| Size | Price | Stock | Qty |
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| 10mg |
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Purity: ≥98%
Tiludronate (Tiludronate disodium; Tiludronic Acid disodium) is a novel and potent bisphosphonate agent which prevents postmenopausal bone loss and is used for treatment of Paget's disease of bone (osteitis deformans) in human medicine. In veterinary medicine, tiludronic acid is used to treat navicular disease and bone spavin in horses. Its trade names are Tildren and Equidronate. It is approved for treatment of navicular disease and distal tarsal osteoarthritis in Europe, and was approved for treatment of navicular disease in the United States in 2014. Tiludronate is a non-nitrogenous bisphosphonate that inhibits osteoclasts, the primary cell responsible for the breakdown of bone required for bone remodeling.
Tiludronate disodium is a medication belonging to the non-nitrogenous bisphosphonate class. It acts as a bone resorption inhibitor and is primarily used to treat Paget's disease of bone in humans. In veterinary medicine, it is also used for treating navicular disease and bone spavin in horses. Its chemical structure features a sulfur-containing side chain (4-chlorophenylthio) attached to the bisphosphonate core.| Targets |
- Osteoclast vacuolar H⁺-ATPase (V-ATPase): Tiludronate is a potent inhibitor of the V-ATPase. In chicken osteoclast membrane vesicles, the IC₅₀ for inhibition of proton transport is 0.466 ± 0.026 μM. Inhibition is noncompetitive with respect to ATP, rapid, reversible, and pH-dependent (maximal at pH 7.5-7.8). It does not protect the enzyme from NEM inactivation, suggesting binding at a non-catalytic site. In chicken kidney vesicles, IC₅₀ is 1067 ± 463 μM. In yeast microsomes, IC₅₀ is 3.5 μM. [4]
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| ln Vitro |
The inhibition of proton transport by tiludronate is 5-fold greater in nephrogenic vesicles (IC50=1.1 mM) and 10,000-fold more in vesicles produced from osteoclasts (IC50=466 nM). Additionally, tiludronate efficiently suppresses the activity of pure yeast V-ATPase and inhibits proton transport in yeast microsomal preparations (IC50=3.5 microM). Tiludronate quickly and reversibly inhibits the proton transport process mediated by osteoclast V-ATPase, subject to pH variations [3].
- V-ATPase Inhibition: Tiludronate inhibits proton transport in membrane vesicles derived from chicken osteoclasts (IC₅₀ = 466 nM), chicken kidney (IC₅₀ ~1 mM), and yeast vacuoles (IC₅₀ = 3.5 μM). It also directly inhibits the activity of purified yeast V-ATPase (≈50% inhibition at 40 μM). Tiludronate is 10,000-fold more potent than other bisphosphonates (etidronate, alendronate, YM-175) in inhibiting the osteoclast V-ATPase. [4] - Inhibition of Bone Resorption in Tissue Culture: Tiludronate added to bone tissue culture inhibits calcium release, lysosomal enzyme secretion, and collagen matrix degradation induced by PTH, prostaglandin E2, and interleukin-1. At 10⁻⁴ M, it greatly inhibits 1,25(OH)₂D₃-induced bone resorption in fetal mouse long-bone organ culture. [3] - Effects on Osteoclasts: Tiludronate does not impair the recruitment, migration, or fusion of osteoclast precursors. It acts on mature, polarized osteoclasts by reducing their capacity to secrete protons into the resorption space and by favoring their detachment from the bone matrix, possibly by disrupting the podosomal ringed structure. [3][4] - Anti-inflammatory Effects (Periodontitis Model): In diabetic rats with experimental periodontitis, local administration of tiludronate (1 or 3 mg/kg) decreased the gene expression of IL-1β and, at 3 mg/kg, increased VEGF expression. It also reduced the intensity and extension of the inflammatory infiltrate. [2] |
| ln Vivo |
Tiludronate inhibits bone resorption in a dose-dependent manner. Mature osteoclasts can be affected by tiludronate by decreased proton secretion into the resorption space and increased osteoclast dissociation from the bone matrix. Several models of osteoporosis have also been used to test teludronate. Tiladronate sodium (5–200 mg/kg; oral) reduced the loss of bone mass in a male ovariectomized rat model. This was measured chemically by evaluating the calcium and phosphate content or physically by assessing bone weight and density[3].
