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BISPHOSPHONATE THERAPY IN EQUINE SPORTS MEDICINE
Dane Tatarniuk DVM September 17th, 2014
Bisphosphonates
Developed in the 1800s as industrial chemicals Anti-corrosive Soften water for agricultural irrigation
Medical research began in 1960s First licensed medication was
‘alendronate’ Released by Merck in 1990s
Mechanism of Action
Structural similarity to ‘pyrophosphate’ Inhibit enzymes that utilized
pyrophosphate
Bisphosphonates = 2 phosphate groups Bind to calcium ions Therefore, can accumulate in areas of high
calcium deposits ie, bone
Mechanism of Action
Bisphosphonates bind to calcium Accumulate and persist in bone
Two classes of bisphosphonates, which each act against osteoclasts in different ways1. Non-nitrogenous2. Nitrogenous
Subgroups
Non-nitrogenous bisphosphonates
Metabolized in the cell
Metabolized product replaces triphosphate in ATP
Leads the osteoclast to undergo apoptosis due to lack of cellular energy
Tilduronate
Clodronate
Etidronate
Subgroups
Nitrogenous bisphosphonates
Disrupt enzyme “FDS” Farnesyl diphosphate sythase
FDS enzyme apart of the HMG-CoA reductase pathway Similar to ‘Statin’ family of drugs
Prevents the formation of two metabolites essential for connecting proteins in the cell membrane and cytoskeleton
Pamidronate
Neridronate
Olpadronate
Alendronate
Ibandronate
Risedronate
Zoledronate
Human Medicine
Used to treat bone resorptive disorders Osteoporosis Osteitis deformans (Paget’s Disease) Bone metastasis Multiple myeloma
Used by astronauts aboard long-duration space station missions
Rationale in Equine
Navicular bone remodeling Enlargement of distal border synovial fossa Active osteoblastic & osteoclastic activity
Thickened flexor compact bone Decreased spongiosa
Ostblom et al., 1989 Resorption / Formation Ratio Degenerative Navicular
Ratio = 0.51 Healthy Navicular
Ratio = 0.10
Østblom, L., Lund, C. and Melsen, F. (1989) Navicular bone disease : a comparative histomorphometric study. Equine vet. J. 21, 431-433.
Rationale in Equine
Excessive mechanical forces induce bone remodeling, a component of navicular degeneration
Bisphosphonates inhibit osteoclasts, do not influence osteoblasts Prevent ongoing new bone formation Minimizes ongoing bone resorption seen in navicular
disease
Also need to reduce mechanical stimulus for maximal benefit Combine with rest & therapeutic shoeing
Rationale in Equine
Anti-inflammatory effects? Decrease amount of nitric oxide and
cytokines released from macrophages Monkkonen, 1998
Inhibits secretion of matrix metalloproteinases induced by interleukin-1 in chondrocyte/synovial cells Emonds-Alt, 1985
1) Monkkonen, J., Simila, J. and Rogers, M.J. (1998) Effects of tiludronate and ibandronate on the secretion of proinflammatory cytokines and nitric oxide from macrophages in vitro. Life Sci. 62, PL95-P102.2) Emonds-Alt, X., Breliere, J.C. and Roncucci, R. (1985) Effects of 1-hydroxyethylidene-1,1 bisphosphonate and (chloro-4 phenyl) thiomethylene bisphosphonic acid (SR 41319) on the mononuclear cell factor-mediated release of neutral proteinases by articular chondrocytes and synovial cells. Biochemical. Pharmacol. 34, 4043-4049.
Rationale in Equine
FDA acknowledges in their FAQ that the exact mechanism of how bisphosphonates improve navicular syndrome remains unknown
Availability
Licensed in Europe for navicular disease since early 2000s
Until recently, only available in North American via a drug import license
FDA approval, Spring 2014:
‘TILDREN’ (Tiludronate) Manufacturer: Ceva Sante Animale
‘OSPHOS’ (Clodronate) Manufacturer: Dechra, LTD.
Potency?
Equine formulations are lower potency compared to newer formulations used now in human medicine
Etidronate 1
Clodronate 10
Tiludronate
10
Pamdronate 100
Neridronate 100
Olpadronate 500
Alendronate 500
Ibandronate 1000
Risedronate 2000
Zoledronate 10000
Efficacy?
Monitor response Radiographs
Difficult to appreciate small changes in bone mineral density
Scintigraphy Likely not sensitive enough to detect changes
Long-term treatment for osteoporosis in humans Only 1 to 7% increase in bone mineral
density Subtle changes
Complications
Colic Altered motility
35% incidence during FDA field study Transient, last ~90 minutes
Occur during or shortly after administration (4hr)
Rationale for slow dosing, dilute in IV fluids
Nephrotoxicity
Complications
Alters electrolyte homeostasis
Bone fragility disorder Influences normal remodeling, cannot
easily repair microfractures
Chronic pain Documented with long-term use in humans
Complications
FDA recommendations:
Do not use in horses with renal compromise
Increased risk if previously using other nephrotoxic drugs Ie, phenylbutazone, Banamine No concurrent NSAID use (+/- 48 hours) Baseline creatinine & BUN profile
Do not use in horses with electrolyte disruptions Hypocalcaemia Hyperkalemia
Complications
FDA disclaimers:
Have not been studied in horses < 4 years old What is the effect on skeleton of growing &
maturing animals?
