NEM Novel Joint Care Supplement
Abstract
Natural Eggshell Membrane (NEM®) is a relatively novel supplement that has been used to treat osteoarthritis as well as joint and connective tissue disorders. There is in vitro evidence that NEM® suppresses tumor necrosis factor-alpha production in peripheral blood mononuclear cell cultures, thus indicating a potentially promising anti-inflammatory action in humans. However, the amount of human clinical research conducted on NEM® is limited and the majority of the supportive data is derived from one group of researchers. The natural product industry has embraced NEM® with open arms and incorporated it into many supplements for joint health. This article reviews the four human studies conducted on NEM® to date in chronological order of publication. The first study reviewed was a combination of two pilot studies that demonstrated significant treatment responses. However, it suffered from limited enrollment and no placebo-control. The second study reviewed had a high drop-out rate, but calculated that one out of every five patients should experience a 50% pain reduction within 30 to 60 days. The third study reviewed had significant methodological flaws and demonstrated that NEM® only had an effect on post-exercise pain. The fourth study reviewed was pre-publication so the data are not described, but they showed positive results. Although more evidence is certainly warranted, the studies available lend support to the notion that NEM® is safe and effective. NEM® may serve as an alternative recommendation for patients suffering from joint pain.
Introduction
Natural Eggshell Membrane (NEM®) is a relatively novel supplement that has been used to treat osteoarthritis as well as joint and connective tissue disorders (Ruff 2009). NEM® contains naturally occurring glycosaminoglycans and proteins essential for maintaining healthy articular cartilage. The outer membrane is made of type I collagen and the inner membrane consists of type V collagen (Wong 1984). Type X collagen is also reported to occur in both these membrane structures (Arias 1991). There is in vitro evidence that NEM® suppresses tumor necrosis factor-alpha production in peripheral blood mononuclear cell cultures, thus indicating a potentially promising anti-inflammatory action in humans (Benson 2012). In addition, recent rat studies have demonstrated that oral supplementation with NEM® can also influence later-phase cytokines such as MCP-1, MIP-1α & β, RANTES and VEGF (Ruff 2014). Toxicological studies have shown that oral supplementation in rats up to 2000mg/kg body weight repeated daily for 90 days did not cause any signs of toxicity via multiple evaluation methods (Ruff 2012). However, the amount of human clinical research conducted on NEM® is limited and the majority of the supportive data is derived from one group of researchers. As such, it is imperative that the methodology and results of these trials be analyzed with scrutiny and put into context.
The natural product industry has embraced NEM® with open arms and incorporated it into many supplements for joint health. Although the trials that are available are promising, it is important for health practitioners to analyze the validity of the research available before implementing new potential therapies with patients. This article will review the four human studies conducted on NEM® to date in chronological order of publication. Although more evidence is certainly warranted, the studies available currently lend support to the notion that NEM® is both safe and effective.
STUDY ONE (2009)
Initially, two pilot clinical studies were conducted that evaluated the efficacy of NEM® for the relief of the pain and discomfort associated with joint and connective tissue disorders (Ruff 2009). To be eligible to participate, subjects must have had persistent pain lasting at least three months associated with a joint or connective tissue disorder, with a minimum baseline pain level of 2 on a 0 to 10 analog Likert scale (with 0 equating to no pain and 10 equating to the most severe pain). If currently taking medication, subjects had to undergo a washout period beforehand. Each study lasted for one month. The studies were single center, open-label, and controlled. One trial was single-arm and the other was doublearm. Subjects suspended all current pain relief medications to participate in the study. For the double-arm trial, eligible subjects were randomized to either NEM® formulation X or Y. These two formulations differed in the degree to which they were partially hydrolyzed prior to final ingredient blending (Y approximately 2.5 times more than X).
