Indications for Administration of JHPs

Osteoarthritis—Probably the most common reason that veterinarians recommend administration of JHPs is for use in dogs with musculoskeletal pain related to osteoarthritis. There have been only a limited number of in vivo studies whose results support the use of JHPs in dogs with osteoarthritis. In 1 study,⁷ investigators performed a randomized, double-blind, positive-control trial involving 35 client-owned dogs. Dogs were assigned by use of a systematic randomization procedure to a glucosamine–chondroitin sulfate group or a carprofen group and treated in accordance with the manufacturer's directions. A placebo-control group was not included. Outcome measures were subjective and included lameness, joint mobility, signs of pain, and degree of weight bearing. Dogs were assessed on days 14, 42, 70, and 98 after onset of treatment. Analysis of results revealed significant improvements in signs of pain, weight bearing, and disease severity by day 70, which indicated that supplementation with glucosamine–chondroitin sulfate had a positive effect on osteoarthritis-affected dogs.

In another study,⁸ investigators conducted a randomized, double-blind, placebo-control parallel group study of P54FP in 61 client-owned osteoarthritis-affected dogs. Dogs were orally administered P54FP twice daily and evaluated 4, 6, and 8 weeks after the start of treatment. A significant clinical improvement was detected by the investigators in the dogs following the administration of P54FP, but the objective measure of osteoarthritis (ie, peak vertical force) did not change significantly. Interestingly, there was not a significant clinical improvement in their dogs on the basis of the owners' perceptions.

Effects of the green-lipped mussel (Perna canaliculus) were evaluated in blinded, subjectively assessed trials.^9–11 In one of those studies,⁹ investigators administered green-lipped mussel extract to 81 dogs with presumptive degenerative joint disease. The extract or a placebo was administered for 56 days, and all dogs were then administered the extract for an additional 56-day period (days 57 through 112). By day 56, the dogs administered the extract had a significant improvement in clinical signs but a nonsignificant (P = 0.053) improvement in musculoskeletal scores, compared with results for the dogs administered the placebo. By day 112, there were no differences between the groups.

In 2 other studies^10,11 evaluating the green-lipped mussel, investigators used 31 dogs obtained from an animal shelter. Dogs were allocated to 2 groups (treatment and control group); all dogs were fed the same diet, except the diet for dogs in the treatment group was supplemented with pulverized, freeze-dried, whole-flesh green-lipped mussels (0.3% of the diet). After 6 weeks, dogs in the treatment group had a significant improvement for arthritis score, compared with the results for dogs in the control group.

Finally, a B serrata resin extract was fed to 24 dogs with chronic joint and vertebral disease in a multiple-practice study.¹² Dogs were provided with their regular diet, and the extract was fed (400 mg/10 kg of body weight) once daily for 6 weeks. After 2 weeks, 17 of the 24 (71%) dogs had an improvement for lameness scores. By the end of the study period, a significant reduction in severity of clinical signs (eg, subjective analysis of local pain or stiff gait) was detected, which suggested that B serrata can be used as a palliative support in dogs with osteoarthritis.

It should be mentioned that although no clinical trials have been conducted to evaluate the efficacy of omega-3 fatty acids in dogs or cats with osteoarthritis, in vitro evidence supporting the role of omega-3 fatty acids exists,¹³ and the efficacy of green-lipped mussel products may, at least in part, be attributable to the omega-3 content.¹⁴ Despite the lack of evidence regarding the efficacy of omega-3 fatty acids in animals with osteoarthritis, omega-3 fatty acids are widely recommended as part of a multi-modal approach for the management of osteoarthritis^15,16 and omega-3 fatty acids are reported to have anti-inflammatory effects.^17,18 Further research on the effect of omega-3 fatty acids in animals with osteoarthritis is warranted.

Despite the positive results discussed above, not all investigators have reported significant treatment effects for clinical trials with such products. Efficacy of a glucosamine–chondroitin sulfate product, carprofen, and meloxicam was evaluated in a prospective, double-blind, placebo-control study¹⁹ involving 71 client-owned dogs with osteoarthritis. In that study, investigators detected no improvement in ground reaction forces in the group administered glucosamine–chondroitin sulfate.

Nonetheless, in 1 report,²⁰ a systematic review of the literature revealed that a moderate amount of evidence exists that there is a scientifically valid relationship between administration of green-lipped mussel products, P54FP, polysulfated glycosaminoglycans, and a combination of chondroitin sulfate, glucosamine hydrochloride, and manganese ascorbate (as well as carprofen and etodolac) and clinical benefit in dogs with osteoarthritis.

