Effects of low and high dose intraarticular tiludronate on synovial fluid and clinical variables in healthy horses-a preliminary investigation.
Abstract: To determine effects of intraarticularly administered tiludronate on articular cartilage in vivo, eight healthy horses were injected once with tiludronate (low dose tiludronate [LDT] 0.017 mg, n = 4; high dose tiludronate [HDT] 50 mg, n = 4) into one middle carpal joint and with saline into the contralateral joint. Arthrocentesis of both middle carpal joints was performed pre-treatment, and 10 min, 24 h, 48 h, 7 and 14 days after treatment. Synovial nucleated cell counts and total solids, tiludronate, sulfated glycosaminoglycan (sGAG), chondroitin sulfate 846 epitope (CS-846, a measure of aggrecan synthesis), and collagen type II cleavage neoepitope (C2C) concentrations were determined. Histologic analysis of joint tissues and sGAG quantitation in cartilage was performed at 14 days in HDT horses. Data were analyzed by repeated measures non-parametric ANOVA and Wilcoxon signed-rank test. High dose tiludronate administration produced synovial fluid tiludronate concentrations of 2,677,500 ng/mL, exceeding concentrations that were safe for cartilage in vitro, and LDT administration produced synovial fluid concentrations of 1,353 ng/mL, remaining below concentrations considered potentially detrimental to cartilage. With HDT, synovial fluid total solids concentration was higher at 24 h and 7 days and sGAG concentration was higher at 48 h, compared to control joints. Synovial fluid CS-846 concentration was increased over pre-treatment values in HDT control but not in HDT treated joints at 24 and 48 h. All joints (HDT and LDT control and treated) showed a temporary decrease in synovial fluid C2C concentration, compared to pre-treatment values. Histologic features of articular cartilage and synovial membrane did not differ between HDT treated and control joints. High dose tiludronate treatment caused a transient increase in synovial total solids and temporarily increased proteoglycan degradation in cartilage. Although clinical significance of these changes are questionable, as they did not result in articular cartilage damage, further investigation of the safety of intraarticular HDT in a larger number of horses is warranted.
Publication Date: 2014-09-04 PubMed ID: 25237596PubMed Central: PMC4157236DOI: 10.7717/peerj.534Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
Summary
This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.
The research investigated the impact of different doses of intraarticularly administered tiludronate on the cartilage of healthy horses. It found that a high dose led to temporary increases in the synovial total solids and the degradation of proteoglycan in the cartilage with no damage to the cartilage.
Research Method
- The study was done on eight healthy horses.
- They were injected once with either a low dose (0.017mg, n = 4) or high dose (50mg, n = 4) of tiludronate into one middle carpal joint. The contralateral joint was injected with saline.
- Arthrocentesis of the joints was performed before treatment, and again 10 minutes, 24 hours, 48 hours, 7 days, and 14 days after treatment.
- Researchers measured synovial nucleated cell counts, total solids, tiludronate, sulfated glycosaminoglycan (sGAG), chondroitin sulfate 846 epitope (CS-846, indicates aggrecan synthesis), and collagen type II cleavage neoepitope (C2C) concentrations.
- Histologic analysis of joint tissues and sGAG quantities in cartilage were also carried out 14 days post-treatment in the high dose tiludronate (HDT) horses.
Findings
- High dose tiludronate administration led to significantly higher synovial fluid tiludronate concentrations than were safe for cartilage in vitro.
- Low dose tiludronate horses had lower synovial fluid concentrations that were below levels potentially damaging to cartilage.
- With HDT, there was a higher concentration of synovial fluid total solids at 24 hours and 7 days, and a higher concentration of sGAG 48 hours post-treatment compared to control joints.
- Synovial fluid CS-846 concentration increased in control but not treated joints with HDT at 24 and 48 hours post-treatment.
- All the joints displayed a temporary reduction in synovial fluid C2C concentration compared to pre-treatment levels.
- HDT-treated and control joints exhibited similar histologic features of articular cartilage and synovial membrane.
Conclusion
- The research concluded that high dose tiludronate treatment led to a short-term increase in synovial total solids and temporarily escalated the degradation of proteoglycan in the cartilage.
- Despite this, it did not result in damage to the articular cartilage, meaning its clinical significance might be questionable.
- The study recommends further investigations into the safety of high dose intraarticular tiludronate in a larger number of horses.
Cite This Article
APA
Duesterdieck-Zellmer KF, Moneta L, Ott JF, Larson MK, Gorman EM, Hunter B, Löhr CV, Payton ME, Morré JT, Maier CS.
(2014).
Effects of low and high dose intraarticular tiludronate on synovial fluid and clinical variables in healthy horses-a preliminary investigation.
