Joint health supplements: New ingredients are elbowing their way into the joint health market

Nutritional Outlook, Nutritional Outlook Vol. 24 No. 7, Volume 24, Issue 7

Legacy ingredients are losing ground as emerging products gain validation.

The joint health ingredients market is seeing a flurry of new activity as demand for a new generation of products leads formulators to eschew legacy ingredients like glucosamine and chondroitin in favor of emerging ingredients like collagen and turmeric. To gain validation, these next-generation joint health ingredients are focusing on robust clinical trials and formulation.

The Collagen Craze

Collagen supplements recently made the leap from the beauty aisle to the joint health aisle based on studies showing it may relieve joint pain. Research on the interactions between the various types of collagen is now opening up new opportunities for synergistic, combination joint health supplements blending complementary ingredients in a single product.

One 2021 clinical trial1 examined the effects of Fortigel, a branded bioactive collagen peptide by Gelita (Eberbach, Germany), on knee pain in 180 physically active adults aged 18 to 30 with activity-related joint pain and scores above 20 on the Visual Analog Scale (VAS) for pain. The subjects were given the McMurray test for meniscus injury, the Steinmann I and II tests, and the Butler drawer test to assess ligament stability at baseline and on study conclusion. Subjects received either 5 g of Fortigel (n = 98), or a placebo (n =82), daily for 12 weeks. After 12 weeks, the group receiving collagen peptides experienced an improvement in activity-related joint pain as assessed on the VAS, by the physician, and through self-report. The study authors concluded collagen peptides can reduce knee pain during activity.

Angie Rimel, marketing communications manager for Gelita, says collagen is becoming popular in multi-ingredient products especially. “Collagen is very easy to formulate with,” Rimel says. “There’s a growing trend of blend products, like protein blends or with vitamins or prebiotics.”

Abdul Alkayali, vice president of Certified Nutraceuticals Inc. (Temecula, CA), says some of the most exciting innovation in collagen has to do with a new source: jellyfish. In fact, Alkayali expects invertebrates to replace mammals as the primary source of collagen in the coming years.

“Jellyfish collagen supplies the body with multiple types of collagen peptides and essential minerals that are only found in edible jellyfish collagen,” Alkayali says. “New research on jellyfish has increased tremendously.”

A 2017 60-day prospective single-center observational study2 assessed Certified Nutraceuticals’ branded TendoGuard, a joint health blend including Types I, II, V, and X collagen, as well as hyaluronic acid, chondroitin sulfate, and mucopolysaccharides. This study examined the effects of a 750 mg/day dose of TendoGuard on joint pain and range of motion in 20 men and women aged 45 to 75 with a history of a knee disorder. Subjects were assessed for range of motion via goniometer, pain via the Borg scale, and muscle strength via a sphygmomanometer. After 60 days, the subjects saw improvements in range of motion, pain, and muscle strength. While this study lacked a control group, the study authors concluded that TendoGuard reduced symptoms of joint discomfort.

Studies like these are driving sales of collagen products in the joint health market. Douglas Jones, global sales and marketing manager for Biocell Technology LLC (Irvine, CA), says consumers are looking for clinically validated ingredients that provide noticeable benefits. He expects the joint health market to present opportunities for collagen brands that have clinical research behind them.

“Biocell has seen our collagen sales increase with some customers by over 100% within the last 18 months,” Jones says. “We see consumers looking for at-home solutions to maintain their joint health. The future in joint health is very bright. Millennials are now in their 30s, and this population is very focused on supply-side transparency and branded ingredients with clinical evidence.”

While Millennials represent a growing opportunity for future growth, most joint health consumers are still older adults. A 2021 consumer survey by Lonza (Basel, Switzerland) found that the average joint health consumer is between the ages of 45 and 64. According to Lonza’s research, joint health supplement consumers tend to be well educated and have high incomes. Lindsey Toth, RD, associate director of health ingredients for Lonza, says that with one in six people projected to be 65 years old or older by 2050, now is the time to begin laying the groundwork of consumer education campaigns.

“While collagen has taken center stage in recent years, there is largely little known by consumers about the different types of collagens and the difference in benefits they confer,” Toth says. “Lonza has invested significant research in understanding the benefits of undenatured type II collagen.”