Although the author is not aware of any studies conducted specific to nutritional supplementation in osteoarthritis-affected cats, a multitude of JHPs are available with recommendations for administration to cats. Dosages and efficacy appear to have been presumed or extrapolated from clinical trials performed in other species; however, 1 safety study²¹ performed in 15 cats revealed that no important alterations in hemostatic, biochemical, or hematologic variables were detected after cats received an orally administered chondroprotective agent daily for 30 days.

Post-traumatic or postsurgical administration—A glucosamine hydrochloride–chondroitin sulfate combination product was evaluated in 16 dogs that underwent unilateral CCL transection.²² The dogs were assigned by use of a systematic randomization method to 1 of 4 groups (sham reconstruction, sham reconstruction plus the combination product, CCL reconstruction, and CCL reconstruction plus the combination product, respectively). Dogs provided the glucosamine hydrochloride–chondroitin sulfate product had altered synovial fluid concentrations of 3B3 and 7D4 epitopes, which indicated that this JHP modulated articular cartilage metabolism.

In contrast to the CCL study, investigators reported in a blinded, controlled study²³ that a diet containing high amounts of the omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid did not impact the production or activity of MMPs or TIMP-2 in client-owned dogs with acute rupture of the CCL. At certain time points during the study, concentrations of the inactive proform of MMP-2 and MMP-9 as well as the TIMP-2 concentration were altered in the unaffected limb of the dogs receiving a diet supplemented with fish oil. Analysis of the results of that study suggest that omega-3 fatty acids may be beneficial in joints with mild to moderate inflammation, such as the uninjured limb of dogs with acute unilateral rupture of the CCL in which the dogs preferentially bear more weight on the uninjured contralateral limb than on the affected limb.

Prophylactic administration—One indication that is almost universally overlooked is the use of these products in young, healthy animals before musculoskeletal trauma, injury, or the onset of osteoarthritis. This may be particularly salient in breeds of animals predisposed to joint disorders or in athletic dogs prior to initiating a training program. This potential prophylactic use of JHPs is supported on the basis of a randomized, double-blind, placebo-control trial²⁴ in which a glucosamine hydrochloride–chondroitin sulfate combination product was administered to 32 dogs with experimentally induced synovitis. The study revealed that dogs administered a glucosamine hydrochloride–chondroitin sulfate product for 21 days prior to experimental induction of synovitis had significantly less evidence of joint inflammation (assessed by use of nuclear scintigraphy on day 48), compared with results for dogs in both a control group and a group administered the glucosamine hydrochloride–chondroitin sulfate product only after induction of synovitis. Furthermore, this prophylactically treated group of dogs also had significantly lower lameness scores on days 12 through 19, 23, and 24, compared with lameness scores for the other groups.

The potential prophylactic benefit of JHPs could also be hypothesized on the basis of results from a study on ASU in 24 healthy male Sheepdogs that were allocated by use of a systematic randomization method into 1 of 3 groups (control, low-dose ASU, and high-dose ASU groups, respectively). Samples of synovial fluid were collected before and at the end of the first, second, and third month of the study. In both the low- and high-dose ASU groups, synovial fluid concentrations of TGF-B₁ and TGF-B₂ were significantly higher than concentrations in the control group, which suggested that ASU may exert a disease-modifying effect by stimulating the synthesis of matrix components (such as collagen type II and proteoglycan) via TGF-B, which is capable of counteracting the effects of interleukin-1.²⁵

Potential Contraindications and Safety Issues

Orally administered JHPs are generally considered safe on the basis of the high LD₅₀ values and the dearth of known serious or persistent adverse effects. Despite the widespread sentiment that all JHPs are universally efficacious and safe, potentially important safety issues exist that may contraindicate the administration of JHPs. Veterinarians and consumers should be cognizant of several specific issues related to the administration of JHPs.

Contamination—Pesticides, heavy metals (including cadmium and lead), and dimethyl sulfoxide have been identified as contaminants in some nutritional products.⁵ Furthermore, 2 research groups have identified complex toxin profiles of P canaliculus, including yessotoxins, pectenotoxins, and okadaic acid produced by phytoplanktonic microalgae.^26,27 Cadmium, chromium, copper, lead, and nickel have all been identified in the green-lipped mussel Perna viridis from Hong Kong.²⁸ Organic pollutants such as polychlorinated biphenols, organochlorine pesticides, and dioxin-like compounds have also been identified in P viridis.²⁹ In 1 report,³⁰ noroviruses, hepatitis A virus, and feline calicivirus were identified in mussels, and the hepatitis A virus was persistent in that it retained infectivity after commercial treatment in acidic conditions for up to 4 weeks. Whether these or other viruses pose a public health risk for mussel-containing nutritional products has not been evaluated, but this area is certainly worthy of further research.

