For horses suffering from bone spavin (hock arthritis) and/or navicular disease. Tildren™ is composed of Tiludronic acid, a bisphosphonate which inhibits bone resorption. It has been a licensed product in other parts of Europe for the past few years and has been used successfully in treating lameness caused by bone spavin, back pain, and navicular disease.
How does it work? In normal horses bone is constantly being remodelled (re-shaped) in order to adapt to the biomechanical stresses the environment, and us as riders place on their skeletal structure. There are two types of bone cells, which work in harmony to achieve this fine balance of production and resorption of bone within the skeleton:
Osteoblasts – Are cells responsible for ‘bone synthesis’, they produce collagen and help with mineralization in order to create a dense bony framework.
Osteoclasts – Are cells responsible for ‘bone resorption’ resulting in bone lysis (areas of reduced bone density). Areas of reduced bone density are a pathological change common to most cases of navicular disease and bone spavin and are due to inappropriate resorption of bone (osteolysis). Tildren™ has been designed to reduce this bone resorption by inhibiting the activity of the osteoclasts.
It has also been demonstrated to have anti-arthritic properties by inhibiting the effects of enzymes which degrade the cartilage surface of joints.
Is my horse a candidate for this treatment? The clinical effect of Tildren™ depends on the presence of osteolytic processes causing pain leading to lameness. Tildren™ can only be used after a full lameness work-up has been carried out by your vet. This includes; local anaesthesia (nerve blocks) and appropriate imaging techniques (x-rays, bone scan, MRI (Magnetic resonance imaging) etc.) to confirm the site of pain and type of lesion.
What evidence do we have that it works? At Chiltern, we have been using the drug for several years now, long enough to see the long-term outcome of horses with respect to athletic soundness, and results have been excellent. Double-blind, placebo-controlled clinical trials carried out in horses with bone spavin and navicular disease at other centers have shown a clear improvement following treatment as demonstrated by long-term reduction in lameness and progressive resumption of sporting activity (approx. 60%). For further information visit www.tildren.com
Tildren is similar to other bisphonate drugs used in humans suffering from osteoporosis. Many of the human drugs are administered orally daily, weekly, or monthly. Only a few are given once yearly by injection. Tildren is more similar to the human drugs that are given yearly by injection.
Tildren works by inhibiting the function of cells in the body that remove bone called osteoclasts. In some types of bone cancer, osteoporosis, and osteoarthritis, these cells may actually remove healthy bone and causing pain and additional inflammation.
Tildren is not yet approved by the FDA for use in the United States, so each use must be pre-approved by the FDA in writing. Food and Drug Administration approval is pending, however. Currently, the drug must be imported from France or Great Britain.
If Tildren is selected for treating your horse, the drug is administered intravenously. In the U.S., veterinarians often mix the contents of the entire box (ten vials of powder which has to be reconstituted with sterile water) with a large bag of i.v. fluids, and allow administration over an hour or more with the horse standing quietly. Occasionally, this treatment may be repeated one or more time yearly.
Recently, I have administered the drug using regional limb perfusion for effected areas. This method requires a smaller dose of the drug and may be less expensive.
Efficacy of the drug using regional limb perfusion is not known and has not been studied. Anecdotally, I have treated a small number of patients using this method (usually as a last resort), and I have had variable results (failure and success).
Efficacy of the drug administered as labeled is gaining a growing body of evidence. Recently, an article in the Equine Veterinary Journal suggested that Tildren is effective for treatment of arthritis of the hock. (M. R. GOUGH*, D. THIBAUD1, R. K. W. SMITH, Tiludronate infusion in the treatment of bone spavin: A double blind placebo-controlled trial Equine Veterinary Journal Volume 42, Issue 5, pages 381–387, July 2010).
Another, earlier article published by clinicians at Colorado State University reviewed published data to suggest that Tildren may be useful in treating bone resorption limited to the navicular bone and the distal intertarsal joins of the hock. (L. Kamm, W. McIlwraith, and C. Kawcak, A Review of the Efficacy of Tiludronate in the Horse, Volume 28, Issue 4, Pages 209-214 April 2008).
