Clodronate disodium for treatment of clinical signs of navicular disease – a double-blinded placebo-controlled clinical trial

Abstract

Summary: Navicular disease (also referred to as palmar foot syndrome or navicular syndrome, although not completely the same) causes lameness in many horses of all activity groups.The objective of this study was to compare clodronate efficacy at improving lameness grade in horses with clinical signs of navicular disease to that of horses given placebo. A randomized, multi-center, double-blinded clinical field study was conducted on 146 horses with forelimb lameness due to navicular disease. Navicular disease was confirmed by lameness examination (with diagnostic nerve blocks) and radiography of the affected distal forelimb(s). At study initiation, treated horses received 1.4 mg/kg clodronate disodium IM, and control (placebo) horses received a corresponding IM volume of 0.9 % saline. Primary effectiveness was evaluated at Day 56 using a lameness grading scale, with positive response defined as improvement by at least 1 grade in the limb with the most apparent lameness, with no worsening of the lameness grade (compared to baseline) in the contralateral forelimb. Positive response rates at Days 28 and 180 were also recorded. On Day 56, 75 % of horses in the clodronate group were considered showing a positive response, versus only 3 % in the placebo group (p = 0.003). Of the 86 horses treated with clodronate, 8 horses had an improvement of 3 lameness grades, 45 horses improved by 2 lameness grades and 16 horses improved by one lameness grade. The clodronate positive response rate remained high through Day 180 (65 %). Adverse events (primarily abdominal pain) were generally few, mild, and transient. In this study, clodronate disodium was demonstrated to be safe and effective in reducing the clinical signs of lameness associated with navicular syndrome.

Clodronate disodium does not produce measurable effects on bone metabolism in an exercising, juvenile, large animal model

“…Our results suggested that CLO did not produce any measurable effects on bone metabolism in juvenile sheep subjected to exercise. Our findings are similar to previous reports that showed bisphosphonates administered to large animals (i.e., horses) were clinically effective in reducing musculoskeletal pain [ 20 , 47 , 76 , 77 ], without causing changes in SBB, BMD, micro-CT measurements, and/or BT [ 19 , 20 , 46 , 47 , 76 , 77 ] using FDA-approved doses [ 46 , 78 ]. This may be due to the lower dose used in large animals compared to humans.…”

“…We used a dose in sheep that resembled the pharmacokinetic values of therapeutic CLO administered in horses [48]. The dose used in horses (1.8 mg/kg) has shown clinical efficacy in reducing musculoskeletal pain in multiple studies [20,46,47,77]. However, humans treated for osteoporosis receive 200 mg i. m. every 2 weeks (approximately 2.7 mg/kg based on a 75 kg person) which results in detectable BMD increases [79].…”

“…Given the existing knowledge gap regarding the skeletal effects of bisphosphonates on juvenile populations engaged in exercise, this study aimed to investigate the effects of clodronate disodium (CLO) administration on bone formation and remodeling using juvenile sheep subjected to forced exercise. CLO was selected as it is an FDA-approved bisphosphonate for use in a large animal species [ 46 ], has shown clinical efficacy for musculoskeletal disease [ 46 , 47 ], and the pharmacokinetics have been described in sheep [ 48 ]. Outcome measures included physical examinations, lameness evaluations, SBB, advanced imaging methods, biomechanical testing (BT), and sulfated glycosaminoglycan content (GAG) in cartilage.…”