Alternative therapies for managing mobility: Nonsurgical management of cranial cruciate ligament rupture (Sponsored by Iams)

Osteoarthritis (OA) affects about 20% of canine patients.1 However, that estimate is probably low because there are many dogs with undiagnosed OA for which owners have not sought treatment. Pain response to OA varies greatly among patients, so the management strategy must be tailored to the individual for the best response. The typical OA management armamentarium consists of weight loss, physical therapy, nonsteroidal anti-inflammatory medications, and nutritional supplements. Additional therapies available for managing patient pain from OA include specially formulated diets, synovial fluid supplementation, acupuncture, additional pharmacologic medications, and other forms of complementary medicine.

Since excessive weight or obesity is a major contributing factor to the development and progression of OA, the first line of therapy for treating patient pain associated with OA should be aimed at reducing body weight and, more specifically, minimizing body fat. (For more on the role of weight loss in managing OA, see the Related Link "Current concepts in the management of osteoarthritis" below.) Traditionally, it was thought that obesity affected the outcome of patients with OA through excessive mechanical load on the joints during normal weight bearing.2 In people, there is a strong correlation between obesity and OA of the knee. But there is also a correlation between OA of the hand and obesity, suggesting that systemic and not just mechanical stress contributes to OA development. Adipokines, inflammatory mediators released by white adipose tissue, are known to contribute to insulin resistance, cardiovascular disease, cancer, and OA. Those most commonly studied include adiponectin, leptin, and resistin.

Adiponectin

Adiponectin, identified as a 30-kDa protein, is secreted from the adipose tissue into circulating blood and influences systemic metabolism. Its expression increases insulin sensitivity. In contrast to most secreted proteins from adipose tissue, which rise with increased fat mass, adiponectin levels decrease with increasing adiposity.3 More intriguingly, adiponectin appears to decrease the obesity-related risk factors, unlike other adipose tissue secretory proteins, which contribute to the health risks associated with obesity, diabetes, and cardiovascular disease.

Leptin

Leptin, a 16-kDa protein and a product of the obesity gene, is synthesized and secreted predominantly by adipose tissue. With circulating levels directly proportional to the total amount of body fat, leptin plays an important role in whole body metabolism, regulating food intake and energy balance, as well as assisting in the control of homeostasis, reproductive function, the immune system, and numerous other body functions.4 Binding to receptors of the hypothalamus, leptin signals food satiety and reduces appetite. Evidence suggests that, in general, obese people have unusually high circulating levels of leptin. As leptin levels rise, resistance in target cells develops. Consequently, it no longer acts to control food intake. Furthermore, leptin is proinflammatory and is likely involved in the pathogenesis of OA, but at this time it is unclear whether increased levels are protective, due to the anabolic effects it has on chondrocytes. More recent studies have shown it to be detrimental, since women have higher levels of leptin and also higher incidence of OA.4

Resistin

Resistin is another proinflammatory adipokine. In humans and likely in dogs, it acts primarily by stimulating macrophages to secrete proinflammatory cytokines. Circulating resistin levels are known to increase with increasing fat mass. Resistin causes tissues to be less sensitive to insulin, and high levels of resistin are known to contribute to the development of insulin resistance and type 2 diabetes mellitus.5

Obesity greatly affects the outcome for dogs diagnosed with OA. In one lifelong study, overweight dogs with OA had more radiographic evidence and clinical signs than dogs kept at an ideal body condition score.6 Another study revealed that lameness scores improved for overweight dogs with OA of the hip with a weight loss of at least 11% of body weight.7 An additional study revealed that a combined weight loss and physical therapy program versus weight loss alone improved force plate values in overweight dogs diagnosed with unilateral OA.8 Furthermore, physical therapy reduces pain and inflammation, improves strength and balance, increases range of motion, and restores a more normal joint function. In many cases, medications can also be reduced because of improved pain relief.9

Obesity and cranial cruciate ligament rupture

In addition to the role obesity plays metabolically in the development of OA, it is also considered a risk factor for cranial cruciate ligament rupture (CCLR).10-11 CCLR is the most common orthopedic condition diagnosed in dogs and is known to lead to the development of OA and lameness. Most studies indicate that female dogs have a higher incidence of CCLR,12 which is hypothesized to be because spayed female dogs have a higher incidence of obesity.13 A recent study detected an increased prevalence of CCLR in both male and female sterilized dogs, leading to the hypothesis that a lack of sex hormones predisposes dogs to CCLR.14 However, no studies to date have prospectively determined if there is a correlation between adipokine levels and lameness assessment in dogs undergoing weight loss.

A recent study in dogs with CCLR

Clearly, if one considers the interrelationship of obesity and OA, the subsequent development of OA in dogs with CCLR, and obesity's influence on the development of CCLR, it is not surprising that the inflammation from fat and the corresponding adipokine levels contribute to outcome in overweight dogs with CCLR. Therefore, decreasing body fat mass in dogs with CCLR should improve outcome and could potentially decrease progression of OA.