Around the same time, researchers in Europe found that Tildren may be effective for treatment of horses with intervertebral arthritis (particularly horses with neck pain).( Vi Coudry, D. Thibaud; B. Riccio; F. Audigié; D. Didierlaurent; J-M Denoix. Efficacy of tiludronate in the treatment of horses with signs of pain associated with osteoarthritic lesions of the thoracolumbar vertebral column. American Journal of Veterinary Research. Vol. 68, No. 3, Pages 329-337 March 2007).
Treatment for Lameness Associated with Bone and Cartilage Changes in Horses
TILUDRONIC ACID 50mg/vial.
Tiludronic acid belongs to the bisphosphonate therapeutic class, a class of product with activity on bone metabolism. The main pharmacological property of TILDREN Injection is to reduce bone resorption by inhibiting the activity of osteoclast.
TILDREN Injection acts as a regulator of bone remodelling in all situations involving excessive bone resorption. This regulator effect is not associated with a negative effect of bone formation or bone mineralisation at the recommended therapeutic dosage.
Areas of reduced bone density are a pathological change common to most cases of Navicular Disease and Bone spavin and are due to inappropriate resoption of bone(osteolysis). In double-blind, placebo-controlled clinical trials for both conditions, TILDREN treatment induced a clear improvement as demonstrated by long-term reduction in lameness and progressive resumption of sporting activity.
In another double-blind, placebo-controlled clinical trial into the treatment of back pain associated with bony lesions of the vertebral column, TILDREN treatment induced a clear improvement in back flexibility, however further research is required to add this indication as a registered claim. Other studies have shown that TILDREN treatment can prevent the bone loss, which usually occurs during inactivity in horses, as shown by measurements of bone density in spelling horses.
TILDREN Injection has also demostrated anti-arthritic properties in a model of poly-arthristis in rats. In vitro date identified inhibiting effects on the secretion of enzymes which degrade cartilage matrix.
HORSES: Treatment of lameness associated with bone and cartilage changes such as those observed in Navicular Disease and Bone Spavin.
DOSAGE AND ADMINISTRATION
DOSAGE: 0.1mg Tiludronic acid per kg bodyweight once daily for 10 days by slow intravenous injection. i.e. 10mL (1 vial) of reconstituted solution per 500kg bodyweight per day for 10 days.
CARTON CONTAINS: 10 vials of 50mg freeze-dried powder (Tildren) and 10 vails of 10mL solvent (Water for injection). Each carton provides a 10-day treatment course for a 500kg horse.
Store below 25 celcius (air conditioning) in outer carter.
EFFECT OF TILUDRONATE ON BONE RESOPTION
- Binding of Tiludronate via a covalent bond to the mineral phrase of the bone (the hydroxyapatite). This binding occurs preferentially at the remodelling sites.
- Acidification of th emedium resultingh from the initiation of the resoption process – this breaks the Tilundronate-hydroxyapatite bond. In this way Tildronate is released into the resorption cavity.
- Penetration of Tiludronate into the osteoclast.
- Inhibition of the proton pump…
- Disruption of the cytoskeleton leading to the loss of the ruffled border.
- Formation of a cytotoxic ATP analogue, which causes the death of the osteoclast.
AMINO ACID-AMP + PYROPHOSPHATE ~~~ ATP + AMINO ACIDS.
Tiludronate replaces the pyrophosphate, hence;
AMINO ACID-AMP + TILUDRONATE ~~~ ATP ANALOGUE + AMINO ACID. ACTION OF THE OSTEOBLAST
Osteoblast particularly produce interleukin-6 which activates the osteoclasts and thus initates resorption. Tiludronate inhibits the osteoblastic synthesis of interleukin-6.
EFFECT OF TILUDRONATE ON CALCIUM
- Work carried out by Barbier shows that th eintestinal absorption of calcium is increased in a ‘DOSE DEPENDENT’ manner by Tiludronate, without increasing the excretion of calcium via the urine.
- Moreover, Tildronate facilitates the binding of blood calcium to bone, by increasing the size of existing hydroxyapatite crystals or of crystals being formed.
- Tiludronate limits the release of bone calcium by inhibiting resorption.
THESE RESULTS SHOW THAT TILUDRONATE ENHANCES CALCIUM ABSORPTION AND INCREASES BONE DENSITY
TILUDRONATE IS A REGULATOR OF BONE REMODELLING:
- it reduces bone resorption
- it does not have a negative effect on bone formation
- it has positive effects on mineralisation and increases bone density.
