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quantitative assessment of 2 methods of tiludronate adm for navicular syndrome .pdf

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Titre: Quantitative assessment of two methods of tiludronate administration for the treatment of lameness caused by navicular syndrome in horses

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Quantitative assessment of two methods of tiludronate
administration for the treatment of lameness caused by
navicular syndrome in horses
To determine effects of 2 tiludronate administration protocols on measures
of lameness in horses with navicular syndrome (NS).

Chase T. Whitfield DVM, MS
Mike J. Schoonover DVM, MS
Todd C. Holbrook DVM

12 horses with bilateral forelimb NS.

Mark E. Payton PhD
Kate M. Sippel DVM
Received February 16, 2015.
Accepted May 15, 2015.
From the Department of Veterinary Clinical Sciences,
Center for Veterinary Health Sciences (Whitfield,
Schoonover, Holbrook, Sippel), and the Department of
Statistics, College of Arts and Sciences (Payton), Oklahoma State University, Stillwater, OK 74074.
Address correspondence to Dr. Whitfield (chasetw@

Horses were randomly assigned to receive tiludronate (1 mg/kg), diluted in
5 L of isotonic electrolyte solution and delivered through a jugular vein catheter (systemic treatment group; n = 6), or tiludronate (0.1 mg/kg), diluted
with saline (0.9% NaCl) solution to a total volume of 35 mL and delivered
into the lateral digital vein of each forelimb with an IV regional limb perfusion (IVRLP) technique (IVRLP group; 6). Mean peak vertical ground reaction
force (pVGRF) measured with a stationary force plate and subjective lameness scores (SLSs) were recorded before (day –1) and at predetermined time
points after tiludronate administration on day 0. Mean pVGRFs (standardized
as percentage body weight of force) and mean SLSs for the most lame forelimb and for both forelimbs of horses in each group were compared with day
–1 values to determine treatment effect.
Mean pVGRF for both forelimbs and for the most lame forelimbs of systemically treated horses were significantly increased on days 120 and 200,
compared with day –1 results. No significant difference in mean pVGRF was
observed for IVRLP-treated horses. The SLSs were not improved at any time
point following systemic treatment and were improved only on day 120 following IVRLP.
Tiludronate (1 mg/kg, IV) as a single systemic treatment appeared to be beneficial for horses with NS, but no horses were judged as sound during the
study period. Additional research on IVRLP with tiludronate is needed before
this method can be recommended. (Am J Vet Res 2016;77:167–173)


avicular syndrome is a progressive, inflammatory disease of the equine digit resulting in degeneration of the navicular (distal sesamoid) bone
and associated soft tissue structures. It can affect
horses of any breed or discipline and is one of the
most common causes of forelimb lameness in Western
performance horses.1–3 In addition to exercise modifications and therapeutic farriery, many medical and
surgical treatments have been described.4,5 UnfortuABBREVIATIONS
%BWF Percentage body weight of force
American Association of Equine Practitioners
Intravenous regional limb perfusion
Mean combined forelimb
Mean most lame forelimb
Navicular syndrome
pVGRF Peak vertical ground reaction force
Subjective lameness score

nately, most of these modalities yield inconsistent results. A recent study of horses with NS treated with
a number of medical approaches showed 34 of 56
horses (61%) failed to return to their previous level of
Navicular syndrome is often characterized by specific radiographic changes related to bone remodeling
or resorption of the navicular bone. Therefore, treatment modalities intended to prevent bone resorption
may be advantageous. In human medicine, bisphosphonates are considered to be the most potent inhibitors of bone resorption available.7–9 These drugs bind
to circulating calcium and other divalent metal ions,
then bind to bone mineral at areas of active remodeling,10 where they act directly on osteoclasts causing
decreased recruitment, activity, and lifespan of these
cells.11 Systemic administration of the bisphosphonate
tiludronate has been investigated for the treatment of

