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