CLINICAL RELEVANCE. Mauro Verna, DVM a, Tracy A. Turner, DVM, MS, DACVS a Kari L. Anderson, DVM, DACVR b

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1 Scintigraphic, Radiographic, and Thermographic Appearance of the Metacarpal and Metatarsal Regions of Adult Healthy Horses Treated with Nonfocused Extracorporeal Shock Wave Therapy A Pilot Study* Mauro Verna, DVM a, Tracy A. Turner, DVM, MS, DACVS a Kari L. Anderson, DVM, DACVR b a Veterinary Population Medicine Department b Veterinary Clinical Sciences Department College of Veterinary Medicine University of Minnesota St Paul, MN CLINICAL RELEVANCE Nonfocused extracorporeal shock wave therapy (ESWT) is commonly used in veterinary practice. This study investigated the effects of four nonfocused ESWT treatments, given 2 weeks apart, on bone radiopharmaceutical uptake and radiographic and thermographic appearance in the metacarpal and metatarsal regions in six adult untrained horses. There were no measurable treatment effects determined by thermography (daily), scintigraphy (at 2-week intervals), and radiography (before study initiation and at study completion) between treated and control limbs. It was concluded that no gross evidence of bone remodeling is detectable by conventional clinical assessment when nonfocused ESWT is applied to healthy equine metacarpal or metatarsal bone. INTRODUCTION Extracorporeal shock wave therapy (ESWT) is increasingly being used by veterinarians to treat several musculoskeletal conditions in horses, including suspensory ligament desmitis and osteoarthritis of the low-motion joints of the tarsus. 1 5 ESWT is also used to treat dorsal metacarpal disease ( bucked shins ), which occurs commonly during training of Thoroughbred racehorses. 6 Despite the amount of information supporting the efficacy of ESWT in clinical trials, a complete understanding of this *This project was supported by the University of Minnesota Equine Center, College of Veterinary Medicine, University of Minnesota, with funds provided by the Minnesota Racing Commission, Minnesota Agricultural Experimental Station, and contributions from private donors. Dr. Verna s current address is Olazabal N*3115 Dpto 6'A', Capital Federal (C.P.1428), Argentina. 268

2 M. Verna, T. A. Turner, and K. L. Anderson new treatment s mechanism of action on equine bone and surrounding tissue is lacking. Results seen in laboratory animals have indicated improved bone remodeling, neovascularization, and improved blood supply to tissue treated with shock waves. 7 9 McCarroll and McClure 3 suggested that the clinical improvement seen in horses treated with ESWT may be due to an increase in bone remodeling, but improved blood supply to tissues must also be considered. To our knowledge, however, there are no in vivo studies of horses that underwent a shock wave treatment protocol, commonly used in practice, that clearly demonstrate a substantial increase in bone remodeling as determined by sequential bone-phase scintigraphy or show an improvement in blood supply to the treated tissues. flow to the bone in a specific area. 10 The maximum radiopharmaceutical uptake occurs 8 to 12 days after injury or stimulus. 10 Scintigraphy may detect as little as g of radiopharmaceutical in bone, whereas changes measured in grams must occur before signs of remodeling can be detected using radiography. 11 Thus, scintigraphy provides a feasible means to measure bone remodeling in live horses. Thermography is a noninvasive, noncontacting technique that produces a pictorial representation of the surface temperature of an object. 12 Thermal imaging cameras actually measure emitted infrared radiation. Peak emissivity of skin occurs in the infrared range, making it an outstanding emitter of infrared radiation. In mammalian species, emitted infrared radiation is directly related to the temperature A complete understanding of ESWT s mechanism of action on equine bone and surrounding tissue is lacking. Bone-phase scintigraphy is a highly sensitive modality for assessing the turnover (modeling and remodeling) of bone and blood flow to bone. 10 Bone turnover involves both resorption, mediated by osteoclasts, and bone formation, mediated by osteoblasts. Hydroxyapatite is the prevalent constituent of the inorganic matrix within bone, and only a very small percentage is normally exposed to the interstitial fluid. Increases in bone turnover or remodeling as a result of pathologic or adaptive stimulus will increase exposure of the hydroxyapatite. 