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several equine musculoskeletal disorders characterized by bone resorption.12–14 Signs of abdominal discomfort, transient hypocalcemia, and nephrotoxicosis
have been anecdotally reported secondary to systemic
administration of the drug. Regional limb perfusion
with tiludronate is a practiced method of administration, even though limited literature exists to support
the efficacy of this route.15,16 Antimicrobial administration by IVRLP is commonly performed in equine practice, with the intent to localize a high concentration of
antimicrobials in a desired region of the limb.17 Advantages of this mode of delivery over the systemic label
recommendation include reduced drug expense and,
presumably, lesser potential for adverse effects.
Results of a clinical study12 revealed improvement in SLSs in horses with NS following the addition of systemically administered tiludronate to the
treatment strategy. Although commonly used to evaluate lame horses, subjective lameness assessment has
been shown to be inconsistent between and within
evaluators.18–22 To the authors’ knowledge, no studies in which objective criteria were used to evaluate
the efficacy of tiludronate on lameness in horses with
NS have been published. Objective lameness analysis
with a stationary force plate allows for quantification
of an aspect of locomotion that cannot be assessed
during subjective lameness evaluation. With the horse
in motion, the force plate can measure the pVGRF produced by each limb as it strikes the ground. Degree of
lameness is inversely correlated to pVGRF normalized
to body weight,23,24 and pVGRF has been used to objectively evaluate other treatment modalities in horses
with NS.25–27 The force plate has also been shown to
detect subclinical lameness not appreciated by subjective evaluation.28 The force plate is considered the reference standard for lameness detection and has been
used to validate other objective lameness assessment
The purpose of the study reported here was to
subjectively, by blinded observation, and objectively, by force plate analysis, evaluate the effects of 2
tiludronate administration protocols on lameness in
horses with NS. We hypothesized that horses receiving tiludronate either systemically or by IVRLP would
have both subjective and objective improvement in

Materials and Methods
Horses and inclusion criteria

Client-owned horses brought to the Oklahoma
State University Boren Veterinary Medial Teaching
Hospital for lameness evaluation were prospectively
recruited for enrollment in the study. A signed informed consent form was obtained from owners prior
to study inclusion, and all procedures were approved
by the Oklahoma State University Institutional Animal
Care and Use Committee.
Horses with bilateral grade 2 or 3 forelimb lameness at the time of initial evaluation as described by the

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AAEP guidelines for lameness evaluation (scale of 0 to
5)30 were eligible for study enrollment. In addition, the
horses had a clinically relevant subjective improvement in lameness following palmar digital perineural
analgesia of the most severely lame forelimb, resulting
in a more evident lameness of the contralateral forelimb. Subsequent palmar digital perineural analgesia
of the contralateral forelimb also resulted in a clinically relevant subjective improvement in lameness. Perineural analgesia was performed by injecting 2 mL of
2% mepivicaine hydrochloride SC over the medial and
lateral palmar digital nerves at the proximal aspect of
the respective collateral cartilages. Subjective lameness examination commenced 5 minutes after injection. Standard radiographic views (lateromedial, dorsopalmar, 60° dorsoproximal-palmarodistal oblique, and
45° palmaroproximal-palmarodistal oblique) of the
digit of each forelimb were obtained. Each navicular
bone was scored by a radiologist (KMS) on a subjective 0 (no abnormalities) to 4 (severe radiographic abnormalities) scale focusing on navicular bone texture,
vascular channel appearance, and the shape and borders of the navicular bone.31 A minimum cumulative
score of 2 was required for inclusion.
Horses previously treated with tiludronate and
horses with other radiographic abnormalities in addition to signs of NS (ie, distal interphalangeal joint
osteoarthritis or dystrophic mineralization of the deep
digital flexor tendon) were not included in the study.
For the entire 200-day study period, forced exercise was restricted (force plate evaluation only) and
all horses were allowed free-choice pasture turnout.
To remove any effect of foot imbalance and shoeing, 3
shod horses had their shoes removed and all 4 feet of
each horse were trimmed for balance by the same experienced farrier on days –10, 50, 110, and 170 of the
study (where day 0 was the day of tiludronate treatment). No other palliative treatments were given to
any of the horses through the study period.