Lonza’s branded UC-II collagen, an undenatured type II collagen ingredient, has been found to increase mobility and reduce joint discomfort in clinical studies, Toth says. One of the advantages of this type of collagen, Toth notes, is convenience of delivery. “UC-II collagen can be taken in a tiny, once-daily, easy-to-swallow dose. Pill fatigue and swallowability concerns are a huge barrier for most aging consumers.”

While collagen is an effective ingredient for joint health, not all types of collagen are created equal. Jaume Reguant, healthcare director for Bioiberica (Barcelona, Spain), says formulators who want to work with collagen will need to consider which type of collagen is best for their application.

“Native type II collagen is an effective joint health ingredient and compared to its hydrolyzed counterpart requires a much lower dosage,” Reguant says. “This means it can be incorporated alongside other beneficial ingredients to support joint health.”

“Emerging ingredients like this are facilitating a new era of mobility health that appeals to a wider range of people who see movement as a fundamental part of their physical and mental well-being,” he adds.

One recent animal study3 examined the efficacy of combining Bioiberica’s branded Collavant n2 ingredient (formerly called 2Cool), which is an undenatured type II collagen, and Mobilee, which is a hyaluronic acid matrix ingredient, in a formula that also included Bioiberica’s chondroitin sulfate and glucosamine hydrochloride ingredients. The study assessed the blend’s effects on articular cartilage, synovial membrane, and subchondral bone in 54 rabbits with induced osteoarthritis. The rabbits were randomly assigned to receive a daily dose of either 1) chondroitin sulfate (CS) plus glucosamine hydrochloride (GH) and hyaluronic acid (HA) (n=18), 2) CS plus GH and HA with added Collavant n2 (n=18), or 3) nothing (n=18). Each group was divided into three subgroups (n=6) that were sacrificed after 28, 56, or 84 days. After sacrifice, the rabbits were dissected and evaluated. The rabbits that received the combination of CS, GH, and HA showed milder degenerative changes relative to the control group. The addition of Collavant strengthened this protective effect, the researchers concluded.

Other new research on collagen is demonstrating the viability of a personalized nutrition approach. Liz Clarke, CFS, technical marketing manager for Nitta Gelatin (Morrisville, NC), says new research on joint health ingredients goes beyond providing scientific substantiation of health benefits for the general population. Instead, studies are now zeroing in on clinical personalization for specific demographics like younger athletes or seniors with mobility issues.

One recent randomized, double-blind, placebo-controlled clinical trial4 on Nitta Gelatin’s branded Wellnex Replenwell collagen peptide examined the effects of collagen supplementation on joint pain in healthy male university students aged 18 to 21 who were members of the Josai University running club in Sakado, Japan. The students were randomly assigned to receive either 5 g of Replenwell per day (n = 25) or a maltodextrin placebo (n = 21), for eight weeks. After four weeks, the placebo group saw an increase in levels of interleukin-6 (IL-6), a biomarker of inflammation. The collagen peptide group did not see any significant changes in IL-6 levels. The study found that a daily dose of Replenwell taken for four weeks reduced joint discomfort.

“Personalization is the key here,” Clarke says. “We’re seeing significant results with lower dosage rates for active, younger participants than we have in previous studies looking at the effects on older populations with preexisting joint conditions. While it’s common-sense that different populations would have differing needs, being able to quantify that into dosage requirements is new for collagen.”

Turmeric Gains Ground

One relative newcomer to the joint health market is starting to shake things up and threaten the dominance of legacy ingredients. Recent research is showing that turmeric (Curcuma longa) can reduce joint inflammation in more ways than one.

Eric Anderson, managing director of NXT USA (Metuchen, NJ), says the company’s branded TamaFlex, a patent-pending blend of Tamarindus indica seed and turmeric rhizome extracts, is proving to be effective in addressing joint health issues like comfort, flexibility, and function. One 2019 randomized, double-blind, placebo-controlled study5 examined the effects of TamaFlex in 90 non-arthritic subjects with knee pain and joint discomfort. Subjects were randomized to receive either 250 mg (n=30) or 400 mg (n=30) of TamaFlex per day, or a placebo (n=29), for 90 days. Subjects were assessed via the Six-Minute Walk Test and Stair Climb Test at baseline and after 90 days. Both TamaFlex groups saw an increase in average walking speed and improvements on Six-Minute Walk Test and Stair Climb Test scores compared to placebo, as well as reductions in pain and stiffness.

