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NEM (Natural Eggshell Membrane)

Eggshell membrane in the treatment of pain and stiffness from osteoarthritis of the knee: a randomized, multicenter, double-blind, placebo-controlled clinical study *

Natural Eggshell Membrane (NEM®) is a new novel dietary supplement that contains naturally occurring glycosaminoglycans and proteins essential for maintaining healthy articular cartilage and the surrounding synovium. The randomized, multicenter, double-blind, placebo-controlled Osteoarthritis Pain Treatment Incorporating NEM® clinical study was conducted to evaluate the efficacy and safety of NEM® as a treatment for pain and stiffness associated with osteoarthritis of the knee. Sixty-seven patients were randomly assigned to receive either oral NEM® 500 mg (n = 34) or placebo (n = 33) daily for 8 weeks. The primary endpoint was the change in overall Western Ontario and McMasters Universities (WOMAC) Osteoarthritis Index as well as pain, stiffness, and function WOMAC subscales measured at 10, 30, and 60 days. The clinical assessment was performed on the intent-to-treat population. Supplementation with NEM® produced an absolute rate of response that was statistically significant (up to 26.6%) versus placebo at all time points for both pain and stiffness, but was not significantly improved for function and overall WOMAC scores, although trending toward improvement. Rapid responses were seen for mean pain subscores (15.9% reduction, P = 0.036) and mean stiffness subscores (12.8% reduction, P = 0.024) occurring after only 10 days of supplementation. There were no serious adverse events reported during the study and the treatment was reported to be well tolerated by study participants. Natural Eggshell Membrane (NEM®) is an effective and safe option for the treatment of pain and stiffness associated with knee osteoarthritis. Supplementation with NEM®, 500 mg taken once daily, significantly reduced both joint pain and stiffness compared to placebo at 10, 30, and 60 days. The Clinical Trial Registration number for this study is NCT00750477.

Source: Kevin J. Ruff, Anne Winkler, Robert W. Jackson, Dale P. DeVore, and Barry W. Ritz.“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. (2009): 28(8): 907–914. 

Beneficial effects of natural eggshell membrane versus placebo in exercise-induced joint pain, stiffness, and cartilage turnover in healthy, postmenopausal women*


Purpose: Despite its many health benefits, moderate exercise can induce joint discomfort when done infrequently or too intensely even in individuals with healthy joints. This study was designed to evaluate whether NEM®(natural eggshell membrane) would reduce exercise-induced cartilage turnover or alleviate joint pain or stiffness, either directly following exercise or 12 hours post exercise, versus placebo.

Patients and methods: Sixty healthy, postmenopausal women were randomly assigned to receive either oral NEM 500 mg (n=30) or placebo (n=30) once daily for two consecutive weeks while performing an exercise regimen (50–100 steps per leg) on alternating days. The primary endpoint was any statistically significant reduction in exercise-induced cartilage turnover via the biomarker C-terminal cross-linked telopeptide of type-II collagen (CTX-II) versus placebo, evaluated at 1 and 2 weeks of treatment. Secondary endpoints were any reductions in either exercise-induced joint pain or stiffness versus placebo, evaluated daily via participant questionnaire. The clinical assessment was performed on the per protocol population.

Results: NEM produced a significant absolute treatment effect (TEabs) versus placebo for CTX-II after both 1 week (TEabs −17.2%, P=0.002) and 2 weeks of exercise (TEabs −9.9%, P=0.042). Immediate pain was not significantly different; however, rapid treatment responses were observed for immediate stiffness (Day 7) and recovery pain (Day 8) and recovery stiffness (Day 4). No serious adverse events occurred and the treatment was reported to be well tolerated by study participants.

Conclusion: 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. Clinical Trial Registration number: NCT02751944.

Source: Kevin J Ruff, Dennis Morrison, Sarah A Duncan, Matthew Back, Cem Aydogan, and Jason Theodosakis. “Beneficial effects of natural eggshell membrane versus placebo in exercise-induced joint pain, stiffness, and cartilage turnover in healthy, postmenopausal women” Clin Interv Aging. (2018): 13: 285–295. 

Eggshell membrane: A possible new natural therapeutic for joint and connective tissue disorders. Results from two open-label human clinical studies*

Background: Natural Eggshell Membrane (NEM®) is a novel dietary supplement that contains naturally occurring glycosaminoglycans and proteins essential for maintaining healthy joint and connective tissues. Two single center, open-label human clinical studies were conducted to evaluate the efficacy and safety of NEM® as a treatment for pain and inflexibility associated with joint and connective tissue disorders.

Methods: Eleven (single-arm trial) and 28 (double-arm trial) patients received oral NEM® 500 mg once daily for four weeks. The primary outcome measure was to evaluate the change in general pain associated with the treatment joints/areas (both studies). In the single-arm trial, range of motion (ROM) and related ROM-associated pain was also evaluated. The primary treatment response endpoints were at seven and 30 days. Both clinical assessments were performed on the intent-to-treat (ITT) population within each study.

Results: Single-arm trial: Supplementation with NEM® produced a significant treatment response at seven days for flexibility (27.8% increase; P = 0.038) and at 30 days for general pain (72.5% reduction; P = 0.007), flexibility (43.7% increase; P = 0.006), and ROM-associated pain (75.9% reduction; P = 0.021). Double-arm trial: Supplementation with NEM® produced a significant treatment response for pain at seven days for both treatment arms (X: 18.4% reduction; P = 0.021. Y: 31.3% reduction; P = 0.014). There was no clinically meaningful difference between treatment arms at seven days, so the Y arm crossed over to the X formulation for the remainder of the study. The significant treatment response continued through 30 days for pain (30.2% reduction; P = 0.0001). There were no adverse events reported during either study and the treatment was reported to be well tolerated by study participants.

