Mechanism of Action

Glucosamine is a precursor for glycosaminoglycans (GAGs) and proteoglycans, core components of articular cartilage and synovial fluid. Oral glucosamine is commonly used to:

• Support cartilage matrix maintenance
  
• Promote joint cushioning and resilience
  
• Slow degenerative changes in cartilage structure
  

Glucosamine HCl provides high glucosamine content per gram and is stable in chew formulations.

Clinical Evidence in Dogs

• McCarthy et al. (2007): Dogs with OA received glucosamine/chondroitin or carprofen in a randomized, double-blind, positive-controlled trial. The glucosamine/chondroitin group showed significant improvements in pain and weight-bearing by day 70, approaching the clinical benefits of carprofen over time, though onset was slower.
  
• Lenox et al. and others report improvements in lameness and owner-assessed scores in dogs receiving glucosamine/chondroitin formulations versus baseline or placebo.
  
• Martello et al. (2022): A multi-ingredient supplement containing glucosamine, chondroitin, HA, non-hydrolyzed type II collagen, and botanicals improved OA pain and lameness scores versus placebo over 60 days.
  

Relevance to Happy Hips™

In a product like Happy Hips™, glucosamine serves as a foundational structural substrate complementing immune tolerance mechanism. When combined with MSM, HA, and omega-3s, glucosamine supports cartilage matrix integrity within a multimodal joint strategy.

Mechanism of Action
MSM is an organosulfur compound used widely in canine and equine joint supplements. Proposed actions include:

Serving as a sulfur donor for collagen, keratin, and connective tissue synthesis

Modulation of inflammatory pathways (e.g., reduction of certain cytokines and prostaglandins)

Antioxidant activity and redox modulation

High-purity MSM (e.g., OptiMSM®) undergoes multiple distillation steps to remove contaminants and improve consistency.

Evidence Base
Controlled canine clinical trials specifically on MSM alone are limited; however:

Human randomized trials in knee OA report that MSM (e.g., 3 g twice daily) improves pain and physical function versus placebo, with good tolerability.

Animal models (e.g., murine OA) show MSM can reduce cartilage degeneration in a dose-dependent fashion, suggesting chondroprotective effects.

Veterinary monographs recognize MSM as commonly used for canine arthritis with an acceptable safety profile when used at recommended doses.

Relevance to Happy Hips™

In a stack with glucosamine, GLM, and curcumin, MSM is positioned as an inflammation-modulating and tissue-support component, potentially enhancing comfort and complementing structural support.

Mechanism of Action

Green-lipped mussel provides a complex mixture of lipids including:

• EPA and DHA (long-chain omega-3 fatty acids)
• ETA (eicosatetraenoic acid), less common and highly anti-inflammatory

These lipids modulate leukotriene and prostaglandin synthesis, contributing to reduced joint inflammation and pain.

Clinical Evidence in Dogs

• Bierer & Bui (2002): Arthritic dogs fed GLM showed significant improvements in clinical arthritis scores; the majority had at least a 30% reduction in one or more measures such as joint pain, swelling, or lameness.
• Hielm-Björkman et al. (2007): In a study of 45 dogs with chronic orthopedic pain, GLM supplementation improved pain and functional scores compared to placebo. While NSAIDs produced greater immediate relief, GLM demonstrated beneficial effects with a favorable safety profile.
• Rialland et al. (2013): A GLM-enriched diet improved pain-related behavior and functional outcome measures in OA dogs versus a control diet.
• Corbee (2022): A supplement containing GLM, curcumin, and blackcurrant leaf extract improved OA scores in dogs and cats, supporting GLM’s role in multi-ingredient formulations.

Relevance to Happy Hips™

GLM provides marine-derived omega-3s, including ETA, supporting:

• Joint cushioning and synovial lubrication
• Modulation of inflammatory mediators
• Synergy with curcumin, MSM, and HA in multimodal OA support

Mechanism of Action

Curcumin, the primary active in turmeric, influences multiple pathways relevant to OA:

• Down-regulation of COX-2 and other pro-inflammatory enzymes
• Modulation of NF-κB signaling
• Antioxidant effects, reducing oxidative stress in joint tissues

These actions contribute to reduced pain and inflammation in degenerative joints.