PeerJ, 2, e534.
https://doi.org/10.7717/peerj.534 Publication
Researcher Affiliations
- Department of Clinical Sciences, College of Veterinary Medicine, Oregon State University , Corvallis, OR , USA.
- College of Veterinary Medicine, Oregon State University , Corvallis, OR , USA.
- Department of Clinical Sciences, College of Veterinary Medicine, Oregon State University , Corvallis, OR , USA.
- Department of Clinical Sciences, College of Veterinary Medicine, Oregon State University , Corvallis, OR , USA.
- Department of Biomedical Sciences, College of Veterinary Medicine, Oregon State University , Corvallis, OR , USA.
- Department of Clinical Sciences, College of Veterinary Medicine, Oregon State University , Corvallis, OR , USA.
- Department of Biomedical Sciences, College of Veterinary Medicine, Oregon State University , Corvallis, OR , USA.
- Department of Statistics, Oklahoma State University , Stillwater, OK , USA.
- Department of Chemistry, Oregon State University , Corvallis, OR , USA.
- Department of Chemistry, Oregon State University , Corvallis, OR , USA.
Grant Funding
- P30 ES000210 / NIEHS NIH HHS
References
This article includes 32 references
- Catterall JB, Stabler TV, Flannery CR, Kraus VB. Changes in serum and synovial fluid biomarkers after acute injury (NCT00332254).. Arthritis Res Ther 2010;12(6):R229.
- Coudry V, Thibaud D, Riccio B, Audigié F, Didierlaurent D, Denoix JM. Efficacy of tiludronate in the treatment of horses with signs of pain associated with osteoarthritic lesions of the thoracolumbar vertebral column.. Am J Vet Res 2007 Mar;68(3):329-37.
- Davidson EJ, Orsini JA. Arthrocentesis and synovial fluid analysis. In: Orsini JA, Divers TJ, editors. Equine emergencies: treatment and procedures. 3rd edition. St. Louis, MO: Saunders Elsevier; 2007. pp. 272–273.
- de Grauw JC, van de Lest CH, van Weeren PR. Inflammatory mediators and cartilage biomarkers in synovial fluid after a single inflammatory insult: a longitudinal experimental study.. Arthritis Res Ther 2009;11(2):R35.
- Denoix JM, Thibaud D, Riccio B. Tiludronate as a new therapeutic agent in the treatment of navicular disease: a double-blind placebo-controlled clinical trial.. Equine Vet J 2003 Jun;35(4):407-13.
- Duesterdieck-Zellmer KF, Driscoll N, Ott JF. Concentration-dependent effects of tiludronate on equine articular cartilage explants incubated with and without interleukin-1β.. Am J Vet Res 2012 Oct;73(10):1530-9.
- Dulin JA, Drost WT, Phelps MA, Santschi EM, Menendez MI, Bertone AL. Influence of exercise on the distribution of technetium Tc 99m medronate following intra-articular injection in horses.. Am J Vet Res 2012 Mar;73(3):418-25.
- Ekman L, Nilsson G, Persson L, Lumsden JH. Volume of the synovia in certain joint cavities in the horse.. Acta Vet Scand 1981;22(1):23-31.
- EMEA. Tiludronic acid, disodium salt: summary report—committee for veterinary medicinal products. 2001. Reference Number: EMEA/MRL/774/01-FINAL.
- Emonds-Alt X, Brelière JC, Roncucci R. Effects of 1-hydroxyethylidene-1,1 bisphosphonate and (chloro-4 phenyl) thiomethylene bisphosphonic acid (SR 41319) on the mononuclear cell factor-mediated release of neutral proteinases by articular chondrocytes and synovial cells.. Biochem Pharmacol 1985 Nov 15;34(22):4043-9.
- Francoz D, Desrochers A, Latouche JS. Effect of repeated arthrocentesis and single joint lavage on cytologic evaluation of synovial fluid in 5 young calves.. Can J Vet Res 2007 Apr;71(2):129-34.
- Gough MR, Thibaud D, Smith RK. Tiludronate infusion in the treatment of bone spavin: a double blind placebo-controlled trial.. Equine Vet J 2010 Jul;42(5):381-7.
- Jacobsen S, Thomsen MH, Nanni S. Concentrations of serum amyloid A in serum and synovial fluid from healthy horses and horses with joint disease.. Am J Vet Res 2006 Oct;67(10):1738-42.
- Jubb RW, Fell HB. The breakdown of collagen by chondrocytes.. J Pathol 1980 Mar;130(3):159-67.
- Lamprecht ED, Williams CA. Biomarkers of antioxidant status, inflammation, and cartilage metabolism are affected by acute intense exercise but not superoxide dismutase supplementation in horses.. Oxid Med Cell Longev 2012;2012:920932.
