Formulating for Joint Structure

Joint health is one of the most durable categories in the nutraceutical market, and for good reason: Osteoarthritis (OA) remains the most common joint disease worldwide, generating pain, disability, and enormous socioeconomic cost, with no approved disease-modifying pharmaceutical treatment.¹ Manufacturers formulating in this space can take a few approaches to addressing joint health, one being targeted support of joint structure and the other being managing inflammation. The focus of this article will be targeted support of joint structure, which is typically associated with 4 ingredients: collagen, hyaluronic acid (HA), glucosamine, and chondroitin sulfate. Each targets a different piece of the joint’s architecture—cartilage matrix, synovial fluid, or the immune processes that govern cartilage breakdown—and understanding these distinct mechanisms is essential for building high-quality, effective formulations.

Understanding Joint Structure

Joint cartilage is made mostly of collagen and proteoglycans, with very limited ability to repair itself once damaged. In OA, this tissue breaks down over time due to mechanical wear, inflammation, and enzymes that actively degrade the matrix.² Type II collagen accounts for about 80% of the collagen in cartilage and is largely responsible for holding cartilage together.¹ As OA advances, chondrocytes—the cells that normally build and maintain cartilage—start to shift into an unhealthy state. Instead of producing type II collagen, they begin producing type X collagen and degradative enzymes, accelerating the damage.³ At the same time, the synovial fluid that lubricates and cushions the joint loses HA and becomes thinner, reducing its ability to protect the joint during movement.² Supporting “joint structure,” then, means intervening somewhere in this breakdown process: supplying raw materials the joint can use to rebuild its matrix, calming the inflammatory signals driving the damage, or restoring the physical properties of the fluid that cushions the joint.

2 Forms, 2 Distinct Mechanisms

Collagen supplements are frequently marketed as a single category, but from a formulation science standpoint, hydrolyzed collagen and undenatured (native) type II collagen are functionally distinct ingredients with different manufacturing origins, molecular structures, and—largely nonoverlapping—mechanisms of action.¹

Hydrolyzed collagen (collagen peptides) is produced by enzymatic or chemical hydrolysis of native collagen, breaking the triple-helix structure into a mixture of peptides and free amino acids.¹ This processing sacrifices the triple helix to confer high bioavailability because hydrolyzed peptides resist intracellular and systemic hydrolysis, are absorbed into the bloodstream, and accumulate in cartilage tissue.¹ In vitro research indicates that once in the joints, peptides stimulate chondrocytes to synthesize extracellular matrix macromolecules (proteoglycans and type II collagen), potentially counteracting the degeneration of cartilage tissue.¹ A randomized controlled trial on a branded collagen peptide from Gelita, called Fortigel, found that 12 weeks of supplementation at 5 g/day resulted in a significant reduction of pain at rest and during walking in participants with functional knee and hip pain.⁴

“Collagen supplements are frequently marketed as a single category, but from a formulation science standpoint, hydrolyzed collagen and undenatured (native) type II collagen are functionally distinct ingredients.”

Undenatured (native) type II collagen, typically derived from chicken sternum cartilage, retains its intact triple-helix structure.¹ Its mechanism is an immunological one rather than biosynthetic. Known as oral tolerance, this mechanism is defined as the “active suppression of specific immune response to antigens first encountered in the gastrointestinal tract,” creating a chain of events that results in the secretion of down-regulatory cytokines, which decreases secretion of proinflammatory cytokines.¹ In animal models of rheumatoid arthritis, which is characterized by an autoimmune response against type II collagen, oral tolerance of native collagen has been demonstrated to reduce autoimmune response while also controlling inflammation. In a 2023 randomized, placebo-controlled trial in women with knee osteoarthritis, results showed that participants taking a branded native type II collagen, called Collavant n2 from Bioiberica, at 40 mg/day over 12 weeks saw significant improvements in functionality and Western Ontario and McMaster Universities Arthritis Index scores, compared with placebo.⁵ A different study evaluating a different native type II collagen (UC-II from Lonza Capsugel) found that supplementation at 40 mg/day restored knee flexion compared with placebo.⁶

