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Navicular Syndrome and the Clinical Use of Bisphosphonates

in Equine Practice

Presenter: James D. Conway III, DVM

AAVSB RACE #495-35627

Disclaimer: The presenter is associated with Dechra Veterinary

Products, LLC the MAH of OSPHOS® (clodronate injection)

Overview

Basic Principles of Bisphosphonates

Bone Modeling & Remodeling Navicular Syndrome

Equine Application of Bisphosphonates

Navicular Syndrome

Osphos® (clodronate injection)

Clinical Impact and Case Selection

Efficacy and Safety

Basic Principles of Bisphosphonates

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Bisphosphonate Therapy 1,2

Class of drug that has been used in human medicine for over 30 years

Used for various diseases of abnormal bone metabolism

Animal models

Inhibit osteoclast bone resorption

Achieve positive calcium balance

How Bisphosphonates Work 3

Osteoblasts form bone and osteoclasts resorb bone

Normal bone-balance between formation and resorption

Diseased bone-tissue balance of osteoblasts and osteoclasts is disrupted

Bisphosphonates inhibit bone resorption by encouraging osteoclasts to undergo cell death and reduce bone breakdown

Bisphosphonates 1,2

Mechanism of Action

Bisphosphonates bind to calcium phosphate crystalsAccumulate at areas of high calcium deposition

Inhibit their formation and dissolution

Bisphosphonates inhibit osteoclast functionReduces the number of active osteoclasts

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Bisphosphonate Potency 2

Non-Nitrogenous Bisphosphonates

Etidronate- 1

Clodronate- 10

Tiludronate- 10

Pamidronate- 100

Aledronate- 1,000

Risendronate 5,000

Ibandronate- 10,000

Zoledronate 20,000

Nitrogenous Bisphosphonates

Bone Modelingand Remodeling

Bone Development 2

Osteogenesis

Osteo = Bone

Genesis = New growth

Modeling results in change in shape and size of bone and continues until adulthood as the skeleton matures2

Remodeling is bone resorption and deposition in response to stress and repair of bone2

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Bone Remodeling 1,2

The process of bone remodeling is under the influence of osteoclasts and osteoblasts

Normal Bone Remodeling 1,2

Bone resorption process complete within ~ 3 weeks.

Bone formation process (including mineralization) takes ~ 3 months

Osteoblast activity = Osteoclast activity

“Coupled” to work together

Amount of bone formed equals amount destroyed

No net loss or net gain of bone

Bone Disease 2

Osteoblast activity does not equal osteoclast activity;

mechanism “uncoupled”

Osteoclasts become too aggressive;

results in bone lysis = thinner, weaker bone2

Osteoblasts get too aggressive;

sclerosis occurs = thicker, less pliable bone2

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During times of chronic bone disease and repetitive stress, bone remodeling is accelerated

Bisphosphonates regulate bone metabolism through inhibition of bone resorption via reduction of osteoclast activity

Bisphosphonates help restore balance of osteoclast vs. osteoblast activity by reducing the activity of the osteoclasts

Bone Remodeling and Bisphosphonates

Equine Application of Bisphosphonates

Nuclear Scintigraphy

Pyrophosphate (P-O-P) was linked to 99m Tc in skeletal scintigraphy2

Bisphosphonates (P-C-P) are analogs of pyrophosphate

Image courtesy of Furlong Equine & Associates

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Nuclear Scintigraphy

Image courtesy of Furlong Equine & Associates

Peer-Reviewed Research

Argüelles D et al. 2019. Clinical efficacy of clodronic acid in horses diagnosed with navicular syndrome: A field study using objective and subjective lameness evaluation. Research in Vet Sci Vol125, 298-304. https://doi.org/10.1016/j.rvsc.2019.07.018

Frevel M et al. 2014. Multi-centre field trial to evaluate the effectiveness of clodronic acid for navicular syndrome. EVJ (46), Suppl 47, 2-25. https://doi.org/10.1111/evj.12323_10

Frevel M, King BL, Kolb DS et al. 2017. Clodronate disodium for treatment of clinical signs of navicular disease – a double-blinded placebo-controlled clinical trial. Pferdeheilkunde 33, 271-279

Mitchell A, Watts A, Ebetino F, Suva L. 2019. Bisphosphonates use in the horse: what is good and what is not? BMC Vet Research 15:211 https://doi.org/10.1186/s12917-019-1966-x

Markell R, G S, E.A B, JD C, C D, What do we know about clodronate now?A medical and veterinary perspective, Journal of Equine Veterinary Science (2019), https://doi.org/10.1016/j.jevs.2019.102874

Navicular Syndrome

Bisphosphonates are applicable for the control of clinical signs associated with navicular syndrome in the horse

FDA CVM-approved bisphosphonates for the horse (2014)

Osphos® (clodronate injection)

Tildren® (tiludronate disodium)

Osphos is a registered trademark of Dechra Ltd.