It is important to note that the investigators were not blinded to treatment (as both studies were open-label), or to randomization (in the double-arm trial). The subjects were blinded to randomization in the double-arm trial. The treatments consisted of a once daily supplementation of either NEM® in the singlearm trial, or the two different formulations of NEM® in the double-arm trial, provided in 500mg vegetarian capsules. Subjects visited the clinic at seven and 30 days following the onset of treatment. Compliance was checked by interview and by counting unused doses. Acetaminophen was allowed for pain relief rescue and subjects had to record the time and amount taken in diaries. In the single-arm and double-arm trials, the primary outcome measure was mean effectiveness of NEM® in relieving general pain, and secondary outcome measures were joint flexibility and range-of-motionassociated (ROM) pain. The Likert scale was used during the seven and 30 day clinical assessments.
In the single-arm trial, 11 subjects were enrolled and 10 of them completed the study protocol. For those that completed the study protocol, compliance was over 98%. The mean baseline pain value was 3.6 ± 1.8; the mean flexion ROM was 64.2° ± 36.5°; and the mean ROMassociated pain was 2.9 ± 2.6. Supplementation with NEM® produced a significant response at seven days for flexibility, as a 27.8% increase. At 30 days, there was a significant response for general pain (as a 72.5% reduction), an increase in flexibility (43.7% from baseline), and an improvement in ROM-associated pain (75.9% reduction). Of note, nearly half of the patients in the single-arm trial reported they were pain-free (reported score of 0) by 30 days of supplementation. Rescue pain medication was used very rarely, only once in ever 20-22 days.
In the double-arm trial, a total of 28 subjects were enrolled. 14 subjects were randomized to NEM® X and 14 were randomized to NEM® Y. 26 subjects completed the study, as one participant in each group dropped-out due to lack of efficacy. Compliance was over 96%. Supplementation with NEM® produced a significant response at seven days for both treatment arms (X: 18.4% reduction, Y: 31.3% reduction). The researchers determined that the 12.9% difference was not large and was not clinically meaningful. At 7 days, the Y arm crossed over to the X formulation for the remainder of the study. The significant treatment response continued to 30 days for pain, with a final reduction of 30.2%.
The bottom line from this trial is that there were no adverse events reported during either of the studies and the treatment was reported to be extremely well tolerated by the study participants. The safety profile for NEM® in this study was excellent, excluding the possible concern of egg allergy. In analyzing the limitations of this study, both trials suffered from limited enrollment. The double-arm trial had dropouts due to lack of efficacy. Both trials were open label, thus there is the possibility that the positive outcomes are largely due to a placebo response. The lack of investigator blinding and the fact that two of the main investigators are employed by the sponsor of the study could have further exaggerated any positive results. Overall, this study set the stage for a larger study with some modifications to help address some of these limitations.
STUDY TWO (2009)
The second and arguably more important study to examine is a randomized, double-blind, multicenter, placebo-controlled trial, known as OPTION, or Osteoarthritis Pain Treatment IncorpOrating NEM® (Ruff 2009). This study utilized subjects that suffered from symptomatic osteoarthritis of the knee. Similar to the pilot trials, subjects were required to suspend all current pain medication in order to participate. This time, subjects were randomized to receive either NEM® or placebo, using a permuted-block randomization table consisting of four subjects per block. All parties were blinded to the treatment. The treatment used was a once daily oral dose of NEM® or placebo. Clinic visits took place at 10, 30, and 60 days following the onset of treatment. Compliance was checked in a similar fashion as the previous study.
The primary endpoint was the measurement of the effectiveness of NEM® in relieving pain, stiffness, and discomfort as compared to placebo. The Western Ontario and McMasters Universities (WOMAC) Osteoarthritis Index- Visual Analog Scale was used. An absolute increase in the mean response rate of 35% was considered by the authors to be a clinically meaningful treatment effect. This trial initially had 67 subjects enrolled. However, only 20 in the treatment group and 18 in the placebo group completed the study protocol, due to various issues (stringent pain management requirements, small study sample size, some drop-outs due to lack of efficacy). Compliance was measured as over 97% for those that completed the study.