10 Technetium (Tc) 99m labeled diphosphonate salts, such as Tc 99m labeled disodium oxidronate ( 99m Tc-HDP), are the radiopharmaceuticals used most frequently in the assessment of bone turnover in horses. The diphosphonates bind to hydroxyapatite, and uptake is proportional to the osteoblastic activity and the blood of that object. It has been further shown that skin temperature is a direct indicator of the blood perfusion to that area. 13 This makes thermography an excellent method to evaluate potential vascular effects of treatments on horses when used under standardized conditions. 14 It follows that thermography could be used to evaluate the thermal effects of ESWT on a horse s limb and to develop inferences as to what effect treatment would have on the vascular perfusion of the treated area. There are two major categories of shock wave therapy generators used in veterinary medicine: focused and nonfocused (the latter is also known as radial pressure wave). The focused shock wave generators initiate a pressure wave within a fluid medium, where the fluid is displaced and creates a shock wave that can be focused into the patient s body. Nonfocused 269

3 shock waves are pneumatically generated by compressed air pulses, which move a projectile within a handpiece and generate the radial shock waves by concussion. The nonfocused waves are transmitted radially, decreasing in energy proportional to the square of the distance from the surface. We selected the commonly used nonfocused ESWT for this study as well as the treatment protocol recommended by the manufacturer and typically used in practice. MATERIALS AND METHODS Horses Six lameness-free adult mares from the University of Minnesota s teaching herd were used in the study. Subjects had a mean age of 10 years (range, 5 to 16 years), a mean weight of 480 kg (range, 450 to 550 kg), and thermographically, scintigraphically, and radiographically normal metacarpal and metatarsal areas. The mares were sedentary for at least 6 months before the study and were fed a diet of grass hay and 1 kg of fortified sweet feed or oats per day. Horses were confined to a stall and allowed free access to a paddock (40 40 m) for exercise 4 hours/day, 7 days/week, except for the 2 days/treatment period when they were confined in radiation isolation stalls. Horses The average count/pixel ratio of the treated limbs was not significantly different when compared with the average of the control limbs. The objective of this study was to determine if nonfocused ESWT applied to the dorsal third metacarpal or metatarsal area of adult horses, using a technique commonly used in practice, produces clinically apparent bone remodeling as determined by radiopharmaceutical bone uptake (scintigraphy), changes in skin temperature (thermography), and changes in periosteal and cortical bone appearance (radiography). We hypothesized that if this type of ESWT caused significant bone remodeling, there would be an increase in the uptake of the radiopharmaceutical in scintigraphic scans and potentially periosteal or endosteal reaction detected by radiography. Further, if ESWT increases the circulation to the treated area, an increase in skin temperature should be observed using thermography. were evaluated before each session for any signs of pain on palpation of the metacarpal or metatarsal area and for evidence of lameness at a trot in a straight line. This study was approved by the University of Minnesota Institutional Animal Care and Use Committee. Study Design Before beginning the treatments with nonfocused ESWT, an area 5 cm wide 10 cm long on the middle third of the dorsalmedial aspect of the metacarpus and metatarsus bones was prepared for treatment by clipping the hair using a #40 clipper blade and then shaving the remaining hair. This made for a better contact area for treatment and also visually defined the study area before treatment. Baseline radiographic, thermographic, and scintigraphic examinations were performed on each limb before treatment. One metacarpus and one metatarsus per horse were randomly assigned to the treatment group, and the contralateral limbs served as the controls. Treatment was performed on the entire preselected 5 10 cm area, and that treated site was always the same for each horse throughout the project. Nonfo- 270