“The latest study on TamaFlex showed that it starts working in five days,” Anderson says. “This study, pending publication, explored how TamaFlex impacted subjects with mild to moderate joint pain from osteoarthritis. It showed improvements in pain, stiffness, physical activity, and stair climbing scores by day five.”

Other studies are demonstrating that turmeric can also be an effective joint health ingredient when incorporated into polyphenol blends. A recent open-label feasibility trial6 on Verdure Sciences’ (Noblesville, IN) branded curcumin/polyphenol blend Restoridyn examined the effects of the blend on blood inflammatory proteins and inflammation-associated RNA in 18 half-marathon runners for 29 days before, the day of, and the day after a race.

The participants received 1 g/day of Restoridyn for the first 26 days and 2 g/day on days 27 through 31. The subjects were also permitted to take an additional 1 g/day booster dose on days 1 through 26, but only on days when they ran more than 6 miles. Subjects were assessed for inflammation and soreness via testing for IL-10, IL-13, IL-4, TNF-alpha, and RNA biomarkers, among several others, on days 29 through 31.

The study found that Restoridyn altered several pathways associated with inflammation, B-cell activity, and muscle recovery. Restoridyn downregulated a type of long, non-coding RNA that is known to be involved in inflammation and COX-2 expression.

Kristen Marshall, digital marketing manager at Verdure Sciences, says the joint health market is beginning to diversify into more subcategories and specialized applications. Joint health brands are expanding into multiple functional arenas like exercise recovery and sports nutrition, joint comfort, pain and stiffness, inflammation, and overall healthy lifestyle.

“Joint health has evolved to include an ever-increasing array of applications, functions, and formats,” Marshall says. “We’re seeing many brands diversify their product offerings with innovative delivery forms like topicals, chocolates, functional beverages, and more.”

Research on other forms of turmeric is ongoing, and some of these studies show that an unconventional type of turmeric extract may offer substantial advantages. Brien Quirk, director of research and development for Draco Natural Products (San Jose, CA), says a water-soluble polysaccharide extract sourced from turmeric rhizomes was found to be very effective at relieving symptoms of osteoarthritis in a clinical trial7.

This study—a randomized, single-blind, placebo-controlled trial—examined the effects of NR-INF-02, a branded powdered curcumin rhizome product marketed as Turmacin by Natural Remedies Pvt. Ltd. (Bangalore, India), on pain and knee function in 120 subjects with knee osteoarthritis. Participants were randomly assigned to receive either 1) 400 mg of a placebo twice per day (n=30), or 2) 500 mg of Turmacin twice per day (n=30), 3) 750 mg of glucosamine sulfate twice per day (n=30), or 4) a combination of glucosamine sulfate and Turmacin twice per day (n=30), for 42 days. The subjects were assessed for pain via the VAS and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scales, and joint condition via the Clinical Global Impression Change (CGIC) scale, at baseline and after 21 and 42 days.

After 42 days, the subjects who received Turmacin showed a significant improvement in VAS, WOMAC, and CGIC scores and a significant decrease in the use of pain medication relative to placebo. The study authors concluded that Turmacin is a safe and effective option for relieving pain and improving knee function in osteoarthritis patients.

“Most of the turmeric extracts being sold on the market are standardized to a concentration of 95% curcumin and do not have water-soluble polysaccharides,” Quirk says. “Curcumin is very poorly absorbed, which explains why most turmeric extracts have not shown much benefit except in very large doses. Turmeric extracts that are rich in water-soluble polysaccharides have been ignored until now.”

Eggshell Membrane Powerhouse

Eggshell membrane ingredients are gaining popularity in joint health applications for their rich combination of joint-healthy compounds. Amanda Jepson, senior director of marketing and international sales for Biova LLC (Johnston, IA), says eggshell membrane is a source of multiple, naturally occurring compounds that promote joint health. These include ingredients like collagen, elastin, glucosamine, chondroitin, and several amino acids.