Clinical and Translational Evidence in Dogs

• Innes et al. (2003): A turmeric-based extract (P54FP) improved pain and lameness scores in dogs with elbow or hip OA in a randomized, placebo-controlled trial.
• Colitti et al. (2012): Dietary curcumin in OA dogs modified gene expression profiles in white blood cells, indicating systemic anti-inflammatory and antioxidant effects.
• Comblain et al. (2017): A diet supplemented with curcuminoids, hydrolyzed collagen, and green tea extract (CCOT mixture) led to improved OA clinical scores compared to placebo in a double-blind trial.
• Corbee (2022): As noted, a GLM-curcumin-blackcurrant supplement improved OA measures in clinical companion animal use.

Relevance to Happy Hips™

Curcumin in a joint chew functions as a broad-spectrum anti-inflammatory and antioxidant, reinforcing MSM and GLM. Lipid carriers (e.g., flaxseed) may enhance absorption given curcumin’s fat solubility.

Mechanism of Action

Hyaluronic acid is a major component of synovial fluid and cartilage matrix, contributing to:

• Viscosity and lubrication of the joint
• Shock absorption and smooth articulation
• Maintenance of cartilage hydration

Oral HA is intended to support endogenous HA production and synovial fluid quality.

Clinical Evidence in Dogs

• Aguado et al. (2021): Dogs with OA receiving oral HA for 10 weeks showed increased synovial HA concentrations and favorable changes in biomarkers associated with OA compared to controls.
• Martello et al. (2022): In a multi-ingredient supplement containing HA, glucosamine, chondroitin, and non-hydrolyzed collagen, treated OA dogs showed better pain and lameness scores than placebo over 60 days.
• Ragetly et al. (2025): A supplement containing HA, krill meal, eggshell membrane, and Boswellia serrata improved mobility and OA parameters in dogs in a postoperative orthopedic model, suggesting HA’s contribution in a complex joint-support blend.

Relevance to Happy Hips™

HA is the lubrication support component in a stack like Happy Hips™, synergizing with omega-3s and collagen to promote smoother joint movement and support synovial fluid properties.

Flaxseed oil and meal are rich in alpha-linolenic acid (ALA), a plant-based omega-3 fatty acid that can be partially converted to EPA and DHA and also exerts independent anti-inflammatory effects.

Veterinary references note that flaxseed oil is used to provide:

• Omega-3 and omega-6 fatty acids
• Support for skin, coat, cardiovascular health
• Adjunct support for inflammatory conditions including arthritis.

Within a joint chew, flaxseed primarily functions as:

• A baseline omega-3 source
• A lipid carrier that can assist absorption of fat-soluble actives such as curcumin
• A mild anti-inflammatory adjunct

Several modern canine OA trials have evaluated multi-ingredient formulations conceptually similar to a “full-stack” product like Happy Hips™:

• Martello et al. (2022): A supplement containing glucosamine, chondroitin, HA, non-hydrolyzed type II collagen, and botanicals improved OA-related pain and lameness compared to placebo in a randomized, double-blind clinical trial.[14]
• Comblain et al. (2017): A diet containing curcuminoids, hydrolyzed collagen, and green tea extract improved OA clinical signs vs placebo.[25]
• Corbee (2022): A GLM-curcumin-blackcurrant supplement improved clinical OA scores in dogs and cats, supporting the concept of synergistic nutraceutical stacks.[22]
• Reviews of non-pharmaceutical OA management emphasize that nutraceuticals are best used as part of a multimodal management plan, not as stand-alone treatments.[1–3]

These data support the concept of combining immune-modulating collagen, structural substrates, anti-inflammatory lipids, botanicals, and HA in a single formulation to address different aspects of OA pathophysiology.

Across the ingredient-level literature:

• MSM is widely used in veterinary practice; available data and monographs suggest a good safety profile, though high-dose or long-term use should be supervised.

Caution is appropriate in the following situations:

• Dogs with shellfish allergy (GLM is shellfish-derived).
• Patients with bleeding disorders or anticoagulant therapy (curcumin may influence clotting pathways).
• Autoimmune disease, where immune-modulating collagens should be evaluated case-by-case.
• Diabetes or insulin resistance, where glucosamine intake may warrant closer monitoring.

As with most nutraceuticals, joint supplements are best viewed as adjunctive tools within a broader plan including weight management, physical therapy, and, when necessary, pharmacologic and surgical interventions.

