Introduction

Degenerative joint disease (DJD), also known as osteoarthritis (OA), is a chronic, debilitating disorder affecting a wide range of animal species and humans. It has been reported that OA may affect up to 20% of the canine population over one year of age, and likely a similar percentage of cats (and has increased in incidence 38% in dogs and 67% in cats since 2007 according to data from Banfield Pet Hospitals). It is estimated that more than 11 million dogs, or 1 of out 5 dogs, in the US alone, were affected by OA. It is regarded as the number 1 cause of chronic pain in dogs. Unlike in humans where the DJD is primarily as a result of aging and “wear and tear,” DJD in dogs and cats is typically secondary, initiated by a previous insult to the joint or joint instability. It is a common cause of joint failure with stiffness, loss of mobility, and varying degrees of inflammation and pain. It is a slowly progressive condition for which no specific treatment can restore the articular cartilage to normal. Therefore, early identification of DJD is critical to provide patients with the most effective treatment strategies and relief of clinical signs.

What Is Cartilage?

Cartilage is made up of three main components:

1.  Chondrocytes, which by weight comprise the smallest proportion of the cartilage

2.  Extracellular matrix (ECM), made up of type II collagen fibers and proteoglycans (PG), which serve to trap water within the matrix

3.  Water, which makes up 70% of the cartilage by weight and gives cartilage its unique biomechanical properties

Chondrocytes function to synthesize the components of the ECM and also produce the enzymes that degrade the ECM, thus regulating cartilage anabolism and catabolism. Various cytokines and growth factors balance these anabolic and catabolic activities in healthy cartilage. In a joint affected by DJD, catabolic processes outweigh the anabolic processes. This imbalance is driven by cytokine cascades and inflammatory mediators, such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). It results in reduced proteoglycan concentration, altered aggregation of the PGs and ultimately, reduced ability of the ECM to retain water. Collagen fibers also become disrupted. These cytokines and other cytokines (IL-8, IL-6, etc.) also upregulate the expression of proinflammatory enzymes cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) that lead to increased production of prostaglandin E₂ (PGE₂) and nitric oxide (NO).

Although we tend to focus on the articular cartilage when discussing OA, it is important to remember that OA is a global process within the joint, affecting not only the hyaline cartilage, but the synovial membrane, synovial fluid, and subchondral bone as well. Clinical effects in patients suffering from OA include joint instability, joint malalignment, joint pain and diminished range of motion, joint effusion, and varying degrees of lameness and immobility. The patient, as whole, begins to lose muscle strength and cardiovascular fitness while gaining weight. This catabolic process takes on a “snowball effect” that affects the family interactions with the pet and becomes difficult to reverse. It is important to remember that once patients begin showing these signs, the disease process is typically quite advanced.

Recent years have seen a dramatic shift toward multimodal management strategies for OA management, including anti-inflammatory medications, analgesics, therapeutic modalities, therapeutic exercise, and nutraceuticals or so called “disease-modifying osteoarthritis agents” (DMOAs). The potential benefits of the majority of these recommendations are readily recognized.

Where’s the Evidence for Nutraceuticals?

Adequan (Novartis)

Adequan is probably the most well-known and frequently used DMOA and is chemically referred to as a polysulfated glycosaminoglycan (PSGAG). It is typically given intramuscularly (IM) and studies have shown that it does reach therapeutic levels in serum, synovial fluid, cartilage and tendons. It modifies the progression of OA by maintaining a more normal cartilage histology through stimulation of increased glycosaminoglycan (GAG) synthesis by chondrocytes and inhibition of destructive enzymes such as MMPs. Though experimental evidence of Adequan’s positive anabolic effect on cartilage is conflicting, its ability to decrease cartilage catabolism has been shown in numerous studies on both horses and dogs. Adequan also has a poorly understood anti-inflammatory effect. Ultimately, the PSGAG allows the cartilage to hold more water and makes it more resistant to degradation. For optimal results, Adequan should probably be used earlier in the disease process than it has typically been employed in the past. In dogs, a dosage of 5 mg/kg intramuscularly (IM) twice weekly is commonly recommended.