Have not been used on breeding animals What is the effect on the reproductive tract? Safe to use in pregnant mares?
May have greater bisphosphonate uptake in fetus Influence embryogenesis of the skeleton?
Safe to use in lactating mares? Growing foal
FDA Freedom of Information
Tiludronate
Most common bisphosphonate in equine “TILDREN”
Tildren Field Study
Tildren Field Study
204 horses completed the study 835 screened 136 treated with Tiludronate 68 treated with placebo control (mannitol)
Age: 4 to 20 Variety of breeds, gender, weight
Bilateral in 78% of cases Most cases diagnosed within last 6
months of treatment
Tildren Field Study
Inclusion >4 years old Lameness in forelimb
Grade 2 or 3 Alleviated by palmar digital nerve block Navicular disease noted on standing MRI
exam No major soft tissue involvement
Exclude renal disease horses
Tildren Field Study
Dosage Tiludronate diluted in 1 liter of 0.9% saline Administered IV over 60 minutes
All horses had corrective shoeing concurrently Observers masked to treatment group
Observations 2 weeks 1 month 2 months
Last time point
Tildren Field Study
Efficacy Improvement of 1 grade of lameness or more No worsening of lameness
Results
P-value suspiciously close to 0.05
Tildren Field Study
Complications Colic noted in 41% of Tiludronate treated
horses Colic noted in 10% of placebos Mean duration of colic symptoms was 81
minutes
Expanded dose-pharmacokinetic study
Tildren Safety Study
Sallisaw Equine Clinic, OK 30 horses, 6 horses per group
Group 1 – 1.0mg/kg IV once Group 2 – 1.0mg/kg, IV, 3 doses 1 month apart Group 3 – 3.0mg/kg, IV, 3 doses 1 month apart Group 4 – 5.0mg/kg, IV, 3 doses 1 month apart Group 5 – Control
Tildren Safety Study
Tildren Safety Study
Tildren Safety Study
Tildren-HYPP Safety Study
Heterozygous HYPP positive 12 quarter horses 2 doses of 1.0mg/kg, IV, given 30 days apart
Results No abnormalities in potassium concentration 1 horse with non-descript abnormal clinical signs
Muscle fasciculations, agitation Colic or HYPP?
Determined to be safe in HYPP horses
Clodronate
Brand new product on market “OSPHOS”
OSPHOS Field Study
OSPHOS Field Study
Dosage 1.8mg/kg, not to exceed 900mg total dose Intramuscular
Volume divided into 3 separate injection sites
Pilot – Dose Characterization 29 horses Placebo, 300mg, 900mg, 1500mg
900mg was the lowest effective dose for improving lameness scores
No injection site reactions
OSPHOS Field Study
146 horses in study 86 treated with OSPHOS 28 treated with saline
Various genders, weights Age: 4 – 22 years old Breed
49% Quarter Horses
OSPHOS Field Study
Inclusion Clinical diagnosis of navicular disease
Grade 2/5 or higher Palmer digital nerve block Radiographic evidence of navicular disease No MRI
Exclusion Hindlimb lameness Horses <4 years old Neurectomy Change in shoeing within 2 weeks of enrollment
No changes allowed through study Any indication that pain originated from soft tissue
structures
OSPHOS Field Study
Evaluated lameness subjectively at day 0, 28, 56, 180 Treatment failures at day 56 administered a
second dose of OSPHOS & evaluated at day 180
Considered treatment success if improved by 1 grade by day 56
OSPHOS Field Study
Day 180
OSPHOS Field Study
Adverse Effects
OSPHOS Safety Study
Administered IM, every 28 days, for 6 months
Groups: 1.8 mg/kg (1x) 3.6 mg/kg (2x) 5.4 mg/kg (3x) Saline
OSPHOS Safety Study
Injection Site Inflamed and swollen in 7 of 32 cases Recommend not to give more than 10ml of
OSPHOS per injection site, to reduce this risk.