Conclusions: Natural Eggshell Membrane (NEM®) is a possible new effective and safe therapeutic option for the treatment of pain and inflexibility associated with joint and connective tissue (JCT) disorders. Supplementation with NEM®, 500 mg taken once daily, significantly reduced pain, both rapidly (seven days) and continuously (30 days). It also showed clinically meaningful results from a brief responder analysis, demonstrating that significant proportions of treated patients may be helped considerably from NEM® supplementation. The Clinical Trial Registration numbers for these trials are: NCT00750230 and NCT00750854.

Source: Kevin J. Ruff, Dale P. DeVore, Michael D. Leu, and Mark A. Robinson. “Eggshell membrane: A possible new natural therapeutic for joint and connective tissue disorders. Results from two open-label human clinical studies” Clinical Interventions in Aging. (2009) 4: 235–240.


Calcium plus vitamin D supplementation and joint symptoms in postmenopausal women in the women's health initiative randomized trial*

Background: Low vitamin D intake and levels have been associated with increased joint symptoms in some observational studies but the findings are mixed and evidence from randomized trials sparse.

Objective: To evaluate the influence of supplemental calcium and vitamin D on joint symptoms in the Women's Health Initiative randomized, placebo-controlled, clinical trial.

Design: In post hoc analyses, the results of the Women's Health Initiative randomized clinical trial in which 36,282 postmenopausal women were randomized to receive calcium carbonate (1,000 mg as elemental calcium) with vitamin D-3 (400 IU) daily or placebo were examined in the 6% subgroup of 1,911 participants, oversampled for minorities, who had serial joint symptom assessment. Qualitative information on joint pain and joint swelling was collected by questionnaire before entry and 2 years after randomization. Logistic regression models were used to compare the occurrence and severity of joint symptoms across randomization groups.

Results:At baseline, total calcium and vitamin D intakes from diet and supplements were similar in the two randomization groups. In addition, both joint pain (reported by 73%) and joint swelling (reported by 34%) were commonly reported and comparable in the supplement and placebo groups. Two years after randomization, no statistically significant differences between supplement and placebo groups were seen for joint pain frequency (74.6% compared with 75.1% [P=0.79] for supplement and placebo groups, respectively) or joint swelling frequency (34.6% compared with 32.4% [P=0.29], respectively) or in severity scores for either outcome. Subgroup analyses suggested study participants also using nonprotocol calcium supplements at study entry may have less joint pain with supplement group randomization (interaction P=0.02).

Conclusions: Joint symptoms are relatively common in postmenopausal women. However, daily supplementation with 1,000 mg calcium carbonate and 400 IU vitamin D-3 in a randomized, placebo-controlled clinical trial setting did not reduce the self-reported frequency or severity of joint symptoms.

Source: Rowan T. Chlebowski, Mary Pettinger, Karen C. Johnson, Robert Wallace, Catherine Womack, Yasmin Mossavar-Rahmani, Marcia Stefanick, Jean Wactawski-Wende, Laura Carbone, Bing Lu, Charles Eaton, Brian Walitt, and Charles L .Kooperberg. “Calcium plus vitamin D supplementation and joint symptoms in postmenopausal women in the women's health initiative randomized trial” Journal of the Academy Nutrition and Dietetics (2013): 113(10):1302-10.

The good, the bad, and the ugly of calcium supplementation: a review of calcium intake on human health*


Calcium is an important integrative component of the human body and critical for human health. It has been well established that calcium intake is helpful in the prevention and treatment of osteoporosis, which has become one of the most serious public health problems across the world. However, community-dwelling adults with and without osteoporosis are rarely concerned or even not aware of the potential side effects of high or inappropriate doses of calcium intake. Some recent studies have revealed that excessive calcium intake might increase the risks of cardiovascular diseases. The purpose of this article was to review the health benefits, costs, and consequences of calcium supplementation on osteoporosis/osteoporotic fractures, cardiovascular events, kidney stones, gastrointestinal diseases, and other important diseases. In the end, we suggest that calcium supplementation should be prescribed and taken cautiously, accounting for individual patients’ risks and benefits. Clearly, further studies are needed to examine the health effects of calcium supplementation to make any solid recommendations for people of different genders, ages, and ethnicities.

Source: Kelvin Li, Xia-Fang Wang, Ding-You Li, Yuan-Cheng Chen, Lan-Juan Zhao, Xiao-Gang Liu, Yan-Fang Guo, Jie Shen, Xu Lin, Jeffrey Deng, Rou Zhou, and Hong-Wen Deng. “The good, the bad, and the ugly of calcium supplementation: a review of calcium intake on human health” Clinical Interventions in Aging. (2018): 13: 2443–2452. 

The use of calcium and vitamin D in the management of osteoporosis*


Osteoporosis poses a significant public health issue, causing significant morbidity and mortality. Calcium and vitamin D utilization in the optimization of bone health is often overlooked by patients and health care providers. In addition, the optimal standard of care for osteoporosis should encompass adequate calcium and vitamin D intake. Dietary intake or supplementation with calcium and vitamin D will be reviewed, including recent recommendations for increased vitamin D intake. Compliance to calcium and vitamin D therapy is paramount for effective prevention of osteoporotic fractures. A recently released algorithm (FRAX) estimating absolute fracture risk allows the health care provider to decide when pharmacologic therapy is warranted in addition to calcium and vitamin D. When pharmacologic therapy is advised, continued use of calcium and vitamin D is recommended for optimal fracture risk reduction. A ‘bricks and mortar’ analogy is often helpful when counseling patients and this analogy will be explained. This manuscript reviews relevant data related to calcium and vitamin D use for patients at risk for fracture due to bone loss.