Glucosamine-Chondroitin Combination

Glucosamine is an amino monosaccharide unit of glycosaminoglycan, which is the building block of the cartilage matrix seen within joints. Its mechanism of action may involve inhibition of inflammatory enzyme activity and stimulation of glycosaminoglycans (GAG) synthesis. Chondroitin sulfate is a long-chain polymer of repeating disaccharide units containing galactosamine sulfate and glucuronic acid and constitutes the majority of glycosaminoglycans in cartilage found on the moving surfaces of joints, or articular cartilage. Its bioavailability is well documented with up to 70% absorption after oral administration in animals and humans. Its mechanism of action includes contributing to a pool of substrate available for cartilage matrix deposition, inhibition of proteases, stimulation of glycosaminoglycan, and collagen synthesis. When given in combination, glucosamine and chondroitin sulfate reportedly support cartilage production and protect existing cartilage by inhibiting enzymes in the joints that break down cartilage. In one study, treated canine OA with a combination of glucosamine and chondroitin sulfate showed a significant anti-inflammatory effect against chemically induced inflammatory synovitis in dogs.¹

Avocado Soybean Unsaponifiables (ASU)

The mechanism of action of ASU include suppressing TNF-α, IL-1β, COX-2, iNOS gene expression, and prostaglandin E₂ and nitric oxide production in articular chondrocytes and monocyte/macrophages.² In a canine study, ASU caused an increase in both TGF-β isoforms as compared with the control group. TGF-β is stimulator of extracellular matrix production (type II collagen, proteoglycan) in chondrocytes.³ In another canine study, ASU-supplemented group showed reduced development of early OA cartilage and subchondral bone lesions (macroscopic and microscopic lesion severity, subchondral bone loss) as compared to placebo-treated controls.⁴

A recent study evaluated the effect of ASU, CS and ASU+CS combination upon proinflammatory cytokine (IL-1β, TNF-α) expression and PGE₂ production from synovial lining surrogate cells.⁵ The ASU+CS combination inhibited IL-1β and TNF-α expression and PGE₂ production better than either agent alone.⁵

A similar effect was noted in activated feline chondrocytes when ASU+CS+Glu pre-treated cells were compared to positive (untreated activated cells) and negative (non-activated cells) controls.⁶

Epigallocatechin Gallate

Recently, a study was conducted to evaluate the anti-inflammatory effect of ASU+epigallocatechin gallate (EGCG) on activated equine chondrocyte cell culture.¹⁰ EGCG is a major antioxidant component of green tea and has been reported to inhibit the onset and severity of induced arthritis in mice. Chondrocyte activation caused upregulated gene expression of COX-2 and increased PGE2 production and NF-κB nuclear translocation. Individually, ASU and EGCG marginally inhibited COX-2 expression and PGE2 production in activated chondrocytes. In contrast, ASU+EGCG combination reduced COX-2 expression close to that of non-activated control levels, significantly inhibited PGE2 production and NF-κB translocation. NF-κB is an essential transcription factor for COX-2 induction. Inhibition of the NF-κB pathway is known to attenuate COX-2 expression. This study demonstrates that the anti-inflammatory activity of ASU and EGCG is potentiated when used in combination.⁷ Collectively, a large body of evidence supports the conclusion that ASU+CS+Glu inhibits the expression and production of proinflammatory mediators in multiple species (canine, feline, equine and human) and in multiple joint cell lines(chondrocytes and synovial lining cells). Millis et al. have evaluated 8 hound dogs with chronic induced stifle OA. A recent study arm on this dog colony evaluated Dasuquin (Nutramax Labs), a nutraceutical containing Glu+CS+ASU+EGCG. Dogs treated with Dasuquin showed increased peak vertical force similar to that seen with various nonsteroidal anti-inflammatory drugs (NSAIDs) in a previous study arm.⁸ Although the small study population does not permit meaningful statistical analysis, these data suggest the need for larger scale and longer term evaluation of Dasuquin in the restoration of function and pain relief of dogs with chronic OA.