Tildren is a registered trademark of Bimeda, Inc.

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Navicular Syndrome

Navicular Syndrome ‒ Definition 4

Chronic, intermittent forelimb lameness associated with pain arising from the navicular bone and closely related soft tissue structures including the collateral suspensory ligaments of the navicular bone, distal sesamoidean impar ligament, navicular bursa, and the deep digital flexor tendon.

Also known as:

Podotrochlear Apparatus Syndrome

Caudal Heel Pain

Factors Affecting the Navicular Bone 5

Normal forces acting on the navicular bone:- Compression by deep digital flexor tendon

- Compressive forces downward from P2

- Tension from the supporting ligaments

- Ground forces

Navicular bone is constantly

remodeling to adjust to

changing workload

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Navicular Syndrome-Signalment

~ 1/3 of all chronic forelimb lameness 4

Quarter Horse, Thoroughbreds, Appaloosas, Paints, & Warmbloods commonly affected

Typically between 4-15 years of age

No clear sex predilection

Western and English performance

Navicular Syndrome-Clinical Signs

Unilateral or bilateral forelimb (asymmetrical) lameness

Usually low-grade, slowly progressive

No consistent clinical picture, horse may:- exhibit a short, choppy stride- display toe-first gait- stumble- refuse to jump- show intermittent weight shifting on front feet- tip-toe or appear to be walking on “egg shells”- display increased lameness the day after work- have difficulty turning sharply and going downhill- have difficulty moving on hard/rocky ground- switch leg lameness while on hard ground or when circling

Navicular Syndrome-Diagnostic Tools

Multiple test necessary for accurate diagnosis

History & Physical examination

Lameness evaluation and gait analysis

- Motion analysis software

Hoof pressure response

Nerve and intraarticular/bursal analgesia

Radiography

Other imaging modalities

Ultrasound

Nuclear scintigraphy

Computed tomography (CT)

Magnetic resonance imaging (MRI)

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Navicular Syndrome ‒ Diagnosis

Radiographic changes involve a wide range of remodeling & degenerative changes

Enlarged synovial fossae Cyst-like lesion

Reference radiographs

Navicular Syndrome ‒ Diagnosis

Standing MRI images courtesy of Hallmarq

Navicular Syndrome-Medical Management/Treatment

Multimodal treatment is most effective and includes:

Rest and Rehabilitation

Corrective trimming and shoeing

Medical therapy- Systemic anti-inflammatories

- Vasodilators

- Intraarticular medications

- Non-nitrogenous bisphosphonates

Extracorporeal shock wave therapy

Surgical Treatment (palliative therapy)- Palmar digital neurectomy

- Navicular bursoscopy

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OSPHOS®

(clodronate injection)

OSPHOS® (clodronate injection)

FDA Approved non-nitrogenous bisphosphonate for use in horses

For control of clinical signs associated with navicular syndrome

4 years of age and older

Osphos® is the ONLY intramuscular option

Ready to use injection

Dose 1.8 mg/kg up to a maximum dose of 900 mg per horse;

divide into 3 sites

Proven efficacy and safety

Option to re-administer q3-6 monthsCAUTION: Federal law restricts

this drug to use by or on the

order of a licensed veterinarian.

OSPHOS® Clinical Field Study 7,8

Title/Objective: Evaluation of the clinical efficacy of OSPHOS for the control of the clinical signs associated with navicular syndrome in horses

Multi-site, double-masked, placebo-controlled

3:1 ratio (Osphos:NaCl)

Investigators: United States and EuropeRob Boswell, DVM, PA- Florida

David Kolb, DVM -Wisconsin

John Janicek, DVM, MS, DACVS- Texas

Stuart Shoemaker, DVM, DACVS- Idaho

Bradley King, DVM- Indiana

Michael Frevel, DVM- Germany

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OSPHOS® Clinical Field Study 7,8

Overall Treatment SuccessesDefined as improvement of at least AAEP lameness grade

Day 56 Improvement of Lameness Grades (raw data from Osphos clinical efficacy trial)

• One grade ‒ 16 horses

• Two grades ‒ 45 horses

• Three grades ‒ 8 horses

* Compassionate use was allowed after Day 56 evaluation

Study Day OSPHOS Saline Control

28 67.4% 20.7%

56 74.7% 3.3%

180 65.4% None evaluated*

Excerpts from the Clodronate Roundtable & Use of Bisphosphonate Therapy in Equine Practice