Treatment groups and study design

Horses were randomly divided into 2 groups by
means of a computer randomization program.a On
day 0, horses in the systemic treatment group (n = 6)
received a dose of tiludronate disodiumb (1 mg/kg,
IV) diluted in 5 L of sterile isotonic electrolyte solutionc administered as an IV gravity-flow bolus via an
aseptically placed jugular vein catheter. Also on day 0,
horses in the IVRLP group (n = 6) received the same
tiludronate productb (0.1 mg/kg, IV), diluted with sterile saline (0.9% NaCl) solution to a total volume of
35 mL and delivered with an IVRLP technique into the
lateral digital vein of an affected forelimb. The same
technique, including the same tiludronate dose and
perfusate volume, was performed on the contralateral
forelimb. The IVRLP of both forelimbs was performed
simultaneously; an Esmarch tourniquet was placed at
the mid metacarpus, and a 21-gauge, 19-mm butterfly
catheter was placed into the lateral digital vein of each
forelimb. After the calculated amount of tiludronate

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was administered, a compression bandage was placed
at each catheterization site. The tourniquets were removed 30 minutes after injection of the perfusate. Following treatment, horses were monitored hourly for
7 days for any signs of discomfort. The horses were
then allowed pasture turnout for the remainder of the
study with twice-daily visual observation.
Subjective and objective lameness assessments
were performed on days –1, 14, 30, 60, 120, and 200.
An SLS was assigned for each forelimb on the AAEP
scale by 1 investigator (TCH), who was blinded to
treatment group. Objective lameness assessment was
performed with a ground-mounted stationary force
plate system.d Horses were trotted across the plate at
a controlled speed (2.5 to 2.9 m/s), and pVGRF was
recorded. Six valid observations for each forelimb
were recorded and averaged to determine a mean
pVGRF for each examination. A valid observation was
defined as a run by the horse over the force plate in
which 1 entire forefoot came into contact with the
surface of the plate. Body weight for each horse was
measured with an electronic digital scale just prior
to each force plate evaluation. Mean pVGRF (N) was
recorded and expressed as %BWF for standardization.
The SLSs, %BWF for the most lame forelimb, and the
mean %BWF for both forelimbs were used for analysis.
The forelimb identified as the most lame limb by subjective evaluation and the forelimb that had the lowest
%BWF on day –1 were independently designated as the
most lame limb throughout the study. For both treatment
groups and at each time point, mean SLSs were calculated for the most lame forelimb and for both forelimbs
for each horse, resulting in mLF SLS and mCF SLS, respectively. Similarly, the mean %BWF for the most lame forelimb and for both forelimbs was calculated.The mLF SLS,
mCF SLS, mLF %BWF, and mCF %BWF for each treatment
group on days 14, 30, 60, 120, and 200 were compared
with the respective day –1 values to determine the effect
of treatment on lameness.
The same radiographic views of both forelimbs
obtained at the start of the study were obtained on
day 200. Each navicular bone was scored,31 and the
results were compared with the initial score for the
same bone.

Statistical analysis

A repeated-measures model was used, and the effect of treatment over time was assessed. This model
was used throughout the study. Different covariance
structures were evaluated in the repeated-measures
construct to arrive at the models that best fit the
data. Values of P < 0.05 were considered significant.
All statistical analyses were conducted with statistical
software.e The effects of treatment and time were assessed via repeated-measures ANOVA. Results are reported as mean ± SD.

Twelve Quarter Horses (9 geldings, 2 mares, and 1
stallion) met the study criteria. Mean age of the horses

