May 17, 2018
Joint health is not much different for sports nutrition consumers than it is for the average person. Pain, stiffness and inflammation are the symptomatic complaints in both populations, but dietary supplement companies, selling to any consumers in the United States, are limited to talking about temporary discomfort from activities to avoid disease claims. Where sports nutrition consumers’ joint concerns differ is in the regularity of strenuous activities and the need to recovery quickly enough to maintain exercise and competition schedules.
Joint protection building blocks
One approach to supporting joints for exercise is to deliver ingredients that are naturally found in joints, including the cartilage that protects the ends of the bones inside of joints.
In joint health, glycosaminoglycans (GAGs) are polysaccharides that combine with certain proteins called proteoglycans to form hydrated gels that support connective tissues to help cushion joints. GAGs important to joint health include chondroitin sulfate, keratin sulfate, heparin sulfate and hyaluronan.
A 2015 research review of 43 randomized, controlled trials on adults (n=9,110) with joint problems (knee, hip and hand osteoarthritis [OA]) found a small to moderate improvement in pain and associated symptoms with chondroitin sulfate supplementation than with placebo.1 The researchers noted chondroitin improved knee pain by 20%. The benefit was also apparent when chondroitin was combine with glucosamine, a polysaccharide the body uses to make GAGs.
Most GAGs are sulfated. In cartilage extracellular matrix (ECM), GAGs and proteins are connected by disulfide bonds. Methylsulfonylmethane (MSM) is a not a GAG, but can contribute sulfur to cartilage.
A 2017 research publication showed a combination of MSM, glucosamine and chondroitin sulfate improved joint pain associated with OA, compared to both placebo and glucosamine-chondroitin.2 The researchers measured symptoms using visual analog score (VAS) and Western Ontario and McMaster osteoarthritis index (WOMAC) pain score, a standard questionnaire for scoring knee and hip pain, stiffness and function caused by OA.
On its own, MSM has helped manage post-exercise joint health. A 2017 research publication reported healthy female runners in the 2014 Portland half-marathon who took MSM (as OptiMSM®, from Bergstrom Nutrition) 21 days prior to and two days following the race had reduced muscle and joint pain.3 A subsequent study on half-marathoners confirmed the significance of this benefit from OptiMSM supplementation, and concluded MSM may be effective at reducing exercise-induced joint pain.4
Hyaluronan, known commonly in the nutritional market as hyaluronic acid (HA), is the only non-sulfated GAG in the joint, where it serves as a lubricant. Most research showing joint health benefits from HA involved injections into the joint space, but there are some studies showing similar benefits from oral supplementation. A Japanese trial of knee OA patients demonstrated four weeks of oral supplementation with hyaluronic acid (as Hyabest® J, from Kewpie Corp.) improved WOMAC scores.5
A subsequent long-term trial found oral Hyabest supplementation for 12 months in OA patients improved Japanese Knee Osteoarthritis Measure (JKOM) scores, compared to placebo.6 Researchers noted, the younger the patient, the better the response to HA.
Eggshell membrane has become a popular dietary supplement source of GAGs—including chondroitin sulfate, HA and sulfated glycoproteins. Research showed natural eggshell membrane supplementation (as NEM®, from Stratum Nutrition) reduced pain and stiffness in OA patients.7,8
However, a recently published placebo-controlled trial showed NEM supplementation in healthy, postmenopausal women reduced exercise-induced cartilage turnover after one and two weeks of exercise.9 There was no difference in immediate joint pain, but supplementation resulted in improvements to immediate stiffness, recovery stiffness and recovery pain compared to placebo.
In another trial, moderately active adults taking hydrolyzed water-soluble egg membrane (as BiovaFlex®, from Biova Ltd.) for four weeks in a crossover format (treatment, washout, other treatment) had significantly improved joint range of motion (neck, spine, hips and knees) compared to placebo.10 Researchers further noted back pain was improved in the supplement group, as was joint function and comfort during both regular daily activities and increased physical activity.
Two-thirds of cartilage is comprised of collagen. Cartilage ECM features type II collagen, which contains glycoproteins, proteoglycans and HA. Thus, type II collagen is an increasingly popular supplement ingredient for joint health, including in sports nutrition.
