Navicular syndrome in horses: do tiludronate or clodronate vs placebo improve lameness scores? — POSSIBLE

In horses with navicular syndrome, do tiludronate or clodronate vs placebo improve lameness scores?

Shelf #803 · gate-verified and displayed under the developer's blinded-trial rule

POSSIBLE: The placebo-controlled evidence is one decisive-dose trial for tiludronate and one very small trial for clodronate. In Denoix 2003, a double-blind placebo-controlled trial, tiludronate 1 mg/kg intravenously daily for 10 days gave optimal improvement of lameness and return to normal activity 2-6 months after treatment in horses with navicular disease, while 0.5 mg/kg failed to significantly improve the condition (73 horses enrolled; 50 in the final efficacy analyses - 33 recent and 17 chronic cases). In Mitchell 2019, a single 1.4 mg/kg dose of clodronate in 12 horses with forelimb lameness due to navicular syndrome produced a small but significant decrease in forelimb lameness at 1 week only (P = 0.005), with coaches reporting improved performance more often at week 8 (P = 0.01) and no change in bone turnover markers. Route studies without a placebo arm are weaker: systemic tiludronate 1 mg/kg increased force-plate peak vertical ground reaction force at days 120 and 200 in 6 horses but no horse became sound (Whitfield 2016), and tiludronate by intravenous regional limb perfusion added no improvement over shoeing plus distal interphalangeal joint injection (Schoonover 2018). Design class (a): randomisation and blinding are both established by carded records (Denoix 2003, double-blind placebo-controlled randomised trial; Mitchell 2019, randomised and blinded). The honest limits: the tiludronate benefit rests on one older trial with substantial exclusions from the efficacy analysis and a clear dose threshold, the clodronate trial has 6 horses per group with a lameness signal at a single early time-point, and no carded trial shows horses becoming sound. Drafted Nov 10, 2026 (VetMed build, topic #803); all figures from abstracts fetched and verified at drafting.

Denoix 2003: tiludronate 1 mg/kg improved lameness and return to activity 2-6 months after treatment in navicular disease; 0.5 mg/kg did not significantly improve the condition

Randomised, double-blind, placebo-controlled clinical trial (record's own title and wording: 'a double-blind placebo-controlled clinical trial'; publication types include Randomized Controlled Trial)

Who: Horses: 73 horses with navicular disease enrolled, split into recent and chronic subpopulations and followed for 6 months; 33 recent and 17 chronic cases meeting the selection criteria were maintained in the final efficacy analyses (50 horses). Tiludronate was given at 0.5 mg/kg or 1 mg/kg bodyweight by daily intravenous injections over 10 days, against placebo. Clinical examinations were videorecorded and reviewed blindly by an independent expert.

Result: Horses treated with the higher dose (1 mg/kg) showed optimal improvement of lameness and return to normal level of activity 2-6 months post treatment, and the more recent the onset of clinical signs at treatment, the greater the efficacy. The lower dose (0.5 mg/kg) failed to significantly improve the condition. Treatment did not modify the response to extension and flexion tests. The record's abstract gives no lameness-score numbers or responder percentages, so no absolute effect size can be quoted from this record.

Watch out: Only 50 of 73 enrolled horses reached the efficacy analyses, the abstract reports the benefit qualitatively ('optimal improvement') without figures, and the benefit is dose-specific - the 0.5 mg/kg result is a null at half the effective dose. Navicular 'disease' in this 2003 record predates modern MRI-based case definitions of navicular syndrome.

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;35(4):407-13. PMID: 12880010. Registry ID: none in the record. MeSH: Animals · Bone Resorption/drug therapy/veterinary* · Diphosphonates/therapeutic use* · Dose-Response Relationship, Drug · Double-Blind Method · Female · Foot Diseases/drug therapy/veterinary* · Hoof and Claw* · Horse Diseases/drug therapy* · Horses · Injections, Intravenous/veterinary · Lameness, Animal/drug therapy* · Male · Osteitis/drug therapy/veterinary · Treatment Outcome · Video Recording

Mitchell 2019: a single clodronate dose gave a small significant decrease in forelimb lameness at 1 week only in 12 horses with navicular syndrome (P = 0.005); bone turnover markers did not change

