Product Review – Flexofend Capsules

This is an objective, independently written product review on Flexofend^TM from Azariah pharmaceuticals. The active ingredient, eggshell membrane, exhibits anti-inflammatory activity to reduce pain and stiffness associated with inflammatory processes in the body such as osteoarthritis.

The use of eggshell membrane as a nutraceutical to protect, treat, and repair connective tissues, or to reduce joint pain and inflammation related to osteoarthritis, rheumatoid arthritis or other joint disorders is fairy new.

This review supports the potential benefits when taking a supplement with naturally occurring material found in eggshell membrane.

INGREDIENTS

Flexofend^TM is a natural food-sourced product of pharmaceutical grade quality containing 500 mg of patented NEM^® (eggshell membrane), that contains a natural matrix of the following bioactive molecules, working synergistically to support a healthy inflammatory response:

• Collagen I, V, and X,
• Hyaluronic acid,
• Glucosamine and
• Chondroitin sulfate

NEM^® naturally contains many of the same key nutrients found in healthy joint cartilage including glycosaminoglycans (chondroitin & hyaluronic acid), collagen, and peptides.

Chicken eggs have been a staple of many cultures’ diets for centuries and are well-accepted as being safe to eat. Some cultures are also known to consume the egg shells and eggshell membranes in various ways.¹ Let’s discover why the 2018 Frost & Sullivan Award for the best joint health supplement in it’s category, was given to Stratum Nutrition^® for their NEM^® brand eggshell membrane ingredient.

NEM^® (Eggshell Membrane) 

NEM^® is the most studied eggshell membrane on the market. In human clinical trials, NEM^® has been shown to help support healthy joints against pain, stiffness and cartilage break-down in as little as 4 to 11 days. NEM^® is sustainably sourced from a renewable supply of US-domestic eggshells.

The shell of an egg begins with the formation of the shell membranes upon which the true shell is deposited in crystalline form.²

Why eggshell membrane?

You may ask: who thought of using eggshell membrane? Processed eggshell membrane preparations were patented by Dale Paul DeVore, Chelmsford, MA (US) and Frank Daniel Long, Neosho, MO (US).

The most evident function of the membrane is to act as a supporting structure for the egg prior to deposition of a calcified shell and to provide an organic matrix for the deposition of calcium in eggshell formation.

The material derived from eggshell membrane used in various studies include: processed eggshell membrane, eggshell membrane powder, eggshell membrane isolates, eggshell membrane hydrolysates, or combinations thereof.

NEM^® was the first eggshell membrane approved for strong joint health claims in the Canadian market and is supported by a full portfolio of 16 research studies, including 4 randomized placebo-controlled trials.

In addition to the subjective assessments like joint pain and stiffness, recent healthy population clinical trials have included an objective cartilage degradation biomarker, giving the results additional credibility and substantiation.

Chemical analysis

Chemical analysis of preparations of eggshell membrane has shown them to be primarily comprised of protein fibers which contains a high content of cystine, arginine, glutamic acid, methionine, histidine and proline.³

Eggshell membrane is composed of two individual membranes between egg albumin and eggshell. The membranes are primarily comprised of protein fibers. The fibers appear to be a network or scaffold predominantly containing Type I collagen fibers that are encapsulated in a continuous mantle of proteoglycans and other macromolecules.⁴

Subsequent studies demonstrated the presence of Type V collagen⁵ in eggshell membrane and Type X. Type X collagen functions to inhibit mineralization and establishes a zone protected from mineral deposition.^6,7

More recently, along with its high protein content, significant quantities of glucosamine, chondroitin sulfate, and hyaluronic acid have been detected in eggshell membrane.

Mechanism of action  

Mechanism of action studies suggest that NEM^® may help reduce cartilage degradation associated with normal wear and tear.

To maintain joint health long-term, the integrity of the soft cartilage in the joint itself must be supported. Few supplements address this vital aspect of joint health. Once again, the research backing NEM^® supplementation is impressive. The first study⁸ to delve into the potential for a chondroprotective effect was a study involving the effects of NEM^® on an osteoarthritis-induced animal model.