Metabolic—One area in which there continues to be disagreement is with regard to safety when administering glucosamine-containing products to patients with type 2 diabetes mellitus. In 1 study,³¹ the risk is theoretic and based on findings in animals with experimentally induced disease that have been administered high doses of glucosamine IV. In that study,³¹ oral administration of human glucosamine–chondroitin sulfate supplements to human patients with well-controlled diabetes and other humans without diabetes mellitus or glucose intolerance did not impact short-term glycemic control. Those findings were confirmed in a placebo-controlled, double-blind, randomized clinical trial³² involving 34 human patients with type 2 diabetes mellitus because oral administration of glucosamine–chondroitin sulfate products did not significantly alter glucose metabolism. Finally, a randomized, placebo-controlled, double-blind crossover study³³ was performed in 20 lean and 20 obese human patients, who were orally administered 500 mg of glucosamine or a placebo every 8 hours for 6 weeks. Glucosamine did not cause a significant worsening of insulin resistance or endothelial dysfunction in the lean or obese patients.

In contrast, fasting serum glucose, insulin, and lipid concentrations were evaluated before and after oral administration of glucosamine for 6 weeks.³⁴ In 38 human volunteers with no known abnormalities of glucose homeostasis, those with the poorest underlying insulin sensitivity were at risk for worsening of insulin resistance and vascular function when administered glucosamine, as determined by use of the homeostasis model assessment and quantitative insulin sensitivity check index.

In a study³⁵ involving the use of laboratory or domestic animals, 2 strains of rats bred to be highly sensitive to sugar-induced insulin resistance were administered glucosamine, chondroitin sulfate, and a glucosamine–chondroitin sulfate combination; there was no impact on blood pressure (which is an early sign of insulin resistance) in any of the rats. Furthermore, the safety of glucosamine and chondroitin sulfate for use in dogs and cats has been reported.^21,36

One additional potential safety issue is the use of sodium-containing products (eg, sodium chondroitin sulfate) in animals with chronic renal failure that have been prescribed sodium-restricted diets. Although low-sodium feeds are widely available and marketed for this purpose (apparently to minimize increases in blood pressure), there is little scientific data in human or veterinary medicine to support the hypothesis that limiting sodium intake has any impact on the course of renal disease. The impact of high- and low-sodium diets on blood pressure in cats was evaluated in 2 studies.^37,38 Both studies revealed that dietary sodium did not alter blood pressure (ie, systemic, systolic, diastolic, or mean arterial blood pressures). Furthermore, investigators in one of those studies³⁸ concluded that feeding cats a diet low in sodium chloride may contribute to hypokalemic nephropathy and progressive renal damage. Nonetheless, the amount of sodium included in products containing sodium chondroitin sulfate is likely to be extremely low. Thus, this remains a controversial issue that raises the question as to whether the amount of sodium contained in JHPs is clinically important.

Use of the ACCLAIM System to Identify and Recommend a Quality Product

In addition to identifying animals in which use of JHPs are indicated or potentially contraindicated, veterinarians are also relied on to recommend products to their clients. The ACCLAIM system has been developed to help practitioners rapidly evaluate a JHP so that they can identify and recommend products more likely to be both safe and effective (Appendix). The system includes assessment of manufacturer information, label claims, and ease of calculation of recommended doses.

Conclusions

Clinical trials that support the use of glucosamine, chondroitin sulfate, P54FP, green-lipped mussel products, omega-3 fatty acids, B serata, and ASU in dogs with osteoarthritis, in dogs after trauma or surgery, or in healthy dogs as a prophylactic measure have been reported. Because of the limited number of in vivo studies and therefore the lack of evidence on which to base decisions, there remains a need for additional nonsubjective, randomized, controlled clinical trials in dogs and cats to support the aforementioned indications for the use of JHPs and to further assess the safety of these products. Despite the high LD₅₀ associated with the components of JHPs, potential contraindications associated with nutritional products exist and are worth considering when recommending such products to clients. By adhering to the ACCLAIM system described here, veterinarians can rapidly assess a JHP and confidently recommend a high-quality product, when indicated.