Omega 3 Fatty Acids (Docosahexaenoic Acid, or DHA, and Eicosapentaenoic Acid, or EPA)

The mechanism of action of omega-3 fatty acid is to inhibit the conversion of arachidonic acid (AA). AA is an omega-6 fatty acid producing prostaglandins, leukotrienes, and thromboxanes. These eicosanoids have predominantly vasoactive and proinflammatory effects. Inhibiting the conversion of AA to these eicosanoids is the principal action of most NSAIDs used to treat OA. Eicosanoids produced from EPA and DHA are not potent inflammatory mediators, in contrast to those produced from AA. In a study of dietary supplementation with fish oil omega-3 fatty acids in osteoarthritic dogs showed a significant improvement in weight-bearing (peak vertical force - PVF, improved 82%) as compared with the control group (38%).⁹ The magnitude of improved weight-bearing (+5.6%) was of similar magnitude reported in many NSAID trials. A similar study also showed that food supplemented with fish oil omega-3 fatty acids improved the owner-assessed ability for the ability to rise from a resting position, play, and walk compared with control dogs (whom showed no improvement).¹⁰ Another study showed that a diet supplemented with omega-3 fatty acid allowed for more rapid reduction in carprofen dosage in osteoarthritic dogs as compared to dogs fed a diet with a low omega-3 fatty acid content.¹¹

Green-Lipped Mussel (Perna canaliculus)

Green-lipped mussel (GLM) is a shellfish from New Zealand that obtains nutrients directly from the phytoplankton and minerals in sea water. In all, there have been identified at least 50 nutrients in the GLM, including complex proteins, amino acids, nucleic acids, naturally chelated minerals, enzymes, vitamins, glycosaminoglycans, and fatty acids. GLM has been shown to contain a unique omega-3 fatty acid, eicosatetraenoicacid (ETA), which appears to act as dual inhibitor of arachidonic acid oxygenation by both the cyclooxygenase (COX) and lipoxygenase pathways. In a study, the GLM-enriched diet modified gait in dogs with OA in that the peak vertical force significantly increased over the 60-d period when GLM was introduced into a standardized control diet.¹² Another study showed that GLM alleviated chronic orthopedic pain (veterinary-assessed mobility, owner-evaluated chronic pain index and pain VAS) in dogs compared to control group.¹³

Curcumin

Curcumin is a polyphenol extract from the yellow spice, turmeric. Curcumin has been used for thousands of years in traditional Chinese and Ayurvedic medicine. Curcumin and various curcuminoid extracts have been studied extensively both in vitro and in vivo. In vitro studies have shown anti-inflammatory and antineoplastic effects including decreases in inflammatory cytokines (IL-6, IL-8, COX-2, PGE₂, iNOS, MMP-3, MMP-9) and inhibition of NF-κB and TNF-α signaling. The major challenge with curcumin as an oral supplement is its extremely poor bioavailability (<1%). A recent in vivo study in dogs with OA showed decreased gene expression for inflammatory mediators in dogs receiving curcumin compared to NSAIDs. In this study, the bioavailability of curcumin was enhanced with a phytosome delivery (curcumin combined with phospholipids).

Boswellia serrata

Boswellia serrata is a large tree that grows in India, North Africa, and the Middle East. The resin of this tree, and other members of the Boswellia species, also known as Indian frankincense and has been used for centuries to support joint health. One of the resin extracts, AKBA (3-O-acetyl-11-keto-beta boswellic acid), appears to have the most potent anti-inflammatory effects and has been shown to support structural integrity of joints and connective tissues. In 2003, a randomized, double-blind, placebo-controlled study assessed the efficacy, safety, and tolerability of Boswellia serrata in human osteoarthritis. All patients in the group receiving the active drug reported increased knee flexion, increased walking distance, improvement in capacity to climb stairs and better kneeling, crossed-legged sitting, and squatting ability. In vitro studies have shown significant immunomodulatory and inflammation-modulating effects of Boswellia serrata. Possible modes of action for AKBA include inhibition of the inflammatory mediator 5-lipoxygenase, cytokines (interleukins and TNF-α) and the complement system, as well as inhibition of NF-κB. In a prospective open multicenter study in dogs, statistically significant improvement was noted in lameness and pain in 71% of dogs. In a randomized, placebo-controlled trial in naturally occurring OA in dogs, peak vertical force and daily activity (measured via accelerometers) was improved compared to baseline in groups receiving a supplement containing Boswellia.