This study not only confirmed the reduction in pro-inflammatory cytokines in vitro and animal studies, but also expanded the study parameters to include analysis of biomarkers implicated in joint pathology. NEM^® supplementation can help support and maintain healthy cartilage structure.

CLINICAL EVIDENCE 

The first NEM^® research were two single center, open-label human clinical studies⁹ to evaluate the efficacy and safety of NEM^® as a treatment for pain and inflexibility associated with joint and connective tissue disorders in various joint structures, such as knees, hips, neck, wrist and ankle.

It showed significantly reduced pain, both rapidly (seven days) and continuously (30 days). These clinically meaningful results demonstrates that significant proportions of treated patients may be helped considerably from NEM^® supplementation.

The flexibility score showed a 27.8% increase at 7 days. At 30 days, the general pain reduction was 72.5%, flexibility score increased by 43.7% and Range of Motion-associated pain (ROM) was reduced by a score of 75.9%.

Double-arm trial: Supplementation with NEM^® produced a significant treatment response for pain at seven days for both treatment arms (X: 18.4% reduction; Y: 31.3% reduction). The significant treatment response, 30.2% reduction, continued through 30 days for pain.

There were no adverse events reported during either study and the treatment was reported to be well tolerated by study participants.

The Clinical Trial Registration numbers for these trials are: NCT00750230 and NCT00750854.

Positive results for pain relief within 7 days in these two small trials led to the development of a randomized double-blind, placebo-controlled clinical trial in individuals diagnosed with knee osteoarthritis.¹⁰ The results from this trial demonstrated statistically significant benefits in pain relief.

An unpublished independent placebo controlled trial followed focusing on exercise-induced challenges in individuals with pre-existing joint pain.

Most recently, two independent open label trials were conducted in Germany and Italy that supported the results of increased comfort from the previous trials.^11,12

A 2017 randomized, double-blind, placebo-controlled trial in a healthy population revealed NEM^®’s ability to reduce joint pain associated with exercise in healthy individuals in just 8 days.¹³ NEM^® is the first dietary ingredient that has been shown to reduce exercise-induced pain in truly healthy subjects. It has also demonstrated significant reduction in pain and stiffness in 5 other published clinical trials.^11,14,15,16

These clinical trials consistently show that a once daily 500 mg dose of NEM^® produces a significant reduction in joint stiffness within 4 to 10 days.

NEM^® supplementation has also been shown to decrease levels of the inflammatory marker, CRP.^8,9,17,18 NEM^® has also been shown to influence the functioning of the immune system.¹⁹

CTX-II is a biomarker of cartilage degradation. Elevated levels are found in individuals where there is increased cartilage turnover, such as growing adolescents, endurance athletes, postmenopausal women and overweight individuals.

Postmenopausal women (with elevated levels of CTX-II) were specifically selected for a study as they have more of a propensity to experience joint pain than the general population.

A substantial chondroprotective effect was demonstrated from NEM^® supplementation through a lasting decrease in CTX-II despite exercise.¹³

NEM^®’s effects on decreasing joint inflammation and restoring flexibility have been studied in human clinical trials, as well as in in vitro and animal studies. Statistically significant improvements in flexibility were noted in all of the clinical trials where it was analysed, including the newest trial in a healthy population.

CREDIT: STRATUM NUTRITION

Anti-inflammatory activity of eggshell membrane

Inflammation, as defined in Dorland's Medical Dictionary, is ‘a localised protective response, elicited by injury or destruction of tissues, which serves to destroy, dilute or wall off both the injurious agent and the injured tissue.’

The inflammatory response causes much of the physical discomfort (pain and loss of function) that has come to be associated with different diseases and injuries.

Inflammation is required for efficient self-healing to occur in the body. However, uncontrolled inflammation can further damage the already stressed or injured tissue. NEM^® functions alongside the body to quell inflammation through modulation of the immune system’s release of pro-inflammatory substances.^8,9,17,18

Results clearly demonstrated that processed eggshell membrane and eggshell membrane hydrolysate reduced plasma pro-inflammatory cytokines, typically associated with inflammation and pain.

INFLAMMATORY CONDITIONS

At some point in life, most of us will become very aware of the importance of maintaining our joint health. Flexofend^TM can be used by persons with any condition associated with chronic pain and discomfort as it reduces pro-inflammatory cytokines.