One 2019 study8 on Biova’s branded BiovaFlex water-soluble egg membrane ingredient demonstrated robust results. The 12-week randomized, double-blind, placebo-controlled clinical trial examined the effects of a 450-mg daily dose of BiovaFlex (n = 44) on WOMAC scores and performance on the Six-Minute Walk Test relative to placebo (n = 44).

“The worst-performing subjects in the BiovaFlex group at baseline had the most significant improvement within five days,” Jepson says. “The BiovaFlex group also noted a reduction in joint stiffness within five days.”

New means of measuring the efficacy of ingredients are also lending momentum to the joint health space. Jacqueline Rizo, content coordinator for Stratum Nutrition (Carthage, MO), says that while joint health ingredients have typically been evaluated using pain and stiffness scales, recent innovations have made it possible to measure ingredient efficacy through objective biomarkers like CTX-II, the C-terminal telopeptide fragments of type II collagen.

“One of the significant developments related to NEM”—the company’s flagship eggshell membrane ingredient—“in recent months was the publication of research involved in the development of a clinical trial design for evaluating the effects of joint therapeutics on cartilage turnover,” Rizo says. “This clinical trial marked the first evidence suggesting CTX-II could be used to evaluate the chondroprotective efficacy of joint therapeutics in healthy individuals.”

The trial9 in question, sponsored by Stratum Nutrition’s parent company ESM Technologies (Carthage, MO), followed 60 healthy, postmenopausal women for 14 days. The women received either 500 mg of NEM per day (n=30), or a placebo (n=30), while doing step exercises (50-100 steps per leg) on alternating days. NEM administration resulted in faster recovery from exercise-induced joint pain and stiffness, as well as reduced discomfort, relative to placebo.

MSM—A Flexible Option

While the joint health benefits of methylsulfonylmethane (MSM) have been established for some time, recent clinical trials examining MSM in combination with other joint health ingredients have found that MSM has a synergistic effect.

Tim Hammond, vice president of sales and marketing for Bergstrom Nutrition (Vancouver, WA), says Bergstrom’s branded OptiMSM is ideal for new products because of its relative affordability, strong safety profile, and proven efficacy.

“Extensive research has shown that MSM decreases joint pain, improves stiffness and swelling, and increases the range of motion and physical function of individuals with osteoarthritis,” Hammond says. “OptiMSM’s likely mechanism stems from its ability to decrease pro-inflammatory cytokines, reduce oxidative damage, and supply a rich source of sulfur.”

One 2017 randomized, double-blind, placebo-controlled trial10 examined the performance of a glucosamine-chondroitin sulfate product both with and without MSM in relieving symptoms of osteoarthritis. The subjects, all of whom had either grade I or grade II osteoarthritis according to the Kellgren-Lawrence scale, received either 1) 1,500 mg of glucosamine and 1,200 mg of chondroitin sulfate (n=49), or 2) 1,500 mg of glucosamine, 1,200 mg of chondroitin sulfate, and 500 mg of MSM (n=50), or 3) a matching placebo (n=48) daily for three months. The subjects were assessed for joint pain on the WOMAC and VAS scales at baseline and after 4, 8, and 12 weeks. By the end of the study, the group that received the combination of glucosamine, chondroitin sulfate, and MSM exhibited the most significant improvements in WOMAC and VAS scores.

Botanicals

Various botanicals are showing promise as joint health supplements in clinical trials. Several of these products may present considerable advantages over legacy ingredients. Steve Fink, vice president of marketing for PLT Health Solutions (Morristown, NJ), says botanical ingredients like Boswellia serrata take effect faster and require a lower dosage than some of the established ingredients in the market.

“If we look at the most commonly used natural solutions for mobility support, two things stand out: they require relatively large doses, and they require a long time to show efficacy,” Fink says.

