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Tiludronic acid (INN; also known as tiludronate) is a bisphosphonate used for treatment of Paget's disease of bone (osteitis deformans) in human medicine. It has the tradename Skelid. In veterinary medicine, tiludronic acid is used to treat navicular disease and bone spavin in horses. Its tradenames are Tildren and Equidronate. It is approved for treatment of navicular disease and distal tarsal osteoarthritis in Europe,^[1] and was approved for treatment of navicular disease in the United States in 2014.

Mechanism of action

Tiludronate is a non-nitrogenous bisphosphonate that inhibits osteoclasts, the primary cell responsible for the breakdown of bone required for bone remodeling. Non-nitrogenous bisphosphonates are metabolized by osteoclasts to compounds that then replace a portion of the adenosine triphosphate (ATP) molecule, making it non-functional. These non-functional molecules then competitively inhibit ATP in the cell, reducing cell energy and leading to apoptosis.^[2] Decreased levels of osteoclasts subsequently reduce the degree of breakdown of bone and bone turnover. Non-nitrogenous bisphosphonates are less potent relative to nitrogenous bisphosphonates.

Use in equine medicine

Tiludronate has been used primarily for the treatment of diseases in horses that are associated with inappropriate osteolysis, such as navicular disease^[3] and osteoarthritis. It has specifically been shown to improve lameness in horses with osteoarthritis of the distal hock joints (bone spavin)^[4] and vertebral column.^[5]

Method of administration

Tildren is administered intravenously. It is labeled for 0.1mg/kg dosing, once daily for 10 days by slow intravenous injection, which for a 500kg horse works out to be 1 vial per day. However, one study giving all 10 doses at once (1 mg/kg IV as a single CRI) was found to have the same pharmacological effects, and is used clinically.^[6] It may be given systemically or locally, by regional limb perfusion. Although RLP is thought to have certain benefits, including decreased cost and reduced risk of adverse effects, some diseases must be treated systemically, such as osteoarthritis of the vertebral column. Systemic administration is often given by adding a 1 mg/kg dose into a 1 liter fluid bag, which is slowly given over 60-90 minutes. Its effects are reported to last 4 months or longer, with a peak effect 6-8 weeks post treatment.^[7] The effects of regional limb perfusion has come into question due to in vitro studies showing that high doses given by RLP or intraarticular injection may damage articular cartilage by chondrocyte apoptosis.^[8] Further studies are needed to evaluate the safety of Tildren administration via RLP.

Adverse reactions and contraindications

Tildren has been shown to have several adverse effects.^[9]

Signs of colic, which is usually self-limiting, occurs in 30-45% of horses.
Tachycardia
Electrolyte disturbances: primarily calcium, magnesium, and potassium, which can last for several hours. Caution should be used in horses with disease processes that could be affected by electrolyte disturbances, such as hyperkalemic periodic paralysis or cardiac disease.
Kidney damage: it is eliminated by the kidney and is not recommended for use in animals with impaired renal function.
Less serious reactions include stiffness of the neck, decreased appetite, fever, and increased urination.

It is not recommended for animals under four years of age, due to lack of studies evaluating its safety in growing animals, nor for pregnant or lactating animals, since its effect on the fetus has not been studied.

References

^ Kamm L, McIlwraith W, Kawcak C. A review of the Efficacy of Tiludronate in the Horse. Journal or Equine Veterinary Science. Vol 28(4): 209-214.
^ Rogers MJ, Crockett JC, Coxon FP, Monkkonen J. 2011. Biochemical and molecular mechanisms of action of bisphosphonates. Bone 49:34-41
^ DENOIX, J.M., THIBAUD, D. and RICCIO, B. (2003), Tiludronate as a new therapeutic agent in the treatment of navicular disease: a double-blind placebo-controlled clinical trial. Equine Veterinary Journal, 35: 407–413. doi: 10.2746/042516403776014226
^ GOUGH, M. R., THIBAUD, D. and SMITH, R. K. W. (2010), Tiludronate infusion in the treatment of bone spavin: A double blind placebo-controlled trial. Equine Veterinary Journal, 42: 381–387. doi: 10.1111/j.2042-3306.2010.00120
^ V. Coudry, D. Thibaud; B. Riccio; F. Audigié; D. Didierlaurent; M Denoix. Efficacy of tiludronate in the treatment of horses with signs of pain associated with osteoarthritic lesions of the thoracolumbar vertebral column. American Journal of Veterinary Research. Vol. 68, No. 3, Pages 329-337 March 2007
^ DELGUSTE, C., AMORY, H., GUYONNET, J., THIBAUD, D., GARNERO, P., DETILLEUX, J., LEPAGE, O. M. and DOUCET, M. (2008), Comparative pharmacokinetics of two intravenous administration regimens of tiludronate in healthy adult horses and effects on the bone resorption marker CTX-1. Journal of Veterinary Pharmacology and Therapeutics, 31: 108–116. doi: 10.1111/j.1365-2885.2007.00936
^ Allen KA, Johns S, Hyman SS, Sislak MD, Davis S, Amory J. How to Diagnose and Treat Back Pain in the Horse. Proc. AAEP. Vol 56: 384-388
^ Duesterdieck-Zellmer KF, Driscoll N, Ott JF. Concentration-dependent effects of tiludronate on equine articular cartilage explants incubated with and without interleukin-1β. American Journal of Veterinary Research. Oct 2012, Vol. 73, No. 10, Pages 1530-1539. doi: 10.2460/ajvr.73.10.1530
^ U.S. Food and Drug Administration. "FDA Provides Equine Veterinarians with Important Information about TILDREN and OSPHOS for Navicular Syndrome in Horses". http://www.fda.gov/AnimalVeterinary/ResourcesforYou/ucm406581.htm. Missing or empty |url= (help); |accessdate= requires |url= (help)

