The use of bisphosphonate medications to treat disorders of the equine musculoskeletal system is becoming common practice.1–10 The ability of bisphosphonates to inhibit bone resorption is a key factor leading to their use because the pathophysiologic processes of many orthopedic diseases of horses are linked to heightened bone turnover.11 Injected bisphosphonates bind to circulating calcium and other divalent metal ions and are transported to the surface of bones where they are incorporated into the bone hydroxyapatite matrix. During bone resorption, bisphosphonates are released from bone and enter osteoclasts, where through several mechanisms they cause a decrease in recruitment, activity, and life span of these cells.
Two bisphosphonates, tiludronate disodium and clodronate disodium, are approved for use in the United States and are labeled for systemic administration in the treatment of navicular syndrome of horses.12,13 Double-blinded placebo-controlled clinical trials1,4 have provided subjective indications that each of these medications is efficacious at the labeled dose and per the route of administration as an adjunct treatment for navicular syndrome; however, signs of transient abdominal discomfort, agitation, hypocalcemia, and nephrotoxicosis have been reported12,13 secondary to systemic administration of labeled doses of both tiludronate and clodronate.
Intravenous regional limb perfusion is a technique widely used to provide effective local delivery of antimicrobials, and this method has been used to administer tiludronate for the treatment of musculoskeletal disease in horses.7,8,10,14 The IVRLP technique is an extralabel use of the medication, and no information regarding dose or frequency of dosing is readily available. In 1 clinical trial,14 investigators evaluated administration of tiludronate (0.1 mg/kg) via a 1-time bilateral digital IVRLP as the sole treatment for navicular syndrome; however, no objective improvement in lameness (as determined by use of force plate measurement of peak vertical force) was detected over the 200-day study period.
The purpose of the study reported here was to subjectively (clinical observation) and objectively (force plate analysis) evaluate effects of 2 doses of tiludronate administered via IVRLP as an adjunct treatment for lameness in horses with navicular syndrome. We hypothesized that therapeutic shoeing and injection of anti-inflammatory medications into the DIPJ of both forelimbs would result in improvements in measures of lameness. We further hypothesized that a high dose of tiludronate administered bilaterally via IVRLP would provide additional improvements in measures of lameness to those seen with therapeutic shoeing and injection of the DIPJs, whereas a low dose of tiludronate or a placebo would provide no further improvements in lameness.
Materials and Methods
Animals
Client-owned horses admitted to the Oklahoma State University Boren Veterinary Medical Teaching Hospital for lameness evaluation were prospectively recruited for enrollment in the study. A signed consent form was obtained from owners prior to inclusion of horses in the study. All procedures were approved by the Oklahoma State University Institutional Animal Care and Use Committee.
Horses with bilateral forelimb lameness (minimum grade of 2 on the AAEP lameness scale15 of 0 to 5) at the time of initial evaluation were eligible for enrollment. In addition, it was required that horses have substantial subjective improvement in lameness following palmar digital perineural analgesia of the LFL, which resulted in more evident lameness of the contralateral forelimb. Subsequent palmar digital perineural analgesia of the contralateral forelimb also resulted in substantial subjective improvement in lameness. Perineural analgesia was performed by injecting 2 mL of 2% mepivacaine hydrochloride SC adjacent to 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. A score for each navicular bone was assigned by a board-certified veterinary radiologist with experience with equine radiography (KMS). A subjective scale (0 = no abnormalities to 4 = severe radiographic abnormalities) that focused on navicular bone texture, vascular channel appearance, and shape and borders of the navicular bone was used.16 A minimum score of 2 for each forelimb navicular bone was required for inclusion. The mean scores for both navicular bones was calculated to determine an overall radiographic score. Horses previously treated with bisphosphonates and horses with other radiographic abnormalities (eg, DIPJ osteoarthritis or dystrophic mineralization of the deep digital flexor tendon) were excluded from the study.
For the 120-day study period, each horse was allowed activity at the discretion of its owner. Treatment with NSAIDs was allowed; however, administration of NSAIDs within 72 hours of a scheduled lameness evaluation was not allowed. Hoof trimming or shoeing during the study period was performed only by the study farriers at prescribed intervals.
Study design
All horses received initial treatment for navicular syndrome consisting of therapeutic shoeing and bilateral injection of anti-inflammatory agents into the DIPJ of both forelimbs (day 0). Trimming and shoeing were performed by 1 of 2 experienced farriers. Farrier choice was based on availability at the time of initial examination, and the same farrier performed all shoeings for a specific horse. The same shoe type was used by both farriers, and trimming and shoeing were performed in a similar manner. Hooves were trimmed, and shoes were nailed to all 4 feet. Openheeled wide-web aluminum 2° heel-wedged shoesa were applied to the feet of the forelimbs, and flat steel shoesb were applied to the feet of the hind limbs. Trimming and shoeing were repeated twice (days 42 and 84) during the study period.