on initial evaluation was 10.8 ± 3.8 years, and mean
body weight was 524.23 ± 41.22 kg. According to history obtained from the owners, the duration of lameness ranged from 1 month to 4 years. Four of the 12
horses had a previous diagnosis of NS and had undergone treatment. Treatments included NSAIDs, distal
interphalangeal joint injections, navicular bursa injections, and therapeutic shoeing. Despite treatment,
these horses continued to have performance-limiting
lameness. None of these horses had any NSAIDs administered within 1 week before initial examination,
and NSAIDs were not administered during the study
period. No synovial injections had been performed
in these 4 horses within the preceding 6 months. In
the remaining 8 horses, NS was newly diagnosed. No
adverse reactions to administration of tiludronate
were observed in either treatment group. No clinical
abnormalities relating to colic or renal disease were
observed during the 7-day postadministration monitoring period.
Radiographic score (scale, 0 to 4) on initial evaluation was 2.33 ± 1.29 for the systemic treatment group
and 2.67 ± 0.98 for the IVRLP group. Four horses had
equal radiographic scores for the left and right forelimb navicular bones. Five horses had more severe radiographic changes in the right forelimb, and 3 had
more severe radiographic changes in the left forelimb.
Subjective navicular bone scores did not change over
the 200-day study period for 11 of the 12 horses. One
horse in the IVRLP group had a combined score of 7
on initial evaluation and 6 on day 200.
Eight horses had a consistently lower mean %BWF
recorded for the same forelimb at every time point
evaluated. Four horses (2 each in the systemic treatment and IVRLP groups) had a lower mean %BWF
that switched between the left and right forelimbs
during the study period. Six horses consistently had
a higher SLS recorded for the same forelimb at every
time point, and for the remaining 6 horses (2 in the
systemic treatment group and 4 in the IVRLP group),
the same forelimb was not consistently found to have
the higher SLS at all study time points. For 11 horses,
the same forelimb was identified as the most lame by
subjective and objective assessments on day –1; for
the remaining horse (in the IVRLP group), subjective
and objective evaluations yielded opposite results.
The day –1 mCF %BWF for the systemic treatment
group was 83.24 ± 10.71% (Figure 1). Following
treatment, mCF %BWF for this group was significantly increased (indicating a lesser degree of lameness),
compared with the day –1 value on days 120 (88.22
± 9.84%; P = 0.04) and 200 (90.8 ± 9.49%; P = 0.003),
with no significant differences detected at other time
points.The mCF %BWF on day –1 for the IVRLP group
was 84.97 ± 4.46%, with no significant differences
from this value at any time points after treatment.
For the systemic treatment group, the day –1 mLF
%BWF (determined by initial objective lameness assessment) was 77.5 ± 12.83% (Figure 2). The mLF
%BWF for this group was significantly increased on

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Figure 1—The mCF pVGRF (expressed as %BWF) for 12
client-owned horses with NS prior to (day –1) and at predetermined time points after treatment with tiludronate disodium
by 1 of 2 methods on study day 0. Horses in the systemic treatment group (black circles; n = 6) received 1 mg of tiludronate/
kg, diluted in 5 L of isotonic electrolyte solution and delivered
as a gravity-flow bolus through a jugular vein catheter, and
horses in the IVRLP group (gray circles; 6) received 0.1 mg of
tiludronate/kg, diluted with saline (0.9% NaCl) solution to a
total volume of 35 mL and delivered simultaneously into the
lateral digital vein of each forelimb with an IVRLP technique.
The mCF value represents mean data for both forelimbs for
all horses in a group. An increase in pVGRF corresponds to a
lesser degree of lameness. *Value is significantly different from
that measured on day –1. Error bars represent the SD.

Figure 3—The mCF SLS before (day –1) and at predetermined
time points after tiludronate treatment (day 0) for the same
horses as in Figure 1.The SLS for each forelimb was assigned by
use of the AAEP guidelines for lameness evaluation (scale of 0
to 5)30 by 1 investigator (TCH), who was blinded to treatment
group of the horses. A decrease in the SLS represents a subjective improvement in the degree of lameness. See Figure 1 for
remainder of key.

Figure 4—The mLF SLS before (day –1) and at predetermined
time points after tiludronate treatment (day 0) for the same
horses as in Figure 1. See Figures 1 and 3 for key.

Figure 2—The mLF pVGRF (expressed as %BWF) prior to
(day –1) and at predetermined time points after tiludronate
treatment (day 0) for the same horses as in Figure 1. See Figure
1 for key.

days 120 (85.61 ± 9.95%; P = 0.008) and 200 (87.06
± 11.21%; P = 0.002), compared with the day –1 value, with no significant differences at any other time
points.The mLF %BWF on day –1 for the IVRLP group
was 79.73 ± 9.2%. Following treatment, the mLF %BWF
was not significantly different from the day –1 value at
any time point for this group.
There were no changes in SLS between initial
evaluation and day –1 of the study period for any
horses.The day –1 mCF SLS for the systemic treatment
group was 2.42 ± 0.49, and that for the IVRLP group
was 2.42 ± 0.58 (Figure 3). The day 120 mCF SLS for
the IVRLP group (1.92 ± 0.49) was significantly (P =
0.02) decreased from the day –1 value, but no other

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significant differences were detected in this variable
for either group.
The day –1 mLF SLS (determined by initial subjective lameness evaluation) for the systemic treatment
group was 2.67 ± 0.52, and that for the IVRLP group
was 2.67 ± 0.82 (Figure 4).The mLF SLS for the IVRLP
group was significantly lower than the day –1 value on
days 60 (1.83 ± 0.41; P = 0.006) and 120 (2.0 ± 0.63; P
= 0.03), but no other significant posttreatment differences were observed in either group.