External links

Prescribing information for Skelid
RxList page
tildren.com

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UpToDate Contents

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1. 骨パジェット病の治療 treatment of paget disease of bone
2. 閉経後女性における骨粗鬆症に対するビスホスホネート投与 the use of bisphosphonates in postmenopausal women with osteoporosis
3. ビスホスホネートの薬理学 pharmacology of bisphosphonates
4. 転移性癌患者におけるビスホスホネートおよびデノスマブ bisphosphonates and denosumab in patients with metastatic cancer
5. 多発性骨髄腫患者のビスフォスフォネート製剤の使用 the use of bisphosphonates in patients with multiple myeloma

English Journal

Effects of locally administered tiludronic acid on experimental periodontitis in rats.

Furlaneto FA1, Nunes NL, Oliveira Filho IL, Frota NP, Yamamoto KO, Lisboa MR, Ervolino E, Taba M Jr, Rêgo RO, Messora MR.
Journal of periodontology.J Periodontol.2014 Sep;85(9):1291-301. doi: 10.1902/jop.2014.130581. Epub 2014 Feb 6.
BACKGROUND: It appears there are no studies evaluating the influence of the bisphosphonate tiludronic acid (TIL) on periodontitis. The purpose of this study is to evaluate via microtomographic, histopathologic, histometric, and immunohistochemical analyses the effects of local administration of TIL
PMID 24502611

HPLC/ESI-MS(n) method for non-amino bisphosphonates: application to the detection of tiludronate in equine plasma.

Popot MA1, Garcia P2, Hubert C2, Bolopion A2, Bailly-Chouriberry L2, Bonnaire Y2, Thibaud D3, Guyonnet J3.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.J Chromatogr B Analyt Technol Biomed Life Sci.2014 May 1;958:108-16. doi: 10.1016/j.jchromb.2014.03.018. Epub 2014 Mar 26.
Tiludronate is a non-nitrogen-containing biphosphonate drug approved in equine veterinary medicine for the treatment of navicular disease and bone sparvin in horse. Its hydrophilic properties and its strong affinity for the bone have made the control of its use quite difficult. After an initial step
PMID 24732148

Interaction between a bisphosphonate, tiludronate, and biomimetic nanocrystalline apatites.

Pascaud P1, Gras P, Coppel Y, Rey C, Sarda S.
Langmuir : the ACS journal of surfaces and colloids.Langmuir.2013 Feb 19;29(7):2224-32. doi: 10.1021/la3046548. Epub 2013 Feb 4.
Bisphosphonates (BPs) are well established as successful antiresorptive agents for the prevention and treatment of bone diseases such as osteoporosis and Paget's disease. The aim of this work was to clarify the reaction mechanisms between a BP molecule, tiludronate, and the nanocrystalline apatite s
PMID 23317459

「チルドロン酸」

Tiludronic acid
Systematic (IUPAC) name
	{[(4-Chlorophenyl)thio]methylene}bis(phosphonic acid)
Clinical data
Trade names	Skelid
AHFS/Drugs.com	International Drug Names
Identifiers
CAS Registry Number	89987-06-4
ATC code	M05BA05
PubChem	CID: 60937
DrugBank	DB01133
ChemSpider	54905
UNII	6PNS59HP4Y
KEGG	D08599
ChEMBL	CHEMBL1350
Chemical data
Formula	C7H9ClO6P2S
Molecular mass	318.609 g/mol
	SMILES c1cc(ccc1SC(P(=O)(O)O)P(=O)(O)O)Cl;
	InChI 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) ; Key:DKJJVAGXPKPDRL-UHFFFAOYSA-N ;
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