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.

Tiludronate concentrations and cytologic findings in synovial fluid after intravenous regional limb perfusion with tiludronate in horses

“…However, these findings have not yet been confirmed in vivo. Synovial fluid tiludronate concentrations >2,000,000 ng/ml after intraarticular administration of 50 mg tiludronate into equine middle carpal joints were not associated with worse cartilage histology scores or decreased proteoglycan content at two weeks after treatment when compared to saline treated joints in four horses ( Duesterdieck-Zellmer et al, 2014 ). Nevertheless, tiludronate treated joints showed temporarily increased proteoglycan degradation and amelioration of increases in aggrecan synthesis compared to control joints, as determined by synovial fluid biomarkers.…”

“…Tiludronate analysis was performed as previously described ( Duesterdieck-Zellmer et al, 2014 ) using high performance liquid chromatography (XBridge phenyl column, Waters, Milford, Massachusetts, USA) followed by mass spectrometry (API 4000; Applied Biosystems, Grand Island, New York, USA) . Briefly, tiludronate in all samples was methylated with 0.2 M trimethylsilyldiazomethane in acetone.…”

Tiludronate infusion in horses previously submitted to bone scintigraphy

“…Nowadays, intravenous administration of tiludronic acid is frequently used for the treatment of navicular disease or distal tarsal joint osteoarthritis and it has been demonstrated to be a successful therapy for these diseases in some horses. On the other hand, studies have shown that tiludronate also exerts some direct effects on cartilage and chondrocytes (Duesterdieck-Zellmer et al 2012, Duesterdieck-Zellmer et al 2014. Detrimental effects on cartilage and chondrocytes have been observed as the result of high synovial fluid tiludronate concentration (Duesterdieck-Zellmer et al 2012, Duesterdieck-Zellmer et al 2014) hence extra-label administration of tiludronate such as via regional limb perfusion or intraarticular injection may be harmful dependent on the dose used.…”

Science‐in‐brief: Bisphosphonate use in the racehorse: Safe or unsafe?

“…There are many mechanisms of therapeutic action in OA [29,30]: bisphosphonates may stabilise the subchondral bone or even protect chondrocytes from undergoing apoptosis. and the drug will enter the systemic circulation from this route [32]. In both man and horses, it is generally accepted that bisphosphonates can result in amelioration of clinical signs dues to OA [3,7,31].…”

“…Tiludronate is also known to induce synovial inflammation when administered i.a. and the drug will enter the systemic circulation from this route [32]. Systemic or low dose i.v.…”