- Liljebrink Y, Bergh A. Goniometry: is it a reliable tool to monitor passive joint range of motion in horses?. Equine Vet J Suppl 2010 Nov;(38):676-82.
- Lucia JL, Coverdale JA, Arnold CE, Winsco KN. Influence of an intra-articular lipopolysaccharide challenge on markers of inflammation and cartilage metabolism in young horses.. J Anim Sci 2013 Jun;91(6):2693-9.
- Mahaffey EA. Synovial fluid. In: Cowell RL, Tyler RD, editors. Diagnostic cytology and hematology of the horse. 2nd edition. St. Louis, MO: Mosby; 2002. pp. 163–170.
- McIlwraith CW. Use of synovial fluid and serum biomarkers in equine bone and joint disease: a review.. Equine Vet J 2005 Sep;37(5):473-82.
- McIlwraith CW, Frisbie DD, Kawcak CE, Fuller CJ, Hurtig M, Cruz A. The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the horse.. Osteoarthritis Cartilage 2010 Oct;18 Suppl 3:S93-105.
- Nieves JW, Cosman F. Atypical subtrochanteric and femoral shaft fractures and possible association with bisphosphonates.. Curr Osteoporos Rep 2010 Mar;8(1):34-9.
- Oke SL, Hurtig MB, Keates RA, Wright JR, Lumsden JH. Assessment of three variations of the 1,9-dimethylmethylene blue assay for measurement of sulfated glycosaminoglycan concentrations in equine synovial fluid.. Am J Vet Res 2003 Jul;64(7):900-6.
- Poole AR, Ionescu M, Swan A, Dieppe PA. Changes in cartilage metabolism in arthritis are reflected by altered serum and synovial fluid levels of the cartilage proteoglycan aggrecan. Implications for pathogenesis.. J Clin Invest 1994 Jul;94(1):25-33.
- Rizkalla G, Reiner A, Bogoch E, Poole AR. Studies of the articular cartilage proteoglycan aggrecan in health and osteoarthritis. Evidence for molecular heterogeneity and extensive molecular changes in disease.. J Clin Invest 1992 Dec;90(6):2268-77.
- Rogers MJ, Crockett JC, Coxon FP, Mönkkönen J. Biochemical and molecular mechanisms of action of bisphosphonates.. Bone 2011 Jul;49(1):34-41.
- Ross MW. Manipulation. In: Ross MW, Dyson SJ, editors. Diagnosis and management of lameness in the horse. 2nd edition. St. Louis, MO: Elsevier Saunders; 2011. pp. 80–88.
- Tarcomnicu I, Gheorghe MC, Silvestro L, Savu SR, Boaru I, Tudoroniu A. High-throughput HPLC-MS/MS method to determine ibandronate in human plasma for pharmacokinetic applications.. J Chromatogr B Analyt Technol Biomed Life Sci 2009 Oct 1;877(27):3159-68.
- Vachon AM, Keeley FW, McIlwraith CW, Chapman P. Biochemical analysis of normal articular cartilage in horses.. Am J Vet Res 1990 Dec;51(12):1905-11.
- van den Boom R, van de Lest CH, Bull S, Brama RA, van Weeren PR, Barneveld A. Influence of repeated arthrocentesis and exercise on synovial fluid concentrations of nitric oxide, prostaglandin E2 and glycosaminoglycans in healthy equine joints.. Equine Vet J 2005 May;37(3):250-6.
- Wagner AE, McIlwraith CW, Martin GS. Effect of intra-articular injection of orgotein and saline solution on equine synovia.. Am J Vet Res 1982 Apr;43(4):594-7.
- White KK, Hodgson DR, Hancock D, Parry BW, Cordell C. Changes in equine carpal joint synovial fluid in response to the injection of two local anesthetic agents.. Cornell Vet 1989 Jan;79(1):25-38.
- Zhu LS, Lapko VN, Lee JW, Basir YJ, Kafonek C, Olsen R, Briscoe C. A general approach for the quantitative analysis of bisphosphonates in human serum and urine by high-performance liquid chromatography/tandem mass spectrometry.. Rapid Commun Mass Spectrom 2006;20(22):3421-6.
Citations
This article has been cited 1 times.- Hunter BG, Duesterdieck-Zellmer KF, Larson MK. Tiludronate concentrations and cytologic findings in synovial fluid after intravenous regional limb perfusion with tiludronate in horses. PeerJ 2015;3:e889.
Use Nutrition Calculator
Check if your horse's diet meets their nutrition requirements with our easy-to-use tool Check your horse's diet with our easy-to-use tool
Talk to a Nutritionist
Discuss your horse's feeding plan with our experts over a free phone consultation Discuss your horse's diet over a phone consultation
Submit Diet Evaluation
Get a customized feeding plan for your horse formulated by our equine nutritionists Get a custom feeding plan formulated by our nutritionists