Peak bone mass is usually achieved by age 30; therefore, physical activity and obtaining the recommended doses of calcium and vitamin D in adolescence and young adulthood will ensure peak bone mass development (Table 1) (IOM 1997). Calcium is an essential element in the human body and is necessary to many cell functions. Calcium is not only important to bone health, but it is also essential for neuromuscular activity, blood coagulation, and normal cardiac function. It is a vital component of bone architecture and is required for deposition of bone mineral throughout life. Although the body stores more than 99% of its calcium in the bones and teeth, it is also found in the extracellular fluid (ECF) or plasma. It is the levels of plasma calcium that dictate calcium balance. If the plasma level decreases, bone resorption increases to restore plasma levels. Adequate intake of calcium is necessary to maintain this balance.

Source: John A. Sunyecz. “The use of calcium and vitamin D in the management of osteoporosis” Therapeutics and Clinical Risk Management. (2008): 4(4): 827–836. 


Effects of a ginger extract on knee pain in patients with osteoarthritis*


Objective: To evaluate the efficacy and safety of a standardized and highly concentrated extract of 2 ginger species, Zingiber officinale and Alpinia galanga (EV.EXT 77), in patients with osteoarthritis (OA) of the knee.

Methods: Two hundred sixty-one patients with OA of the knee and moderate-to-severe pain were enrolled in a randomized, double-blind, placebo-controlled, multicenter, parallel-group, 6-week study. After washout, patients received ginger extract or placebo twice daily, with acetaminophen allowed as rescue medication. The primary efficacy variable was the proportion of responders experiencing a reduction in "knee pain on standing," using an intent-to-treat analysis. A responder was defined by a reduction in pain of > or = 15 mm on a visual analog scale.

Results: In the 247 evaluable patients, the percentage of responders experiencing a reduction in knee pain on standing was superior in the ginger extract group compared with the control group (63% versus 50%; P = 0.048). Analysis of the secondary efficacy variables revealed a consistently greater response in the ginger extract group compared with the control group, when analyzing mean values: reduction in knee pain on standing (24.5 mm versus 16.4 mm; P = 0.005), reduction in knee pain after walking 50 feet (15.1 mm versus 8.7 mm; P = 0.016), and reduction in the Western Ontario and McMaster Universities osteoarthritis composite index (12.9 mm versus 9.0 mm; P = 0.087). Change in global status and reduction in intake of rescue medication were numerically greater in the ginger extract group. Change in quality of life was equal in the 2 groups. Patients receiving ginger extract experienced more gastrointestinal (GI) adverse events than did the placebo group (59 patients versus 21 patients). GI adverse events were mostly mild.

Conclusion: A highly purified and standardized ginger extract had a statistically significant effect on reducing symptoms of OA of the knee. This effect was moderate. There was a good safety profile, with mostly mild GI adverse events in the ginger extract group.

Source: R. D. Altman, and K. C. Marcussen. “Effects of a ginger extract on knee pain in patients with osteoarthritis” Arthritis and Rheumatism. (2001): 44(11):2531-8.

Zingiber officinale: A Potential Plant against Rheumatoid Arthritis*


Rheumatoid arthritis (RA) is an autoimmune disease particularly affecting elderly people which leads to massive bone destruction with consequent inflammation, pain, and debility. Allopathic medicine can provide only symptomatic relief. However, Zingiber officinale is a plant belonging to the Zingiberaceae family, which has traditionally been used for treatment of RA in alternative medicines of many countries. Many of the phytochemical constituents of the rhizomes of this plant have therapeutic benefits including amelioration of RA. This review attempts to list those phytochemical constituents with their reported mechanisms of action. It is concluded that these phytochemicals can form the basis of discovery of new drugs, which not only can provide symptomatic relief but also may provide total relief from RA by stopping RA-induced bone destruction. As the development of RA is a complex process, further research should be continued towards elucidating the molecular details leading to RA and drugs that can stop or reverse these processes by phytoconstituents of ginger.

Source: Abdullah Al-Nahain, Rownak Jahan, and Mohammed Rahmatullah. “Zingiber officinale: A Potential Plant against Rheumatoid Arthritis” Arthritis. (2014): 2014: 159089. 

The clinical effectiveness of Ginger (Zingiber officinale) in adults with osteoarthritis *


Background: Osteoarthritis (OA) is a degenerative joint disease, which is associated with increased pain and disability, and a simultaneous decline in the quality of life of sufferers. While there is no cure for OA, there are numerous treatments that aim to reduce sufferers' symptoms and disability and improve their quality of life. Medications, which have long been integral interventions for the management of OA, have recently been found to cause harm in some patients. Simultaneously, the increasing recognition of complementary and alternative therapies as part of mainstream health care, has seen many sufferers of OA use these therapies. Ginger has been commonly prescribed by herbalists for sufferers of OA due to its anti-inflammatory and circulatory stimulant effects. However, to date there has been no systematic review of the literature to evaluate the clinical effectiveness of Ginger for OA.

Objective: The objective of this systematic review was to evaluate the safety and effectiveness of Ginger in adults with OA.

Data sources: A comprehensive search was undertaken on 18 electronic databases from their inception to January 2007, including AARP Ageline, AMED, AMI, BioMed central gateway, CAM on PubMed, CENTRAL, CINAHL, Cochrane library, Current controlled trials, Current contents connect, DARE, Dissertations Abstract International, EMBASE, Health Source Nursing/Academic edition, International Pharmaceutical Abstract, MEDLINE, Natural medicines comprehensive database and TRIP.

Review methods: Randomised controlled trials or clinical controlled trials were sought, which evaluated the effectiveness of mono-preparations of ginger in adults with OA of the knee or hip. Critical appraisal of study quality was undertaken using Joanna Briggs Institute critical appraisal instruments. Data extraction was via the Joanna Briggs Institute standard data extraction form for evidence of effectiveness.

