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A Randomized Controlled Trial Evaluating Methylsulfonylmethane Versus Placebo to Prevent Knee Pain in Military Initial Entry Trainees.

Methylsulfonylmethane (MSM) is a sulfur-containing compound, a metabolite of dimethyl sulfoxide, and occurs naturally at low levels in many common foods including fruits and vegetables. (1,2) Basic science literature supports that MSM is rapidly absorbed, well distributed, and completely excreted from the body. (3)

Methylsulfonylmethane has been shown to exert some anti-inflammatory and antioxidant effects, which has led to the use of MSM as a dietary supplement. (4-6) Animal and human studies have demonstrated beneficial effects in ulcerative colitis and lower extremity edema. (7,8) MSM has also shown promise as an ergogenic antioxidant in untrained men and women initiating an exercise regimen. (4,6) Recent medical trials in humans with MSM in the treatment of osteoarthritis have demonstrated that MSM was superior to placebo in controlling pain related to mild-to-moderate osteoarthritis of the knee, is at least as effective as celecoxib and significantly reduces the patient's need for anti-inflammatory drugs. (3,8) Furthermore, multiple trials have demonstrated multiple positive effects with no significant adverse effects of MSM use. (3,8-10)

The attrition rate during initial entry military training has become one of the most serious and costly concerns for all military services. Injuries account for 5 to 22-fold greater days lost to training than illnesses." Among trainees, 80% to 90% of the lost to training days were due to training-related injuries. (12) The cumulative incidence of injuries requiring an outpatient visit in the initial 8 weeks of US Army Initial Entry Training is 25% to 55%. (12) The cumulative incidence of overuse injuries in trainees was 37% and comprised 80% of all injuries. (13) Discharge rates due to injury vary between 0.3% and 8.3% for initial entry Soldiers, but have been reported as high as 36% for Soldiers not completing their initial contractual obligation. (11-15) Following this, studies from the US Army Center for Health Promotion and Preventive Medicine* have demonstrated that intervention strategies can successfully reduce injuries without compromising mission effectiveness. (15)

The purpose of this study was to evaluate the use of 3 mg (750 mg tablets with 2 tablets twice daily) of orally administered MSM to improve patient reported outcome measures at 30 and 60 days. Our hypothesis was that the patients taking the MSM would demonstrate improved patient-reported outcomes at 30 and 60 days following initiation of supplementation during their training program as compared to placebo.

Methods

A randomized, double-blind, placebo controlled trial was conducted under an Institution Review Board approved protocol. A total of 180 men and women ranging in age from 18 to 40 years were enrolled from the Army initial Basic Officer Leadership Course (BOLC) at Joint BAsc San Antonio-Fort Sam Houston, Texas. All trainees were invited to participate during the initial week of BOLC, a course that covers approximately 8 weeks of training, including 4 weeks spent in field conditions. Interested subjects were then screened and examined by one of the study investigators. Exclusionary criteria included a history of cancer, current statin use, use of other anti-inflammatories such as NSAIDS or pain medicine such as nareotics, a history of renal or hepatic dysfunction, a history of cardiac abnormality, current pregnancy, or other medical condition that would prevent full participation in the study.

Randomization was conducted using an unbound random number generator that was maintained by the dispensing pharmacy and blinded from all study investigators until completion of the study. The 2 arms of study intervention consisted of OptiMSM methylsulfonylmethane (Bergstrom Nutrition, Vancouver, WA) and a matched placebo. Both of these were provided in 750 mg tablets and participants were instructed to take 2 tablets twice daily for 8 weeks or until the completion of their training program.

Patient reported outcome measures were obtained at the time of study enrollment, at 30-day follow-up and at 60-day follow-up. Measures included were the Knee Osteoarthritis Outcome -Score (KOOS) and the Profile of Moods States (POMS). The KOOS consists of 5 subscales: Pain, other Symptoms, Function in Daily Living (ADL), Function in Sport and Recreation, and Knee Related Quality of Life (QOL). The Profile of Mood States (POMS) measures present mood state (disturbance) by a list of adjectives. The POMS measures 6 dimensions of affect or mood, including tension-anxiety, depression-dejection, anger-hostility, vigor-activity, fatigue-inertia, and confusion-bewilderment. This study uses the fatigue-inertia subset as an endpoint.