Navicular syndrome is a chronic, progressive degenerative condition with a wide range of palliative
treatments.4,5 Several proposed pathophysiologic
mechanisms exist by which NS develops, all of which
ultimately lead to excessive bone resorption.32 Bonemodifying drugs such as tiludronate are reported to
slow the resorptive process in bone undergoing active
remodeling,33 suggesting that these drugs would be a

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promising therapeutic option to prolong the life span
or athletic career of affected horses. To reduce the
confounding effects associated with additional medical treatments and therapeutic shoeing, horses in the
present study were treated with tiludronate and regular trimming by an experienced farrier only. Forced
exercise was also restricted, and the horses were allowed free-choice pasture turnout. Other investigators
have evaluated the effects of tiludronate on signs of
pain, lameness, or both in combination with other palliative treatments, resulting in a lack of consistency in
the treatment regimens of the study cohorts.12,14 Additionally, to our knowledge, our study is the first to
use force plate analysis to objectively evaluate the effect of tiludronate treatment on pVGRF over time in
horses with NS.
In the present study, horses receiving tiludronate
as a systemic treatment (1 mg/kg, IV via a jugular vein
catheter) responded favorably to treatment as determined objectively by changes in mean pVGRFs (normalized to body weight). We identified significant (P
< 0.05) decreases in objectively assessed lameness for
the most lame forelimb and for both forelimbs combined at 120 and 200 days after tiludronate administration. The fact that it took 120 days for a detectable response to treatment could be explained by the depot
properties of the drug and the bone remodeling process of the navicular bone. During the remodeling process, bisphosphonates bind the hydroxyapatite crystals and form a depot of the drug that can influence
bone remodeling over time.33 The half-life of tiludronate in equine bone is unknown, but alendronate, a
nitrogenous bisphosphonate, has been reported to
have a half-life of approximately 11 years in humans.34
The bone resorption-formation cycle of the navicular
bone is disrupted in horses affected with NS, resulting in net bone resorption leading to the degenerative
radiographic changes often seen.35 Also, the new bone
formation phase has been found to be 7 times as long
as the bone resorption phase in horses with NS.36 In
humans, the entire bone remodeling process can last
up to 7 months.37 Thus, inhibition of osteoclastic bone
resorption and gradual new bone formation could allow for less bone pain and a gradual improvement in
lameness. At the time of treatment, the horses in the
present study could have been in a highly resorptive
phase in the bone remodeling cycle, and inhibition of
osteoclast activity and resulting reduction of bone pain
is a likely reason for improvement. Bisphosphonates
have also been shown to have anti-inflammatory properties through inhibition of cytokine and nitric oxide
secretion from monocytes in other species, and these
properties could have improved lameness in horses
that underwent systemic treatment with tiludronate
regardless of the cause of NS.38–40 Furthermore, other
concurrent causes of lameness could also have responded to the anti-inflammatory effects of this drug.
Additionally, the effect of consistent hoof trimming,
pasture turnout, and free-choice exercise may have
contributed to the change in soundness over time.

