U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ACHIRAL
Molecular Formula C7H9ClO6P2S
Molecular Weight 318.608
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of TILUDRONIC ACID

SMILES

OP(O)(=O)C(SC1=CC=C(Cl)C=C1)P(O)(O)=O

InChI

InChIKey=DKJJVAGXPKPDRL-UHFFFAOYSA-N
InChI=1S/C7H9ClO6P2S/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)

HIDE SMILES / InChI
Tiludronic acid is a bisphosphonate characterized by a (4-chlorophenylthio) group on the carbon atom of the basic P-C-P structure common to all bisphosphonates. Tiludronate is a first generation (non-nitrogenous) bisphosphonate in the same family as etidronate and clodronate. Tiludronate affects calcium metabolism and inhibits bone resorption and soft tissue calcification. Of the tiludronate that is resorbed (from oral preparation) or infused (for intravenous drugs), about 50% is excreted unchanged by the kidney. The remainder has a very high affinity for bone tissue, and is rapidly absorbed onto the bone surface. Tiludronic acid is marketed under the tradename Skelid. In vitro studies indicate that tiludronate disodium acts primarily on bone through a mechanism that involves inhibition of osteoclastic activity with a probable reduction in the enzymatic and transport processes that lead to resorption of the mineralized matrix. Bone resorption occurs following recruitment, activation, and polarization of osteoclasts. Tiludronate disodium appears to inhibit osteoclasts through at least two mechanisms: disruption of the cytoskeletal ring structure, possibly by inhibition of protein-tyrosine-phosphatase, thus leading to detachment of osteoclasts from the bone surface and the inhibition of the osteoclastic proton pump. SKELID is indicated for treatment of Paget's disease of bone (osteitis deformans).

Approval Year

TargetsConditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
SKELID

Approved Use

SKELID is indicated for treatment of Paget's disease of bone (osteitis deformans).

Launch Date

1997
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
1.1 mg/L
200 mg 1 times / day multiple, oral
dose: 200 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TILUDRONIC ACID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
2.3 mg/L
400 mg 1 times / day multiple, oral
dose: 400 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TILUDRONIC ACID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
4.7 mg/L
600 mg 1 times / day multiple, oral
dose: 600 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TILUDRONIC ACID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
7.8 mg/L
800 mg 1 times / day multiple, oral
dose: 800 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TILUDRONIC ACID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
10.3 mg × h/L
200 mg 1 times / day multiple, oral
dose: 200 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TILUDRONIC ACID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
25 mg × h/L
400 mg 1 times / day multiple, oral
dose: 400 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TILUDRONIC ACID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
46.8 mg × h/L
600 mg 1 times / day multiple, oral
dose: 600 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TILUDRONIC ACID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
80 mg × h/L
800 mg 1 times / day multiple, oral
dose: 800 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TILUDRONIC ACID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
78 h
400 mg 1 times / day multiple, oral
dose: 400 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TILUDRONIC ACID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
65.7 h
600 mg 1 times / day multiple, oral
dose: 600 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TILUDRONIC ACID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
72 h
800 mg 1 times / day multiple, oral
dose: 800 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
TILUDRONIC ACID plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
800 mg 1 times / day steady, oral
Studied dose
Dose: 800 mg, 1 times / day
Route: oral
Route: steady
Dose: 800 mg, 1 times / day
Sources:
healthy, 18 - 45 years
n = 10
Health Status: healthy
Age Group: 18 - 45 years
Sex: M
Population Size: 10
Sources:
1200 mg 1 times / day steady, oral
Higher than recommended
Dose: 1200 mg, 1 times / day
Route: oral
Route: steady
Dose: 1200 mg, 1 times / day
Sources:
unhealthy, 57 - 87 years
n = 6
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 57 - 87 years
Sex: M+F
Population Size: 6
Sources:
Other AEs: Gastrointestinal disturbance...
Other AEs:
Gastrointestinal disturbance (3 patients)
Sources:
600 mg 1 times / day steady, oral
Studied dose
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 68 years
n = 28
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 68 years
Sex: M+F
Population Size: 28
Sources:
DLT: Gastrointestinal symptom NOS...
Other AEs: Nausea, Diarrhoea...
Dose limiting toxicities:
Gastrointestinal symptom NOS (75%)
Other AEs:
Nausea (7 patients)
Diarrhoea (7 patients)
Arthralgia (2 patients)
Dyspepsia (5 patients)
Skeletal pain (3 patients)
Vomiting (6 patients)
Sources:
400 mg 1 times / day steady, oral
Recommended
Dose: 400 mg, 1 times / day
Route: oral
Route: steady
Dose: 400 mg, 1 times / day
Sources:
unhealthy, 72 years
n = 29
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 72 years
Sex: M+F
Population Size: 29
Sources:
DLT: Gastrointestinal symptom NOS...
Dose limiting toxicities:
Gastrointestinal symptom NOS (31%)
Sources:
AEs