Triamcinolone acetonidec (10 mg) and sodium hyaluronated (20 mg) were injected into the DIPJ of both forelimbs. Injection was accomplished through a dorsal approach by use of a 20-gauge, 1.5-inch needle. A light bandage then was applied to cover the injection site. Owners were instructed to remove the bandage in 4 to 6 hours. Flunixin meglumine (1.1 mg/kg, IV, once) was administered immediately after DIPJ injections.
Horses were assigned into 1 of 3 groups (5 horses/group) by use of a predetermined numeric order developed with a computer randomization program.e On day 14, each forelimb of the horses in the LDT group was injected via IVRLP with 0.1 mg of tiludronatef/kg diluted with saline (0.9% NaCl) solution to a total volume of 35 mL, each forelimb of the horses in the HDT group was injected via IVRLP with 0.2 mg of tiludronate/kg diluted with saline solution to a total volume of 35 mL, and each forelimb of the horses in the placebo group was injected via IVRLP with 35 mL of saline solution. The IVRLP of both forelimbs of a horse was performed concurrently. For each forelimb, a 4-inch-wide rubber tourniquet was placed on the midmetacarpus of each forelimb, and a 23-gauge, 19-mm butterfly catheter was inserted into the lateral digital vein. After the 35 mL of perfusate was administered, the catheters were removed, and a compression bandage was applied to the catheterization sites. Tourniquets were removed 30 minutes after injection of the perfusate. The IVRLP treatments were repeated at days 24 and 34.
Data collection
Subjective and objective lameness assessments were performed on day 0 (before shoeing and again immediately after shoeing but before DIPJ injections) and on days 14, 34, 60, and 120. Assessments on days 14 and 34 were obtained before IVRLP. An SLS was assigned for each forelimb by use of the AAEP lameness scale15 by 1 investigator (MJS) who was not aware of the treatment group for each horse. Objective lameness assessment was performed by use of a ground-mounted stationary force plate system.g Horses were trotted across the force plate at a controlled speed (2.5 to 3.1 m/s), and vertical ground reaction force was recorded. A valid observation was defined as a trial for which 1 entire foot of a forelimb came into contact with the surface of the force plate. Six valid observations for each forelimb were recorded. Body weight for each horse was measured with an electronic digital scale immediately before each force plate evaluation, and vertical ground reaction force (measured in Newtons) was converted into %BW for standardization. The PVGRF was recorded, and VI was calculated as mean vertical force × time (ie, %BW•s). Mean values for the 6 observations were calculated and recorded as the mean PVGRF and mean VI for each limb. The SLS, PVGRF, and VI of the LFL and the mean value for the CFL were used for analysis. The LFL was identified subjectively on the basis of the SLS and objectively as the forelimb with the lower PVGRF and VI at day 0 evaluation before shoeing.
Statistical analysis
Mean SLS, PVGRF, and VI of the LFL and CFL of all 15 horses recorded on days 0 and 14 were compared to determine effects of therapeutic shoeing with and without the effects of DIPJ injections on lameness. Mean SLS, PVGRF, and VI of the LFL and CFL for each group on days 34, 60, and 120 were compared with mean values on day 14 to determine effects of IVRLP treatment on lameness. Comparisons were also made among groups to determine differences in treatment outcomes.
A repeated-measures model and a statistical software programh were used to assess effects of treatment over time. An autoregressive period 1 covariance structure was used to account for intrahorse variation. An ANOVA was used to assess effects of treatment and time. These effects were adjusted for farrier and navicular bone score. Results were reported as mean ± SD. Significance was set at values of P < 0.05.