Results: Five randomised controlled trials were identified from the search, of which three met the inclusion criteria. The methodological quality of the included studies was good. However, given that studies were clinically, and methodologically heterogeneous, meta-analysis could not be conducted. Instead, evidence was summarised in narrative form. For changes in pain severity, studies comparing ginger extract (n = 110) to placebo (n = 111) reported mixed findings in support of the use of Ginger. Studies comparing ginger to an active control found participants who received Ibuprofen (n = 96) had a greater change in median pain intensity compared with participants who received Ginger (n = 110), and while findings were statistically significant for only one of the two studies, the results had limited clinical significance. Similarly, while two placebo-controlled studies reported differences between ginger (n = 70) and placebo (n = 71) for changes in disability and functional capacity, the difference was statistically and clinically significant for only one study. In one study comparing ginger to an active control, participants receiving Ibuprofen (n = 56) reported a statistically significant improvement in disability and functional capacity over time when compared with participants receiving Ginger (n = 56). In terms of safety, Ginger was well tolerated when compared with Ibuprofen, with infrequent reports of mild, and predominantly gastrointestinal, adverse effects.

Conclusion: Current evidence is weak for the use of Ginger in adults with OA of the knee and/or hip. Much of this can be attributed to significant heterogeneity between studies. Improvements in research design, instrumentation and ginger dosage, which more closely reflect current clinical practice, may help to demonstrate the safe and effective use of Ginger in OA sufferers.

Source: Matthew J. Leach, and Saravana Kumar. “The clinical effectiveness of Ginger (Zingiber officinale) in adults with osteoarthritis” International Journal of Evidence-Based Healthcare. (2008): 6(3):311-20.

Turmeric Root Extract

Efficacy of Turmeric Extracts and Curcumin for Alleviating the Symptoms of Joint Arthritis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials*

Although turmeric and its curcumin-enriched extracts have been used for treating arthritis, no systematic review and meta-analysis of randomized clinical trials (RCTs) have been conducted to evaluate the strength of the research. We systemically evaluated all RCTs of turmeric extracts and curcumin for treating arthritis symptoms to elucidate the efficacy of curcuma for alleviating the symptoms of arthritis. Literature searches were conducted using 12 electronic databases, including PubMed, Embase, Cochrane Library, Korean databases, Chinese medical databases, and Indian scientific database. Search terms used were “turmeric,” “curcuma,” “curcumin,” “arthritis,” and “osteoarthritis.” A pain visual analogue score (PVAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) were used for the major outcomes of arthritis. Initial searches yielded 29 articles, of which 8 met specific selection criteria. Three among the included RCTs reported reduction of PVAS (mean difference: −2.04 [−2.85, −1.24]) with turmeric/curcumin in comparison with placebo (P < .00001), whereas meta-analysis of four studies showed a decrease of WOMAC with turmeric/curcumin treatment (mean difference: −15.36 [−26.9, −3.77]; P = .009). Furthermore, there was no significant mean difference in PVAS between turmeric/curcumin and pain medicine in meta-analysis of five studies. Eight RCTs included in the review exhibited low to moderate risk of bias. There was no publication bias in the meta-analysis. In conclusion, these RCTs provide scientific evidence that supports the efficacy of turmeric extract (about 1000 mg/day of curcumin) in the treatment of arthritis. However, the total number of RCTs included in the analysis, the total sample size, and the methodological quality of the primary studies were not sufficient to draw definitive conclusions. Thus, more rigorous and larger studies are needed to confirm the therapeutic efficacy of turmeric for arthritis.

Source: James W. Daily, Mini Yang, Sunmin Park. “Efficacy of Turmeric Extracts and Curcumin for Alleviating the Symptoms of Joint Arthritis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials” Journal of Medicinal Food (2016): 19(8): 717–729.

Efficacy and mechanism of action of turmeric supplements in the treatment of experimental arthritis *


Objective: Scientific evidence is lacking for the antiarthritic efficacy of turmeric dietary supplements that are being promoted for arthritis treatment. Therefore, we undertook studies to determine the antiarthritic efficacy and mechanism of action of a well‐characterized turmeric extract using an animal model of rheumatoid arthritis (RA).

Methods: The composition of commercial turmeric dietary supplements was determined by high‐performance liquid chromatography. A curcuminoid‐containing turmeric extract similar in composition to these supplements was isolated and administered intraperitoneally to female Lewis rats prior to or after the onset of streptococcal cell wall–induced arthritis. Efficacy in preventing joint swelling and destruction was determined clinically, histologically, and by measurement of bone mineral density. Mechanism of action was elucidated by analysis of turmeric’s effect on articular transcription factor activation, microarray analysis of articular gene expression, and verification of the physiologic effects of alterations in gene expression.

Results: A turmeric fraction depleted of essential oils profoundly inhibited joint inflammation and periarticular joint destruction in a dose‐dependent manner. In vivo treatment prevented local activation of NF‐κB and the subsequent expression of NF‐κB–regulated genes mediating joint inflammation and destruction, including chemokines, cyclooxygenase 2, and RANKL. Consistent with these findings, inflammatory cell influx, joint levels of prostaglandin E2, and periarticular osteoclast formation were inhibited by turmeric extract treatment.

Conclusion: These translational studies demonstrate in vivo efficacy and identify a mechanism of action for a well‐characterized turmeric extract that supports further clinical evaluation of turmeric dietary supplements in the treatment of RA.

Source: Janet L. Funk, Jennifer B. Frye, Janice N. Oyarzo, Nesrin Kuscuoglu. “Efficacy and mechanism of action of turmeric supplements in the treatment of experimental arthritis” Arthritis and Rheumatology (2006).

Safety and efficacy of curcumin versus diclofenac in knee osteoarthritis: a randomized open-label parallel-arm study*

Background: The purpose of this study was to compare the efficacy and safety of curcumin with those of diclofenac in the treatment of knee osteoarthritis (OA).