4 M. Verna, T. A. Turner, and K. L. Anderson cused ESWT treatment was performed once every 2 weeks for a total of four treatment cycles. After each treatment, horses were stabled for 12 days with 4 hours of daily turnout. Thermography was performed daily for 11 days beginning 24 hours after each treatment cycle. Bone-phase scintigraphy was performed 12 days after each treatment. Radiography was repeated 14 days after the completion of the fourth treatment. Extracorporeal Shock Wave Therapy The Swiss DolorClast Vet System (EMS Corp. USA, Dallas, TX) was used to generate and apply the nonfocused shock waves. Before each subsequent nonfocused ESWT session, the preselected areas were reclipped, reshaved, and prepared with coupling gel to obtain maximum skin contact and minimize the loss of shock wave energy at the applicator tip skin the metacarpi and plantar and lateral images of the metatarsi were obtained for 60 seconds with a matrix using a low-energy general-purpose collimator; a lead blocker was placed to shield gamma radiation from other limbs. The region of interest (ROI) analysis was performed using the lateral images. The first manually generated ROI included the entire proximal metaphysis and was drawn just below the carpal or tarsal joint to include the normal, relatively increased uptake in the metaphysis. The second manually generated ROI was the predetermined 5 10 cm area in the middle third of the dorsal half of the metacarpus (the treated region). The average count density was determined within each ROI. The ratio between the mean counts/pixel in the proximal metaphysis (reference area) and the mean counts/pixel in the middiaphysis (interested The average temperature of the treated limbs was not significantly different when compared with the average temperature of the control limbs. interface. Each horse was sedated with detomidine hydrochloride (0.01 mg/kg IV) and restrained in stocks. Each session consisted of 2,000 impulses/treatment at a pressure of 2.5 bars and a frequency of 8 Hz (energy density of mj/mm 2 ). The coupling gel was removed after treatment. Scintigraphy Bone-phase scintigraphic images were obtained using 1.15 GBq/100 kg (150 mci total) of 99m TC-HDP, administered IV 90 minutes before the scan. Horses were positioned with the metacarpal or metatarsal region in vertical alignment, bearing weight on all limbs, and standing squarely. Dorsal and lateral images of area) for all limbs was calculated to standardize the scintigraphic values between scans. Thermography Thermographic images were obtained using a DTIS 500 thermal camera (Emerge Vision Systems, Sebastian, FL). The thermal imaging tool was used in a temperature-controlled room at a similar hour each time to minimize external variables. Thermal images were assessed using the evet thermal imaging software package (emerge Interactive, Sebastian, FL) to objectively determine the difference in temperature (Celsius) of the clipped area of dorsomedial cannon bone between treated and control limbs. Clipping the hair creates a zone of 271

5 warmer temperature (>2 C) in the leg. 12 In this case, the zone would be the 5 10 cm area and would be easily identified on the thermal image. All the quantitative analyses of the scintigraphic and thermographic studies were performed by one person (MV), who was not blinded to treatment group. However, operator bias was reduced by using computer software to obtain objective measurements in the same Statistical Analyses Radiopharmaceutical uptake data were analyzed in a split plot design by a repeated measures analysis using PROC MIXED (SAS, 1996, SAS Institute, Cary, NC). The model included limb (front versus hind), treatment within limb, and number of treatments as main effects and their interactions. Horses were considered as a random variable. Thermal variation was analyzed in a split-split plot design by a repeated measures analysis using PROC MIXED. The model included limb (front versus hind), treatment within limb, Nonfocused ESWT does not appear to have any appreciable effect on bone remodeling, superficial skin temperature, or radiographic appearance in untrained adult horses. fashion each time from an easily identified, predetermined treatment area. Radiography Radiographs of each limb were taken with the MinXray HF80+ (MinXray, Northbrook, IL), standardized at 70 kvp, 15 ma, and 0.1 second with a focal distance of 1 m for each projection. Two radiographic projections (lateromedial and dorso-45 -latero-palmaro/plantaro-medial view) of each limb were obtained before and after the ESWT treatment protocol. A board-certified radiologist (KLA) reviewed the radiographs and was blinded to treatment versus control limb status. Each radiograph was evaluated for evidence of