- Inhibition of Bone Resorption (Animal Models): Tiludronate dose-dependently inhibits bone resorption in various models. In thyroparathyroidectomized (TPTX) rats with retinoid-induced bone resorption, oral doses of 50-100 mg/kg/day completely inhibit resorption. In sciatic neurectomized rats, it prevents bone loss and reduces osteoclast numbers attached to trabeculae. In ovariectomized (OVX) rats and dogs, it prevents bone loss and normalizes elevated bone remodeling. [3] - Prevention of Postmenopausal Bone Loss (Human Clinical Trial): In a randomized, double-blind, 12-month study in 76 healthy postmenopausal women (menopause 3-10 years), oral tiludronate (100 mg/day for 6 months, then placebo for 6 months) prevented bone loss. Lumbar spine BMD decreased by 2.1% (SE 0.8%) in the placebo group but did not change significantly in the tiludronate group (+1.33 [0.8]%). Corrected urinary hydroxyproline and calcium were significantly decreased in the tiludronate group. [1] - Protective Effect in Periodontitis (Diabetic Rat Model): In streptozotocin-induced diabetic rats with experimental periodontitis, local administration of tiludronate (1 or 3 mg/kg injected into gingival tissue every other day for 10 days) reduced alveolar bone resorption (micro-CT). The 3 mg/kg dose decreased attachment loss, increased trabecular number, and decreased trabecular separation. Both doses reduced TRAP-positive multinucleated cells, and the 3 mg/kg dose reduced RANKL immunolabeling. [2] |
| Enzyme Assay |
- V-ATPase Proton Transport Assay (Acridine Orange Fluorescence): Membrane vesicles (10-15 μg chicken osteoclast or 50-60 μg chicken kidney) were incubated in acidification buffer (150 mM KCl, 20 mM HEPES-KOH, 5 mM MgCl₂, pH 7.45, 5 μM acridine orange, 1.25 μM valinomycin) for 7 min at 25°C. Proton transport was initiated by adding 1.5 mM ATP. The initial rate of fluorescence quenching (ex 490 nm, em 520 nm) was measured, reflecting acidification. IC₅₀ values were calculated using a four-parameter logistic equation. The effects of preincubation time, reversibility (by 20-fold dilution), pH dependence (6.5-8.1), and ATP concentration (50-1000 μM) on inhibition were assessed. NEM (3.8 μM) was used to test for protection of the catalytic cysteine. [4]
- Purified Yeast V-ATPase Activity Assay (³²P liberation): Purified yeast V-ATPase (1.1 μg) was preincubated for 10 min at 37°C in reaction buffer (150 mM KCl, 20 mM HEPES-KOH, 5 mM MgCl₂, pH 7.45) with or without tiludronate. The reaction was started by adding 10 mM ATP + [γ-³²P]ATP. After 20 min at 37°C, the reaction was stopped with perchloric acid/phosphate, and the ³²P was extracted and counted. [4] |
| Cell Assay |
Activity is typically assessed using mature osteoclasts isolated from neonatal rabbit long bones and cultured on ivory slices. Cells are treated with increasing concentrations of tiludronate (e.g., 10⁻⁸ M to 10⁻⁴ M) for 48-72 hours. Inhibition of bone resorption is evaluated by measuring the area of resorption pits (e.g., Toluidine Blue staining) or by measuring the release of C-terminal telopeptides of type I collagen (CTX) into the culture medium.
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| Animal Protocol |
- Human Clinical Trial (Postmenopausal Bone Loss): 76 healthy postmenopausal women (menopause <96 months) were randomized to receive either oral tiludronate (100 mg tablet daily) or placebo for 6 months, followed by 6 months of placebo for all. BMD (L2-L4) was measured by dual-photon absorptiometry at 0, 6, and 12 months. Fasting urinary hydroxyproline/creatinine and calcium/creatinine ratios were measured. [1]
- Diabetic Rat Periodontitis Model: 3-month-old male Wistar rats were injected with streptozotocin (60 mg/kg, i.p.) to induce diabetes. After 7 days, experimental periodontitis was induced by placing a cotton ligature around the right mandibular first molars. Tiludronate solutions (1 or 3 mg/kg body weight in 40 μL) were injected into the buccal gingival tissue every other day (days 8, 10, 12, 14, 16). Animals were euthanized on day 18. Mandibles were collected for micro-CT, histology (H&E, TRAP, RANKL, OPG, CC3 immunohistochemistry), and qRT-PCR (IL-1β, VEGF). [2] - Retinoid-Induced Bone Resorption Model (TPTX Rats): Thyroparathyroidectomized rats were given retinoid derivatives to stimulate bone resorption. Tiludronate was administered orally (0.04-0.32 mmol/kg/day) or subcutaneously (0.016 mmol/kg/day). The rise in serum calcium was measured as an indicator of bone resorption. [3] |
| ADME/Pharmacokinetics |
The oral dose used was 100 mg daily, and the drug was well-tolerated, with a side-effect profile similar to placebo. [1]
- Tiludronate is known to bind strongly to hydroxyapatite in bone, leading to a long skeletal retention time and residual activity after treatment discontinuation. [3] |
| Toxicity/Toxicokinetics |
