875.
6: Mass E. The stunning clodronate. J Exp Med. 2023 Jun 5;220(6):e20230339. doi: 10.1084/jem.20230339. Epub 2023 Mar 28. PMID: 36976179; PMCID: PMC10067525.
7: Frediani B, Giusti A, Bianchi G, Dalle Carbonare L, Malavolta N, Cantarini L, Saviola G, Molfetta L. Clodronate in the management of different musculoskeletal conditions. Minerva Med. 2018 Aug;109(4):300-325. doi: 10.23736/S0026-4806.18.05688-4. PMID: 29947493.
8: Moretti A, Paoletta M, Liguori S, Ilardi W, Snichelotto F, Toro G, Gimigliano F, Iolascon G. The Rationale for the Intra-Articular Administration of Clodronate in Osteoarthritis. Int J Mol Sci. 2021 Mar 7;22(5):2693. doi: 10.3390/ijms22052693. PMID: 33799992; PMCID: PMC7962069.
9: Saviola G, Abdi-Ali L, Povino MR. CLODRONATE: OLD DRUG, NEW USES. J Biol Regul Homeost Agents. 2015 Jul-Sep;29(3):719-22. PMID: 26403413.
10: Kanis JA, McCloskey EV, Beneton MN. Clodronate and osteoporosis. Maturitas. 1996 May;23 Suppl:S81-6. doi: 10.1016/0378-5122(96)01018-3. PMID: 8865146.
11: Markell R, Saviola G, Barker EA, Conway JD, Dujardin C. What Do We Know About Clodronate Now? A Medical and Veterinary Perspective. J Equine Vet Sci. 2020 May;88:102874. doi: 10.1016/j.jevs.2019.102874. Epub 2019 Nov 23. PMID: 32303308.
12: Koike T, Miura K, Hatta Y, Nakamura H, Hirabayashi Y, Yuda M, Harada T, Hirai S, Tsuboi I, Aizawa S. Macrophage depletion using clodronate liposomes reveals latent dysfunction of the hematopoietic microenvironment associated with persistently imbalanced M1/M2 macrophage polarization in a mouse model of hemophagocytic lymphohistiocytosis. Ann Hematol. 2023 Dec;102(12):3311-3323. doi: 10.1007/s00277-023-05425-w. Epub 2023 Sep 1. PMID: 37656190.
13: Plosker GL, Goa KL. Clodronate. A review of its pharmacological properties and therapeutic efficacy in resorptive bone disease. Drugs. 1994 Jun;47(6):945-82. doi: 10.2165/00003495-199447060-00007. PMID: 7521833.
14: van Rooijen N, van Kesteren-Hendrikx E. Clodronate liposomes: perspectives in research and therapeutics. J Liposome Res. 2002 Feb-May;12(1-2):81-94. doi: 10.1081/lpr-120004780. PMID: 12604042.
15: Dando TM, Wiseman LR. Clodronate : a review of its use in the prevention of bone metastases and the management of skeletal complications associated with bone metastases in patients with breast cancer. Drugs Aging. 2004;21(14):949-62. doi: 10.2165/00002512-200421140-00005. PMID: 15554753.
16: Hurst M, Noble S. Clodronate: a review of its use in breast cancer. Drugs Aging. 1999 Aug;15(2):143-67. doi: 10.2165/00002512-199915020-00007. PMID: 10495073.
17: Martos-Fernández M, Saez-Barba M, López-López J, Estrugo-Devesa A, Balibrea- Del-Castillo JM, Bescós-Atín C. Pentoxifylline, tocopherol, and clodronate for the treatment of mandibular osteoradionecrosis: a systematic review. Oral Surg Oral Med Oral Pathol Oral Radiol. 2018 May;125(5):431-439. doi: 10.1016/j.oooo.2018.02.004. Epub 2018 Feb 14. PMID: 29550081.
18: Arthur CM, Patel SR, Sharma A, Zerra PE, Chonat S, Jajosky RP, Fasano RM, Patel R, Bennett A, Zhou X, Luckey CJ, Hudson KE, Eisenbarth SC, Josephson CD, Roback JD, Hendrickson JE, Stowell SR. Clodronate inhibits alloimmunization against distinct red blood cell alloantigens in mice. Transfusion. 2022 May;62(5):948-953. doi: 10.1111/trf.16872. Epub 2022 Apr 26. PMID: 35470900; PMCID: PMC9491148.
19: Ghinoi V, Brandi ML. Clodronate: mechanisms of action on bone remodelling and clinical use in osteometabolic disorders. Expert Opin Pharmacother. 2002 Nov;3(11):1643-56. doi: 10.1517/14656566.3.11.1643. PMID: 12437497.
20: Knych HK, Finno CJ, Katzman S, Ryan D, McKemie DS, Kass PH, Arthur RM. Clodronate detection and effects on markers of bone resorption are prolonged following a single administration to horses. Equine Vet J. 2023 Jul;55(4):696-706. doi: 10.1111/evj.13866. Epub 2022 Aug 23. PMID: 35871470.