periosteal or endosteal reaction or changes on the dorsal cortex of the metacarpus or metatarsus bone. Each radiograph was scored for the presence or absence of periosteal reaction, endosteal reaction, and dorsal cortical irregularities. days posttreatment within number of treatments, and number of treatments as main effects and their interactions. Horses were considered as a random variable. Normal distribution of data and analysis of homogeneity of variances were confirmed using Shapiro Wilk and Levene tests, respectively. A paired Student s t-test was used to compare differences between means. Significance was set at P <.05. A trend was considered to be present at P <.10. Data are expressed as mean ± SEM. RESULTS No adverse reactions to the ESWT were noted during or immediately after treatment or during the entire study. Scintigraphy All the possible interactions between limbs, treatments, and number of treatments were evaluated. No interactions were found, and, therefore, only the main effects are reported. The average count/pixel ratio between the middiaphysis and the proximal metaphysis differed (P <.0001) between the fore- (0.72 ± 272

6 M. Verna, T. A. Turner, and K. L. Anderson 0.015) and hindlimbs (0.80 ± 0.019). Therefore, the data were analyzed separately between foreand hindlimbs. In the forelimbs, the average count/pixel ratio of the treated limbs (0.72 ± 0.024) was not significantly different when compared with the average of the control limbs (0.71 ± 0.018) in any of the four treatment periods (Figure 1). Similarly, in the hindlimbs, the average count/pixel ratio of the treated limbs (0.81 ± 0.029) was not significantly different from the average of the control hindlimbs (0.79 ± 0.024) in any of the four treatment periods (Figure 2). The average count/pixel ratio between the middiaphysis and the proximal metaphysis of the foreand hindlimbs differed among the number of treatments over time (P <.0001) for the treated limbs as well as the control limbs. Thermography All the possible interactions between limbs, number of treatments, and days after treatment within numbers of treatment were evaluated, and no interactions were found; therefore, only the main effects are reported. The mean temperature of the forelimbs (29.41 ± C) was lower (P <.0005) than the mean temperature of the hindlimbs (31.34 ± C). Thus, fore- and hindlimb data were analyzed separately. In the forelimbs, the average temperature of the treated limbs (29.41 ± C) was not signif- Forelimb Count/Pixel Ratio Scintigraphy Revealed No Significant Differences between Treated and Control Forelimbs ESWT Treatment Treated Control Figure 1. The mean (±SEM) count/pixel ratio between the middiaphysis and the proximal metaphysis of treated and control forelimbs after each of the four ESWT treatments. Hindlimb Count/Pixel Ratio Scintigraphy Revealed No Significant Differences between Treated and Control Hindlimbs ESWT Treatment Treated Control Figure 2. The mean (±SEM) count/pixel ratio between the middiaphysis and the proximal metaphysis of treated and control hindlimbs after each of the four ESWT treatments. 273

7 Average Forelimb Temperature ( C) Thermography Revealed No Significant Differences between Treated and Control Limbs Days after ESWT Figure 3. The daily mean (±SEM) posttreatment skin temperature as measured by thermography for all four treatments for treated and control forelimbs. icantly (P <.496) different when compared with the average temperature of the control limbs (29.40 ± C) in any of the four treatment periods. Similarly, in the hindlimbs, the average temperature of the treated limbs (31.40 ± C) was not significantly (P <.061) different when compared with the average temperature of the control limbs (31.27 ± C) in any of the four treatment periods (Figure 3). The mean temperature of the control and treated forelimbs differed among the number of treatments (P <.001). Similarly, the mean temperature of the control and treated hindlimbs differed among the number of treatments (P <.01). The daily variation in temperature of the treated and control limbs within each treatment revealed no significant difference (forelimbs, P =.10; hindlimbs, P =.08) among any of the days (Figure 3). Radiography There was no evidence of periosteal or endosteal reaction or modification of the dorsal cortex in any of the baseline or posttreatment radiographs. Discussion This study documented the scintigraphic, radiographic, and thermographic appearance of the metacarpal and metatarsal areas of adult untrained horses that received nonfocused ESWT. The effect of nonfocused ESWT was assessed using the energy recommended by the manufacturer of mj/mm 2 (2,000 impulses at 2.5 to 3 bar and a frequency of 8 MHz); this is the regimen frequently used in practice. 