Event Date: May 14, 2019

Objective:

To aggregate cross-disciplinary opinions and experiences from leading equine experts on the use of bisphosphonates in horses

Panelists

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Clinical Impact

FDA approved in 2014 to control the clinical signs of navicular syndrome in horses 8

A non-nitrogenous bisphosphonate drug—has changed the way in which equine practitioners manage sports medicine

Another tool in their toolbox

More targeted approach

Increased client education and partnership

Clinical Impact

“ I t h i n k [ c l o d r on a t e ] g i v e s u s a n o t h e r t o o l i n o u r t o o l b o x

t o a d d r e s s s o m e o f t h e s e i s s u e s t h a t h a v e p o t e n t i a l l y

b e e n r e f r a c t o r y t o o t h e r t r e a t m e n t m o d a l i t i e s . I n m y

p r a c t i c e i t i s j u s t p a r t o f w h a t I d o [ … ] . T h e r e w i l l b e

s h o e i n g c h a n g e s , w o r k c h a n g e s , l o o k i n g a t f o o t i n g . I t ’ s

s o r t o f t h e h o l i s t i c a p p r o a c h . ”

- Sarah le Jeune, DVM, DACVS, DACVSMR

Clinical Impact

“ [ C l o d r o n a t e h a s ] r e a l l y o p e n e d u p a g r e a t

c o n v e r s a t i o n w i t h o u r c l i e n t s a n d t h e a b i l i t y t o

h a v e a c o n v e r s a t i o n a b o u t w h a t i s b e s t f o r y o u r

h o r s e , h o w d o w e t r e a t y o u r h o r s e , l o n g - t e r m

m a n a g e m e n t , a n d l o o k i n g a t t h e w h o l e h o r s e r a t h e r

t h a n , ‘ J u s t g i v e a d r u g ’ , o r ‘ J u s t d o a n i n j e c t i o n . ”

- Richard Markell, DVM, MRCVS, MBA

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Case Selection

Clinical picture (history, PE, lameness work-up)

Diagnostic anesthesia

Radiographic and/or MRI evidence of Bone Changes

Evaluate for Concurrent Soft Tissue Injury

Risk vs Benefit (Precautions/Contraindications)

What is your case selection criteria?

Case Selection

B a s e d u p o n MR I f i n d i n g s I b e l i e v e t h a t t h e m o s t r e s p o n s i v e

b o n e c h a n g e s , s u c h a s t h o s e a s s o c i a t e d w i t h t h e n a v i c u l a r

b o n e o r t h e i n s e r t i o n o n t h e d i s t a l p h a l a n x , r a t h e r t h a n s o f t

t i s s u e i s s u e s , a r e a g o o d p l a c e f o r O S P H O S t o b e u s e d .

- Myra Barrett, DVM, DACVR

I a g r e e , I s e e a l o t o f s i g n i f i c a n t i m p r o v e me n t w h e n

O S P H O S i s u s e d t o t r e a t b o n e c h a n g e s : “ I t h i n k u p u n t i l

t h i s p o i n t t h e r e h a s n ’ t b e e n a r e a l l y g o o d s o l u t i o n t h a t w a s

r e l i a b l e a s f a r a s h e l p i n g w i t h t h e p r e s u m p t i v e p a i n p a r t o f

t h e b o n e c h a n g e s [ s c l e r o s i s ] w e ’ r e s e e i n g . ”

- Josh Zacharias, DVM, DACVS, DACVSMR

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Case Selection

“ T h e a g e o f t h e h o r s e m a t t e r s , a s d o e s t h e w o r k t h e

h o r s e h a s b e e n d o i n g . ”

- S t e v e n C o l b u r n , D V M

Clinical Efficacy

Short-term Outcomes

Long-term Outcomes

Rehabilitation and return to work protocols

Re-dosing decision based upon clinical findings

What do you expect short-term?

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Clinical Efficacy – Short-Term

“ S o t h e i m p r o v e me n t , i f w e t a l k a b o u t h e e l p a i n [ … ] , w e ’ r e

l o o k i n g f o r a n i n c r e a s e o r a n i m p r o v e m e nt i n t h e i r l a m e nes s

g r a d e s . A n d f o r m e i t ’ s n o t u n u s u a l f o r t h o s e t o i m p r o v e a t

l e a s t 2 l a m e n e s s g r a d e s . I m e a n , I k i n d o f e x p e c t t h a t . ”

- C h r i s R a y, D V M, D A C V S

What do you expect long-term?

