Eventually we all suffer from some sort of joint pain and ultimately, except for the lucky few, succomb to osteoarthritis. Osteoarthritis (OA), presents in multiple ways. Typically, stiffness after long periods of sitting; decresed range of motion; pain with motion; swelling, etc. We all reach for something in the cabinet, usually an antiinflammatory of some sort. What really works? What do the studies say? Is there any good evidence? Hopefully I can direct you towards some sort of relief. Likely will only offer false hopes, as not everyone will get the relief they are looking for.
This will be a series of posts concentrating on different supplements and the studies that support or have little support available. By no means will this be an exhaustive search, but merely a guide.
Methylsulfonylmethane (MSM)
Chondroitin and glucosamine
Collagen
Hyaluronic acid
Vitamin C
Vitamin D
Methylsulfonylmethane (MSM)
Methylsulfonylmethane (MSM) is a supplement rich in organic sulfur, recommended for alleviating joint and muscle pain, with reported benefits in slowing the progression of anatomical joint issues, particularly in knee osteoarthritis (OA). It naturally occurs in methyl-S-methane compounds and can be obtained through the oxidation of dimethylsophoxide with H2O2. Best used when combined with other supplements (glucosamine and chondroitin) to reduce swelling, pain, and stiffness.
Mechanism of Action
Anti-Inflammatory Properties:
MSM acts as an anti-inflammatory agent by inhibiting NF-κB and p65-S536 phosphorylation, reducing the expression of interleukins (IL-1, IL-6, IL-1β) and TNF-α.
Downregulation of Inflammasome:
It downregulates NF-κB production of the NLRP3 inflammasome, blocking the activation signal from mitochondrial-generated ROS.
Reduction of Oxidative Stress:
MSM reduces the expression of cyclooxygenase-2 and nitric oxide synthase, influencing the balance of reactive oxygen species (ROS) and antioxidant enzymes.
Pleiotropic Effects:
MSM improves osteoblast differentiation through the Jak2/STAT5b pathway, upregulating the master gene RUNX2 and stimulating osteogenic differentiation.
Efficacy and Safety
Anti-Arthritic Potential:
In vitro and animal studies show promising anti-arthritic effects.
Human Studies:
Human studies, often small-scale and in combination with chondroitin and glucosamine, suggest MSM's effectiveness in reducing pain, swelling, and stiffness.
Combination Therapies:
Combining MSM with other therapies, such as glucosamine, chondroitin, demonstrates significant improvements in pain, intensity, and swelling, particularly in knee OA.
Safety:
MSM appears well-tolerated and safe, as per the FDA's Generally Recognized as Safe (GRAS) notification, especially at dosages under 4845.6 mg/day.
While MSM shows promise in alleviating joint-related issues, further large-scale and long-term clinical trials are needed to fully quantify its efficacy, particularly in comparison to other supplements like chondroitin and glucosamine.
Chondroitin and glucosamine
Chondroitin and glucosamine are commonly used nutraceuticals for osteoarthritis (OA) patients due to their analgesic and chondroprotective effects. Glucosamine, found in two forms (sulphate and hydrochloride), is a constituent of glycosaminoglycans in cartilage and synovial fluid. Chondroitin, a major component of articular cartilage, contributes to osmotic pressure, providing resistance and elasticity during loading conditions. Studies tend to be somewhat contrasting, but over all reveal moderate joint pain relief and reduce inflammation in the joint. Usually taken for up to 3 months before results can be seen.
Mechanisms of Action
Anti-Inflammatory Effects:
Glucosamine and chondroitin act as anti-inflammatory agents by reducing pro- inflammatory cytokines like IL-1, IL-6, and TNF-α.
They suppress the NF-κB and MAPK pathway, inhibiting inflammation in OA.
Immune-modulatory activity includes inhibiting catabolic enzymes and downregulating cytokines.
Antioxidant Properties:
Both exhibit antioxidant activities, with glucosamine sulphate showing greater efficacy.
They reduce ROS production, preventing cellular damage and collagen degradation.
Tissue Regeneration:
In vivo studies demonstrate improved tissue regeneration, enhancing cartilage repair and suppressing osteoclastic cell differentiation.
Efficacy and Safety
Efficacy:
Clinical trials show contrasting results, with some indicating pain relief and improved function.
Meta-analyses suggest moderate effects on OA-related pain and joint inflammation but limited impact on joint-space narrowing.