As a consequence of its various pharmacological properties, Tiludronate is very beneficial in the treatment of lameness where bone pathology is involved, in particular, where radiographs show that osteolysis and sclerosis are features of the pathology.
EFFECT ON CARTILAGE
In vitro studies have shown that Tiludronate inhibits the secretion, mediated by interleukin-1, of enzymes that degrade the cartilaginous matrix.
These enzymes (collagenase and proteoglycan-degrading enzyme) are produced by chondrocytes and the synovial cells.
This property of Tiludronate may be beneficial in treating degenerative osteo-articular pathologies.
STUDY OF THE BONE DISTRIBUTION IN HORSES OF TILUDRONATE AS A FUNCTION OF TIME
- 8 horses (4 males, 4 females).
- 0.1 mg/kg/day (as C tiludronate) for 10 consecutive days via the IV route.
- Study duration: 6 months.
MEASUREMENT OF THE TILUDRONATE CONCENTRATION: DO + 10 DAYS, DO + 3 MONTHS, DO + 6 MONTHS IN THE FEMUR, THE THIRD TARSAL BONE, THE THIRD METACARPAL BONE AND THE NAVICULAR BONE.
- The same distribution pattern was observed for males and females, however, the dose bound in the bone was lower for the females.
- The bone concentration varied as a function of the bone studied.
- The concentration in the bone diminished very slowly between 0 and 3 months; the reduction was more marked after 6 months.
PERCENTAGE OF HORSES WITHDRAWN FROM THE TRIAL AFTER 1 OR 2 MONTHS DUE TO AN INSUFFICIENT RESPONSE TO THE TREATMENT.
A FAILURE RATE
The investigators could withdraw a horse from the study, if the response to treatment was considered to be insufficient at the 1-month or 2-month examination.
- 55% OF THE HORSES IN THE PLACEBO GROUP WERE WITHDRAWN FROM THE STUDY.
- NO HORSE IN THE TILDREN GROUP WAS WITH DRAWN FROM THE STUDY.
EVALUATION OF THE DEGREE OF LAMENESS
In the placebo group: in the first 2 months there was a reduction in the number of horses presenting with moderate to extreme lameness. After 2 months there was a relapse and at 6 months, 90% of the horses in this group were lame.
IN THE TILDREN GROUP:
There was a progressive and long lasting improvement. After 6 months, 60% of the horses were no longer lame or showed only mild signs, demonstrating the mid-to long-term effect of Tildren.
LEVEL OF ACTIVITY
The horse’s level of activity is an essential criteria in evaluating the benefit of a treatment. For the treatment to be truly satisfactory, it is important that the horse can resume its sporting activity.
The level of activity is evaluated as a function of the type of activity normally carried out by the horse on a scale of 0 (very little activity).
ACTIVITY WAS CONSIDERED TO HAVE BEEN RESUMED IF THE SCORE WAS 6 OR 7.
In the Tildren group, a progressive and gradual recovery was noted in the horses’s activity.
In the placebo group, the number of horses recovering normal activity levels fluctuated from one consultation to another. At 6 months, none of the horses had a normal level of activity.
After 6 months: more that 67% of the horses had recovered a normal level of activity.
There was a significant difference between the Tildren group and the placebo group: p=0.01
PERCENTAGE OF HORSES WITHDRAWN FROM THE TRIAL AFTER 1 OR 2 MONTHS DUE TO AN INSUFFICIENT RESPONSE TO THE TREATMENT.
A FAILURE RATE
The investigators could withdraw a horse from the study, if the response to treatment was considered to be insufficient at the 1-month or 2-month examinations.
The failure rate corresponds to the percentage of horses withdrawn from the study because of a response deemed to be insufficient. The rate was measured in each group.
As can be seen in the graph, by the 2-month examination the two groups were very significantly different:
- 38 of the horses in the placebo group were withdrawn from the study.
- No horses in the TILDREN group were withdrawn from the study.
After 1 month, almost 60% of the treated horses were either no longer lame or were slightly lame.
- After 2 months, there was a clear increase in the number of horses who were either no longer lame or only slightly lame: 70% of the horses.
- This improvement was long-lasting. After 6 months, almost 60% of the horses were no longer lame or showed only mild signs, demonstrating the mid-to long-term effect of Tildren.