Results
Fifteen horses (8 geldings and 7 mares) met the study criteria. Mean ± SD age of all horses at initial evaluation was 12.5 ± 3.9 years; mean age was 10.8 ± 2.3 years, 13.4 ± 4.2 years, and 13.4 ± 5.5 years for the LDT, HDT, and placebo groups, respectively. Mean body weight of all horses at initial evaluation was 496.8 ± 51.3 kg; mean body weight was 501.1 ± 46.8 kg, 497.1 ± 59.4 kg, and 492.4 ± 64.0 kg for the LDT, HDT, and placebo groups, respectively. On the basis of medical history obtained from the owners, the duration of lameness ranged from < 1 month to > 5 years. Navicular syndrome had previously been diagnosed and treated in 9 horses; treatments included systemic administration of anti-inflammatories only (n = 1), therapeutic shoeing only (1), intra-articular injection of the forelimb DIPJs only (1), and combinations of these and other therapies (6). Despite these treatments, the horses continued to have performance-limiting lameness. No NSAIDs were administered to these horses within 1 week of initial evaluation, and no injections into synovial joints were performed during the 6 months preceding the study. This was the initial diagnosis of navicular syndrome in the 6 remaining horses.
Mean ± SD overall radiographic scores of the forelimb navicular bones for all horses at initial evaluation was 3.1 ± 0.71; mean score was 3.2 ± 0.76, 2.4 ± 0.42, and 3.7 ± 0.27 for the LDT, HDT, and placebo groups, respectively. Seven horses had severe radiographic abnormalities (mean score, 3.8; range, 3.5 to 4.0), whereas the remaining 8 had moderate abnormalities (mean, 2.5; range, 2 to 3). All 5 horses of the HDT group had moderate abnormalities, and the 5 horses of the placebo group had severe abnormalities. In the LDT group, 2 horses had radiographic scores classified as severe abnormalities, and 3 horses had radiographic scores classified as moderate abnormalities.
Eight horses (3 LDT, 3 HDT, and 2 placebo) had a consistently lower PVGRF and VI on the same forelimb at every evaluation point. Seven horses (2 LDT, 2 HDT, and 3 placebo) had a lower PVGRF and VI that changed between the left and right forelimb during the study. Nine horses (2 LDT, 4 HDT, and 3 placebo) were consistently subjectively more lame on the same forelimb for the entire duration of the study, and the LFL of 6 horses (3 LDT, 1 HDT, and 2 placebo) changed between the left and right forelimb at 1 or more evaluations during the study. For 14 horses, the same forelimb was identified as more lame by subjective and objective assessment before shoeing; for the remaining horse (placebo group), subjective and objective analysis before shoeing yielded opposite limbs as the LFL. One horse (HDT group) was subjectively and objectively more lame in the LFL 14 days after shoeing, compared with the lameness before shoeing on day 0. The subjective AAEP lameness grade was 3 on day 0 and 4 on day 14, whereas the PVGRF and VI on day 0 was 78.53 %BW and 19.24 %BW•s, respectively, and on day 14 was 71.05 %BW and 17.39 %BW•s, respectively. The other 14 horses had the same lameness or improvements of lameness in the LFL at 14 days, compared with results before shoeing on day 0.
Mean SLSs of the LFL and CFL at each evaluation point for each treatment group and all 15 horses were plotted (Figure 1). Mean SLS of the LFL did not differ significantly at any evaluation within each group (LDT, P = 0.63; HDT, P = 0.90; and placebo, P = 0.25) or for all 15 horses (P = 0.10). Similarly, mean SLS of the CFL did not differ significantly at any evaluation within each group (LDT, P = 0.72; HDT, P = 0.77; and placebo, P = 0.06) or for all 15 horses (P = 0.12). Mean SLS did not differ significantly among treatment groups at any evaluation for the LFL (range of P, 0.27 to 0.66) or CFL (range of P, 0.21 to 0.74).
Mean ± SD values of the SLS for the LFL (A) and CFL (B) of 15 client-owned horses with navicular syndrome. Therapeutic shoeing was performed on all horses; horses then received an anti-inflammatory injection into the DIPJ of both forelimbs (day 0). On day 14, all 15 horses (black squares) received 1 of 3 IVRLPs consisting of 0.1 mg of tiludronate/kg (LDT [black triangles]; n = 5), 0.2 mg of tiludronate/kg (HDT [white circles]; 5), or 35 mL of saline (0.9% NaCl) solution (placebo [black circles]; 5); IVRLP treatments were repeated on days 24 and 34. Values after shoeing on day 0 were obtained after therapeutic shoeing but before anti-inflammatory injection in the DIPJs. Values on days 14 and 34 were obtained before IVLRP on those days. A decrease in SLS represents a subjective improvement in the degree of lameness. Lameness grades were assigned by use of the AAEP lameness scale (scale, 0 to 5).