Safety:
Mild and transient effects like diarrhea, abdominal pain, nausea, and headache were reported, with no significant differences between options (glucosamine alone, chondroitin alone, or their combination) and placebo.
Glucosamine and chondroitin may offer a modest to moderate effect in relieving OA-related symptoms, but further examination is needed to reconcile discrepancies in their effectiveness across studies.
Collagen
Collagen, an extracellular matrix protein abundant in skin, tendons, cartilage, and bone, is a key component in maintaining structural integrity. Type II collagen, predominant in articular cartilage, forms fibrils crucial for tensile strength. Commercially available as a nutritional supplement, collagen undergoes hydrolysis for enhanced bioavailability.
Question remains as to which type is best taken orally, with the intended results. The over all consensus is decrease in inflammation and building of some cartilage.
Mechanism of Action
Cartilage Regeneration:
Hydrolyzed collagen fosters cartilage regeneration by elevating extracellular matrix macromolecule synthesis.
Labeled collagen peptide administration demonstrates significant improvement in skin and cartilage collagen levels.
Immunomodulation:
Collagen modulates humoral and cellular immune responses, activating immune cells in the gut-associated lymphoid tissue.
Transformation of naive T cells into anti-inflammatory T regulatory cells aids in reducing joint inflammation and promoting cartilage repair.
Biologically Active Substances:
Proline and hydroxyproline, biologically active collagen components, induce hyaluronic acid synthesis and inhibit hypertrophic chondrocyte differentiation.
Collagen peptides in a rat OA model reduce type II collagen degradation and inflammation, indicating anti-inflammatory and chondroprotective effects.
Collagen supplementation emerges as a promising avenue for joint health, offering potential anti-inflammatory and chondroprotective benefits
Hyaluronic acid
Hyaluronic acid (HA) is a mucopolysaccharide found in synovial fluid, known for its viscoelasticity, moisture retention, and biocompatibility. Acting as a lubricant, shock absorber, and joint stabilizer, HA regulates water balance and flow resistance. HA is typically administered with an injection into the joint. However, orally does show some benefit,studies are limited. Likely provides some analgesic effects, with decreasing sensitivity around the joint, as well as providing lubirication with decreased friction of joint motion.
Mechanism of Action
Chondroprotection:
HA reduces chondrocyte apoptosis (death) and enhances proliferation by binding to CD44 receptors, inhibiting IL-1β expression, and reducing MMP (inflammatory) production.
Binding to cd4 sites aiding in chondroprotection, impacting subchondral bone by suppressing MMP-13 and IL-6.
Anti-Inflammatory Effects:
Orally administered HA binds to TLR4 in the intestine, increasing SOCS3 secretion, suppressing pro-inflammatory cytokines (IL-8, IL-6, PGE2, TNFα).
Binding to ICAM-1 downregulates NF-kB, decreasing IL-6 production.
N-acetyl Glucosamine and Proteoglycan Synthesis:
N-acetyl glucosamine, a component of HA, exhibits chondroprotective and anti- inflammatory activities, stimulating proteoglycan synthesis.
Mechanical and Analgesic Effects:
HA contributes to joint lubrication, preventing degeneration by reducing friction.
Possesses analgesic effects by decreasing mechanical sensitivity of ion channels and reducing action of joint-sensitized nociceptors.
Mechanical and Analgesic Effects
HA contributes to joint lubrication, preventing degeneration by reducing friction.
Possesses analgesic effects by decreasing mechanical sensitivity of ion channels and reducing action of joint-sensitized nociceptors.
Efficacy and Safety
Radiolabeled HA from oral supplementation is absorbed, distributed to skin, bone, and synovial joints, with prolonged retention.
Studies suggest oral HA supplementation alleviates knee OA symptoms, improving scores like JKOM and WOMAC.
Long-term RCTs with standardized HA are needed to address study limitations and recommend HA as a nutraceutical in clinical practice.
Oral HA supplementation at dosages up to 200 mg/day for up to 12 months is confirmed to be safe in humans.
Hyaluronic acid emerges as a promising treatment for osteoarthritis, offering chondroprotection, anti-inflammatory effects, and safety in oral supplementation.
Vitamin C
Vitamin C, also known as ascorbic acid, was discovered in 1923 by Szent-Gyorgyi and later synthesized by Howarth and Hirst. This water-soluble molecule is abundant in citrus fruits, peppers, tomatoes, strawberries, broccoli, Brussels sprouts, turnips, and leafy vegetables. Recognized for its potent antioxidant properties, vitamin C reacts with aqueous-free radicals and reactive oxygen species (ROS), mitigating oxidative damage.