1 5 The results from this study suggest that nonfocused ESWT as applied in the present study does not have any appreciable effect on bone remodeling, superficial skin temperature, or radiographic appearance in untrained adult horses as evaluated by sequential scintigraphy, thermography, and radiography. It is possible that microscopic changes in the metacarpal or metatarsal bone or periosteum occurred with the nonfocused ESWT treatment; however, because this was a nonterminal study, histopathologic changes could not be evaluated. In one of the first terminal studies in horses, one treatment with 1,000 pulses of the focused ESWT (Orthowave MTS, Konstanz, Switzerland) applied over the dorsal aspect of the middiaphysis of the metacarpal and metatarsal bones resulted in limited subperiosteal and endosteal hemorrhage (observed grossly at the focal point after treatment) and areas of reddening of the bone surface at the focal point. 15 Treated Control 274

8 M. Verna, T. A. Turner, and K. L. Anderson Microscopically, the walls of the vessels in the osteons were disrupted; however, no evidence of microfractures was observed in the bone tissue. 15 In the study by McClure and associates, 15 very high energy densities (0.89 and 1.80 mj/mm 2 ) were achieved using an alternate type of generator (electrohydraulic) compared with the present study. McClure et al did not use radiographic or scintigraphic assessment of the bone, and thus that information cannot be compared. However, those authors make the point that relatively low energy levels do not stimulate bone formation. 15 The results of the present study corroborate that statement because they indicate that the nonfocused ESWT technique and treatment regimen commonly used in practice do not stimulate enough bone remodeling to be detectable by bone-phase scintigraphy and radiographic appearance. This does not indicate that the treatment does not have a clinical effect; it means only that the treatment did not affect the clinical parameters measured in normal horses. One of the major weaknesses of this study is the small number of horses used, which reduced the power of the statistics. This was a pilot study, and the small number of individuals was related to the high costs of the modalities used in a sequential basis. To reduce the impact of this aspect on the statistics, we standardized many factors (e.g., level of exercise, diet, age) that otherwise are very difficult to standardize in clinical cases. It is possible that studies using larger groups of animals could reveal statistically significant changes in scintigraphic bone uptake. However, the results of the present study suggest that veterinarians should not expect a detectable difference in bone scans in an individual patient after nonfocused ESWT treatment on normal bone. The sensitivity of radiography to assess bone turnover is not optimal because 30% of the total mineral content needs to be added or removed to be detected radiographically. 10 The use of bone densitometry could potentially have increased the objectivity of this modality. Radiography was chosen because it is the most commonly available diagnostic technique for equine practitioners, and this modality has been used in previous clinical case reports to evaluate changes in the treated area with ESWT. 1,5 A variety of factors may have contributed to the lack of treatment effect observed in the present study, including the specific mechanism of shock wave generation, the nature of the waveforms generated, and the transmission of those waves through treated tissue. It is possible that a different type of shock wave generator may have been able to induce scintigraphic, thermographic, or radiographic changes in the normal equine metacarpal and/or metatarsal bones. The pneumatic generator selected for this study produces shock waves that are transmitted radially from the source to the treated tissue, and the waveforms generated are different from those produced by focus-type generators. 16 Additional factors, such as energy flux density of the shock wave and the number of pulses, may also influence the effect of ESWT on treated bone. 17 A recent publication of an in vitro study showed that the shock wave generated by a focus device did not produce a significant difference in the modulus of elasticity or microstructural changes of equine cortical bone when compared with a nonfocused generator using a similar amount of energy (0.15 and 0.16 mj/mm 2, respectively) for 2,000 pulses. 18 Neither treatment (focused or nonfocused generator) was able to induce detectable microstructural changes of the equine cortical bone. 18 However, an in vivo study comparing the two types of generators should also be undertaken to evaluate whether there are any detectable differences in living equine tissue. 275