Citation: American Journal of Veterinary Research 79, 12; 10.2460/ajvr.79.12.1313
Mean PVGRF for the LFL and CFL measured at each evaluation for each group and for all 15 horses was plotted (Figure 2). A significant (P = 0.01) increase in mean PVGRF of the LFL for all 15 horses was detected at days 14, 34, and 60, compared with the mean value before shoeing on day 0. Mean PVGRF of the CFL for all 15 horses was higher, but not significantly (P = 0.07) different at any measured time point of the 120-day evaluation period. Within each treatment group, mean PVGRF did not differ significantly for the LFL (LDT, P = 0.71; HDT, P = 0.48; and placebo, P = 0.09) or CFL (LDT, P = 0.57; HDT, P = 0.16; and placebo, P = 0.11). Mean PVGRF of the LFL did not differ significantly (range of P, 0.07 to 0.52) among treatments at any evaluation. Mean PVGRF of the CFL was significantly (P = 0.04) higher for the HDT group, compared with the mean value for the LDT and placebo groups, at 120 days. Mean PVGRF of the CFL did not differ significantly (range of P, 0.16 to 0.38) at any other evaluation.
Mean ± SD values of the PVGRF for the LFL (A) and CFL (B) of 15 client-owned horses with navicular syndrome. An increase in PVGRF represents an improvement in the degree of lameness. *Value for all horses at this time point differs significantly (P < 0.05) from the value for all horses before shoeing on day 0. †Within a time point, value differs significantly (P < 0.05) from the values for the other groups. See Figure 1 for remainder of key.
Citation: American Journal of Veterinary Research 79, 12; 10.2460/ajvr.79.12.1313
Mean VI of the LFL and CFL measured at each evaluation for each treatment group and for all 15 horses was plotted (Figure 3). A significant (P = 0.018) increase in the mean VI of the LFL for all horses was detected at days 14, 34, 60, and 120, compared with the mean VI before shoeing on day 0. A significant (P = 0.01) increase in the mean VI of the CFL for all horses was detected at days 14, 34, and 120, compared with the mean VI before shoeing. Mean VI of the LFL did not differ at any evaluation, compared with the value before shoeing, for the LDT (P = 0.62) and HDT (P = 0.25) groups. Mean VI of the LFL at 14 days was significantly (P = 0.04) increased for the placebo group, compared with the value before shoeing. Mean VI of the CFL did not differ significantly within each treatment group (LDT, P = 0.81; HDT, P = 0.63; and placebo, P = 0.39). Mean VI did not differ significantly among treatments at any time for the LFL (range of P, 0.05 to 0.97) or CFL (range of P, 0.52 to 0.79).
Mean ± SD values of the VI for the LFL (A) and CFL (B) of 15 client-owned horses with navicular syndrome. An increase in VI represents an improvement in the degree of lameness. ‡Value for the placebo group at this time point differs significantly (P < 0.05) from the value for the placebo group before shoeing on day 0. See Figures 1 and 2 for remainder of key.
Citation: American Journal of Veterinary Research 79, 12; 10.2460/ajvr.79.12.1313
Discussion
Results for the study reported here supported the hypothesis that therapeutic shoeing and bilateral anti-inflammatory injections into the DIPJs of the forelimbs objectively improve lameness in horses with navicular syndrome; however, subjective evaluation did not support this hypothesis. The hypothesis that additional subjective and objective improvement would be observed after administration of HDT via IVRLP also was not supported. As expected, the described administration of LDT and saline solution via IVRLP offered no further subjective or objective improvement in lameness over the conventional treatments of therapeutic shoeing and anti-inflammatory injections of the DIPJs.
The lack of improvement in lameness after administration of tiludronate via IVRLP in the present study is consistent with results of a study14 conducted to evaluate a single IVRLP of 0.1 mg of tiludronate/kg as the sole treatment for horses with navicular syndrome. In the authors’ experience, tiludronate rarely is used as the only treatment for horses with navicular syndrome. Clinical management of navicular syndrome often involves a multimodal approach17,18; thus, it can be unclear as to which treatment or combination of treatments causes the observed outcome. Therefore, the study reported here was designed to evaluate tiludronate administered via IVRLP as an adjunct treatment to therapeutic shoeing and anti-inflammatory injections in the DIPJs.
Therapeutic farriery that reduces the biomechanical forces exerted on the navicular apparatus is considered the foundation of treatment for navicular syndrome.18 Although many shoeing principles are important, raising the heel decreases the force applied to the navicular bone by as much as 24%,19 and application of wide-web aluminum shoes containing a 3° heel wedge objectively improves lameness in horses with navicular syndrome.20 The forelimbs of all horses in the present study were shod with wide-web aluminum shoes containing a 2° heel wedge to maintain consistency in shoeing treatment. This shoe type was chosen on the basis of the aforementioned reports19,20 and the authors’ clinical impression about the benefits for this type of shoeing in treating cases of navicular syndrome. Not all horses with navicular syndrome respond equally to a specific type of farriery.18 One horse in the study reported here had a worsening of lameness in the LFL at 14 days, compared with lameness before shoeing, as determined by both subjective and objective analysis, which is consistent with results of other studies.20,21 Another therapeutic shoeing method may have resulted in a different, perhaps better, response to farriery for that horse and possibly for the entire study population.