The 30-day follow-up was conducted while the subjects were in the middle of their field-training exercises. These involve 4 weeks spent in field conditions which include sleeping in tents and performing daily activities such as carrying gear, marehing, combatives training, rifle and handgun firing, land navigation, and more. Physical fitness training was included for all trainees during their entire BOLC course. The 60-day follow-up was conducted when subjects had returned to a classroom setting and prior to their graduation from the course.

Statistical analysis was conducted using descriptive statistics, one-way ANOVA with repeated measures, and paired t tests where appropriate. A moderate Bonferroni correction was used and significance set at 0.025 due to comparisons being made at 30 and 60 days. The application SAS 9.2 (SAS Institute Inc, Cary, NC) was used for all statistical analysis.

Results

As shown in the Figure, a total of 180 subjects were enrolled in the study and initiated treatment. Of these, 13 subjects randomized to the MSM group and 9 subjects randomized to the placebo group were withdrawn from the study for an adverse event related to an injury sustained during training. Data was available on 124 subjects for the 30-day collection and 62 subjects for the 60-day collection. A summary of group demographic characteristics is presented in Table 1. There were no significant differences in height (m), weight (kg), body mass index (BMI), or gender. The MSM group was significantly older (28 vs 26 years) than the placebo group.

There were no significant differences in any KOOS or POMS subscalcs at baseline, 30 days, or 60 days (Table 2). Whereas no significant changes in the KOOS subscalc for MSM were seen from baseline to 30 days (3.41 [+ or -] 2.68, P=.0135) or baseline to 60 days (5.81 [+ or -] 3.51, P=.0013), improvement in the quality of life subscale for placebo was seen from baseline to 30 days and baseline to 60 days (Table 3).

When analyzing the POMS from baseline to 30 days, subscalc worsening was seen for MSM in Anger (3.38 [+ or -] 0.72, P<.0001), Vigor (1.62 [+ or -] 0.70, P=.193), and Fatigue (2.62 [+ or -] 0.51, P<0001), and for Placebo in Depression (2.28 [+ or -] 0.55, P<.0001), Anger (2.46 [+ or -] 0.69, P=.0004), Vigor (1.64 [+ or -] 0.66, P=.0137), Fatigue (2.83 [+ or -] 0.49, P<.0001), and Confusion (0.82 [+ or -] 0.34, P=.0148) (Table 3). These differences were not seen at baseline to 60 days.

Comment

This study found that those patients who took 3 mg MSM daily displayed no improvements in any KOOS or POMS subscale when compared to placebo when taken for 30 days or 60 days in a high-impact, initial entry military training population. Subjects taking MSM supplementation for 30 days or 60 days also did not have appreciable improvements in cither patient-reported outcome measure. No differences were found in adverse events between groups.

Several studies have previously demonstrated the efficacy of MSM as an adjunct for the treatment of osteoarthritis by using the Western Ontario and McMaster Universities Osteoarthritis index (WOMAC) as an outcome measure. In a double-blind, randomized, controlled trial, Debbi et al displayed significant differences in WOMAC physical function and total scores, and VAS pain scores with 3.375 g MSM orally administered daily. (10) Kim et al also displayed significant decreases in WOMAC pain and physical function impairment when 6 grams of MSM was administered orally. (16) Likewise, Pagonis et al found significant decreases in all WOMAC subscales at 26 weeks with 6 g MSM administered orally. (17)

In contrast to those studies, the current study used the KOOS as a primary outcome measure as it encompasses a greater degree of symptoms and range of injuries and is more responsive than the WOMAC. Using this validated patient reported outcome measure, as expected, the scores increased from baseline to the 30-day point, which is related to the increased physical demands placed on the subjects during their time in field conditions. Of particular note is that subscale scores were not significantly improved when compared directly to placebo at cither the 30-day or 60-day time points. This difference may be representative of the difference in patient population, the lower total MSM ingestion, or the more demanding activities expected of a military training population compared to the general patient with osteoarthritis.

To our knowledge, this is the first study that uses the POMS to further assess the physical and mental wellbeing of those individuals taking supplemental MSM. In this study, Anger, Fatigue and Vigor worsened from baseline to 30 days for the MSM group, then again during a time of increased physical and emotional stressed placed on the subjects as part of their field military training period. Similar increases in mood abnormalities were also seen in the placebo group, which correlates to the physical, mental, and emotional demands that accompany military training.