Methods: In this randomized, open-label, parallel, active controlled clinical study, 139 patients with knee OA were randomly assigned to receive either a curcumin 500-mg (BCM-95®) capsule three times daily or a diclofenac 50-mg tablet two times daily for 28 days. Patients underwent assessment at baseline and days 7, 14, and 28. The main outcome measure was severity of pain using visual analogue scale score at days 14 and 28. Knee Injury and Osteoarthritis Outcome Score (KOOS) (at days 14 and 28), anti-flatulent effect (at day 7), anti-ulcer effect, weight-lowering effect, and patient’s and physician’s global assessment of therapy at day 28 were included as secondary outcome measures. Safety after treatment was evaluated by recording adverse events and laboratory investigation.

Results: At days 14 and 28, patients receiving curcumin showed similar improvement in severity of pain and KOOS scale when compared with diclofenac, and the difference was not statistically significant. At day 7, the patients who received curcumin experienced a significantly greater reduction in the number of episodes of flatulence compared with diclofenac (P < 0.01). At day 28, a weight-lowering effect (P < 0.01) and anti-ulcer effect (P < 0.01) of curcumin were observed. None of the patients required H2 blockers in the curcumin group, and 19 patients required H2 blockers in the diclofenac group (0% versus 28%, respectively; P < 0.01). Adverse effects were significantly less in the curcumin group (13% versus 38% in the diclofenac group; P < 0.01). Patient’s and physician’s global assessment of therapy was similar in the two treatment groups.

Conclusion: Curcumin has similar efficacy to diclofenac but demonstrated better tolerance among patients with knee OA. Curcumin can be an alternative treatment option in the patients with knee OA who are intolerant to the side effects of non-steroidal anti-inflammatory drugs.

Source: Dhaneshwar Shep, Chitra Khanwelkar, Prakashchandra Gade, and Satyanand Karad. “Safety and efficacy of curcumin versus diclofenac in knee osteoarthritis: a randomized open-label parallel-arm study” Trials. (2019): 20: 214. 

Black Pepper (Piperine)

Anti-inflammatory and antiarthritic effects of piperine in human interleukin 1β-stimulated fibroblast-like synoviocytes and in rat arthritis models*


Introduction: The objective of this study was to determine the anti-inflammatory, nociceptive, and antiarthritic effects of piperine, the active phenolic component in black pepper extract.

Methods: The in vitro anti-inflammatory activity of piperine was tested on interleukin 1β (IL1β)-stimulated fibroblast-like synoviocytes derived form patients with rheumatoid arthritis. The levels of IL6, matrix metalloproteinase (MMPs), cyclo-oxygenase 2 (COX-2), and prostaglandin E2 (PGE2) were investigated by ELISA and RT-PCR analysis. The analgesic and antiarthritic activities of piperine were investigated on rat models of carrageenan-induced acute paw pain and arthritis. The former were evaluated with a paw pressure test, and the latter by measuring the squeaking score, paw volume, and weight distribution ratio. Piperine was administrated orally to rats at 20 and 100 mg/kg/day for 8 days.

Results: Piperine inhibited the expression of IL6 and MMP13 and reduced the production of PGE2 in a dose dependant manner at concentrations of 10 to 100 μg/ml. In particular, the production of PGE2 was significantly inhibited even at 10 μg/ml of piperine. Piperine inhibited the migration of activator protein 1 (AP-1), but not nuclear factor (NF)κB, into the nucleus in IL1β-treated synoviocytes. In rats, piperine significantly reduced nociceptive and arthritic symptoms at days 8 and 4, respectively. Histological staining showed that piperine significantly reduced the inflammatory area in the ankle joints.

Conclusions: These results suggest that piperine has anti-inflammatory, antinociceptive, and antiarthritic effects in an arthritis animal model. Thus, piperine should be further studied with regard to use either as a pharmaceutical or as a dietary supplement for the treatment of arthritis.

Source: Jun Soo Bang, Da Hee Oh, Hyun Mi Choi, Bong-Jun Sur, Sung-Jig Lim, Jung Yeon Kim, Hyung-In Yang, Myung Chul Yoo, Dae-Hyun Hahm, and Kyoung Soo Kim. “Anti-inflammatory and antiarthritic effects of piperine in human interleukin 1β-stimulated fibroblast-like synoviocytes and in rat arthritis models” Arthritis Research and Therapy (2009):  11(2): R49.

Dietary supplement for nutritionally promoting healthy joint function*


A dietary supplement for nutritionally promoting healthy joint function in human subjects is disclosed. The supplement includes as a major ingredient a protein derived from the enzymatic hydrolysis of collagen in combination with lesser proportions of glucosamine sulfate, ginkgo biloba, borage oil powder, turmeric, Boswellia Serrata, ashwagandha, piper nigrum extract, and an herbal blend.

Source: Hastings, Carl W., David J. Barnes, and Christine A. Daley. “Dietary supplement for nutritionally promoting healthy joint function.” U.S. Patent No. 6,224,871. 1 May 2001.

Bioperine, Absorption & Bioavailability*


BioPerine® has been found to enhance the gastrointestinal absorption of nutrients by at least 30% in a double-blind and in vivo studies. BioPerine® has been clinically tested with several nutrient groups, including fat-soluble vitamins (ß-carotene), water-soluble vitamins (vitamin B6, vitamin C), curcumin, coenzyme Q10. It was shown to significantly enhance the bioavailability of these supplemented nutrients through increased gastrointestinal absorption. Studied nutrients were measured by amounts present in the blood when administered with BioPerine® as compared to the control group receiving the above nutrients alone. 

Source: Javaid, Nadia. “BioPerine, Absorption & Bioavailability.”