Injection of corticosteroids and hyaluronate into the DIPJ is commonly used for the treatment of navicular syndrome.17,20,22 Corticosteroids are potent anti-inflammatory agents and have positive clinical effects in horses with osteoarthritic lameness for up to 70 days after intra-articular injection.23 Intra-articular injection of triamcinolone acetonide and hyaluronate are protective of equine chondrocytes in lipopolysaccharide-challenged explants, and the combination also provides additional benefits.24 Although to our knowledge no studies have been conducted to evaluate diffusion of perfusate from the DIPJ in horses with navicular syndrome, diffusion of triamcinolone acetonide from the DIPJ into the adjacent navicular bursa readily occurs in clinically normal horses.22 For these reasons, in combination with the authors’ clinical experiences, bilateral injection of triamcinolone acetonide and sodium hyaluronate into the DIPJs was chosen as the local anti-inflammatory treatment.
No significant improvement in mean subjective or objective measures of lameness was observed immediately after shoeing, compared with values obtained before shoeing, for any treatment group or for all 15 horses in the present study. This is consistent with results of another study20 conducted to evaluate a similar shoeing method for the treatment of horses with navicular syndrome, and it emphasizes that an adaptation period is needed before the biomechanical effects of therapeutic shoeing become evident. Significant improvement in objective lameness at 14 days, compared with lameness before shoeing, was observed only in the LFL of the placebo group; however, when all 15 horses were evaluated, objective improvement of lameness in the LFL was detected as significant increases in mean PVGRF and VI and in the CFL as a significant increase in mean VI. The evaluation period also enabled us to assess the effects of the anti-inflammatory injections in the DIPJs in addition to the therapeutic shoeing. Thus, the improvement in lameness at day 14 could have been entirely attributable to the triamcinolone acetonide–sodium hyaluronate injection into the DIPJs, although this was considered unlikely because improvements in lameness with therapeutic shoeing alone have been reported in other studies.20,21 The reason there was a significant effect for the entire population (n = 15) and not each treatment group (5 horses/group) was likely a result of greater power with the larger sample size.
For the present study, therapeutic shoeing and anti-inflammatory injections into the DIPJs were performed 14 days before the first IVRLP. This allowed the initial effect of therapeutic shoeing and injections of the DIPJs to be assessed and to establish a pretreatment (after shoeing but before injection of the DIPJs) value before the start of the IVRLPs. Subsequent evaluations were compared with data obtained at 14 days to determine the effect of each IVRLP protocol as adjunct treatments. No further improvement was evident for any treatment group at 60 or 120 days, which indicated a lack of efficacy for these protocols. This lack of response is consistent with that of another study14 in which there was no objective improvement in lameness within 200 days after treatment with a 1-time bilateral IVRLP of 0.1 mg of tiludronate/kg in horses with navicular syndrome. Systemic administration of lower-than-recommended doses of tiludronate (0.5 mg/kg, IV) also yielded no improvement in subjectively assessed lameness in a larger, similarly treated population of horses.1
Evaluation at 60 and 120 days in the study reported here represented 26 and 86 days after the third tiludronate IVRLP, respectively. In another study,1 systemic administration of tiludronate resulted in the most substantial improvement in lameness at 66 days after treatment, and the most substantial benefit was reported 2 to 6 months after treatment. In the present study, the LDT and placebo groups had lower mean PVGRF and VI values, which indicated an increase in lameness at 120 days (86 days after the third IVRLP treatment), whereas the mean PVGRF and VI for the HDT group was higher, which indicated a decrease in lameness for this treatment group; however, none of the changes represented significant differences. Additionally, PVGRF for the HDT group was significantly higher than for the LDT and placebo groups at 120 days. It is possible that a longer evaluation period, perhaps ≥ 6 months, may have allowed us to detect significant increases in PVGRF and VI for the HDT group or that the concurrent administration of HDT prolonged the improvement seen with therapeutic shoeing and anti-inflammatory injection of the DIPJs in horses with navicular syndrome.