Vitamin C has been shown to have antioxidative properties and demonstrate slowing of arthritis progression in multiple studies. Although more significantly, osteoarthritis appears to be closely related with intake of vitamin C.
Mechanism of Action
Antioxidant Function:
Vitamin C acts primarily as an antioxidant and antiradical supplement.
It exists in both reduced (ascorbate) and oxidized forms as dehydroascorbic acid, remaining biologically active.
Reaction with Free Radicals:
Ascorbic acid reacts directly with free radicals through single-electron oxidation.
This process produces the ascorbyl radical, transforming into ascorbate and dehydroascorbate.
Indirect Protection of Other Vitamins:
Vitamin C indirectly protects other vitamins, such as A and E, from oxidation.
Role in Osteoarthritis (OA):
In the context of OA, a non-inflammatory joint condition, vitamin C is crucial.
Emerging evidence suggests pro-inflammatory mediators' involvement in OA pathogenesis.
Contribution to OA Prevention:
Vitamin C acts as an electron donor in the synthesis of type II collagen, contributing to OA prevention.
It serves as a sulfate carrier in glycosaminoglycan synthesis and acts as a co-factor for mono-oxygenase enzymes.
Maintenance of Enzyme Activity:
Vitamin C maintains optimal enzyme activity in collagen, carnitine, and neurotransmitter synthesis.
Depletion of Sulphated Proteoglycans:
The depletion of sulphated proteoglycans in the articular cartilage's extracellular matrix is considered a relevant expression of OA.
Potential Solution for OA:
Vitamin C deficiency might be a risk factor for OA development.
Supplementation, especially when combined with conventional or unconventional therapies, may be a potential solution.
Efficacy and safety
Prevention of OA Progress:
Vitamin C has multiple abilities to prevent osteoarthritis (OA) progression.
It modulates apoptosis processes, including procaspase-3 and procaspase-9, and Bax expression.
It also influences the expression of pro-inflammatory cytokines and MMPs, in addition to its well-known antioxidative properties.
In Vitro and In Vivo Studies:
In an in vitro chondrosarcoma cell line (SW1353), treatment with 100 µM of vitamin C prevents oxidative stress, apoptosis, and proteoglycan loss induced by monosodium iodoacetate (MIA).
Similar results were observed in in vivo OA rats induced by MIA and supplemented with 100 mg/kg of vitamin C.
Risk Reduction in Humans:
Increased intake of vitamin C may decrease the risk of OA progression and cartilage loss in humans, linked to its antioxidative capacity.
Circulating Vitamin C Levels and Knee OA:
Some studies show a non-correlation between circulating vitamin C levels and incident radiographic knee OA.
Cohort Study Findings:
A prospective cohort study with 1023 participants suggests that individuals without baseline knee OA, who self-reported vitamin C supplement usage, were 11% less likely to develop knee OA.
Vitamin C supplementation was potentially useful in preventing incident knee OA in participants with radiographic knee OA at baseline.
Cross-Sectional Analysis:
A cross-sectional analysis with 4685 participants indicates that radiographic knee OA is significantly associated with vitamin C intake.
Additional Benefits:
Vitamin C decreases lipoperoxides linked with hip bone loss.
It may reduce the use of painkillers and improve the quality of life, possibly acting as a cofactor for the enzyme involved in endomorphin-1 synthesis.
Considerations for Future Studies:
Given the economic burden of OA, the use of vitamin C as a simple, inexpensive supplement merits consideration.
Long-term randomized controlled trials (RCTs) are needed to determine optimal concentrations, administration routes, doses, and frequencies, as well as potential mechanisms of action in OA disease.
Safety and Effectiveness:
Overall, vitamin C appears to be a safe and effective adjunctive therapy for acute and chronic pain relief in specific patient groups.
Vitamin D
Vitamin D plays a crucial role in maintaining overall health, and its impact extends to joint health. While traditionally known for its role in bone health and calcium absorption, emerging research suggests a connection between vitamin D and joint function. Joint-related conditions, particularly osteoarthritis, have been investigated in relation to vitamin D levels.
Studies have been performed to research the potential benefits of vitamin D in preventing and managing joint disorders. Vitamin D appears to have an influence on bone turnover, cartilage degradation, and its anti-inflammatory properties indicate a potential role in the development and progression of conditions like knee osteoarthritis. Additionally, vitamin D supplementation has been investigated for its ability to alleviate joint pain.