Recent Developments in Delivery, Bioavailability, Absorption and Metabolism of Curcumin: the Golden Pigment from Golden Spice*

Curcumin (diferuloylmethane) is a yellow pigment present in the spice turmeric (Curcuma longa) that has been associated with antioxidant, anti-inflammatory, anticancer, antiviral, and antibacterial activities as indicated by over 6,000 citations. In addition, over one hundred clinical studies have been carried out with curcumin. One of the major problems with curcumin is perceived to be the bioavailability. How curcumin should be delivered in vivo, how bioavailable is it, how well curcumin is absorbed and how it is metabolized, is the focus of this review. Various formulations of curcumin that are currently available are also discussed.

Besides these natural compounds have been also used to increase the bioavailability of curcumin. One of them is piperine, a major component of black pepper, known as inhibitor of hepatic and intestinal glucuronidation and is also shown to increase the bioavailability of curcumin. This effect of piperine on the pharmacokinetics of curcumin has been shown to be much greater in humans than in rats. In humans, curcumin bioavailability was increased by 2,000% at 45 minutes after co-administering curcumin orally with piperine, whereas in rats, it has been found that concomitant administration of piperine 20 mg/kg with curcumin 2 g/kg increased the serum concentration of curcumin by 154% for a short period of 1-2 hours post drug. The study shows that in the dosages used, piperine enhances the serum concentration, extent of absorption and bioavailability of curcumin in both rats and humans with no adverse effects [95].

Another study also showed that piperine (20 mg/kg orally) when administered with curcumin (2 g/kg orally) enhances the bioavailability of the latter up to 20-fold more in epileptic rats [111]. Enhanced bioavailability of curcumin was also evidenced by other researcher when curcumin was administered orally concomitant with piperine. Intestinal absorption of curcumin was also found relatively higher when administered concomitantly with piperine, and it stayed significantly longer in the body tissues [112]. In view of these findings, curcumin-piperine (Cu-Pi) nanoparticles has been prepared by various methods [113]. The bioavailability, cellular uptake and biological effects of this nanoparticles are being tested.

Source: Sahdeo Prasad, PhD, Amit K. Tyagi, PhD, and  Bharat B. Aggarwal, PhD. “Recent Developments in Delivery, Bioavailability, Absorption and Metabolism of Curcumin: the Golden Pigment from Golden Spice” Cancer Research and Treatment (2014): 46(1): 2–18.

Boswellia Serrata

A commercialized dietary supplement alleviates joint pain in community adults: a double-blind, placebo-controlled community trial*


Background: The purpose of this study was to assess the effect of 8-weeks ingestion of a commercialized joint pain dietary supplement (InstaflexTM Joint Support, Direct Digital, Charlotte, NC) compared to placebo on joint pain, stiffness, and function in adults with self-reported joint pain. InstaflexTM is a joint pain supplement containing glucosamine sulfate, methylsulfonylmethane (MSM), white willow bark extract (15% salicin), ginger root concentrate, Boswellia Serrata extract (65% boswellic acid), turmeric root extract, cayenne, and hyaluronic acid.

Methods: Subjects included 100 men and women, ages 50-75 years, with a history (>3 months) of joint pain, and were randomized to Instaflex™ or placebo (3 colored gel capsules per day for 8 weeks, double-blind administration). Subjects agreed to avoid the use of non-steroidal anti-inflammatory drugs (NSAID) and all other medications and supplements targeted for joint pain. Primary outcome measures were obtained pre- and post-study and included joint pain severity, stiffness, and function (Western Ontario and McMaster Universities [WOMAC]), and secondary outcome measures included health-related quality of life (Short Form 36 or SF-36), systemic inflammation (serum C-reactive protein and 9 plasma cytokines), and physical function (6-minute walk test). Joint pain symptom severity was assessed bi-weekly using a 12-point Likert visual scale (12-VS).

Results: Joint pain severity was significantly reduced in Instaflex™ compared to placebo (8-week WOMAC, ↓37% versus ↓16%, respectively, interaction effect P = 0.025), with group differences using the 12-VS emerging by week 4 of the study (interaction effect, P = 0.0125). Improvements in the ability to perform daily activities and stiffness scores in Instaflex™ compared to placebo were most evident for the 74% of subjects reporting knee pain (8-week WOMAC function score, ↓39% versus ↓14%, respectively, interaction effect P = 0.027; stiffness score, ↓30% versus ↓12%, respectively, interaction effect P = 0.081). Patterns of change in SF-36, systemic inflammation biomarkers, and the 6-minute walk test did not differ significantly between groups during the 8-week study.

Conclusions: Results from this randomized, double-blind, placebo-controlled community trial support the use of the Instaflex™ dietary supplement in alleviating joint pain severity in middle-aged and older adults, with mitigation of difficulty performing daily activities most apparent in subjects with knee pain.

Source: Nieman, David C., et al. “A commercialized dietary supplement alleviates joint pain in community adults: a double-blind, placebo-controlled community trial.” Nutrition journal 12.1 (2013): 154.

Boswellia Serrata, A Potential Anti-inflammatory Agent: An Overview *


The resin of Boswellia species has been used as incense in religious and cultural ceremonies and in medicines since time immemorial. Boswellia serrata (Salai/Salai guggul), is a moderate to large sized branching tree of family Burseraceae (Genus Boswellia), grows in dry mountainous regions of India, Northern Africa and Middle East. Oleo gum-resin is tapped from the incision made on the trunk of the tree and is then stored in specially made bamboo basket for removal of oil content and getting the resin solidified. After processing, the gum-resin is then graded according to its flavour, colour, shape and size. In India, the States of Andhra Pradesh, Gujarat, Madhya Pradesh, Jharkhand and Chhattisgarh are the main source of Boswellia serrata. Regionally, it is also known by different names. The oleo gum-resins contain 30-60% resin, 5-10% essential oils, which are soluble in the organic solvents, and the rest is made up of polysaccharides. Gum-resin extracts of Boswellia serrata have been traditionally used in folk medicine for centuries to treat various chronic inflammatory diseases. The resinous part of Boswellia serrata possesses monoterpenes, diterpenes, triterpenes, tetracyclic triterpenic acids and four major pentacyclic triterpenic acids i.e. β-boswellic acid, acetyl-β-boswellic acid, 11-keto-β-boswellic acid and acetyl-11-keto-β-boswellic acid, responsible for inhibition of pro-inflammatory enzymes. Out of these four boswellic acids, acetyl-11-keto-β-boswellic acid is the most potent inhibitor of 5-lipoxygenase, an enzyme responsible for inflammation.