Conditions with an inflammatory component includes: osteoarthritis; rheumatoid arthritis; rheumatism; bursitis; degenerative spinal disc disease; a degenerative condition causing joint, tendon, ligament or soft tissue pain; and trauma to joints, tendons, ligaments or soft tissue.

Articular cartilage is the smooth, white tissue that covers the ends of bones where they come together to form joints and makes it easier for the bones to glide over each other with very little friction. A joint injury can result in swelling, heat, tenderness, pain, stiffness and range limitation of the joint (inflammation).

The best way to avoid possible cartilage damage later on in life is to provide your cartilage with support long before the issues start to develop. NEM^® is the first dietary ingredient to demonstrate cartilage protection in only one week in a human clinical trial conducted in healthy individuals. This was in fact demonstrated by a reduction in a biomarker of cartilage degradation induced through exercise.¹³

Fortunately, in most cases, the rebuilding of cartilage can keep up with the increased degradation. This is not always true for post-menopausal women because of the role of estrogen in cartilage rebuilding. For these particularly vulnerable individuals, NEM^® supplementation can help provide an extra level of support.

Osteoarthritis (OA) indicate a significant increase in pro-inflammatory biomarkers leading to chronic inflammation and possibly one of the major reasons why the disease is so deteriorating in nature.

Osteoarthritis is a degenerative disease characterized by joint pain and stiffness that can cause physical dysfunction and decreased quality of life. OA is a common disease that occurs most often in people over 50 years of age, but also in younger population. The knee is one of the most commonly affected joints. The structural changes of articular cartilage, synovial membrane and subchondral bone are due to a combination of risk factors, including aging, obesity, being female, genetics and joint injury. In knee OA, the cartilage of the knee joint gradually roughens, becomes thin or wears away causing bone rubbing on bone and pain. OA develops slowly and the joint pain and stiffness usually worsen as the disease progresses

A randomized, multicenter, double-blind, placebo-controlled Osteoarthritis Pain Treatment Incorporating NEM^® clinical study¹⁰ was conducted to evaluate the efficacy and safety of NEM^®as a treatment for pain and stiffness associated with osteoarthritis of the knee.

Supplementation with NEM^® produced an absolute rate of response that was statistically significant (up to 26.6%) versus placebo (for both pain and stiffness), but was not significantly improved for function and overall WOMAC scores, although trending toward improvement.

The WOMAC measures five items for pain (score range 0 to 20), two for stiffness (score range 0 to 8), and 17 for functional limitation (score range 0 to 68).

Rapid responses were seen for mean pain sub-scores (15.9% reduction) and mean stiffness sub-scores (12.8% reduction) occurring after only 10 days of supplementation.

Supplementation with NEM^® significantly reduced both joint pain and stiffness compared to placebo at 10, 30, and 60 days.

Another single-center, 2-month openlabel, study was designed to evaluate the efficacy of NEM^®in the reduction of joint pain, stiffness and functional disability in patients with moderate to severe knee OA and safety and tolerability of NEM^® supplementation.

This study demonstrated that NEM^® supplementation resulted in rapid (10 days) responses for WOMAC pain (19.8% reduction) and stiffness (12.9% reduction).

The reduction of pain and stiffness was continuous over the study period and by the end of the follow-up period (60 days) the reduction of pain and stiffness was substantial (51.9% reduction and 51.6% reduction, respectively).

According to the sixth clinical trial¹⁵ involving NEM^® and the largest trial to date, the use of NEM^® in the context of OA consistently yields statistically significant and clinically meaningful results. The combination of quick symptom relief (7 days) coupled with continuing long-term relief (90 days) is impressive from a food-based ingredient, and should be clinically beneficial for those suffering from OA.

Medication-based therapies in OA comprise different drugs, including analgesics (e.g. paracetamol, hydrocodone) or non-steroidal anti-inflammatory drugs (NSAIDs) (e.g. ibuprofen, celecoxib, etc.), alone or in combination. These therapies have shown limited effectiveness in clinical studies or may have significant and serious side effects.^{20 to 23}

NEM^® has the added benefit as the use of analgesics significantly dropped over the study period. The reduction of use of these drugs adds to the safety benefit of NEM^® supplementation. 