After analysis, the results showed that supplementation with NEM® produced a response rate ranging from 10.3% to 26.6% improvement better than placebo at all time points for both pain and stiffness (but not for function and overall WOMAC, these results were insignificant despite improvements).
The responses for pain and stiffness were rapid, occurring after only 10 days of supplementation. There were no adverse events associated with the treatment. The NNTs for at least a 50% reduction in pain at 10, 30, and 60 days were calculated. Clinically, the NNTs indicate that one out of every five patients should experience a 50% pain reduction within 30 to 60 days. For stiffness, the NNTs indicate that at 60 days, nearly one out of every two patients would experience a 50% reduction in stiffness. The limitations of this study included a limited initial enrollment, a high drop-out rate (43%), and a smaller mean treatment effect than anticipated.
STUDY THREE (2012)
One study was conducted and published more recently by the company Precision Nutrition Inc. on a product containing an encapsulated version of NEM® named Fast Joint Care+ (FJC+) (Berardi 2012). Although this study was not published in a peer-reviewed journal and was an independent research study, the information provided can still be examined. In this study, 60 adults experiencing chronic joint pain were supplement with FJC+ or placebo for four weeks. They completed a weekly exercise protocol that challenged their irritated joint. Subjects then rated their joint pain immediately and one day after the exercise challenge. The results showed that post-exercise joint pain in the FJC+ group decreased by four3. four%, while the placebo group experienced a 30.6% decrease in pain over the four weeks. It is important to note that there were large differences in Joint Pain Index scores at baseline for the treatment group and placebo group. The FJC+ group had a baseline score within the four0-50 range (indicating more pain), while the placebo group had Joint Pain Index scores in the 20-30 range (indicating less pain). The exact numbers were not reported directly in the study. This discrepancy would set the stage for a larger potential decrease in pain for the treatment group, which is exactly what happened. This challenges the internal validity of the study. In addition, there were no significant differences in joint pain scores across the four weeks of supplementation, indicating similar joint pain decreases in both the FJC+ group and the placebo group. Overall, this study appears to lend support to the safety of eggshell membrane, but not to its efficacy beyond immediately post-exercise.
STUDY FOUR (Pre-Publication)
A fourth human trial on NEM® has been completed by the company ESM Technologies, LLC and it is currently pre-publication (Danesch pre-publication). The trial is multicentered and open-label. It includes 44 subjects with knee and/or hip osteoarthritis. Currently, the data from this study cannot be shared publicly, but the results have been seen by this author, and permission has been given to report that the effects that were seen with NEM® were positive.
Conclusion
NEM® is a relatively novel supplement that has been used to treat osteoarthritis as well as joint and connective tissue disorders. The total quantity of human trials on NEM® is lacking. The first study reviewed was a combination of two pilot studies that demonstrated significant treatment responses. However, it suffered from limited enrollment and no placebo-control. The second study reviewed was the OPTION study, offering the most robust data on NEM® to date. Despite a high drop-out rate (43%), this study used NNTs to calculate that one out of every five patients should experience a 50% pain reduction within 30 to 60 days. With regards to stiffness, the NNTs indicated that at 60 days, nearly one out of every two patients would experience a 50% reduction. The third study reviewed had significant methodological flaws and demonstrated that NEM® only had an effect on post-exercise pain. The fourth study reviewed was pre-publication so the data were not examined closely, but still showed positive results. Overall, all trials to date have identified that NEM® is extremely safe when taken orally, with the possible exception in cases of egg allergy. The data presented suggests rapid improvements in pain and stiffness, particularly in osteoarthritis. Further well-conducted trials will provide clearer conclusions. For the time being, NEM® serves as an alternative recommendation for patients suffering from joint pain.
Author Disclosure
This author has witnessed patients reporting decreased pain after short periods of use of 500mg daily of NEM® in combination with 135mg of Boswellia serrata. Multiple patients with osteoarthritis and one case of ankylosing spondylitis reported decreased pain shortly after the initiation of treatment, while one case of rheumatoid arthritis reported no response. This author has no competing interests.
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