The original European-labeled dose for tiludronate in horses was 0.1 mg/kg given by IV bolus once daily for 10 consecutive days, which resulted in a total dose of 1.0 mg/kg. Investigators of a pharmacokinetic study25 concluded that a single IV constant rate infusion of 1.0 mg/kg was as effective as the 10-day protocol, and the label for tiludronate use in the United States currently describes a single 1.0-mg/kg infusion.12 The horses in the HDT group in the present study received 3 IVRLPs/forelimb (6 IVRLPs/horse), which equated to a dose of 1.2 mg/kg over a 20-day period; thus, the total amount of tiludronate administered exceeded the labeled dose for systemic administration, and the intermittent dosing frequency was similar to that for the original European-labeled systemic dosing protocol. Systemic administration of tiludronate at a total dose of 1.0 mg/kg has resulted in improvements in subjective1 and objective14 measures of lameness in horses with navicular syndrome. In the present study, subjective or objective improvements in lameness were not detected in the HDT group after IVRLP administration of tiludronate; however, the HDT group was significantly less lame at 120 days, compared with lameness in the LDT and placebo groups. Nonetheless, the multiple IVRLPs for the HDT protocol would likely cause the total cost of treatment to be more expensive than the cost for the labeled dose; thus, use of the HDT IVRLP protocol would lose much of its appeal.
Currently, tiludronate is commonly administered by IVRLP for the treatment of resorptive bone disorders of the limbs of horses,7,8,10,14,26 although accurate dosing information is not available for specific conditions. The IVRLP of tiludronate (0.08 to 0.1 mg/kg) has resulted in synovial fluid concentrations as high as 35,700 ng/mL at 30 to 35 minutes after administration.26 Cartilage explants treated with high concentrations (≥ 19,000 ng/mL) of tiludronate had a higher rate of chondrocyte apoptosis and those treated with low concentrations (≤ 1,900 ng/mL) had a lower rate of apoptosis, compared with results for control explants.27 Thus, the tiludronate doses used in the study reported here (0.1 and 0.2 mg/kg for each limb) may be detrimental to articular cartilage of the joints of the distal portions of the limbs. In contrast, an in vivo study28 conducted to evaluate intra-articular administration of tiludronate revealed that a mean tiludronate concentration of 2,577,500 ng/mL in the synovial fluid of the middle carpal joint of 4 horses did not induce lameness and did not appear to have long-term negative effects on joint tissues. This is consistent with the results of the present study because no significant increase in lameness was observed at day 34, 60, or 120, compared with lameness at day 14. It is possible that any lameness associated with a transient joint disease secondary to the tiludronate IVRLPs had resolved by the next scheduled evaluation or that any benefit for the tiludronate IVRLP on the navicular syndrome lameness was counteracted by a tiludronate-induced arthropathy in the distal portion of the limbs.
Mean SLS did not differ significantly during the study for any treatment group, whereas objective improvement was detected at day 14 for all horses, compared with values before shoeing, and for the HDT group at 120 days, compared with values for the LDT and placebo groups. Subjective lameness assessment has a poor correlation with objective assessment,29 and the AAEP lameness scale15 is less likely to detect subtle changes in lameness severity.14 The use of a scale with more detailed lameness scoring criteria may have allowed for detection of minor kinematic changes in lameness in the present study.
The present study had several limitations. A larger sample size may have improved the power of the study to detect differences within and among treatments over time. Randomization in the study did not result in a similar distribution of radiographic navicular bone scores for the horses in the various treatment groups. The placebo and LDT groups consisted of horses with navicular bones with more severe abnormalities, compared with those of the HDT group. This indicated that the placebo and LDT groups likely comprised horses with more severe disease that may have been less likely to respond to treatment.