Clinical Efficacy – Long-Term

“ [ B i s p h o s ph o n a t e s h a v e ] b e e n a g a m e c h a n g e r i n

n a v i c u l a r d i s e a s e . I c a n n o w m a n a g e i t m u c h b e t t e r

t h a n I c o u l d 1 0 o r 1 5 y e a r s a g o . I t h a s a l s o a l l o w e d

m e n o w […], t o h a v e s o m e m o r e e f f e c t i v e t o o l s i n

c o n j u n c t i o n w i t h t h e o t h e r t o o l s I ’ m u s i n g . S o t h a t ’ s

h o w i t w o r k e d f o r m e . ”

- K e n t A l l e n , D V M

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“ T h e h o r s e s h o u l d l o o k b e t t e r a f t e r 1 4 d a y s a n d s h o u l d b e g o o d a f t e r 4 w e e k s ; t h e t r e a t m e n t a p p r o a c h a l w a y s n e e d s t o b e m u l t i m o d a l . ”

“ I d o n ’ t l i k e t o r e s t h o r s e s u n l e s s t h e y ’ r e v e r y l a m e

( s i m i l a r t o t h e h u m a n s i d e ) . I ’ v e c h a n g e d m y

m a n a g e m e n t a p p r o a c h t o a p a c k a g e t h a t i s m o r e

a g g r e s s i v e s o t h e h o r s e s a r e o u t o f c o m m i s s i o n f o r l e s s

t i m e . ”

- Marc Koene, DVM

Clinical Efficacy – Multimodal Approach

Clinical Efficacy – Re-dosing

“ I t h i n k w e n e e d t o b e c a r e f u l a n d t h o u g h t f u l a s r e a l l y t h e m e d i c a l m a n a g e r s o f t h a t h o r s e t o d i s c o u r a g e j u s t a r o u t i n e r e - d o s i n g a n d I d o n ’ t b e l i e v e i n p r e e m p t i v e o r p r e v e n t a t i v e m e d i c a t i o ns . ”

- R i c h a r d Ma r k e l l , D V M, MR C V S , MB A

Safety

For horses 4 years and older

Reproductive considerations

Gastrointestinal signs

Renal toxicity

NSAIDs Contraindicated

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OSPHOS® Specific Safety Info 7

In field studies, the most common side effects reported were signs of discomfort or nervousness, cramping, pawing, and/or colic within 2 hours post-tx

- Majority of horses clinical signs resolved with 10-15 minutes of hand walking

NSAIDs should not be used concurrently with OSPHOS- Horses should be well-hydrated prior to and after the administration of OSPHOS

- Water intake and urine output should be monitored for 3-5 days post-treatment;any changes from baseline should elicit further evaluation

OSPHOS should not be used in pregnant or lactating mares, or mares intended for breeding

Use of OSPHOS in patients with conditions affecting renal function or mineral or electrolyte homeostasis is not recommended

What safety considerations do you have?

Safety

Nitrogenous ≠ Non-Nitrogenous

Judicious Use

Long Term Safety Considerations

Richbourg HA, Mitchell CF, Gillett AN. (2018) Tiludronate and clodronate do not affect bone structure

or remodeling kinetics over a 60 day randomized trial. BMC Veterinary Research. 14:105-115.

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Safety

“ A n d t h a t s a f e t y f a c t o r , I t h i n k , i s i m p o r t a n t i n b r i n g i n g u p

t h e c o n v e r s a t i o n a b o u t n i t r o g e n o u s b i s p h o s p h o n a t e s , [ … ]

a n d t h e n i t r o g e n o u s h a v e a v e r y d i f f e r e n t p a t h w a y o f

p h a r m a c o l o g y. T h e y a r e a r o u n d f o r a l o n g , l o n g , l o n g t i m e ,

y e a r s a n d y e a r s . T h e y c a n c r e a t e i s s u e s t h a t w e ’ r e n o t

a w a r e o f a n d t h e s a f e t y d a t a h a s n o t b e e n d o n e o n t h o s e

n i t r o g e n o u s o n e s [ … ] . T h e c a u t i o n w i t h t h e n i t r o g e n o u s

o n e s i s r e a l a n d i m m i n e n t a n d s h o u l d b e d i s c u s s e d . ”

- R i c h a r d Ma r k e l l , D V M, MR C V S , MB A

Safety

" I w a s a c t u a l l y p r e t t y h a p p y w i t h t h e f i n d i n g s . I t m e a n s t h a t w e

c a n u s e [ c l o d r o n a t e ] , t h a t w e k n o w i s v e r y e f f e c t i v e i n k e e p i n g

h o r s e s w i t h n a v i c u l a r s y n d r o m e i n w o r k a n d a b l e t o p e r f o r m w i t h

a n d f o r t h e i r o w n e r s , w i t h o u t t h e r i s k t h a t w e s e e i n p e o p l e o f

a t y p i c a l f r a c t u r e s . “

-Ashlee Watts, PhD, DVM, DACVS

Mitchell A, Wright G, Sampson SN (2019) Clodronate improves lameness in horses

without changing bone turnover markers Equine Veterinary Journal. 51: 356–363.