AEs

AESignificanceDosePopulation
Gastrointestinal disturbance 3 patients
1200 mg 1 times / day steady, oral
Higher than recommended
Dose: 1200 mg, 1 times / day
Route: oral
Route: steady
Dose: 1200 mg, 1 times / day
Sources:
unhealthy, 57 - 87 years
n = 6
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 57 - 87 years
Sex: M+F
Population Size: 6
Sources:
Arthralgia 2 patients
600 mg 1 times / day steady, oral
Studied dose
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 68 years
n = 28
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 68 years
Sex: M+F
Population Size: 28
Sources:
Skeletal pain 3 patients
600 mg 1 times / day steady, oral
Studied dose
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 68 years
n = 28
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 68 years
Sex: M+F
Population Size: 28
Sources:
Dyspepsia 5 patients
600 mg 1 times / day steady, oral
Studied dose
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 68 years
n = 28
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 68 years
Sex: M+F
Population Size: 28
Sources:
Vomiting 6 patients
600 mg 1 times / day steady, oral
Studied dose
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 68 years
n = 28
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 68 years
Sex: M+F
Population Size: 28
Sources:
Diarrhoea 7 patients
600 mg 1 times / day steady, oral
Studied dose
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 68 years
n = 28
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 68 years
Sex: M+F
Population Size: 28
Sources:
Nausea 7 patients
600 mg 1 times / day steady, oral
Studied dose
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 68 years
n = 28
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 68 years
Sex: M+F
Population Size: 28
Sources:
Gastrointestinal symptom NOS 75%
DLT, Disc. AE
600 mg 1 times / day steady, oral
Studied dose
Dose: 600 mg, 1 times / day
Route: oral
Route: steady
Dose: 600 mg, 1 times / day
Sources:
unhealthy, 68 years
n = 28
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 68 years
Sex: M+F
Population Size: 28
Sources:
Gastrointestinal symptom NOS 31%
DLT, Disc. AE
400 mg 1 times / day steady, oral
Recommended
Dose: 400 mg, 1 times / day
Route: oral
Route: steady
Dose: 400 mg, 1 times / day
Sources:
unhealthy, 72 years
n = 29
Health Status: unhealthy
Condition: Paget's disease of bone
Age Group: 72 years
Sex: M+F
Population Size: 29
Sources:
PubMed