9 CONCLUSION The commonly used manufacturer s protocol and recommended settings for four treatments of nonfocused ESWT (Swiss DolorClast Vet System) on normal adult metacarpal and metatarsal bone does not produce evidence of bone remodeling as detected by scintigraphy or gross evidence as seen by radiography. Further nonfocused ESWT does not appear to cause changes in the local perfusion to the treated area as detected by thermography. This study therefore suggests that the successful outcome described in clinical patients suffering such musculoskeletal conditions as suspensory ligament desmitis, osteoarthritis of the low-motion joints of the tarsus, and dorsal metacarpal disease treated with nonfocused ESWT is probably not the result of a marked increase in bone remodeling or an increase in circulation that speeds the healing process. However, further studies are necessary to determine if the effect of nonfocused ESWT depends on the presence of an underlying lesion in the bone or whether a horse s age or training status may have some influence on the ability to detect changes in the parameters measured in this study. ACKNOWLEDGMENTS The authors thank Stephanie Valberg, DVM, PhD, DACVIM, University of Minnesota College of Veterinary Medicine, for assistance with the preparation of this manuscript. REFERENCES 1. Boening KJ, Loffeld S, Weitkamp K, Matuschek S: Radial extracorporeal shock wave therapy for chronic insertion desmopathy of the proximal suspensory ligament. Proc AAEP: , Quirion PA: Radial shock wave therapy on equine orthopedic problems. J Equine Vet Sci 20: , McCarroll GD, McClure S: Extracorporeal shock wave therapy for treatment of osteoarthritis of the tarsometatarsal and distal intertarsal joints of the horse. Proc AAEP: , Crowe OM, Dyson SJ, Wright IM, et al: Treatment of chronic or recurrent proximal suspensory desmitis using radial pressure wave therapy in the horse. Equine Vet J 36: , Stack-Aguirre EP, Quirion PA, Waldsmith JK, et al: Clinical results of the use of an extracorporeal shock wave therapy device for the treatment of chronic lameness conditions in horses. Proc Assoc Equine Sport Med:14 17, Palmer SE: Treatment of dorsal metacarpal disease in 29 Thoroughbred racehorses with radial extracorporeal shock wave therapy. Proc NAVC:12 16, Delius M, Drainert K, Al Diek Y, et al: Biological effects of shock waves: In vivo effect of high energy pulses on rabbit bone. Ultrasound Med Biol 21: , Haupt G: Use of extracoproeal shock waves in the treatment of pseudoarthoris, tendinopathy and other orthopedic diseases. J Urol 158:4 11, Wang CJ, Wang FS, Yang KD, et al: Shock wave therapy induces neovascularization at the tendon-bone junction. A study in rabbits. J Orthop Res 21: , Dyson SJ, Pilsworth RC, Twardock AR, Martinelli MJ: Equine Scintigraphy. Newmarket, Suffolk, UK, EVJ, Butler JA, Colles CM, Dyson SJ, et al: Clinical Radiology of the Horse, ed 2. Oxford, UK, Blackwell Science, Turner TA, Purohit RC, Fessler JF: Thermography: A review in equine medicine. Compend Contin Educ Pract Vet 8(11): , Love TJ: Thermography as an indicator of blood perfusion. Ann NY Acad Sci 335: , Turner TA, Wolfsdorf K, Jourdenais J: Effect of heat, cold, biomagnets and ultrasound on skin circulation in the horse. Proc AAEP: , McClure SR, VanSickle D, White R: Extracorporeal shock wave therapy: What is it? What does it do to equine bone? Proc AAEP: , Cleveland RO, Chitnis PU: Comparison of the acoustic and cavitation fields produced by shock wave therapy devices with different generating principles [abstract 2]. Proc 5 th Int Congr Int Soc Musculoskeletal Shockwave Ther:2, Available online at www. ISMST.com; accessed August McClure SR, Van Sickle D, White R, et al: Effect of extracorporeal shock wave therapy on bone. Vet Surg 33:40 48, Pauwels FET, McClure SR, Amin V, et al: Effects of extracorporeal shock wave therapy and radial pressure wave therapy on elasticity and microstructure of equine cortical bone. Am J Vet Res 65: ,