- Human Clinical Trial Tolerability: In the 12-month study, tiludronate (100 mg/day) was well-tolerated. 5 of 76 patients withdrew due to nausea and gastric irritation (3 active, 2 placebo). No significant changes in safety indices (blood cell counts, γ-glutamyltransferase, serum creatinine) were observed. [1]
- Bone Tolerance (Preclinical): Tiludronate does not impair bone mineralization at doses that effectively inhibit bone resorption. In growing monkeys, continuous administration for 6 months at doses up to 16 times the pharmacologically active dose did not induce osteomalacia. In OVX dogs, bone strength was maintained or increased. It did not impair fracture healing in beagle dogs. The therapeutic margin is larger than that of etidronate. [3] - Lack of Osteonecrosis Risk: As a non-nitrogen-containing bisphosphonate, tiludronate is not associated with the risk of osteonecrosis of the jaw, which is linked to aminobisphosphonates. [2] |
| References | |
| Additional Infomation |
Tiludronate sodium is the disodium salt of teludronate, a first-generation non-nitrogenous bisphosphonate and an analogue of endogenous pyrophosphate. Tiludronate adsorbs onto hydroxyapatite cells. Although the exact mechanism of its action is not fully elucidated, teludronate appears to inhibit protein tyrosine phosphatase (PTP) in osteoclasts, thereby disrupting the cytoskeletal ring structure and inhibiting osteoclast bone resorption activity. Furthermore, teludronate also appears to inhibit vacuolar proton ATPase (V-ATPase) in osteoclasts. In summary, this may reduce osteoclast numbers, inhibit abnormal bone resorption, and decrease bone turnover.
- Mechanism of Action (Anti-resorptive): Tiludronate's primary mechanism is direct inhibition of the osteoclast vacuolar H⁺-ATPase (V-ATPase), the proton pump responsible for acidifying the bone resorption lacuna. This inhibits the solubilization of hydroxyapatite and the activity of lysosomal enzymes. It also promotes the detachment of mature osteoclasts from the bone matrix. Unlike some bisphosphonates, its effect is not mediated by inhibiting protein prenylation. The (4-chlorophenyl)-thiomethylene side chain is critical for V-ATPase inhibition, as other bisphosphonates are much less potent. [3][4] - Anti-inflammatory Properties: Tiludronate inhibits the secretion of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) by activated macrophages and in periodontal tissues. This may contribute to its protective effects in periodontitis. [2][3] - Clinical Use: Tiludronate is used to treat Paget's disease of bone and has been studied for postmenopausal osteoporosis. It is not approved in all countries. [1][3] |
| Molecular Formula |
C7H7CLNA2O6P2S
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| Molecular Weight |
362.5719
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| Exact Mass |
361.892
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| Elemental Analysis |
C, 23.19; H, 1.95; Cl, 9.78; Na, 12.68; O, 26.48; P, 17.09; S, 8.84
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| CAS # |
149845-07-8
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| Related CAS # |
Tiludronate;89987-06-4;Tiludronate-d5 sodium
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| PubChem CID |
60936
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| Appearance |
White to off-white solid powder
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| Boiling Point |
600.7ºC at 760mmHg
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| Flash Point |
317.1ºC
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| Vapour Pressure |
2.79E-15mmHg at 25°C
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| LogP |
2.947
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
19
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| Complexity |
320
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1=CC(=CC=C1SC(P(=O)(O)[O-])P(=O)(O)[O-])Cl.[Na+].[Na+]
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| InChi Key |
SKUHWSDHMJMHIW-UHFFFAOYSA-L
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| InChi Code |
InChI=1S/C7H9ClO6P2S.2Na/c8-5-1-3-6(4-2-5)17-7(15(9,10)11)16(12,13)14/h1-4,7H,(H2,9,10,11)(H2,12,13,14)/q2*+1/p-2
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| Chemical Name |
[(4-chlorophenyl)sulfanyl-[hydroxy(oxido)phosphoryl]methyl]-hydroxyphosphinate disodium
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| Synonyms |
Tiludronate disodium; Tiludronic Acid disodium; TILUDRONATE DISODIUM; 149845-07-8; Tiludronic acid disodium salt; sr 41319b; Tiludronate sodium; Tiludronic acid; Skelid; Tildren; Equidronate.
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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 : ~62.5 mg/mL (~172.38 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.7581 mL | 13.7904 mL | 27.5809 mL | |
| 5 mM | 0.5516 mL | 2.7581 mL | 5.5162 mL | |
| 10 mM | 0.2758 mL | 1.3790 mL | 2.7581 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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