PubMed

TitleDatePubMed
Biological and clinical assessment of a new bisphosphonate, (chloro-4 phenyl) thiomethylene bisphosphonate, in the treatment of Paget's disease of bone.
1988
A possible mechanism of the specific action of bisphosphonates on osteoclasts: tiludronate preferentially affects polarized osteoclasts having ruffled borders.
1995 Aug
Human pharmacokinetics of tiludronate.
1995 Nov
Current management strategies for hypercalcemia.
2003
New insights into the molecular mechanisms of action of bisphosphonates.
2003
Bisphosphonate resistance in Paget's disease of bone.
2003 Aug
Bisphosphonates antagonise bone growth factors' effects on human breast cancer cells survival.
2003 Jul 7
Tiludronate as a new therapeutic agent in the treatment of navicular disease: a double-blind placebo-controlled clinical trial.
2003 Jun
Medical treatment of vertebral osteoporosis.
2003 Oct
Management of Paget's disease of bone.
2004 Aug
Effect of bisphosphonate treatment in patients with Paget's disease of the skull.
2004 Jan
Long-term biochemical response after bisphosphonate therapy in Paget's disease of bone. Proposed intervals for monitoring treatment.
2004 Jul
Steroid-free medium discloses oestrogenic effects of the bisphosphonate clodronate on breast cancer cells.
2004 Nov 1
In vitro toxicity of bisphosphonates on human neuroblastoma cell lines.
2004 Sep
The role of bisphosphonates in the management of advanced cancer with a focus on non-small-cell lung cancer. Part 1: Mechanisms of action, role of biomarkers and preclinical applications.
2005
Non-isomerized C-telopeptide fragments are highly sensitive markers for monitoring disease activity and treatment efficacy in Paget's disease of bone.
2005 Apr
[Paget's disease and its therapeutic management].
2005 Apr 23
Prediction of genotoxicity of chemical compounds by statistical learning methods.
2005 Jun
Tiludronate inhibits prostaglandin F2alpha-induced vascular endothelial growth factor synthesis in osteoblasts.
2005 May 31
[Treatment of Paget's disease of bone with zoledronic acid].
2005 Nov-Dec
Comparative effects of antiresorptive agents on bone mineral density and bone turnover in postmenopausal women.
2006
Gateways to clinical trials.
2006 Apr
-511 C/T IL1B gene polymorphism is associated to resistance to bisphosphonates treatment in Paget disease of bone.
2006 Apr
Medical management of Paget's disease of bone: indications for treatment and review of current therapies.
2006 Dec
Biochemical response to bisphosphonate therapy in pagetic patients with skull involvement.
2006 Jul
Effects of bisphosphonates on prostaglandin E2 and thromboxane B2 production in human whole blood and monocytes stimulated by lipopolysaccharide and A23187.
2006 Jul-Aug
Minodronate suppresses prostaglandin F2alpha-induced vascular endothelial growth factor synthesis in osteoblasts.
2006 Mar
Relative binding affinities of bisphosphonates for human bone and relationship to antiresorptive efficacy.
2006 May
Management of age-related osteoporosis and prevention of associated fractures.
2006 Sep
Efficacy of tiludronate in the treatment of horses with signs of pain associated with osteoarthritic lesions of the thoracolumbar vertebral column.
2007 Mar
Treatment with tiludronate has a similar effect to risedronate on Paget's disease activity assessed by bone markers and bone scintigraphy.
2007 Mar-Apr
Use of zoledronic acid in the treatment of Paget's disease.
2007 Oct
Pharmacological effects of tiludronate in horses after long-term immobilization.
2007 Sep
Optimizing dosing frequencies for bisphosphonates in the management of postmenopausal osteoporosis: patient considerations.
2008
Comparative pharmacokinetics of two intravenous administration regimens of tiludronate in healthy adult horses and effects on the bone resorption marker CTX-1.
2008 Apr
Treatment of Paget's disease of bone: a survey of clinical practice in Australia.
2008 Jun
Determination of bisphosphonate active pharmaceutical ingredients in pharmaceuticals and biological material: a review of analytical methods.
2008 Nov 4
Paget disease of bone: therapeutic options.
2008 Oct
Once-yearly zoledronic acid in hip fracture prevention.
2009
Paget's disease 2: exploring diagnosis, management and support strategies.
2009 Feb 24-Mar 2
Bisphosphonates in oncology: evidence for the prevention of skeletal events in patients with bone metastases.
2009 Sep 21
Bisphosphonates: molecular mechanisms of action and effects on bone cells, monocytes and macrophages.
2010
Prolonged unilateral disuse osteopenia 14 years post external fixator removal: a case history and critical review.
2010
Bisphosphonates and risk of atrial fibrillation: a meta-analysis.
2010
Effect of dodecylmaltoside (DDM) on uptake of BCS III compounds, tiludronate and cromolyn, in Caco-2 cells and rat intestine model.
2010 Apr
Tiludronate infusion in the treatment of bone spavin: a double blind placebo-controlled trial.
2010 Jul
Long-term treatment with bisphosphonates and their safety in postmenopausal osteoporosis.
2010 Jul 21
Five-year follow-up of Japanese patients with Paget's disease of the bone after treatment with low-dose oral alendronate: a case series.
2010 May 31
Bisphosphonate protonation states, conformations, and dynamics on bone mineral probed by solid-state NMR without isotope enrichment.
2010 Sep
Arylamino methylene bisphosphonate derivatives as bone seeking matrix metalloproteinase inhibitors.
2013 Nov 1
Patents