Source: M. Z. Siddiqui. “Boswellia Serrata, A Potential Antiinflammatory Agent: An Overview” Indian Journal of Pharmaceutical Sciences (2011): 73(3): 255–261.

Efficacy and tolerability of Boswellia serrata extract in the treatment of osteoarthritis of knee – A randomized double-blind placebo-controlled trial*


Summary: Osteoarthritis is a common, chronic, progressive, skeletal, degenerative disorder, which commonly affects the knee joint. Boswellia serrata tree is commonly found in India. The therapeutic value of its gum (Guggulu) has been known. It possesses good anti-inflammatory, anti-arthritic and analgesic activity. A randomized double-blind placebo-controlled crossover study was conducted to assess the efficacy, safety, and tolerability of Boswellia serrata Extract (BSE) in 30 patients of osteoarthritis of the knee, 15 each receiving active drug or placebo for eight weeks. After the first intervention, washout was given and then the groups were crossed over to receive the opposite intervention for eight weeks. All patients receiving drug treatment reported a decrease in knee pain, increased knee flexion and increased walking distance. The frequency of swelling in the knee joint was decreased. Radiologically there was no change. The observed differences between drug-treated and placebo being statistically significant, are clinically relevant. BSE was well tolerated by the subjects except for minor gastrointestinal ADRs. BSE is recommended in the patients of osteoarthritis of the knee with possible therapeutic use in other arthritis.

Source: N. Kimmatkara, V. Thawanib, L. Hingoranic, R. Khiyanid. “Efficacy and tolerability of Boswellia serrata extract in the treatment of osteoarthritis of knee – A randomized double-blind placebo-controlled trial” Phytomedicine (2003): V10, Issue 1; P3-7.

Type II Collagen

Effects of Native Type II Collagen Treatment on Knee Osteoarthritis: A Randomized Controlled Trial*


Objective: The aim of this randomized controlled study was to evaluate the efficacy of oral native type II collagen treatment on the symptoms and biological markers of cartilage degradation, when given concomitantly with acetaminophen in patients with knee osteoarthritis.

Materials and Methods: Thirty-nine patients diagnosed with knee osteoarthritis were included and randomly distributed into two groups: one treated with 1500 mg/day of acetaminophen (group AC; n=19) and the other treated with 1500 mg/day of acetaminophen plus 10 mg/day of native type II collagen (group AC+CII; n=20) for 3 months. Visual Analogue Scale (VAS) at rest and during walking, Western Ontario McMaster (WOMAC) pain, WOMAC function, and Short Form-36 (SF-36) scores, were recorded. Coll2-1, Coll2-1NO2 and Fibulin-3 levels were quantified in urine as biomarkers of disease progression. ClinicalTrials.gov: NCT02237989.

Results: After 3 months of treatment, significant improvements compared to baseline were reported in joint pain (VAS walking), function (WOMAC) and quality of life (SF-36) in the AC+CII group, while only improvements in some subscales of the SF-36 survey and VAS walking were detected in the AC group. Comparisons between the groups revealed a significant difference in VAS walking score in favour of the AC+CII group as compared to AC group. Biochemical markers of cartilage degradation in urine did not significantly improve in any of the groups.

Conclusion: All in all, these results suggest that native type II collagen treatment combined with acetaminophen is superior to only acetaminophen for symptomatic treatment of patients with knee osteoarthritis.

Source: Fulya Bakilan, Onur Armagan, Merih Ozgen, Funda Tascioglu, Ozge Bolluk, and Ozkan Alatas. “Effects of Native Type II Collagen Treatment on Knee Osteoarthritis: A Randomized Controlled Trial” The Eurasian Journal of Medicine (2016): 48(2): 95–101.

Effects of oral administration of type II collagen on rheumatoid arthritis*


Rheumatoid arthritis is an inflammatory synovial disease thought to involve T cells reacting to an antigen within the joint. Type II collagen is the major protein in articular cartilage and is a potential autoantigen in this disease. Oral tolerization to autoantigens suppresses animal models of T cell-mediated autoimmune disease, including two models of rheumatoid arthritis. In this randomized, double-blind trial involving 60 patients with severe, active rheumatoid arthritis, a decrease in the number of swollen joints and tender joints occurred in subjects fed chicken type II collagen for 3 months but not in those that received a placebo. Four patients in the collagen group had complete remission of the disease. No side effects were evident. These data demonstrate the clinical efficacy of an oral tolerization approach for rheumatoid arthritis.

Source: Trentham, David E., et al. “Effects of oral administration of type II collagen on rheumatoid arthritis.” Science 261.5129 (1993): 1727-1730.