Navicular syndrome in the present study was diagnosed on the basis of radiography rather than MRI. For any disease or injury, an accurate diagnosis is critical to enable clinicians to apply the best or most appropriate treatments. Historically, navicular syndrome has been diagnosed on the basis of clinical signs, response to perineural anesthesia, and radiography. It has been reported30 that MRI is superior to other imaging modalities for the evaluation of bone and soft tissues of the digits. The navicular apparatus is a complex anatomic unit, and injury or disease to 1 or more of its parts can lead to similar clinical manifestations; however, the most appropriate treatment for specific disorders can differ greatly. It is the authors’ experience that many horses with lameness isolated to a digit are treated on the basis of radiographic evaluation of the navicular bones without the benefit of MRI because of the cost, availability, and other logistics often involved. Inclusion criteria for the study reported here were intended to mimic the diagnosis of navicular syndrome by an equine practitioner who may not have the added benefit of MRI evaluation. Thus, a wide variation of the exact injury or disease of the navicular apparatus can be assumed for the study participants. A more intricate understanding of the precise cause or causes of lameness for each horse could have resulted in refined inclusion criteria that resulted in the selection of only those horses with bone disease and excluded ones with soft tissue injuries or multiple injuries less likely to respond to tiludronate treatment.7
Although the traditional treatments of therapeutic shoeing and injection of the DIPJs did result in objective improvement for all 15 horses in the study reported here, no additional improvement in subjective or objective measures of lameness was evident with either tiludronate dose or the placebo. Horses in the HDT group were objectively less lame at 120 days, compared with lameness of the LDT and placebo groups, but were not less lame when compared with the improvement achieved with conventional treatments of therapeutic shoeing and anti-inflammatory injections of the DIPJs. Thus, there was no clear evidence that the HDT protocol was efficacious for causing improvements in lameness measures in horses with navicular syndrome, and further studies are warranted before IVRLP administration of tiludronate can be recommended. Systemic administration of a single IV constant rate infusion of tiludronate would appear to be a more cost-effective and efficacious method than use of the IVRLP protocols described in the present study.
Acknowledgments
Supported by the Oklahoma State University Center for Veterinary Health Sciences Research Advisory Committee and by Ceva Animal Health LLC. Funding sources did not have any involvement in the study design, data analysis and interpretation, or writing and publication of the manuscript.
The authors declare that there were no conflicts of interest.
ABBREVIATIONS
| %BW | Percentage of body weight |
| AAEP | American Association of Equine Practitioners |
| CFL | Combined forelimbs |
| DIPJ | Distal interphalangeal joint |
| HDT | High-dose tiludronate |
| IVRLP | IV regional limb perfusion |
| LDT | Low-dose tiludronate |
| LFL | More severely lame forelimb |
| PVGRF | Peak vertical ground reaction force |
| SLS | Subjective lameness score |
| VI | Vertical impulse |
Footnotes
Alu Triumph Degree, Royal Kerckhaert BV, Rapenburg, Netherlands.
SX 7, Royal Kerckhaert BV, Rapenburg, Netherlands.
Kenalog-10, Bristol-Myers Squibb Co, Princeton, NJ.
Hylartin V, Zoetis Inc, Parsippany, NJ.
Microsoft Excel 2011, version 14.4.9, Microsoft Corp, Redmond Wash.
Tildren, Ceva Animal Health LLC, Lenexa, Kan.
Kistler Instrument Corp, Amherst, NY.
SAS, version 9.4c, SAS Institute Inc, Cary, NC.
References
1. Denoix JM, Thibaud D, Riccio B. Tiludronate as a new therapeutic agent in the treatment of navicular disease: a double-blind placebo-controlled clinical trial. Equine Vet J 2003;35:407–413.
2. Coudry V, Thibaud D, Riccio B, et al. Efficacy of tiludronate in the treatment of horses with signs of pain associated with osteoarthritic lesions of the thoracolumbar vertebral column. Am J Vet Res 2007;68:329–337.
3. Gough MR, Thibaud D, Smith RK. Tiludronate infusion in the treatment of bone spavin: a double blind placebo-controlled trial. Equine Vet J 2010;42:381–387.
4. Frevel M, King BL, Kolb DS, et al. Clodronate disodium for treatment of clinical signs of navicular disease—a double-blinded placebo-controlled clinical trial. Pferdeheilkunde 2017;33:271–279.
5. Katzman SA, Nieto JE, Arens AM, et al. Use of zoledronate for treatment of a bone fragility disorder in horses. J Am Vet Med Assoc 2012;240:1323–1328.
6. Helweg MJ, Metzemacher S, Schulze T, et al. Bone oedema like lesion of the second phalanx causing a non-weight bearing lameness in a 4 years old Trakehner mare. Pferdeheilkunde 2014;30:165–170.
7. Vanel M, Olive J, Gold S, et al. Clinical significance and prognosis of deep digital flexor tendinopathy assessed over time using MRI. Vet Radiol Ultrasound 2012;53:621–627.
8. Mizobe F, Nomura M, Kato T, et al. Signal changes in standing magnetic resonance imaging of osseous injury at the origin of the suspensory ligament in four Thoroughbred racehorses under tiludronic acid treatment. J Equine Sci 2017;28:87–97.
9. Allen AK, Johns S, Hyman SS, et al. How to diagnose and treat back pain in the horse, in Proceedings. Am Assoc Equine Pract 2010;384–388.