Post-workout stiff joints

The Natural & Non-Prescription Health Products Directorate recently approved updated cartilage protection claims for joint pain and stiffness,  due to moderate intensity aerobic exercise.

NEM^® helps with workout recovery and post-workout pain related issues.

NEM^® has just been selected as a finalist in the upcoming NutraIngredients Awards 2022 for the Ingredient of the Year: Sports Nutrition category.

Despite its many health benefits, moderate exercise can induce joint discomfort when done infrequently or too intensely even in individuals with healthy joints. Active, healthy people deal with exercise-induced pain, stiffness and cartilage breakdown on a daily basis.

A study¹⁶ was designed to evaluate whether NEM^® would reduce exercise-induced cartilage turnover or alleviate joint pain or stiffness, either directly following exercise or 12 hours post exercise, versus placebo.

NEM^® rapidly improved recovery from exercise-induced joint pain (day 8) and stiffness (day 4) and reduced discomfort immediately following exercise (stiffness, day 7). Moreover, a substantial chondroprotective effect was demonstrated via a decrease in the cartilage degradation biomarker CTX-II.

MANUFACTURING

NEM^® is manufactured in a FDA-inspected, NSF-certified GMP facility. Shell membranes are removed from the shell and washed thoroughly in three washings of deionized water, air-dried for four hours and freeze-dried. The powder is placed in nutraceutical capsules, formed into tablets.

The composition of NEM^® has been found to be quite consistent between different manufacturing batches, as well as with differing sources of eggs.

NEM^® is a registered trademark of ESM Technologies, LLC (USA). ESM has developed a ‘green’ manufacturing process to efficiently and effectively separate eggshell membrane from eggshells on a commercial scale to create an essentially shell-free eggshell membrane.²⁴

CONCLUSION 

Flexofend^TM can be considered as a safe, cost-effective, natural intervention for inclusion as part of comprehensive clinical protocol in the management of patients with knee OA, even in patients with more severe grade 2 and 3 OA, connective tissue disorders and inflammation.

Flexofend^TM claims can be backed up with 16 published clinical studies for:

1. cartilage protection against further breakdown
2. joint stiffness reduction
3. joint pain reduction

DOSAGE 

Take one capsule per day, with or without food. There is one month’s supply in a box. Each capsule contains: 500mg NEM^®

Do not exceed the recommended daily dose. Not recommended for children.

SIDE EFFECTS AND WARNINGS

If you are allergic to eggs, consult your health care practitioner before taking this product.

Real-time stability studies have demonstrated that NEM^® can be stored under ambient conditions for later use for up to 3 years from the date of manufacture. NEM^® has self-affirmed GRAS status and was evaluated for safety via in vitro and in vivo toxicological studies.

NEM^® did not exhibit any cytotoxic effects at a dose of 100 μg in an in vitro human cell viability assay after incubation for up to 20 h. NEM^® was evaluated for cytotoxicity, genotoxicity, and oral toxicity and has a safety profile of up to 50× the human dose of 500 mg/day.

NEM^® did not exhibit any genotoxic effects in an in vitro assay of four strains of histidine-dependent Salmonella typhimurium and one strain of tryptophan-dependent Escherichia coli at a dose of up to 5000 μg/plate.

NEM^® did not exhibit any signs of acute toxicity in rats at a single oral dose of up to 2000 mg/kg body weight, nor signs of toxicity (via urinalysis, hematology, clinical chemistry, or histopathological evaluation) in rats at a repeated oral dose of up to 2000 mg/kg body weight per day for 90 days.

Flexofend^TM is safe to use with other chronic medication and medical conditions.

Non-GMO, Halal & Kosher certified and Shellfish free. Free from sugar, lactose, gluten, GMO, soya & pesticides. No artificial additives, flavours, colourants & preservatives. For more information, visit Flexofend.co.za

The information published here, does not intend to diagnose, treat, cure or prevent any disease. The product reviewed has not been evaluated by any regulatory body and is not intended to diagnose treat, cure or prevent any disease. The information given here is not meant to be a substitute for seeing a health professional. It is our opinion only, based on several years of research, in consultation with world experts. We’re sure you’ll find it useful, but please use it wisely and always exercise common sense.