Astaxanthin

This ingredient is naturally found in reddish-colored marine algae (Haematococcus pluvialis). It belongs to a group of compounds known as oxygenated carotenoids. Astaxanthin has potent antioxidant and anti-inflammatory properties. It scavenges free radicals and decreases the development of nitric oxide. It is one of the most powerful antioxidants in nature. As comparison, it is 6000 times stronger than vitamin C, 800x stronger than CoQ10, 550x stronger than vitamin E, 75x stronger than α-lipoic acid, and 36x stronger than β-carotene. Astaxanthin reduces and prevents damage from free radicals by donating an electron. This will neutralize the free radical without developing another. In a study, dogs that were fed astaxanthin showed enhanced immune response. Another prospective study in dogs showed astaxanthin alleviates age-related oxidative and inflammatory damage and enhances mitochondrial function. This effect was greater in geriatric than young dogs. Also, in a study where exercise-conditioned dogs were fed supplemental astaxanthin, they demonstrated increased plasma triglyceride levels pre-exercise and prevention of exercise-induced decreases in plasma glucose concentrations compared to controls. This shows astaxanthin may mitigate exercise-induced fatigue and improve exercise performance.

Velvet Antler

The underlying mechanisms of velvet antler (VA) remain poorly understood. Molecules identified as having potentially important local roles in antlers include parathyroid hormone–related peptide and retinoic acid (RA). Both are present in the blastema and in the rapidly growing antler where they regulate the differentiation of fibroblasts, chondrocytes, osteoblasts, and osteoclasts in vitro. VA powder was evaluated on client-owned dogs with osteoarthrosis in a clinical double-blind, and placebo-controlled study. Gait analysis measured with a force plate, clinical signs assessed by an orthopedic surgeon, performances in daily life activities and vitality assessed by the owners, and complete blood analyses were obtained. Gait, performance in daily life activities, and vitality were significantly improved on VA. No clinical changes were revealed on blood analyses.¹⁴

Zeel

Zeel inhibit the metalloproteinases (MMPs), which are enzymes such as hyaluronidase. It also has inhibitor effects on the production of leukotriene B4 by 5-lipoxygenase (5-LOX) and on the synthesis of prostaglandin PGE₂ by COX-1 and 2 enzymes. In a study, dogs with moderate to severe OA receiving the HCP Zeel for 8 weeks had significantly less pain than their placebo peers.

Eggshell Membrane

Eggshell membrane (EM) is the thin, proteinaceous layer between the raw eggshell and the egg white, and is made primarily of proteins (>88%) and naturally rich in elastin, collagen and glycosaminoglycans (GAGs). In vitro study has shown that eggshell membrane suppresses the release of TNF-α from stimulated peripheral blood mononuclear cells. A recent prospective, randomized, double-blind, placebo-controlled study showed supplementation with EM, ∼13.5 mg/kg (6 mg/lb) taken once daily, significantly reduced joint pain and improved joint function rapidly (CBPI 1 week) and demonstrated a lasting improvement in joint pain (VCSA 6 weeks) leading to an improved quality of life (CBPI 6 weeks). Moreover, serum CTX-II (type II collagen) levels in EM-supplemented dogs was significantly improved versus placebo at 6 weeks.¹⁵

Vitamin D₃

Vitamin D₃ is important for supporting healthy bone structure. Unlike in humans, Vit D₃ in dogs is primarily absorbed from dietary sources with negligible absorption from the sun. After oral ingestion, Vit D₃ is converted in the liver to 25-hydroxyvitamin D and then further hydroxylated in the kidney to its biologically active form 1,25 dihydroxyvitamin D (or calcitriol). In recent studies, a multitude of chronic illnesses have been associated with Vit D₃ deficiencies in people.