Restoring the Synovial Environment

HA in the joints acts as a lubricant, shock absorber, and joint structure stabilizer.² HA concentration and molecular weight decline while osteoarthritis progresses with aging. Although much of existing research on the effects of HA on joints involves the injection of HA into the joints, research does indicate that high-molecular-weight HA, such as Mobilee from Bioiberica, is absorbed and distributed to connective tissues through oral administration, with animal research showing a reduced degree of synovial effusion and increased concentration of HA in synovial fluid. Human research has shown that compared with placebo, 3 months of oral supplementation improved knee muscle strength in individuals with mild joint discomfort. Subsequent human research has confirmed that HA supplementation can significantly reduce pain intensity and synovial effusion and improve muscle strength parameters compared with placebo.⁷

Classic Ingredients Have Room for Growth

Glucosamine and chondroitin sulfate are the longest-standing ingredients used in joint health formulations and are frequently combined in finished products. Glucosamine is a precursor substrate for glycosaminoglycan and proteoglycan synthesis, theoretically supporting cartilage matrix production, whereas chondroitin sulfate, a sulfated glycosaminoglycan naturally present in cartilage, is thought to inhibit degradative enzymes and stimulate proteoglycan synthesis while also drawing water into the cartilage matrix to support its compressive properties.⁸

“The evidence base supports chondroitin sulfate primarily as a symptom-modifying agent and glucosamine sulfate primarily as a potential structure-modifying agent, rather than treating “glucosamine chondroitin” as a single, undifferentiated ingredient pair.”

A 2024 systematic review and meta-analysis in Inflammopharmacology evaluated 25 randomized controlled trials of glucosamine sulfate, chondroitin sulfate, and their combination in knee OA.⁸ The meta-analysis found that chondroitin sulfate produced a significant reduction in pain intensity and improved physical function compared with placebo, whereas glucosamine sulfate produced a significant reduction in tibiofemoral joint space narrowing—a radiographic marker of structural cartilage preservation—but did not significantly improve symptom scores.⁸ Interestingly, the meta-analysis did not find that the combination of glucosamine and chondroitin sulfate showed significant improvements in symptoms of function, but the authors noted that the limited number of combination-specific trials (only 3 of the 25 included randomized controlled trials [RCTs]) constrains firm conclusions about whether coadministration was beneficial, and they call for larger multicenter RCTs specifically designed to test the combination.⁸ For formulators, this is a meaningful distinction: The evidence base supports chondroitin sulfate primarily as a symptom-modifying agent and glucosamine sulfate primarily as a potential structure-modifying agent, rather than treating “glucosamine chondroitin” as a single, undifferentiated ingredient pair with a unified mechanism.

Both glucosamine and chondroitin sulfate are animal derivatives, but new technology is changing how these ingredients can be produced. Gnosis by Lesaffre, for example, is using fermentation to manufacture chondroitin sulfate, creating the ingredient MyCondro. The benefit of this ingredient, beyond being vegan, is that compared with animal-derived versions, it has better bioavailability and can therefore be more beneficial at smaller doses.

The fourth most abundant mineral element after calcium, phosphorus, and potassium is sulfur, which is present in large amounts in hair, skin, nails, and cartilage. Methylsulfonylmethane (MSM) is 34% sulfur and is considered to be a source of sulfur in the aforementioned tissues. Research indicates that MSM has both chondrogenic and anti-inflammatory effects.⁹ A 2023 randomized, placebo-controlled trial investigated the effects of a branded MSM, called OptiMSM from Balchem Human Nutrition & Health, on 88 participants with mild knee pain at a dose of 200 mg/day for 12 weeks. Results showed that those taking MSM experienced significantly lower Japanese Knee Osteoarthritis Measure scores compared with placebo, indicating that MSM may alleviate wake-up and standing pain and improve general health and quality of life for individuals with mild knee pain.⁹

Potential Synergies and Formulating Finished Products

Each of these ingredients can be effective in a joint health formulation, and the choice of ingredient or ingredients will depend on several factors. The finished format, for example, would be an important factor when choosing between hydrolyzed or native collagen ingredients. Additionally, as research on glucosamine and chondroitin sulfate demonstrates, the combination of ingredients does not always lead to enhanced benefits. Therefore, formulas with multiple ingredients designed to address joint health from multiple mechanisms would benefit from their own research to demonstrate effectiveness.

