Effects of clodronate disodium on markers of inflammation and cartilage metabolism in juvenile horses challenged with intra-articular lipopolysaccharide.

Abstract

Perceived chondroprotective and anti-inflammatory benefits of bisphosphonates in the juvenile horse has led to extra-label use without supportive data regarding intra-articular effects on cartilage metabolism and inflammation. Thirty-two yearling Quarter Horses were stratified into 4 treatment groups by age (500 ± 13 d), BW (336 ± 26 kg), sex (n = 16 female; n = 16 male) and initial bone optical density for a 140-d study. The study consisted of two exercise phases: Phase 1 (d 0-84) emulated sales preparation and Phase 2 (d 99-140) mimicked early exercise training. Horses were housed individually (3.6 m × 7.3 m stalls) and fed to meet nutritional requirements. All horses received iso-volumetric intramuscular injections of 1.8 mg/kg BW clodronate disodium (CD) (OSPHOS) or saline (vehicle) on d 0, 42, 84, and 126. Specifically, the treatment groups consisted of the saline control (0×; n = 8), and clodronate injected once (1×; n = 8; d 84), twice (2×; n = 8; d 0, 84), or four times (4×; n = 8; d 0, 42, 84, 126). Horses underwent an intra-articular lipopolysaccharide (LPS) challenge post treatment administration on d 126. Synovial fluid was collected prior to LPS injection (h 0) and at 6, 12, 24, and 336 h post injection. Synovial fluid concentrations of carboxypropeptide of type II collagen (CPII), collagenase cleavage neopeptide (C2C), and prostaglandin E2 (PGE2) were determined by ELISA. Intra-articular LPS increased CPII, C2C, PGE2 and CPII: C2C (P ≤ 0.01). There tended to be a treatment × time interaction in CPII (P = 0.06) where CPII was greatest in 2× with 1× and 0× being the lowest, 4× concentrations were between this range at 24 h post-injection. Likewise, CPII: C2C tended to be influenced by treatment (P = 0.06) with 2× and 4× having greater synthesis: degradation ratio than 1× and 0×. There was a treatment × time × carpus interaction (P = 0.02) in which 1×, 2× and 4× CD groups had greater synovial PGE2 concentrations at 6 h post-injection in the LPS joint compared to 0×. The results of this study indicate that administration of CD increases intra-articular inflammation (PGE2) but does not affect cartilage degradation (C2C) and only tends to increase cartilage synthesis (CPII) according to biomarkers measured.