10. Carpenter RS. How to treat dorsal metacarpal disease with regional tiludronate and extracorporeal shock wave therapies in thoroughbred racehorses, in Proceedings. Am Assoc Equine Pract 2012;546–549.
11. Kamm L, McIlwraith W, Kawcak C. A review of the efficacy of tiludronate in the horse. J Equine Vet Sci 2008;28:209–214.
12. Tildren (tiludronate disodium) [package insert]. Lenexa, Kan: Ceva Animal Health LLC, 2015.
13. Osphos (clodronate disodium injection) [package insert]. Overland Park, Kan: Dechra Veterinary Products, 2014. Available at: www.osphos.com/includes/pdf/Dechra-Osphos-Legal-Package-Insert.pdf. Accessed Dec 28, 2017.
14. Whitfield CT, Schoonover MJ, Holbrook TC, et al. Quantitative assessment of two methods of tiludronate administration for the treatment of lameness caused by navicular syndrome in horses. Am J Vet Res 2016;77:167–173.
15. AAEP. AAEP lameness scale. Available at: aaep.org/horsehealth/lameness-exams-evaluating-lame-horse. Accessed Dec 28, 2017.
16. Dik KJ, van den Broek J. Role of navicular bone shape in the pathogenesis of navicular disease: a radiological study. Equine Vet J 1995;27:390–393.
17. Dabareiner RM, Carter GK, Honnas CM. Injection of corticosteroids, hyaluronate, and amikacin into the navicular bursa in horses with signs of navicular area pain unresponsive to other treatments: 25 cases (1999–2002). J Am Vet Med Assoc 2003;223:1469–1474.
18. Dabareiner RM, Carter GK. Diagnosis, treatment, and farriery for horses with chronic heel pain. Vet Clin North Am Equine Pract 2003;19:417–441.
19. Willemen MA, Savelberg HH, Barneveld A. The effect of orthopaedic shoeing on the force exerted by the deep digital flexor tendon on the navicular bone in horses. Equine Vet J 1999;31:25–30.
20. Schoonover MJ, Jann HW, Blaik MA. Quantitative comparison of three commonly used treatments for navicular syndrome in horses. Am J Vet Res 2005;66:1247–1251.
21. Ostblom LC, Lund C, Melsen F. Navicular bone disease: results of treatment using egg bar shoeing technique. Equine Vet J 1984;16:203–206.
22. Boyce M, Malone ED, Anderson LB, et al. Evaluation of diffusion of triamcinolone acetonide from the distal interphalangeal joint into the navicular bursa in horses. Am J Vet Res 2010;71:169–175.
23. McIlwraith CW. The use of intra-articular corticosteroids in the horse: what is known on a scientific basis? Equine Vet J 2010;42:563–571.
24. Bolt DM, Ishihara A, Weisbrode SE, et al. Effects of triamcinolone acetonide, sodium hyaluronate, amikacin sulfate, and mepivacaine hydrochloride, alone and in combination, on morphology and matrix composition of lipopolysaccharide-challenged and unchallenged equine articular cartilage explants. Am J Vet Res 2008;69:861–867.
25. Delguste C, Amory H, Guyonnet J, et al. Comparative pharmacokinetics of two intravenous administration regimens of tiludronate in healthy adult horses and effects on the bone resorption marker CTX-1. J Vet Pharmacol Ther 2008;31:108–116.
26. Hunter BG, Duesterdieck-Zellmer KF, Larson MK. Tiludronate concentrations and cytologic findings in synovial fluid after intravenous regional limb perfusion with tiludronate in horses. PeerJ 2015;3:e889.
27. Duesterdieck-Zellmer KF, Driscoll N, Ott JF. Concentration-dependent effects of tiludronate on equine articular cartilage explants incubated with and without interleukin-1β. Am J Vet Res 2012;73:1530–1539.
28. Duesterdieck-Zellmer KF, Moneta L, Ott JF, et al. Effects of low and high dose intraarticular tiludronate on synovial fluid and clinical variables in healthy horses—a preliminary investigation. PeerJ 2014;2:e534.
29. Keegan KG, Wilson DA, Wilson DJ, et al. Evaluation of mild lameness in horses trotting on a treadmill by clinicians and interns or residents and correlation of their assessments with kinematic gait analysis. Am J Vet Res 1998;59:1370–1377.
30. Widmer WR, Buckwalter KA, Fessler JF, et al. Use of radiography, computed tomography and magnetic resonance imaging for evaluation of navicular syndrome in the horse. Vet Radiol Ultrasound 2000;41:108–116.