For example, a 2023 retrospective observational study evaluating the benefits of a blend containing Boswellia serrata, native type II collagen, curcumin, and HA found that the combination significantly improved joint pain, range of motion, and quality of life after 2 months of supplementation. Of course, a more rigorous study would be beneficial to replicate and confirm these results.¹⁰ A 2018 in vitro study evaluating the anti-inflammatory effects of MSM and HA on chondrocyte cultures found that the ingredients counteracted the negative effects of IL-1β and modulated the NF-κB pathway.¹¹

It is important to note that joint health degradation is not reversible, but supplements like these can help manage symptoms and improve quality of life. Although use of these products has historically been reactive, there is an opportunity for more proactive use to help maintain healthy joints as individuals age.

References

1. Martínez-Puig D, Costa-Larrión E, Rubio-Rodríguez N, Gálvez-Martín P. Collagen supplementation for joint health: the link between composition and scientific knowledge. Nutrients. 2023;15(6):1332. doi:10.3390/nu15061332 

2. Gupta RC, Lall R, Srivastava A, Sinha A. Hyaluronic acid: molecular mechanisms and therapeutic trajectory.Front Vet Sci. 2019;6:192. doi:10.3389/fvets.2019.00192 

3. Hidayat M, Phatama KY, Saputra TMD, et al. Hyaluronic acid prevent further cartilage damage of osteoarthritis based on expression of collagen type II and collagen type X. Open Access Maced J Med Sci. 2022;10(B):757-763. doi:10.3889/oamjms.2022.8748 

4. Schulze C, Schunck M, Zdzieblik D, Oesser S. Impact of specific bioactive collagen peptides on joint discomforts in the lower extremity during daily activities: a randomized controlled trial. Int J Environ Res Public Health. 2024;21(6):687. doi:10.3390/ijerph21060687 

5. Santana ÉTN, da Cunha Machado S, Brandão Lima VN, et al. Comparison between exercise therapy and non-hydrolyzed collagen (NHC-type II) in functionality and quality of life in women with knee osteoarthritis. Wien Klin Wochenschr. 2023;135:291-300. doi:10.1007/s00508-022-02037-8 

6. Schön C, Knaub K, Alt W, Durkee S, Saiyed Z, Juturu V. UC-II undenatured type II collagen for knee joint flexibility: a multicenter, randomized, double-blind, placebo-controlled clinical study. J Integr Complement Med. 2022;28(6):540-548. doi:10.1089/jicm.2021.0365 

7. Sánchez J, Bonet ML, Keijer J, et al. Blood cells transcriptomics as source of potential biomarkers of articular health improvement: effects of oral intake of a rooster combs extract rich in hyaluronic acid. Genes Nutr. 2014;9(5):417. doi:10.1007/s12263-014-0417-3 

8. Rabade A, Viswanatha GL, Nandakumar K, Kishore A. Evaluation of efficacy and safety of glucosamine sulfate, chondroitin sulfate, and their combination regimen in the management of knee osteoarthritis: a systematic review and meta-analysis. Inflammopharmacology. 2024;32(3):1759-1775. doi:10.1007/s10787-024-01460-9 

9. Toguchi A, Noguchi N, Kanno T, Yamada A. Methylsulfonylmethane improves knee quality of life in participants with mild knee pain: a randomized, double-blind, placebo-controlled trial. Nutrients. 2023;15(13):2995. doi:10.3390/nu15132995 

10. Kamat YD, Das B, Thakkar K, Mahajan M. A retrospective observational study evaluating the synergistic effect of a novel combination of alfapin + native type 2 collagen + mobilee (hyaluronic acid) + CurQlife (curcumin) nutraceuticals in the symptomatic improvement of knee osteoarthritis.Cureus. 2023;15(3):e36123. doi:10.7759/cureus.36123 

11. Cheleschi S, Fioravanti A, De Palma A, et al. Methylsulfonylmethane and mobilee prevent negative effect of IL-1β in human chondrocyte cultures via NF-κB signaling pathway. Int Immunopharmacology. 2018;65:129-139. doi:10.1016/j.intimp.2018.10.004