Flexofend^TM have not been evaluated by the SAHPRA.

TESTIMONIALS 

1. ‘I can truly boldly state that I benefit greatly from the use of Flexofend.  My biggest problem was the acute arthritis pain in my hands, which resulted in me no longer being able to open a jam bottle for a long time if it was only slightly tightly closed.  I also stopped playing the church organ about five years ago because of arthritis and, out of sheer disappointment, even sold my beloved house organ. Today I regret it because since I started using Flexofend daily in March 2020, my hands have started to feel noticeably better.  Within months, the arthritis pain had not only almost completely disappeared, but I had regained the full use of both my hands so that today, less than a year after my first dose, I can effortlessly and pain-free unscrew the tightest screw lids.  I'm convinced this is largely due to the daily use of Flexofend.'  ~ Riaan Cruywagen, TV broadcaster
2. ‘I used Flexofend™ this past month and just would like testify that Flexofend™ has helped me very much. I have experienced the worst pain for 2 months. I couldn't get into my bed or car, nor could I go shopping anymore. Somewhere a muscle or nervous fast-pressed and caused the severe pain. Fortunately, my path crossed with Flexofend™. Since I am using Flexofend™ the pain has gone. I can walk again, get self into my bed and drive my car, and can go shopping. It is simply the best product and I recommend it 100%.' ~ Helena Catsman
3. ‘Today I want to say thank you very much. My worst pains are much better… can make a fist! Even my hips and lower back pain don't burn like that anymore.' ~ Annatjie Strydom