In a previous study12 to evaluate the effect of
tiludronate on lameness associated with NS, horses
that received systemic tiludronate treatment (1 mg/
kg, IV) had improvement in SLSs and returned to
normal activity within 2 to 6 months after treatment,
which was in contrast to our subjective observations.
In the present study, there was no improvement in
SLS in horses that received the same treatment. The
substantially smaller number of horses and restriction
of other palliative treatments and different subjective
lameness evaluators in this study are potential reasons
for the differences in SLS changes between the 2 studies.The differences in subjective effects may also have
been attributed to differences in populations or uses
of the horses (Western performance horses vs horses
used for jumping or pleasure).
Tiludronate is commonly administered by IVRLP
in equine practice for the treatment of resorptive
bone lesions in horses, with anecdotal reports of decreased lameness associated with treatment. The doses and regimens used are variable with no scientific
reports of efficacy in improving lameness caused by
NS in horses.There is 1 report15 describing tiludronate
administration (50 mg/horse, every other week for a
total of 3 treatments) via IVRLP in conjunction with
extracorporeal shockwave treatment and a modified
exercise program to treat dorsal metacarpal disease in
racehorses, and it has been reported that IVRLP with
tiludronate (0.1 mg/kg) does not significantly alter
cytologic variables of the synovial fluid from the navicular bursa, distal interphalangeal joints, and metacarpophalangeal joints in horses.16 The IVRLP dose
used in the present study was determined on the basis of the previous IVRLP studies and our clinical use
of this dose in horses. In our study, the mCF %BWF
and mLF %BWF in horses that underwent IVRLP with
tiludronate did not improve. This lack of response
is similar to findings in a previous study12 in which
horses treated with a lower than recommended dose
of tiludronate (0.5 mg/kg, IV) had no improvement in
subjectively assessed lameness. Additionally, human
studies7,8 have found a dose-effect relationship with
tiludronate administration and response to treatment.
Future studies evaluating higher doses or serial IVRLP
treatments over time are needed to determine whether there could be any benefit from this route of administration. In the present study, significant (P < 0.05)
improvements in SLS were found at 60 days (mLF) and
120 days (mLF and mCF) for horses that underwent
IVRLP, but these findings did not correspond to objective data collected at the same time points.
The differences observed between the subjective
and objective data in this study could be attributable
to a number of factors. The subjective AAEP lameness
scale used in the present study may not be sensitive
enough to discern subtle improvements in lameness.
For example, horses with a wide range of lameness severities can fall into the grade 3 category on the AAEP
lameness scale of 0 to 5.These horses are consistently
lame under all circumstances, but the lameness can

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be very mild or severe.A more detailed lameness scale
may have provided better discrimination, allowing for
differences to be detected from baseline. Also, subjective analysis uses an assessment of horse movement to
determine degree of lameness (kinematics), whereas
objective analysis is a strict measurement of pVGRF
(kinetics).Therefore, the 2 lameness evaluation modalities evaluate different variables to determine degree
of lameness. Subjective lameness assessment has been
shown to have poor agreement with objective assessment, in addition to having a low reliability.18–22
The present study had several limitations that
should be considered when evaluating the results. A
larger sample size may have improved the power of our
study to detect differences attributable to treatments.
Horses in this study had subjectively decreased lameness following bilateral palmar digital perineural anesthesia and had radiographic evidence of degeneration
of the navicular bone; however, other causes for signs
of pain in the heel region could not be ruled out for
this study population. Multiple soft tissue structures in
the caudal heel region commonly contribute to lameness in horses with NS.41,42 Although not performed in
this study, the application of more advanced imaging
such as MRI, CT, and nuclear scintigraphy would have
allowed for a more specific diagnosis or recognition
of any other coexisting condition that may not have
been responsive to tiludronate treatment. Radiographic
evaluation may poorly define or underestimate changes of the navicular bone secondary to NS.43 Magnetic
resonance imaging is superior to radiography in identifying soft tissue changes in the caudal heel region.43
Use of MRI has also been shown to allow detection of
bone lesions in the caudal heel region not detected by
radiographic methods.44 Computed tomography can
also be used to better identify the extent of navicular
bone changes, compared with radiography.43 Nuclear
scintigraphy is more sensitive for identification of bone
resorption, compared with radiography, because ≥ 50%
of the bone mineral has to be lost before lysis can be appreciated radiographically.4 Because of the complex nature of the podotrochlear apparatus, specific changes in
certain structures may respond more or less favorably
to tiludronate treatment. However, it is our experience
that many horses are diagnosed as having NS and are
given tiludronate treatment without the use of these
advanced imaging modalities.
It should be noted that none of the horses in the present study were judged as sound by objective or subjective measures during the 200-day posttreatment period.
However, improvement in mCF %BWF and mLF %BWF
was achieved in horses that received systemic tiludronate treatment. Therefore, tiludronate administered at 1
mg/kg, IV, as a single systemic treatment appears to be
a beneficial adjunctive treatment for horses with NS but
may not be effective as a sole treatment. Objective improvement in lameness was achieved within 120 days
after this treatment in horses of the present study, but
other palliative treatments would likely be necessary to
achieve soundness. Additional research evaluating differ172

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ent IVRLP regimens is needed before this route of administration can be recommended.

Supported by the Department of Veterinary Clinical Sciences,
Oklahoma State University, and by the Center for Veterinary Health
Sciences, the Research Advisory Committee, Oklahoma State University. The authors declare that there were no conflicts of interest.



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