Recommendation:
The Institute of Medicine (IOM) recommended vitamin D in 2011 for bone health, emphasizing its role in improving calcium absorption, bone mineral density, and preventing vitamin D deficiency-related conditions like rickets/osteomalacia.
Prevalence of Deficiency:
Despite sources like fatty fish and fortified products, vitamin D deficiency is widespread, affecting <20% in northern Europe, 30–60% in western, southern, and eastern Europe, and up to 80% in Middle East countries. Severe deficiency (serum 25(OH)D < 30 nmol/L or 12 ng/mL) is found in >10% of Europeans.
Mechanism of Action
Immunoregulation:
Vitamin D influences inflammation by regulating white cell response, reducing pro-inflammatory cytokines TNF-α and IL-1, crucial in cartilage degradation.
Vitamin D Receptors (VDRs):
Studies indicate increased VDR expression in damaged cartilage, stimulating MMPs production, contributing to cartilage and bone degradation.
Osteoblasts and Bone Resorption:
• Vitamin D affects osteoblasts, regulating RANKL/OPG ratio and influencing bone resorption.
Efficacy and Safety
Conflicting Evidence:
Studies show conflicting evidence on the relationship between vitamin D deficiency and OA initiation. Observational studies indicate varying results regarding pain, radiologic OA, and cartilage volume loss.
Supplementation Effects:
While some studies suggest vitamin D supplementation's potential positive effects on pain, radiologic OA, and cartilage volume loss, large-scale longitudinal studies are needed for conclusive evidence.
Safety:
Vitamin D supplementation (1000–2000 IU/daily) is generally considered safe, but the upper limit depends on factors like plasmatic levels, dose, regimen, sex, and age.
Conclusion:
Urgent Need for Further Research: Conflicting evidence necessitates large-scale, diverse studies to determine vitamin D's role in OA conclusively.
Other supplements
Avocado/Soybean Unsaponifiables (ASU):
Effective in pain reduction based on human Randomized Controlled Trials (RCTs).
In a 3-month RCT, daily intake significantly reduced NSAID intake and Lesquesne pain score.
Combination with chondroitin sulfate showed a 50% decrease in WOMAC scores.
Boswellia Serrata:
Rich in anti-inflammatory boswellic acids, including 3-O-acetyl-11-keto-beta-boswellic acid (AKBA).
Decreases pain (VAS, WOMAC pain), increases knee/hip flexion, walking distance, and affects swelling frequency in OA patients.
Significant improvement in pain-free walking distance observed with N-acetylglucosamine, ginger, and B. serrata combination.
Capsaicin:
Extracted from chili pepper, acts as an agonist binding to TRPV1 channels.
Reduces mean WOMAC pain, stiffness, and functional scores compared to placebo in people with OA.
Curcumin:
Chondroprotective, antioxidative, and anti-inflammatory effects.
In a 6-week trial, oral curcumin (2 g/day) comparable to ibuprofen (800 mg/day) in pain reduction and improved mobility.
Decreases inflammatory markers in the serum, including IL-1β, IL-6, soluble CD40 ligand, sVCAM-1, and Coll2-1.
Ginger Powder:
Supplementation (1 g/day) reduces inflammatory markers and decreases pain on standing, after walking, and WOMAC stiffness scores.
Polyphenols from Pomegranate Juice, Pine Bark, and Green Tea:
Demonstrate anti-inflammatory and antioxidative efficacy in relieving OA pain.
EGCG from green tea, pycnogenol, and anthocyanins from pomegranate juice show positive results in VAS pain score, WOMAC score, and physical function subscore.
Omega-3 Fatty Acids (EPA and DHA):
Improve WOMAC pain, stiffness, and physical function scores.
Reduce NSAID use after 3 months of treatment, especially when co-administered with glucosamine sulfate, Urtica dioica, zinc, and vitamin E.
These nutraceuticals show promise in managing osteoarthritis symptoms, with various studies supporting their effectiveness. It's advisable to consult with a healthcare professional before incorporating them into a treatment plan.
Disclaimer:
No content on this site, regardless of date, should ever be used as a substitute for direct medical advice from your doctor or other qualified clinician.
References
Nutraceutical Approach to Chronic Osteoarthritis: From Molecular Research to Clinical Evidence
by Alessandro Colletti and Arrigo F. G. Cicero
Int. J. Mol. Sci. 2021, 22(23), 12920; https://doi.org/10.3390/ijms222312920
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