In addition, an observational study in people showed that participants with low intake of dietary vitamin D and lower serum levels of vitamin D were approximately 3 times more likely to exhibit progression of established knee osteoarthritis than those with higher levels. Another study noted that vitamin D may be related to the processes that impede or give rise to locomotor conditions and could play a major role in modulating oxidative stress, participating in immune responses, and contributing to cell differentiation.

Summary

There is a strong and compelling body of evidence supporting the role of nutraceuticals in joint health in veterinary practice. The final question is “how confident are you that the product you are recommending contains what the label says that it does?” A study of randomly selected nutraceuticals showed that 84% of the products tested did not meet their label claims with contents ranging as low as 0% of the claimed content in some products. Contamination with unwanted ingredients is also a problem within this relatively unregulated industry. For a small fee, Consumer Labs (consumerlab. com) provides independent laboratory testing of various products contents and purity.

The use of joint nutraceuticals in dogs prior to the development of OA is controversial. No controlled studies have been reported that document the efficacy of nutraceuticals in preventing the development of OA. However, because of their reported effects on improving cartilage matrix and reducing levels of inflammatory mediators within the joint, many clinicians have advocated the prophylactic use of joint nutraceuticals, particularly in athletic dogs that might be susceptible to joint injury. Additional research is needed to confirm the value of prophylactic use of joint nutraceuticals.

Summary

Joint nutraceuticals have been shown, through in vitro studies and controlled clinical trials, to be useful in the treatment of OA. They can be used for long-term management of patients with all stages of OA and carry minimal risk. The use of joint nutraceuticals can significantly reduce the need for NSAIDs and other medications in patients with OA.

Amongst all the appealing supplements that are purported to have a ‘protective’ effect on the development of OA, nothing has been proven to have the degree of protection as calorie restriction has. Although glucosamine and chondroitin sulfate have been found to have a mild analgesic effect in moderate-to-severe pain patients,^16,17 the same study found no significant effect of these supplements on disease progression over a 2-year period,¹⁸ whereas other studies have found a small beneficial effect of glucosamine sulfate on disease progression¹⁹. Indeed, there seems to be some evidence of a small structure modifying effect of glucosamine sulfate (particularly in the mild OA cases) in a few human clinical studies.^20,21

References

1.  Canapp SO Jr, McLaughlin RM Jr, Hoskinson JJ, et al. Scintigraphic evaluation of dogs with acute synovitis after treatment with glucosamine hydrochloride and chondroitin sulfate. Am J Vet Res. 1999;60:1552–1557.

2.  Au RY, Al-Talib TK, Au AY, et al. Avocado soybean unsaponifiables (ASU) suppress TNF-α, IL-1β, COX-2, iNOS gene expression, and prostaglandin E₂ and nitric oxide production in articular chondrocytes and monocyte/macrophages. Ostearthritis Cartilage. 2007;15:1249–1255.

3.  Altinel L, Saritas ZK, Kose KC, et al. Treatment with unsaponifiable extracts of avocado and soybean increases TGF-β1 and TGF-β2 levels in canine joint fluid. Tohoku J Exp Med. 2007;211:181–186.

4.  Boileau C, Martel-Pelletier J, Caron J, et al. Protective effects of total fraction of avocado/soybean unsaponifiables on the structural changes in experimental dog osteoarthritis: inhibition of nitric oxide synthase and matrix metalloproteinase-13. Arthritis Res Ther. 2009,11(2):R41.