In contrast, Fink says Boswellia extracts and other botanicals have been found to take effect in as little as five days and to be effective with doses as low as 100 mg. PLT’s branded Boswellia serrata, Dynagenix Muscle+Joint Formula, is a low-dose joint health ingredient that can be formulated in RTD products, powders, and more. One 2019 randomized, double-blind, placebo-controlled clinical trial examined the effects of Dynagenix Muscle+Joint Formula in 50 healthy, active men aged 25 to 40. In this unpublished study, subjects received 60 mg of Boswellia serrata per day (n=25), or a matching placebo (n=25), for 10 days. Subjects underwent an eccentric exercise regimen, which involves muscles contracting and lengthening in quick succession, on day 7. The subjects were assessed for muscle and joint soreness via the VAS, knee range of motion, overall stiffness, and biomarkers of inflammation like IL-6 and cytokines at baseline and once daily on days 7 through 10. The subjects who received Boswellia serrata experienced a reduction in joint soreness and a faster recovery of knee range of motion relative to the control group.

Another rich source of emerging joint health botanicals is the world of traditional Chinese medicine. David Liu, PhD, is the chief technology officer for Chenland Nutritionals (Irvine, CA). Liu says the reputation of certain joint health ingredients in traditional folk medicine systems like traditional Chinese medicine and Ayurveda is prompting researchers to take a closer look at these ingredients.

“With the development and utilization of omics and bioinformatics in these research fields, the scientific implication of herbal formulas has been elucidated, which has led to a better understanding of and acceptance by the western science community,” Liu explains. “Herbs like Dioscorea nipponica, Andrographis paniculata, and Acacia catechu have been clinically studied for their efficacies in relieving joint discomfort related to knee osteoarthritis.”

Chenland recently completed a six-month, open-label human clinical trial on its JointAlive ingredient, which contains extracts of Epimedium brevicornum Maxim, Dioscorea nipponica Makino, and Salvia miltiorrhiza Bunge. Liu says that in this yet-to-be-published trial, JointAlive was 85% effective at reducing WOMAC scores. He says this trial also found that JointAlive begins to relieve joint discomfort in as little as two days.

Chenland is also actively pursuing a randomized, double-blind, placebo-controlled clinical trial11 on JointAlive in partnership with KGK Science (London, ON, Canada). This study, which is currently recruiting participants, will examine the efficacy of JointAlive in alleviating joint pain and improving knee function in an otherwise healthy population with mild to moderate knee osteoarthritis. Liu says the last subject will be enrolled in September 2021, and a final report on the clinical trial is expected by the end of this year.

Formulators are also looking toward botanical ingredients that are quite well known for applications in food. Steve Holtby, president and CEO of Soft Gel Technologies Inc. (Los Angeles, CA), says one emerging joint health ingredient is better known for its role in making beer.

“Hops, the ingredient used to add a touch of bitterness to most brews, has been studied because of its joint health properties,” Holtby explains. Soft Gel Technologies’ Perluxan softgels, derived from hops (Humulus lupulus) “contain a unique botanical anti-inflammatory agent that has been clinically demonstrated to quickly relieve minor joint pain.”

Soft Gel Technologies exclusively markets Perluxan as a resin. Pharmachem Laboratories (Kearny, NJ), a division of Ashland (Wilmington, DE) that has performed extensive research12 on Perluxan, owns the trademark for Perluxan as a powder.

One randomized, double-blind, parallel-design trial13 on 19 subjects pitted Perluxan against ibuprofen. The subjects were randomly assigned to receive either 1) 400 mg of ibuprofen once per day, 2) a softgel containing 450 mg of the hops resin once per day, or 3) a 300-mg capsule containing a powdered form of the hops resin four times per day, for 14 days. Both hops formulations inhibited COX-2 as well as ibuprofen starting nine hours after the initial dose; however, the hops formulations did not inhibit COX-1, while ibuprofen did.

“It was interesting to note that the hops resin softgel was only administered once over a nine-hour period but was as effective as ibuprofen,” Holtby says. “The Perluxan softgel had a faster onset of action and gradually reduced pain-causing enzymes over the period of the study.”

Other botanical blends are also showing promise in joint health. Indena’s (Milan, Italy) branded Mitidol, a blend of ginger (Zingiber officinale) and paracress (Acmella oleracea), underwent a pilot study that was published in 2020. This study14, a single-group pretest-posttest quasi-experimental trial, examined the effects of Mitidol on pain, inflammation, and knee function in 50 subjects aged 40 to 75 with knee osteoarthritis. All subjects received two 350-mg tablets of Mitidol daily for four weeks (n=50); there was no placebo group. The subjects were assessed for WOMAC and Tegner Lysholm Knee Scoring Scale scores at baseline and after 15 and 30 days. They were also evaluated for pain on the Visual Analogue Scale, quality of life via the 36-Item Short-Form Health Survey, and biomarkers of inflammation via C-reactive protein and erythrocyte sedimentation rate testing at baseline and after 30 days.

