Concentration-dependent effects of tiludronate on equine articular cartilage explants incubated with and without interleukin-1β

Abstract

Tiludronate had biphasic concentration-dependent effects on cartilage explants that were independent of PGE(2) secretion or MMP gene expression. Low tiludronate concentrations had some chondroprotective effects, whereas high tiludronate concentrations were detrimental to equine articular cartilage. Administration of tiludronate intra-articularly to horses may be detrimental, dependent on the dose used. In vivo studies are needed before intra-articular tiludronate administration to horses can be recommended.

Effects of low and high dose intraarticular tiludronate on synovial fluid and clinical variables in healthy horses—a preliminary investigation

“…The target tissue for tiludronate has traditionally been bone (EMEA, 2001), but tiludronate also exerts direct effects on cartilage and chondrocytes (Duesterdieck-Zellmer, Driscoll & Ott, 2012; Emonds-Alt, Breliere & Roncucci, 1985), especially after extra-label local administration via regional limb perfusion or intraarticular injection, since these routes of administration potentially result in high synovial fluid concentrations. In-vitro data suggests that synovial fluid tiludronate concentrations of 19,000 ng/mL and above promote chondrocyte apoptosis and release of sGAGs from articular cartilage matrix, whereas concentrations of 1,900 ng/mL and below may ameliorate sGAG release and chondrocyte apoptosis in equine joints (Duesterdieck-Zellmer, Driscoll & Ott, 2012).…”

“…In-vitro data suggests that synovial fluid tiludronate concentrations of 19,000 ng/mL and above promote chondrocyte apoptosis and release of sGAGs from articular cartilage matrix, whereas concentrations of 1,900 ng/mL and below may ameliorate sGAG release and chondrocyte apoptosis in equine joints (Duesterdieck-Zellmer, Driscoll & Ott, 2012). Subsequently, the dose for the LDT group was chosen to produce synovial fluid tiludronate concentrations approximating 1,900 ng/mL.…”

“…Chondrocyte apoptosis was assessed on cartilage sections using the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) method ( in situ Cell Death Detection Kit, AP, Roche) as described previously (Duesterdieck-Zellmer, Driscoll & Ott, 2012). …”

“…However, no information is available concerning safety, efficacy, or appropriate doses of these routes of administration. Based on in-vitro results (Duesterdieck-Zellmer, Driscoll & Ott, 2012), the extra-label use of tiludronate via intraarticular injection or regional limb perfusion, especially in high doses, may result in deleterious effects for articular cartilage. While it is common belief among veterinarians who have been using this drug in an extra-label fashion, that no untoward effects exist, this view is scientifically unfounded.…”

“…Concentration-dependent effects of tiludronate on articular cartilage in-vitro (Duesterdieck-Zellmer, Driscoll & Ott, 2012) raise concerns about the safety of higher doses administered intraarticularly. More specifically, tiludronate concentrations of ≥19,000 ng/mL increased chondrocyte apoptosis and release of glycosaminoglycans from equine articular cartilage explants, suggesting that doses resulting in synovial fluid concentrations of ≥19,000 ng/mL may promote articular cartilage damage (Duesterdieck-Zellmer, Driscoll & Ott, 2012). Anecdotally, the intraarticular dose of tiludronate is 50 mg per joint, which is likely to result in synovial fluid concentrations above 19,000 ng/mL when injected into the middle carpal joint, based on an estimated synovial fluid volume of 15 mL for this joint (Ekman et al, 1981).…”