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Safety 7,8

“ S o w e l o o k e d a t t w o t i m e p o i n t s o n d e n s i t y j u s t t o s e e i f

t h e r e w a s a c h a n g e d u e t o t h e i n f l u e n c e o f [ c l o d r o n a t e ]

t r e a t m e n t d u r i n g t h a t t i m e . A n d t h e r e w a s n o t a t a n y o f t h e

t r e a t m e n t d o s e s . W h e n y o u l o o k a t t h e d a t a [ f r o m t h e

c l o d r o n a t e s a f e t y s t u d y ] [ … ] w h a t I l o o k a t i s t h a t i t w a s n o t

o n l y p r o v e n s a f e a t [ t h e r e c o m m e n d e d ] d o s e , b u t i t h a s a

v e r y w i d e s a f e t y m a r g i n . “

- Chris Kawcak, PhD, DVM, DACVS, DACVSMR

OSPHOS® (clodronate injection) Summary

The application of bisphosphonates in equine practice is due to the body of evidence for efficacy and safety in navicular syndrome

At least 2/3 of horses experienced a minimum of 6 months of improvement from a one-time intramuscular dose

“Improvement produced by clodronate was apparent by Day 28…and was in the absence of any ancillary treatment that could have confounded the result” 6

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Key Points

Bisphosphonates have become a useful pharmaceutical application in veterinary medicine

Understanding bone modeling and remodeling has become crucial in applying bisphosphonates to equine practice

A multimodal approach to treating navicular syndrome is essential for a successful outcome and bisphosphonates have become an integral tool in that approach

Dechra Support

Dedicated Equine Sales Team

Equine Professional Services Veterinarians

24 Hour Veterinary Technical Support via (866)933-2472

www.osphos.com

www.equinelameness.com

References1. Fleish, H. Bisphosphonates in Bone Disease, From the Laboratory to the Patient. Academic Press, San Diego, CA 2000.

2. Bartl, R. et al. Bisphosphonates in Medical Practice, Actions, Side Effects, Indications, Strategies. Springer, Heidelberg, Germany

2007.

3. FDA Provides Equine Veterinarians with Important Information about TILDREN and OSPHOS for Navicular

Syndrome in Horses; http://www.fda.gov/AnimalVeterinary/ResourcesforYou/ucm406581.htm?source=govdelivery&utm_medium=email&utm_source=gov

delivery

4. Adam’s and Stashak’s Lameness in Horses-6th ed./ [edited by] Gary M. Baxter. Wiley-Blackwell, West Sussex, UK 2011; pp 475-

593.

5. Ostblom I., Lund C, Melsen F. Histological study of navicular bone disease. Equine Vet J. 1982 Jul; 14 (3): 199-202

6. Frevel, et al. Multi-centre field trial to evaluate the effectiveness of clodronic acid (as disodium clodronate) for navicular syndrome

BEVA Presentation, 2014.

7. Osphos (clodronate injection) package insert (rev Dec 2018) available at www.dechra-us.com

8. Osphos Freedom of Information available at www.osphos.com or

https://animaldrugsatfda.fda.gov/adafda/app/search/public/document/downloadFoi/923

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OSPHOS® (clodronate injection)Fair & Balance Statement

As with all drugs, side effects may occur. In field studies and post‐approval experience the most common side effects reported were signs of discomfort, nervousness, and colic. Other signs reported were: renal insufficiency/failure,

anorexia, lethargy, hypercalcemia, behavioral disorders, hyperkalemia, hyperactivity, recumbency, hyperthermia, injection site reactions, muscle tremor,

urticaria, hyperglycemia, and fracture. In some cases, death has been reported as an outcome of these adverse events. The safe use of OSPHOS has not been evaluated in horses less than 4 years of age or breeding horses. OSPHOS should

not be used in pregnant or lactating mares, or mares intended for breeding. NSAIDs should not be used concurrently with OSPHOS. Concurrent use of

NSAIDs with OSPHOS may increase the risk of renal toxicity and acute renal failure. Use of OSPHOS in patients with conditions affecting renal function or

mineral or electrolyte homeostasis is not recommended. Refer to the prescribing information for complete details or visit www.dechra‐us.com.

Q & A