Sample Use Guides

A single 400-mg daily oral dose of SKELID (Tiludronic acid), taken with 6 to 8 ounces of plain water only, should be administered for a period of 3 months. Beverages other than plain water (including mineral water), food (see below), and some medications. Patients should not lie down for at least 30 minutes after taking this medication. SKELID should not be taken within 2 hours of food.
Route of Administration: Oral
In Vitro Use Guide
The ability of tiludronate to inhibit proton transport was 5-fold higher in kidney-derived chicken vesicles (IC50 = 1.1 mM) and 10,000-fold higher in vesicles derived from chicken osteoclasts (IC50 = 466 nM). Tiludronate also potently inhibited proton transport in yeast microsomal preparations (IC50 = 3.5 uM) and inhibited the activity of purified yeast V-ATPase.
Name Type Language
TILUDRONIC ACID
INN   MART.   MI   WHO-DD  
INN  
Official Name English
TILUDRONATE [VANDF]
Common Name English
SR-41319
Code English
Tiludronic acid [WHO-DD]
Common Name English
TILUDRONATE
VANDF  
Common Name English
SR 41319
Code English
TILUDRONIC ACID [MART.]
Common Name English
TILUDRONIC ACID [MI]
Common Name English
tiludronic acid [INN]
Common Name English
Classification Tree Code System Code
NCI_THESAURUS C67439
Created by admin on Sat Dec 16 16:16:13 GMT 2023 , Edited by admin on Sat Dec 16 16:16:13 GMT 2023
NDF-RT N0000007707
Created by admin on Sat Dec 16 16:16:13 GMT 2023 , Edited by admin on Sat Dec 16 16:16:13 GMT 2023
WHO-ATC M05BA05
Created by admin on Sat Dec 16 16:16:13 GMT 2023 , Edited by admin on Sat Dec 16 16:16:13 GMT 2023
NDF-RT N0000175579
Created by admin on Sat Dec 16 16:16:13 GMT 2023 , Edited by admin on Sat Dec 16 16:16:13 GMT 2023
LIVERTOX 965
Created by admin on Sat Dec 16 16:16:13 GMT 2023 , Edited by admin on Sat Dec 16 16:16:13 GMT 2023
WHO-VATC QM05BA05
Created by admin on Sat Dec 16 16:16:13 GMT 2023 , Edited by admin on Sat Dec 16 16:16:13 GMT 2023
Code System Code Type Description
SMS_ID
100000077201
Created by admin on Sat Dec 16 16:16:13 GMT 2023 , Edited by admin on Sat Dec 16 16:16:13 GMT 2023
PRIMARY
CAS
89987-06-4
Created by admin on Sat Dec 16 16:16:13 GMT 2023 , Edited by admin on Sat Dec 16 16:16:13 GMT 2023
PRIMARY
EVMPD
SUB11060MIG
Created by admin on Sat Dec 16 16:16:13 GMT 2023 , Edited by admin on Sat Dec 16 16:16:13 GMT 2023
PRIMARY
IUPHAR
7604
Created by admin on Sat Dec 16 16:16:13 GMT 2023 , Edited by admin on Sat Dec 16 16:16:13 GMT 2023
PRIMARY
WIKIPEDIA
TILUDRONIC ACID
Created by admin on Sat Dec 16 16:16:13 GMT 2023 , Edited by admin on Sat Dec 16 16:16:13 GMT 2023
PRIMARY
EPA CompTox
DTXSID10237966
Created by admin on Sat Dec 16 16:16:13 GMT 2023 , Edited by admin on Sat Dec 16 16:16:13 GMT 2023
PRIMARY
ChEMBL
CHEMBL1350
Created by admin on Sat Dec 16 16:16:13 GMT 2023 , Edited by admin on Sat Dec 16 16:16:13 GMT 2023
PRIMARY
RXCUI
11476
Created by admin on Sat Dec 16 16:16:13 GMT 2023 , Edited by admin on Sat Dec 16 16:16:13 GMT 2023
PRIMARY
DRUG BANK
DB01133
Created by admin on Sat Dec 16 16:16:13 GMT 2023 , Edited by admin on Sat Dec 16 16:16:13 GMT 2023
PRIMARY
FDA UNII
6PNS59HP4Y
Created by admin on Sat Dec 16 16:16:13 GMT 2023 , Edited by admin on Sat Dec 16 16:16:13 GMT 2023
PRIMARY
MERCK INDEX
m10868
Created by admin on Sat Dec 16 16:16:13 GMT 2023 , Edited by admin on Sat Dec 16 16:16:13 GMT 2023
PRIMARY Merck Index
RXCUI
57230
Created by admin on Sat Dec 16 16:16:13 GMT 2023 , Edited by admin on Sat Dec 16 16:16:13 GMT 2023
ALTERNATIVE
MESH
C058651
Created by admin on Sat Dec 16 16:16:13 GMT 2023 , Edited by admin on Sat Dec 16 16:16:13 GMT 2023
PRIMARY
NCI_THESAURUS
C72091
Created by admin on Sat Dec 16 16:16:13 GMT 2023 , Edited by admin on Sat Dec 16 16:16:13 GMT 2023
PRIMARY
DRUG CENTRAL
2666
Created by admin on Sat Dec 16 16:16:13 GMT 2023 , Edited by admin on Sat Dec 16 16:16:13 GMT 2023
PRIMARY
PUBCHEM
60937
Created by admin on Sat Dec 16 16:16:13 GMT 2023 , Edited by admin on Sat Dec 16 16:16:13 GMT 2023
PRIMARY
INN
6325
Created by admin on Sat Dec 16 16:16:13 GMT 2023 , Edited by admin on Sat Dec 16 16:16:13 GMT 2023
PRIMARY
LACTMED
Tiludronate
Created by admin on Sat Dec 16 16:16:13 GMT 2023 , Edited by admin on Sat Dec 16 16:16:13 GMT 2023
PRIMARY