The subjects saw a significant decrease in VAS scores in the left and right knees after 10 and 11 days, respectively. WOMAC scores also decreased throughout the study, from a group average of 44 to 38. The group’s average Lysholm score increased from 65 at baseline to 73 after 30 days, indicating an improvement in knee function.

While several of the studies on botanicals for joint health have focused on aging older adults, this market is beginning to see interest from younger consumers—and Annie Eng, CEO of HP Ingredients (Bradenton, FL), says the next generation of joint health supplement users is already looking for clinically validated preventative maintenance products.

“The joint support market continues on a fast track of development as the Millennial generation, who are very active and health-conscious, begin to be proactive about joint care,” Eng says. “To ensure they and like-minded older adults have access to products that work to preserve joint structure and promote joint function, we are launching a new human clinical trial.”

This new study, led by Juan Hancke, PhD, is a randomized, double-blind, placebo-controlled clinical trial. The study will examine the effects of daily consumption of HP Ingredients’ branded Andrographis paniculata product, ParActin, on knee function in knee osteoarthritis patients. The study will follow the subjects for one year. Earlier this year, ParActin received a natural product license from Health Canada.15

Exciting Times Ahead

The joint health space is seeing significant disruption and innovation. Emerging ingredients are gaining momentum as clinical trials prove their efficacy, carving out a place in the market next to more established competitors. As the joint health market continues to grow, products like turmeric, botanicals, and collagen will gain further traction. As this space grows more competitive, success in joint health will depend on convincing consumers that your ingredient stands on a strong foundation of science.

Sidebar: Hyaluronic Acid Normalizes Synovial Fluid

Michael Grenner, sales manager of food and nutrition raw materials, North America, at Bloomage Biotechnology USA (Hawthorne, NJ), says natural, non-GMO, and organic ingredients are growing in the joint-health space.

Grenner says hyaluronic acid is showing up in joint health formulations in combination with MSM, chondroitin, and other ingredients. Bloomage’s Haplex Plus contains sodium hyaluronate, the salt form of hyaluronic acid (HA). Studies have shown that HA can normalize synovial fluid16, relieve joint pain17, and protect cartilage from denaturation18.

Sidebar: Pea Reduces Joint Pain

One recent study19opened the door for a new joint-health contender. A 2021 randomized, double-blind, placebo-controlled trial found that a 350-mg daily dose of Gencor’s (Irvine, CA) Levagen, a branded palmitoylethanolamide (PEA) ingredient, reduced Visual Analogue Scale scores for joint pain in healthy adults aged 25 to 70. While the placebo group (n = 39) also saw a reduction in scores, that reduction lasted only 10 days before scores began to rise again, while the PEA group’s (n = 35) scores decreased over the entire course of the study.

“PEA demonstrated in the study its anti-inflammatory and analgesic properties, along with its ability to influence the endocannabinoid system,” says Maggie McNamara, marketing director for Gencor. “PEA downregulates multiple pro-inflammatory and nociceptive pathways and is known to inhibit glial cell activity.”

Sidebar: New Form of Chondroitin Improves Knee Function in OA Patients

While chondroitin sulfate has a long history of use in joint health, concerns around sourcing are leading to innovations in this ingredient. Xavier Berger, marketing manager for mobility and joint health at Gnosis by Lesaffre (Lille, France), says consumer concerns around animal welfare and cross-contamination have prompted formulators to source chondroitin from plants. Gnosis’s branded chondroitin product Mythocondro is one example of this trend.

“Mythocondro helps reduce the risk of osteoarthritis and joint degeneration,” Berger says. “Additional benefits include pain relief, anti-inflammatory activity, and increased articular function.”

One recent clinical trial20 on Mythocondro found that a 600 mg/day dose reduced inflammation, WOMAC scores, and C-reactive protein levels in obese adults with moderate knee osteoarthritis after eight weeks.

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