Navicular 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 Unfortunately, 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 performance.6
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 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 devices.29
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 lameness.
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 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 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.
Results
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.
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.
Citation: American Journal of Veterinary Research 77, 2; 10.2460/ajvr.77.2.167
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 days 120 (85.61 ± 9.95%; P = 0.008) and 200 (87.06 ± 1l.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.
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.
Citation: American Journal of Veterinary Research 77, 2; 10.2460/ajvr.77.2.167
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 significant differences were detected in this variable for either group.
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.
Citation: American Journal of Veterinary Research 77, 2; 10.2460/ajvr.77.2.167
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.
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.
Citation: American Journal of Veterinary Research 77, 2; 10.2460/ajvr.77.2.167
Discussion
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 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 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 different IVRLP regimens is needed before this route of administration can be recommended.
Acknowledgments
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.
ABBREVIATIONS
| %BWF | Percentage body weight of force |
| AAEP | American Association of Equine Practitioners |
| IVRLP | Intravenous regional limb perfusion |
| mCF | Mean combined forelimb |
| mLF | Mean most lame forelimb |
| NS | Navicular syndrome |
| pVGRF | Peak vertical ground reaction force |
| SLS | Subjective lameness score |
Footnotes
Microsoft Excel 2011, version 14.4.9, Microsoft Corp, Redmond, Wash.
Tildren, Ceva Santé Animale, Libourne, France.
Plasmalyte, Abbott Laboratories, North Chicago, Ill.
Kistler Instrument Corp, Amherst, NY.
SAS, version 9.2c, SAS Institute Inc, Cary, NC.
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