Randomised, blinded, placebo-controlled trial (record's own wording: horses 'were randomised to receive either 1.4 mg/kg clodronate ... or an equivalent volume of LRS ... in a blinded manner'; the record calls the comparator 'placebo')

Who: Horses: 12 university-owned equestrian team competition horses with a history of forelimb lameness due to navicular syndrome, randomised to a single treatment with clodronate 1.4 mg/kg (n = 6) or an equivalent volume of lactated Ringer's solution (control, n = 6). Lameness evaluations 1 week before and 1, 2, 3 and 8 weeks after administration; coach questionnaires for ridden performance; blood bone turnover markers (CTX-I, osteocalcin) weekly for 8 weeks before and after.

Result: A small but significant decrease in forelimb lameness was detected in clodronate-treated horses 1 week after treatment (P = 0.005); there were no significant differences in hindlimb lameness, and no lameness difference is reported at weeks 2, 3 or 8. Coaches identified an improvement in performance significantly more often in clodronate vs control horses at week 8 (P = 0.01). There were no differences in bone turnover markers CTX-I or osteocalcin, or in in vitro bone cell recruitment.

Watch out: Six horses per group: the lameness signal is a single time-point in a very small trial, the week-8 performance outcome is a subjective coach questionnaire, and two control horses received intra-articular anti-inflammatory medication after treatment, which the authors note may have altered lameness results. The abstract gives no lameness-score values, so the size of the 'small' decrease cannot be stated.

Mitchell A, Wright G, Sampson SN, Martin M, Cummings K, Gaddy D, Watts AE. Clodronate improves lameness in horses without changing bone turnover markers. Equine Vet J. 2019;51(3):356-363. PMID: 30153345. Registry ID: none in the record. MeSH: Animals · Biomarkers/blood · Clodronic Acid/therapeutic use* · Collagen Type I/blood*/metabolism · Female · Forelimb · Horse Diseases/blood/drug therapy* · Horses · Lameness, Animal/drug therapy* · Male · Osteocalcin/blood*/metabolism

Whitfield 2016: systemic tiludronate 1 mg/kg increased force-plate ground reaction force at days 120 and 200 in horses with navicular syndrome, but no horse became sound and subjective lameness scores did not improve after systemic treatment

Randomised comparison of two tiludronate administration routes, no placebo group (record's own wording: 'Horses were randomly assigned'; blinding not stated in the record)

Who: Horses: 12 horses with bilateral forelimb navicular syndrome, randomly assigned to systemic tiludronate 1 mg/kg diluted in 5 L isotonic electrolyte solution via a jugular catheter (n = 6) or tiludronate 0.1 mg/kg by intravenous regional limb perfusion (IVRLP) into the lateral digital vein of each forelimb (n = 6), given once on day 0. Mean peak vertical ground reaction force (pVGRF) by stationary force plate and subjective lameness scores were recorded before (day -1) and at predetermined time points after treatment.

Result: Mean pVGRF for both forelimbs and for the most lame forelimb in systemically treated horses was significantly increased on days 120 and 200 compared with day -1. No significant difference in mean pVGRF was observed for IVRLP-treated horses. Subjective lameness scores were not improved at any time point after systemic treatment and were improved only on day 120 after IVRLP. The authors conclude systemic tiludronate appeared beneficial, but no horses were judged as sound during the study period. The abstract gives no pVGRF values, so the size of the force-plate change cannot be stated.

Watch out: There is no placebo or untreated group - both arms received tiludronate - so improvement over time cannot be separated from natural history or regression to the mean, and the objective (force plate) and subjective (lameness score) outcomes point in different directions for the two routes. Six horses per group.

Whitfield CT, Schoonover MJ, Holbrook TC, Payton ME, Sippel KM. Quantitative assessment of two methods of tiludronate administration for the treatment of lameness caused by navicular syndrome in horses. Am J Vet Res. 2016;77(2):167-73. PMID: 27027711. Registry ID: none in the record. MeSH: Animals · Bone Density Conservation Agents/administration & dosage/therapeutic use* · Diphosphonates/administration & dosage/therapeutic use* · Forelimb · Horse Diseases/drug therapy* · Horses · Injections, Intravenous · Lameness, Animal/drug therapy*