Based on these considerations, we elected to study a specific, common cause of OA (unilateral CCLR) and to compare the outcome of medical management alone versus standard surgical therapy. In a prospective, randomized study, we used objective and subjective measures of lameness and quality of life in overweight and obese dogs with unilateral CCLR to compare outcomes in dogs that underwent both surgical and nonsurgical management and dogs that underwent nonsurgical management alone. We hypothesized that dogs treated for CCLR with the combination of surgical and nonsurgical management would have a better outcome than those treated with nonsurgical management alone.

The 40 dogs included in the study were overweight (body condition score > 5/9) but in good general health, and they had no clinical signs of orthopedic disease other than from unilateral CCLR. We randomly assigned dogs to either the surgical or nonsurgical management group. All dogs in the surgery group underwent a tibial plateau leveling osteotomy (TPLO). Both groups received individualized weight reduction plans with a therapeutic low-calorie, weight loss food; a physical therapy protocol consisting of supervised and at-home sessions; and daily NSAID medication for 12 weeks of the study.

We evaluated subjects at four points: Day 0, Week 6, Week 12, and Week 24. At each evaluation, we performed a physical examination, collected blood for adipokine measurements (adiponectin, resistin, and leptin, not collected at Week 6), and performed subjective and objective gait analyses. Also, the owners completed two quality of life questionnaires (including the Canine Brief Pain Inventory*). At the Day 0, Week 12, and Week 24 time points, we also performed blood work (not at Week 24), calculated body fat percentage (using dual energy x-ray absorptiometry), and took radiographs of the stifle. (Radiographs were also taken at Week 6 for the surgery group.)

To date, not all of the 40 dogs have completed the 24-week portion of the study. Preliminary findings reveal no differences in age, gender, breed, duration of injury, body weight, body condition score, and body fat percentage between the surgical and nonsurgical groups at Day 0. In addition, these early analyses reveal that there is no difference in ground reaction forces between the surgical and nonsurgical groups at any time point.

Dogs lost an average of 1.7 kg of their body weight (4.5%) by Week 6 and 4.95 kg (10.5%) by Week 12. Dogs had a decrease in their body condition score of 0.5 by Week 6 and 1.5 by Week 12, with an average score of both groups of 5.25/9 by Week 12. The average body fat percentage for all dogs was 31.9% at Day 0 and 23.2% at Week 12. Matched pair analysis revealed a significant difference (P value < 0.005) in weight, body condition score, and body fat percentage between Day 0 and Week 12 for dogs in both groups. Finally, the results from the owner questionnaires suggest that dogs in both groups improved significantly, although the results have not been statistically evaluated yet.

Preliminary multivariate analyses (n=14) were performed to test for correlations between the change in adipokine levels, body fat percentage, weight, amount of fat tissue (grams), amount of lean tissue (grams), and ground reaction force index from Day 0 to Week 12 and Week 24 time points. The correlations were first tested by group (surgical versus nonsurgical) and then regardless of group. There were no significant correlations. Then, analyses were performed to test for correlations between specific values for adipokines, weight, and ground reaction force index at the Week 6 time point and adipokine levels, weight, body fat percentage, weight, amount of fat tissue (grams), amount of lean tissue (grams), and ground reaction force index at the Day 0, Week 12 and Week 24 time points. The analyses were again performed based on group (surgical versus nonsurgical) and regardless of group.

For the surgical group, there was no relevant correlation between any of the variables evaluated. For the nonsurgical group, relevant correlations were all specific to leptin levels and correlated at each time point to one or more of the variables: body fat percentage, weight, and amount of fat tissue (grams). No correlations were noted for any of the variables for ground reaction force index. When evaluated regardless of group, relevant correlations were again all specific to only leptin levels and correlated at only the Day 0 and Week 24 time point to one or more of the variables: body fat percentage, weight, and amount of fat tissue (grams). There was again no correlation to ground reaction force index.

The early findings of this study revealed significant early improvement in limb function in dogs with a CCLR injury regardless of treatment group. This improvement was demonstrated both subjectively, as evidenced by owner questionnaire and clinical observation, and objectively, as evidenced by significant improvement in their ground reaction forces (Table 1). Weight loss and a decrease in body fat composition were accomplished in all dogs by the 12-week evaluation. Further analyses will be performed once all dogs have completed the 24-week time point.

Table 1. Average values for ground reaction force index, leptin levels, and body fat percentage

This study reveals that nonsurgical management plays an important role in the early recovery of dogs with a unilateral CCLR injury and may provide for an acceptable outcome for patients. A correlation in circulating adipokine levels to ground reaction force index was not confirmed in the preliminary analyses, but repeat analyses will be performed once all dogs have completed this study. Leptin levels did have a good correlation to body fat percentage, weight, and amount of fat tissue, as previously reported, and could be used to help clinicians determine an ideal patient-specific body fat percentage more explicitly than a body condition score.

*The CBPI is a questionnaire with two dimensions: severity and interference. The severity dimension consists of a four-question 0-10 numerical rating scale assessment of the severity of pain. The responses from those four questions can be averaged to obtain a severity score for the dog. The interference dimension consists of a six-question 0-10 numerical rating scale assessment of how the pain interferes with the dog's normal functioning. The responses from those six questions can be averaged to obtain an interference score. In addition, there is a one-question Likert scale global assessment of the dog's overall quality of life, which gives the owner the opportunity to address the relative importance of the pain.

Vicki Wilke, DVM, PhD, DACVS, Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108.

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