Limitations of Current Evidence

• Many trials have durations of 8–16 weeks; long-term (multi-year) controlled data remain limited.
• Formulations vary markedly between studies, so conclusions are ingredient-level rather than product-specific.
• Effect sizes are variable across individuals; some dogs respond more robustly than others.
• High-quality randomized controlled trials exist for GLM, curcumin-collagen blends, and HA-containing supplements, but fewer for MSM alone.

Despite these limitations, the cumulative evidence supports the use of these actives, particularly GLM, as components of multimodal OA management.

1. Pye C. Current evidence for non-pharmaceutical, non-surgical management of canine osteoarthritis. J Small Anim Pract. 2024.
2. Brondeel C. Mesenchymal stem cell therapy in canine osteoarthritis: A review. 2021.
3. Cornell University Riney Canine Health Center. How joint supplements can help with orthopedic conditions.
4. D’Altilio M, et al. Therapeutic efficacy and safety of undenatured type II collagen singly or in combination with glucosamine and chondroitin in arthritic dogs. Vet Ther. 2007.
5. Gupta RC, et al. Comparative therapeutic efficacy and safety of undenatured type II collagen vs glucosamine and chondroitin in arthritic dogs. 2011.
6. Stabile M, et al. Evaluation of clinical efficacy of undenatured type II collagen alone and in combination with cimicoxib in dogs with osteoarthritis. 2022.
7. Stabile M, et al. Effects of a feed supplement containing undenatured type II collagen and Boswellia serrata in dogs with osteoarthritis: randomized cross-over trial. PLOS ONE. 2024.
8. Lenox CE, et al. Effects of glucosamine–chondroitin supplementation in dogs with osteoarthritis. JAVMA. 2010.
9. McCarthy G, et al. Randomised double-blind, positive-controlled trial of glucosamine and chondroitin in dogs with osteoarthritis. Vet J / J Small Anim Pract. 2007.
10. Kampa N, et al. Study of the effectiveness of glucosamine and chondroitin in dogs with osteoarthritis. 2023.
11. Martello E, et al. Efficacy of a dietary supplement in dogs with osteoarthritis: randomized, placebo-controlled, double-blind clinical trial. PLOS ONE. 2022.
12. VCA Animal Hospitals. Methylsulfonylmethane (MSM) – veterinary drug monograph.
13. Whole Dog Journal. MSM for dogs – research overview and practical use.
14. Kim LS, et al. Efficacy of methylsulfonylmethane (MSM) in osteoarthritis of the knee: randomized controlled trial. Osteoarthritis Cartilage. 2006.
15. Schlemmer U, et al. Phytate in foods and significance for humans: context for sulfur and mineral interactions. Mol Nutr Food Res. 2009.
16. Bierer TL, Bui LM. Improvement of arthritic signs in dogs fed green-lipped mussel (Perna canaliculus). J Nutr. 2002.
17. Hielm-Björkman A, et al. Green-lipped mussel alleviates chronic orthopedic pain in dogs. Vet J. 2007.
18. Rialland P, et al. Effect of a green-lipped mussel–enriched diet on pain and functioning in dogs with osteoarthritis. Can J Vet Res. 2013.
19. Corbee RJ. Efficacy of a nutritional supplement containing green-lipped mussel, curcumin and blackcurrant leaf extract in dogs and cats with osteoarthritis. Vet Med Sci. 2022.
20. Innes JF, et al. Randomised double-blind placebo-controlled trial of a turmeric extract (P54FP) in canine osteoarthritis. 2003.
21. Colitti M, et al. Transcriptome modification of white blood cells after dietary curcumin in osteoarthritic dogs. Res Vet Sci. 2012.
22. Comblain F, et al. Diet containing curcuminoids, hydrolyzed collagen and green tea extract in dogs with osteoarthritis (CCOT mixture). BMC Vet Res. 2017.
23. Aguado CIS, et al. Effects of oral hyaluronic acid administration on synovial biomarkers in dogs with osteoarthritis. Animals. 2021.
24. Aguado CIS, et al. Synovial fluid hyaluronic acid and biomarker changes after oral HA supplementation in dogs with OA. 2021 (companion paper).
25. Ragetly GR, et al. Efficacy of a joint supplement containing eggshell membrane, hyaluronic acid, krill meal, astaxanthin and Boswellia in dogs. Front Vet Sci. 2025.
26. VCA Animal Hospitals. Flaxseed oil – veterinary monograph, omega-3 benefits in dogs.
27. Manufacturer and clinical summaries on flaxseed and omega-3 supplementation in canine inflammatory and joint conditions.sdf