5.  Grzanna MW, Ownby SL, Heinecke LF, et al. Inhibition of cytokine expression and prostaglandin E₂ production in monocyte/macrophage-like cells by avocado/soybean unsaponifiables and chondroitin sulfate. J Complement Integr Med. 2010;7(1):art10. (doi:10.2202/1553-3840.1338).

6.  Punke JP, Au RY, Au AY, et al. Modulation of prostaglandin E₂ production in feline articular chondrocytes propagated on monolayer and dynamic microcarrier culture. Proc Am Coll Vet Surg Conf. 2007, poster session.

7.  Heinecke LF, Grzanna MW, Au AY, et al. Inhibition of cyclooxygenase-2 expression and prostaglandin E₂ production in chondrocytes by avocado soybean unsaponifiables and epigallocatechin gallate. Osteoarthritis Cartilage. 2010;8:220– 227.

8.  Millis DL. Unpublished data, 2011.

9.  Roush JK, Cross AR, Renberg WC, et al. Evaluation of the effects of dietary supplementation with fish oil omega-3 fatty acids on weight bearing in dogs with osteoarthritis. J Am Vet Med Assoc. 2010;236:67–73.

10.  Roush JK, Dodd CE, Fritsch DA, et al. Multicenter veterinary practice assessment of the effects of omega-3 fatty acids on osteoarthritis in dogs. J Am Vet Med Assoc. 2010;236:59–66.

11.  Fritsch DA, Allen TA, Dodd CE, et al. A multicenter study of the effect of dietary supplementation with fish oil omega-3 fatty acids on carprofen dosage in dogs with osteoarthritis. J Am Vet Med Assoc. 2010;36:535–539.

12.  Rialland P, Bichot S, Lussier B, et al. Effect of a diet enriched with green-lipped mussel on pain behavior and functioning in dogs with clinical osteoarthritis. Can J Vet Res. 2013;77(1):66–74.

13.  Hielm-Björkman A, Tulamo R-M, Salonen H, Raekallio M. Evaluating complementary therapies for canine osteoarthritis Part I: green-lipped mussel (Perna canaliculus). Evid Based Complement Alternat Med. 2009;6(3):365–373.

14.  Moreau M, Dupuis J, Bonneau NH, Lécuyer M. Clinical evaluation of a powder of quality elk velvet antler for the treatment of osteoarthrosis in dogs. Can Vet J. 2004;45(2):133–139.

15.  Ruff KJ, Kopp KJ, Von Behrens P, Lux M, Mahn M, Back M. Effectiveness of NEM® brand eggshell membrane in the treatment of suboptimal joint function in dogs: a multicenter, randomized, double-blind, placebo-controlled study. Vet Med (Auckl). 2016;7:113–121.

16.  Clegg DO, Reda DJ, Harris CL, Klein MA, O’Dell JR, Hooper MM, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med. 2006;354(8):795–808.

17.  Hochberg MC, Clegg DO. Potential effects of chondroitin sulfate on joint swelling: a GAIT report. Osteoarthritis Cartilage. 2008;16 suppl 3:S22–4.

18.  Sawitzke AD, Shi H, Finco MF, Dunlop DD, Bingham CO 3rd, Harris CL, et al. The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: a report from the glucosamine/chondroitin arthritis intervention trial. Arthritis Rheum. 2008;58(10):3183–91.

19.  Bruyere O, Honore A, Ethgen O, Rovati LC, Giacovelli G, Henrotin YE, et al. Correlation between radiographic severity of knee osteoarthritis and future disease progression. Results from a 3-year prospective, placebo-controlled study evaluating the effect of glucosamine sulfate. Osteoarthritis Cartilage. 2003;11(1):1–5.

20.  Reginster JY, Neuprez A, Lecart MP, Sarlet N, Bruyere O. Role of glucosamine in the treatment for osteoarthritis. Rheumatol Int. 2012;32(10):2959–67.

21.  Richy F, Bruyere O, Ethgen O, Cucherat M, Henrotin Y, Reginster Jy. Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis: a comprehensive meta-analysis. Arch Intern Med. 2003;163(13):1514–22.