A glycosylated, undenatured type-II collagen ingredient derived from chicken sternum (as UC-II®, from InterHealth/Lonza) improved joint function and pain in healthy, active adults with post-exercise joint pain, but no arthritis or joint pain at rest.11 The trial found knee flexion and extension improved in those taking UC-II for 120 days, compared to those taking placebo; the UC-II group also took longer to feel pain after exercise than baseline and placebo, and five UC-II patients reported no post-exercise pain.
Similar benefits were noted in research on a type II collagen derived from hormone- and antibiotic-free chicken sternum ingredient (as BioCell Collagen®, from BioCell Technology), which also contains GAGs such as chondroitin sulfate and HA. A 2012 study showed BioCell supplementation for 70 days in patients with progressive hip or knee OA helped manage symptoms, including pain measured by VAS and WOMAC scores, as well as improved physical activities, compared to placebo.12 Researchers in another randomized, controlled trial found BioCell supplementation for six months improved knee OA symptoms, such as pain (as measured by WOMAC, VAS scores), compared to both placebo and a combination of glucosamine and chondroitin.13
Collagen peptides supply amino acids—including glycine, proline and hydroxyproline—to stimulate and protect chondrocyte cells, and promote the synthesis of new cartilage ECM.14,15
Six months of hydrolyzed type I collagen peptide (as Peptan®, from Rousselot) reduced joint pain and increased joint mobility (per WOMAC and Lysholm knee pain scores) in patients with OA.16
A 2017 study of collagen peptides (as FORTIGEL®, from Gelita) involved athletic subjects with activity-related knee joint discomfort due to overloading or incorrect loading of the joint during physical activity.17 Researchers found a statistically significant improvement in activity-related pain intensity in the FORTIGEL group compared to placebo.
A supplement combining FORTIGEL and fucoidan brown algae (as ACTEN®, from Acten) reduced VAS scores for pain and Lequesnealgo algo-functional index (LAI) for severity of OA , similar to the comparison protocol combining glucosamine, chondroitin sulfate, HA and vitamin C (important for formation of connective tissue).18
Bone morphogenetic proteins (BMPs) are growth factors that can stimulate cartilage growth. A protein complex containing BMPs and other growth factors (as Cyplexinol®, from ZyCal Bioceuticals Inc.) taken by older adults (55 years and up) who had moderate-to-severe symptomatic OA hip or knee pain increased quality of life and decreased symptoms such as pain and stiffness (per WOMAC scores).19
Bioactive milk proteins (as Osteol™, from Nexira) not only protect cartilage but also may quell joint inflammation, according to unpublished research combining Osteol with glucosamine and chondroitin. The combination reduced inflammatory markers, including tumor necrosis factor alpha (TNF-a).
The inflammation battle
A growing list of natural ingredients to limit and reduce inflammation has garnered attention in the joint health market, including exercise consumers.
Omega-3 fatty acids, especially docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are directly involved in the inflammatory cascade facilitated by COX (cyclooxygenase) and LOX (lipoxygenase) enzymes that produce anti- and pro-inflammatory mediator and signaling compounds (e.g., resolvins). For instance, resolvin D1 helps resolve inflammation and preserve tissue integrity.
In vitro research demonstrated resolvin D1 is active in synovial fluid (a component of joints), and regulates inflammatory cytokines and oxidative stress that impact OA progression.20
Research on omega-3s and joint health focus on rheumatoid arthritis (RA), an autoimmune disease, not the wear-and-tear of OA or temporary inflammation related to exercise. However, the appearance and actions of omega-3-signaling derivatives, such as resolvins in the joint, suggest potential benefits for sports nutrition joint management.
One study involving OA patients found daily fish oil supplementation significantly improved knee performance, compared to controls and based on VAS scores.21 Another trial reported DHA supplementation in women protected against range of motion loss often caused by strenuous eccentric exercise.22
Cetylated fatty acids (derived from bovine tallow oil) work similarly to omega-3s to help reduce inflammation and cartilage degradation. A study of OA patients who took cetylated fatty acids (as Celadrin®, from Pharmachem) found improved knee range of motion and overall function after just over two months of supplementation, compared to those taking placebo.23 Much of the other published research on Celadrin involves topical application, although the benefits to pain and function management are worth noting.