Collagen gene expression during the development of avian synovial joints: Transient expression of types II and XI collagen genes in the joint capsule*


The developmental sequence of the embryonic joint has been well studied morphologically. There are, however, no definitive studies of cell function during joint development. In order to begin to understand the differentiation events that contribute to the joint formation, we examined the expression of collagen mRNAs encoding types I, IIA, IIB, and XI. In situ hybridization was performed on chicken embryo hind limb buds and digits from day 7 to day 18 (Hamburger and Hamilton stage 31–44). In the day 7 (stage 31) limb bud, there was a condensation of mesenchyme forming the primitive tarsal and metatarsal bones that showed abundant expression of type IIA procollagen message, but no type IIB or type α1(XI) message. By day 8 (stage 33), co‐expression of types IIA, and type XI procollagen mRNAs was observed in the condensations, with an expression of IIB restricted to early chondrocytes with a metachromatically staining matrix. At this stage, DNA fragmentation characteristic of apoptosis was observed in cells near the midline of the Interzone region between the developing anlagen, and in areas between and around the individual digits of the paddle. The presumptive apoptotic cells were more numerous at day 9 (stage 35), and were not found in the developing joint at subsequent time points, including the initiation of spatial cavitation of the joint. From days 11–18, type IIA procollagen mRNA was expressed in flattened cells at the surface of the anlagen, and in the perichondrium and in the developing joint capsule; type IIB mRNA message was found only in chondrocytes. Type XI mRNA was expressed by all type II‐expressing cells. Alpha 1(I) mRNA was expressed early by cells of the Interzone and capsule, but as cavitation progressed, the type I expressing cells of the Interzone merged with the superficial layer of the articular surface. Thus, at the time of joint cavitation, there was a distinct pattern of expression of procollagen messages at the articular surface, with type I being outermost, followed by morphologically similar cells expressing type IIA, then chondrocytes expressing type IIB. The progenitor cells expressing type IIA message define a new population of cells. These cell populations contribute to the molecular heterogeneity of the articular cartilage, and these same populations likely exist in the developing joints of other species. The transient transcription of type II and type XI collagen genes, characteristic of chondrocytes, by cells in the joint capsule demonstrates that these cells may have chondrogenic potential.

Source: Nalin, Andrew M., Theodore K. Greenlee Jr, and Linda J. Sandell. “Collagen gene expression during development of avian synovial joints: transient expression of types II and XI collagen genes in the joint capsule.” Developmental dynamics 203.3 (1995): 352-362.

Efficacy and tolerability of an undenatured type II collagen supplement in modulating knee osteoarthritis symptoms: a multicenter randomized, double-blind, placebo-controlled study*


Background: Undenatured type II collagen (UC-II) is a nutritional supplement derived from chicken sternum cartilage. The purpose of this study was to evaluate the efficacy and tolerability of UC-II for knee osteoarthritis (OA) pain and associated symptoms compared to placebo and to glucosamine hydrochloride plus chondroitin sulfate (GC).

Methods: One hundred ninety one volunteers were randomized into three groups receiving a daily dose of UC-II (40 mg), GC (1500 mg G & 1200 mg C), or placebo for a 180-day period. The primary endpoint was the change in total Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) from baseline through day 180 for the UC-II group versus placebo and GC. Secondary endpoints included the Lequesne Functional Index (LFI), the Visual Analog Scale (VAS) for pain and the WOMAC subscales. Modified intent-to-treat analysis were performed for all endpoints using analysis of covariance and mixed model repeated measures, while incremental area under the curve was calculated by the intent-to-treat method.

Results: At day 180, the UC-II group demonstrated a significant reduction in overall WOMAC score compared to placebo (p = 0.002) and GC (p = 0.04). Supplementation with UC-II also resulted in significant changes for all three WOMAC subscales: pain (p = 0.0003 vs. placebo; p = 0.016 vs. GC); stiffness (p = 0.004 vs. placebo; p = 0.044 vs. GC); physical function (p = 0.007 vs. placebo). Safety outcomes did not differ among the groups.

Conclusion: UC-II improved knee joint symptoms in knee OA subjects and was well-tolerated. Additional studies that elucidate the mechanism for this supplement's actions are warranted.

Source: James P. Lugo, Zainulabedin M. Saiyed, Nancy E. Lane. “Efficacy and tolerability of an undenatured type II collagen supplement in modulating knee osteoarthritis symptoms: a multicenter randomized, double-blind, placebo-controlled study” Nutrition Journal (2016): 15:14.

  1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2711914/
  2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5822842/
  3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2697588/
  4. https://pubmed.ncbi.nlm.nih.gov/23954097/
  5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5274536/
  6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276611/
  7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2621390/
  8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6316542/
  9. https://pubmed.ncbi.nlm.nih.gov/11710709/
  10. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4058601/
  11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3665023/
  12. https://pubmed.ncbi.nlm.nih.gov/21631828/
  13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4965662/
  14. https://journals.lww.com/jclinrheum/fulltext/2017/09000/omega_3_fatty_acids_in_rheumatic_diseases__a.6.aspx
  15. https://www.sciencedirect.com/science/article/abs/pii/S0304395907000413
  16. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2533717/
  17. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624173/
  18. https://www.sciencedirect.com/science/article/abs/pii/S0049017210800174
  19. https://www.tandfonline.com/doi/abs/10.1080/03008207.2017.1385605
  20. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5003001/
  21. https://pubmed.ncbi.nlm.nih.gov/17075840/
  22. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460672/
  23. https://www.liebertpub.com/doi/full/10.1089/jmf.2016.3705
  24. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2688199/
  25. https://pubchem.ncbi.nlm.nih.gov/patent/US-6224871-B1
  26. https://lionedgenutrition.com/bioperine-absorption-bioavailability/
  27. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3918523/
  28. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5295089/
  29. https://nutritionj.biomedcentral.com/articles/10.1186/1475-2891-12-154
  30. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3309643/
  31. https://pubmed.ncbi.nlm.nih.gov/12622457/
  32. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970562/
  33. https://pubmed.ncbi.nlm.nih.gov/8378772/
  34. https://pubmed.ncbi.nlm.nih.gov/8589432/
  35. https://pubmed.ncbi.nlm.nih.gov/26822714/
  36. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4729158/
  37. https://ard.bmj.com/content/52/11/817
  38. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2688199/