Schoonover 2018: tiludronate by regional limb perfusion gave no further lameness improvement over shoeing plus joint injection in navicular syndrome (the treatment made no difference within groups); high-dose horses were objectively less lame than low-dose and placebo only at day 120

Placebo-controlled trial of tiludronate IVRLP as an adjunct (publication type: Clinical Trial, Veterinary; record's MeSH includes Random Allocation; blinding not stated in the record)

Who: Horses: 15 horses with bilateral forelimb navicular syndrome. All horses received therapeutic shoeing and anti-inflammatory injection into the distal interphalangeal joint of both forelimbs on day 0, then on day 14 one of three intravenous regional limb perfusions - tiludronate 0.1 mg/kg (low-dose, n = 5), tiludronate 0.2 mg/kg (high-dose, n = 5) or saline placebo (n = 5) - repeated at days 24 and 34. Lameness was evaluated subjectively and by force plate at days 0, 14, 34, 60 and 120.

Result: For all horses, mean peak vertical ground reaction force was increased at 14 days (after shoeing and joint injection). No difference in mean subjective lameness score or mean peak vertical ground reaction force was detected within groups at any time. Mean force for both forelimbs combined was higher for the high-dose group than the low-dose and placebo groups only at 120 days. The authors conclude the tiludronate IVRLP protocols provided no further improvement in lameness over therapeutic shoeing and anti-inflammatory joint injection.

Watch out: A null for the perfusion route as an adjunct, in 5 horses per group, on top of active co-treatment (shoeing plus joint injection) that itself improved force measures - it does not test systemic tiludronate, and the single day-120 between-group difference sits against an overall within-group null.

Schoonover MJ, Whitfield CT, Young JM, Sippel KM, Payton ME. Quantitative assessment of intravenous regional limb perfusion of tiludronate as an adjunctive treatment for lameness caused by navicular syndrome in horses. Am J Vet Res. 2018;79(12):1313-1320. PMID: 30457899. Registry ID: none in the record. MeSH: Administration, Intravenous · Animals · Bone Density Conservation Agents/pharmacokinetics*/therapeutic use · Diphosphonates/pharmacology*/therapeutic use · Female · Foot Diseases/veterinary* · Forelimb · Gait · Horse Diseases/drug therapy* · Horses · Lameness, Animal/drug therapy* · Male · Random Allocation · Syndrome · Tarsal Bones/abnormalities*/drug effects

Synthesis: systemic tiludronate 1 mg/kg improved lameness in one double-blind placebo-controlled trial and clodronate showed a small one-week lameness signal in 12 horses; perfusion-route tiludronate added nothing - POSSIBLE

Synthesis

Who: Synthesis of the cards above: Denoix 2003 (73 horses enrolled, 50 in efficacy analyses, double-blind placebo-controlled tiludronate dose trial), Mitchell 2019 (12 horses, randomised blinded clodronate vs control), Whitfield 2016 (12 horses, randomised systemic vs perfusion tiludronate, no placebo) and Schoonover 2018 (15 horses, placebo-controlled tiludronate perfusion adjunct trial).

Result: (1) Tiludronate systemic: 1 mg/kg daily for 10 days improved lameness and return to activity at 2-6 months in the blinded placebo-controlled trial, while 0.5 mg/kg did not; a single systemic 1 mg/kg dose later raised force-plate force at days 120 and 200 without any horse becoming sound. (2) Clodronate: one 1.4 mg/kg dose reduced forelimb lameness significantly at week 1 only, with no bone-marker change. (3) Perfusion route: no added benefit over shoeing plus joint injection. The evidence supports a real but modest and dose-dependent lameness benefit for systemic bisphosphonate treatment - POSSIBLE, held below LIKELY by the single old pivotal trial, the tiny clodronate sample, and the absence of soundness outcomes.

Watch out: This shelf covers navicular syndrome only; tiludronate results in other equine bone conditions (for example bone spavin or thoracolumbar osteoarthritis) are different questions and are not carded here. No carded record reports horses returning to soundness, and long-term or repeated-dose safety and bone effects are outside these records.

Synthesis of Denoix JM et al. PMID: 12880010; Mitchell A et al. PMID: 30153345; Whitfield CT et al. PMID: 27027711; Schoonover MJ et al. PMID: 30457899. Registry IDs as on the individual cards.

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