A bulk of the anti-inflammatory push in the joint market has come from botanical ingredient research. Many botanicals contain compounds that impact inflammation, as evidenced by documented influence on inflammatory biomarkers, but not all have been researched specifically on joint health endpoints.
The Ayurveda botanical Boswellia serrata targets inflammation by inhibiting enzymes such as LOX that tend to trigger pro-inflammatory mediators, such as interleukin (IL) and TNF-a.24
One study found 113 of 522 genes induced by TNF-a were sensitive to boswellia extract (as 5-LOXIN®, from PLT), which inhibited expression of metalloproteinase (MMP) enzymes that can degrade cartilage ECM, including collagen.25 In a study of OA patients, 5-LOXIN supplementation improved joint pain and function.26 The researchers reported an analysis of synovial fluid revealed 5-LOXIN significantly reduced levels of the pro-inflammatory marker MMP-3.
Boswellia has shown additional joint benefits when combined with fellow anti-inflammatories N-acetyl-glucosamine and ginger. In a published study, this combination (as Movardol®, from Leonardo Medica) exhibited a positive effect on joint function and pain-free walking distance after one, three and six months of supplementation.26 Results showed WOMAC scores improved, and both inflammatory markers and reactive oxidative species (ROS) decreased in the supplement group.
Boswellia has also been combined with recent botanical darling curcumin (Curcuma longa), a compound found in turmeric. Three months of curcumin (as CuraMed®, from EuroPharma USA) taken alone or with boswellia (as Curamin®, from EuroPharma USA) lowered pain-related symptoms in OA patients, although the combination was reported as more effective due to synergistic effects.27
Curcumin targets COX (cyclooxygenase) via curcuminoids that inhibit inflammatory enzymes and signaling molecules (cytokines). In a study of OA patients with knee OA, a combination of curcuminoids (as Curcumin C3 Complex®, from Sabinsa) and piperine (as Bioperine®, from Sabinsa) improved joint pain and function — as measured by WOMAC, VAS and LFI scores — compared to placebo.28
Researchers reported in 2010 a curcumin-phosphatidylcholine complex (as Meriva®, from Indena) was safe and efficacious in decreasing joint pain and increasing joint function in OA patients.29 Subsequent study revealed Meriva taken with glucosamine more quickly provided benefits to joint symptoms in OA patients than a combination of Meriva and chondroitin sulfate.30
Longvida® brand curcumin (from Verdure Sciences) was also shown to reduce inflammatory markers, including TNF-a and IL-8.X
In addition to boswellia and curcumin, India’s traditional medicine candidates for joint health products include Terminalia chebula, the fruit from which is a key ingredient in the popular Ayurveda formula called Triphala. T. chebula contains constituents with antioxidant and anti-inflammatory properties helpful in joint health, especially for sports nutrition consumers.
In 2017, researchers reported an ingredient derived from T. chebula (as AyuFlex®, from Natreon) improved knee pain and function in healthy adults with knee discomfort following exercise/activity, but not at rest.31 The study involved men and women who took either a high or low dose of AyuFlex or placebo for 84 days, and researchers measured symptoms using modified-Knee Injury & Osteoarthritis Outcomes Score (mKOOS) global and modified-WOMAC subscales (discomfort, stiffness and function). They also looked at overall/whole-body joint health, low-back health, knee mobility, willingness and ability to exercise, and a six-minute walk test for distance and range of motion of pain-free knee flexion/extension. Further, they analyzed inflammatory biomarkers such as high sensitivity C-reactive protein (hsCRP) and TNF-a, and ECM/Connective Tissue (COMP).
The mKOOS and mWOMAC scores improved significantly in both AyuFlex dose groups, compared to baseline. Increased VAS scores in both supplement groups indicated improved knee discomfort from activity/exercise, whole-body joint function, and performance and recovery from a six-minute walk. VAS scores also demonstrated decreased knee joint soreness following a leg extension challenge and lower COMP levels in both supplement groups, compared to baseline.
In other research, AyuFlex, combined with a proprietary chromium complex (as Crominex® 3+, from Natreon), reduced joint discomfort and swelling, compared to baseline and placebo, but not as much as did AyuFlex alone.32 Crominex is a blend of chromium III mixed with Phyllanthus emblica and shilajit, a mineral pitch.