REFERENCES

1. (PDF) Safety evaluation of a natural eggshell membrane-derived product. Available from: https://www.researchgate.net/publication/221747675_Safety_evaluation_of_a_natural_eggshell_membrane-derived_product [accessed Mar 29 2022].
2. M. Britton and K. K. Hale, JR. Amino Acid Analysis of Shell Membranes of Eggs From Young and Old Hens Varying in Shell Quality. Poultry Science 56:865-871, 1977.
3. William J Stadelman, Debbie Newkirk, Lynne Newby. Egg Science and Technology. CRC Press. 1995 ISBN 9781560228554 (https://www.routledge.com/Egg-Science-and-Technology/Stadelman-Newkirk-Newby/p/book/9781560228554)
4. T-M, et. al., Matrix Biology, 14:507-513, 1994.
5. Wong, M, et. al., Biology, 104:28-36, 1984.
6. Arias, J. L., et. al., Connective Tissue Research, 26: 37-45, 1991.
7. Aria, J. L., et. al., Matrix, 11: 313-320, 1991; Arias, J. L., et. al., Connective Tissue Research, 36: 21-33, 1997.
8. Sim BY, Bak JW, Lee HJ, Jun JA, Choi HJ, Kwon CJ, Kim HY, Ruff KJ, Brandt K and Kim DH. Effects of natural eggshell membrane (NEM) on monosodium iodoacetate-induced arthritis in rats. J Nutr Health, 48(4):310-318, 2015.
9. Ruff, K.J., DeVore, D.P., Leu, M.D., and Robinson, M.A. Eggshell Membrane: A Possible New Natural Therapeutic For Joint & Connective Tissue Disorders. Results From Two Open-label Human Clinical Studies. Clinical Interventions in Aging, 4, 235-240, 2009.
10. Ruff, K.J., Winkler, A., Jackson, R.W., DeVore, D.P., and Ritz, B.W.Eggshell Membrane in the Treatment of Pain and Stiffness from Osteoarthritis of the Knee: A Randomized, Multicenter, Double Blind, Placebo Controlled Clinical Study. Clinical Rheumatology, 28, 907-914, 2009.
11. Brunello, E., and Masini, A. NEM® Brand Eggshell Membrane Effective in the Treatment of Pain and Stiffness Associated with Osteoarthritis of the Knee in an Italian Study Population. International Journal of Clinical Medicine, 7, 169- 175, 2016.
12. Danesch, U., Seybold, M., Rittinghausen, R., Treibel, W., and Bitterlich, N. NEM Brand Eggshell Membrane Effective in the Treatment of Pain Associated with Knee and Hip Osteoarthritis: Results from a Six Center, Open Label German Clinical Study. Journal of Arthritis, 3(3), 136, 2014.
13. Ruff, K.J., Morton, K., Duncan, S.A., Back, M., Ismail, A., Ryan, A.S. Eggshell Membrane+Fish Oil Combination (Move3®) Reduces Exercise-Induced Joint Pain, Stiffness and Cartilage Turnover in Healthy Adults: Results from a Randomized, Double-Blind, Placebo-Controlled Study. International Journal of Physical Medicine and Rehabilitation, 8(3), 1000551, 2020.
14. Damjanov, N., Novkovic, S., Basaric, M., Nikolic, A.K., Vagic, K., Pejnovic, N., Karic, V. NEM® Brand Eggshell Membrane in the Treatment of Pain and Stiffness Associated with Knee Osteoarthritis: An Open Label Clinical Study. Journal of Arthritis, 8(5), 1000287, 2019.
15. Eskiyurt, N., Saridoğan, Senel K., Günaydin, R., Erdal, A., Özyiğit, E., Akarirmak, Ü., Şendur, Ö., Barut, K., Gülseren, A., Özsoy, T., Tuncer, T., Karataş, Ö., İrdesel, J., Ketenci, A., and Aydogan, C. Efficacy and Safety of Natural Eggshell Membrane (NEM®) in Patients with Grade 2/3 Knee Osteoarthritis: A Multi-Center, Randomized, Double-blind, Placebo-Controlled, Single-crossover Clinical Study. Journal of Arthritis, 8: 285, 2019.
16. Ruff, K.J., Theodosakis, J., Morrison, D., Duncan, S.A., Back, M., and Aydogan, C. Eggshell Membrane: Beneficial effects of natural eggshell membrane versus placebo in exercise-induced joint pain, stiffness, and cartilage turnover in healthy, postmenopausal women. Clinical Interventions in Aging, 13, 285-295, 2018.
17. Wedekind, K.J., Ruff, K.J., Atwell, C.A., Evans, J.L., and Bendele, A.M. Beneficial Effects of Natural Eggshell Membrane (NEM) on Multiple Indices of Arthritis in Collagen-Induced Arthritic Rats. Modern Rheumatology, 27(5), 838- 848, 2016.
18. Ruff, K.J., Durham, P.L., O’Reilly, A., and Long, F.D. Eggshell membrane hydrolyzates activate NF-κB in vitro: possible implications for in vivo efficacy. Journal of Inflammation Research, 8, 49-57, 2015.
19. Benson, K.F., Ruff, K.J., and Jensen, G.S. Effects of Natural Eggshell Membrane (NEM) on Cytokine Production in Cultures of Peripheral Blood Mononuclear Cells: Increased Suppression of Tumor Necrosis Factor-a Levels After In Vitro Digestion. Journal of Medicinal Food, 15(4), 360-368, 2012. Clinical Trial Design
20. Altman RD. Ibuprofen, acetaminophen and placebo in osteoarthritis of the knee: a six-day double-blind study. Arthritis Rheum 42: S403, 1999.
21. Case JP, Baliunas AJ, Block JA. Lack of efficacy of acetaminophen in treating symptomatic knee osteoarthritis: A randomized, double-blind, placebocontrolled comparison trial with diclofenac sodium. Arch Intern Med 163: 169- 178.
22. Geba GP, Weaver AL, Polis AB, Dixon ME, Schnitzer TJ, et al. (2002) Efficacy of rofecoxib, celecoxib, and acetaminophen in osteoarthritis of the knee: a randomized trial. JAMA 287: 64-71, 2003.
23. Towheed TE, Maxwell L, Judd MG, Catton M, Hochberg MC, et al. Acetaminophen for osteoarthritis. Cochrane Database Syst Rev 1: CD004257, 2006.
24. Safety evaluation of a natural eggshell membrane-derived product. Food and Chemical Toxicology. Volume 50, Issues 3–4, March–April 2012, Pages 604-611