basic principles of bisphosphonates · 7 navicular syndrome navicular syndrome ‒ definition 4...
TRANSCRIPT
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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