Minerals from other unique sources have made an impression on joint health research.
A plant mineral complex, calcium fructoborate (as FruiteX-B®, from Futureceuticals) helped healthy, middle-aged subjects improve symptoms of self-reported knee discomfort in a 2014 study.33 The researchers explained WOMAC and McGill Pain Questionnaire (MPQ) scores at seven and 14 days confirmed knee benefits and reduction in CRP in a subgroup of supplement subjects, but not in the placebo group.
Additional research on FruiteX-B found a high dose reduced CRP levels, compared to baseline measures, but a low dose of the supplement had no such effect.34 However, both doses showed decreased inflammatory cytokine IL-6, while the biomarker IL-1beta and pro-inflammatory cytokine monocyte chemoattractant protein-1 (MCP-1) were reduced only in the high-dose group.
A mineral complex from seaweed (Lithothamnion corallioides) containing bioactive calcium, magnesium and more than 70 other trace minerals appear to inhibit nuclear factor kappa B (NFkB), a pro-inflammatory regulator, and the COX-2 inflammatory pathway, according to in vitro research.35
The seaweed complex (as Aquamin®, from Marigot Ltd.) was the focus of a placebo-controlled trial of patients with moderate-to-severe OA.36 Those taking the mineral complex for 12 weeks experienced reduced pain and stiffness as measured by WOMAC and compared to placebo.
A later publication compared Aquamin alone and in combination with green tea extract (as Sunphenon, from Taiyo Kagaku Co.) and pine bark extract (as Enzogenol, from Enzo Nutraceuticals) on inflammatory biomarkers in OA patients.37 Researchers measured WOMAC scores and serum TNF-a levels, finding no differences between the groups except reduced TNF-a in the combination group. They concluded green tea and pine bark enhance Aquamin’s anti-inflammatory effect.
Ex vivo research has confirmed French maritime pine bark extract (as Pycnogenol®, from Horphag Research) has antioxidant and anti-inflammatory properties, including the ability to inhibit MMP-9, NFkB, COX-1 and COX-2.38,39
In randomized controlled research, Pycnogenol supplementation in OA patients decreased WOMAC scores an average of 56% , compared to a 9.6% reduction in the placebo group.40 The researchers further noted use of arthritis drugs decreased the scores by 63%, compared to only 3% in the placebo group. Pycnogenol reduced treatment costs.
Another human clinical trial found three months of Pycnogenol supplementation in OA patients improved WOMAC scores and alleviated pain via VAS score, while placebo had no benefit.41 The supplement group was also able to reduce use of analgesic drugs, the use of which increased in the placebo group.
Sports and beer often go hand in hand, and hops (Humulus lupulus) may provide inflammation control to allay joint discomfort symptoms. Unpublished research on a hops resin extract (as Perluxan®, from Soft Gel Technologies) found supplementation inhibited the inflammatory COX-2 pathway with only a mild action on COX-1, the pathway linked to gastrointestinal protection. This extract is standardized to alpha acids. However, published research comparing alpha acids with other acids (beta- and iso-alpha-) found in hops showed all the acids blocked inflammatory signaling compounds and limited acute inflammation in vivo.X
Arginine is a popular sports nutrition ingredient for improving blood flow by increasing levels of the vasodilator nitric oxide (NO). However, in a preclinical animal study published in 2017, inositol-stabilized an arginine silicate (as Nitrosigine®, from Nutrition 21) influenced inflammatory markers, including TNF-α, IL-17, IL-6, COX-2 and NF-κB, as well as improving overall arthritis and inflammation score, compared to controls.X The researchers concluded, “[Nitrosigine] may be of physiological benefit to athletes and fitness enthusiasts concerned with joint health and inflammation and to those experiencing joint pain due to inflammation.”
While the sports nutrition market seeks ingredient, research involving athletes, active consumers and exercise regimens, the wealth of research on wear-and-tear OA can offer formulators a good idea of an ingredient’s potential for an exercise-related formulation. By focusing on compounds shown to directly or indirectly impact joint structures and functions, as well as on compounds with demonstrated anti-inflammatory or similar protective properties in joints, a sports nutrition joint supplement or functional food/beverage can better ensure a finished product that is efficacious and appropriate.
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