Clinical Studies
Criteria: Flexion test Palmar digital nerve block Radiographs
Osteophytes, enthesophytes, sclerosis, osteolysis Lameness exam
Graded blindly by 1 observer
Excluded: <2 year olds, surgically treated, fractures, NSAIDs in last 15
days, corticosteroids last 30 days
Same shoeing & trim, no NSAIDs, no joint supplements
Treatment Tiludronate & placebo – same vials,
appearance
GROUP Dose/Day Tiludronate
Placebo Total Dose
1 0.1mg/kg Tiludronate
10 days - 1.0mg/kg
2 0.1mg/kgTiludronate
5 days 5 days 0.5mg/kg
3 Placebo - 10 days 0mg/kg
Inclusion
Baseline Radiographs,
Lameness
Day 1 – 9:
Therapy
Day 10:Lameness Exam Post-
Therapy
Day 38:1 month
Lameness Exam
Day 66:2 month
Lameness Exam
Day 192:6 month
Lameness Exam
Study End
Cases
Split into 2 groups for analysis Acute
Clinical signs appeared within 6 months of treatment Chronic
Clinical signs persisted for 6 months of treatment or longer
Recent Cases No change in extension test No change in radiographic scores Improvement in lameness scores in
1.0mg/kg group Trend, not statistically significant
Chronic Cases No significant differences between treatment
groups at any time point
Ancillary Information 6 horses treated with 1.0mg/kg, considered failures at
2 months 2 horses = second treatment 1 horse = second & third treatment Other 3 horses did not receive additional doses
All 3 horses that were repeat treated deemed successful improvement after 2 months following last dose
Advantages of the study Placebo control Randomized into groups Administered therapy blind Lameness evaluation ‘blind’ video interpretation
Cons Lameness exams subjective
No force plate No statistically significant data
Just trends of improvement
Osteoarthritis of the DIT and TMT joints Remodeling involves osteoclast and osteoblast
activity Influence bone metabolism
Randomized, double blinded, placebo control field study Both attending veterinarian and owner blinded
to treatment vs. placebo At day 60, horses with no improvement could
be treated with dose of tiludronate
Inclusion: Intra-articular localization of lameness to DIT &
TMT joints Grade 3/10 or higher (Europe scale) Radiographic signs of osteoarthritis Lameness of >6 weeks to 1 year duration
Excluded NSAID or joint supplements in last 14 days Intra-articular corticosteroid administration in last
60 days or more than 2 injections in the last year Change in shoeing in last 4 weeks
Blocked the least-lame hind-limb, performed exam, and graded unblocked limb lameness Eliminate influence of bilateral disease
Assessment at day 0, 60, and 120 Re-blocked least-lame limb prior to
assessment If horse increased in lameness, re-blocked
afflicted limb to confirm hocks remains the site of lameness
Enrolled 108 horses
Similar population statistics for treatment and control group
In-study exclusion Final group size
42 Tiludronate 45 placebo
Anecdotal reports of equine vets administering Tiludronate intra-articularly for osteoarthritis Reportedly 50mg injected In a 25 to 30ml joint, results in a
concentration of 1666 to 2000mg/L Label IV dose is 1mg/kg
Peak plasma concentration is 9mg/L
Large discrepancy
Used standard in-vitro cartilage explant model Incubated with recombinant IL-1
Exposed to 6 concentrations of Tiludronate 0, 0.19, 1.9, 19, 190, 1900 (mg/L)
Measured: Prostaglandin E2 Glucosaminoglycan MMP-1, MMP-3, MMP-13 IL-6, IL-8
Prostaglandin E2 No effect in any of the Tiludronate groups
Glucosaminoglycan Lower concentrations (0, 0.19, 1.9,
190mg/L) significantly reduced release of GAGs
Highest concentration (1900mg/L) significant increased release of GAGs
Chondrocyte apoptosis Higher concentrations of Tiludronate (19, 190,
1900 mg/L) significantly increased chondrocyte apoptosis
Cytokines/MMPs All concentrations of Tiludronate significantly
increased matrix metalloproteinase (-1, -3, -13) and IL-8 concentrations
IL-6 concentration was up-regulated with the 0.19mg/L Tiludronate group
Conclusion Intra-articular concentrations of Tiludronate
greater than 19mg/L appear to be detrimental to articular cartilage
Intra-articular concentrations of Tiludronate less than 1.9mg/L do not appear to have any negative effect on articular cartilage
Avoid administering intra-articular or regional limb Concentration is high – damages cartilage
Immobilized limbs in casts for 8 weeks to induce osteopenia 2 groups (n=8), placebo or Tiludronate (1.0mg/kg IV, 2
doses 28 days apart) Measured:
C-telopeptides of type 1 collagen crosslink (CTX-1) Indicate bone resorption
Alkaline phosphatase Indicate bone formation
Results: Significant decrease in CTX-1 in Tiludronate treated group No difference in bone ALP concentration
Conclusion: Tiludronate works in horses to prevent disuse osteopenia
induced by a cast
Evaluated Tiludronate therapy in 28 horses with osteoarthritis of the thoracolumbar joints
Treatment (14) & control (14) groups 1.0mg/kg IV slow infusion
Evaluated on day 60 and 120 Measured dorsal flexibility, subjective
interpretation of improvement
Other Bisphosphonates
Pamidronate:
Zoledronate:
QUESTIONS?
Take Home
Notable complications can occur with therapy
FDA approval does not equal efficacy. Questionable science.
Pathogenesis of navicular disease and influence of bisphosphonates on said pathogenesis remain unknown
With advent of OSPHOS, bisphosphonate therapy will likely become more commonly utilized in general equine practice to treat navicular disease