While other studies have evaluated MSM for those patients with documented knee pain, this is the first study to evaluate the use of MSM as a preventative adjunct to improve functional outcome measures. However, despite the enrollment of this study, its conclusions are limited by the loss to follow-up that was experienced from 30 to 60 days as a result of changes in military training needs. This decreased the overall power of this study and may limit the relevant conclusions regarding the effectiveness of MSM over the entire 60-day period.

This study was also conducted in a highly active population with physical demands above those of the average population. As such, the conclusions of this study may be most translatable to a higher level athlete rather than the average person, and further studies evaluating MSM in individuals with average demands is required. Furthermore, the total daily dosage of MSM used in this study was well below that of previous studies finding functional improvements, and also used different outcome measures. This may limit its comparability to findings reported in previous literature.

Conclusions

The results of this study suggest that 3 grams daily of orally administered MSM docs not improve patient reported outcomes over 30 days or 60 days in this young, healthy, active military population as compared to a placebo. The results do not support our tested hypothesis. However, further investigation is warranted to determine if higher doses are more effective and if less active populations might exhibit a greater treatment response.

Acknowledgment

Study-related materials were received from Bergstrom Nutrition, 1000 W 8th St, Vancouver, Washington, through an educational grant.

References

(1.) Magnuson BA, Appleton J, Ames GB. Pharmacokinetics and distribution of [35S] methylsulfanomethane following oral administration to rats. J Agrie Food Chem. 2007;55(3):1033-1038. PMID: 17263509.

(2.) Magnuson BA, Appleton J, Ryan B, Matulka RA. Oral developmental toxicity study of methylsulfanomethane in rats. Food Chem Toxicol. 2007;45(6):977-984. PMID: 17258373.

(3.) Usha PR, Naidu MU. Randomised, double-blind, parallel, placebo-controlled study of oral glucosamine, methylsulfonylmethane and their combination in osteoarthritis. Clin Drug Investig. 2004;24(6):353-363. PMID: 17516722.

(4.) Magrans-Courtney T, Wilborn C, Rasmussen C, et al. Effect of diet type and supplementation of glucosamine, chondroitin, and MSM on body composition, functional status, and markers of health in women with knee osteoarthritis initiating a resistance-based exercise and weight loss program. J Int Soc Sports Nutr. 2011;8(1):8. PMID: 21689421.

(5.) Miller DC, Richardson J, Roberts RW. Clinical Inquires. Does glucosamine relieve arthritis joint pain? J Family Pract. 2003;52(8):645-647. PMID: 12899824.

(6.) Nakhostin-Roohi B, Barmaki S, Khoshkhahesh F, Bohlooli S. Effect of chronic supplementation with methylsulfonylmethane on oxidative stress following acute exercise in untrained men. JPharm Pharmacol. 2011;63(10):1290-1294. PMID: 21899544.

(7.) Amirshahrokhi K, Bohlooli S, Chinifroush MM. The effect of methylsulfonylmethane on the experimental colitis in the rat. Toxicol Appi Pharmacol. 2011;253(3):197-202. PMID: 21463646.

(8.) Tripathi R, Gupta S, Rai S, Mittal PC. Effect of topical application of methylsulfanylmethane (MSM), EDTA on pitting edema and oxidative stress in a double blind, placebo-controlled study. Cell Mol Biol. 201 l;57(l):62-69. PMID: 21366964.

(9.) Notarnicola A, Tafuri S, Fusaro L, et al. The "MESACA" study: methylsulfonylmethane and boswellic acids in the treatment of gonarthrosis. Adv Ther. 20U;28(10):894-906. PMID: 894-906.

(10.) Debbi EM, Agar G, Fichman G, et al. Efficacy of methylsulfonylmethane supplementation on osteoarthritis of the knee: a randomized controlled study. BMC Complement Altern Med. 2011;27(ll):50-59. PMID: 21708034.

(11.) Knapik JJ, Canham-Chervak M, Hauret K, et al. Discharges during US Army Initial Entry Training: injury rates and risk factors. Mil Med. 2001;166(7):641-647. PMID: 11469039.

(12.) Jones BH, Knapik JJ. Physical training and exercise-related injuries. Surveillance, research and injury prevention in military populations. Sports Med. 1999;27(2):111-125. PMID: 10091275.

(13.) Jones BH, Cowan DN, Tomlinson JP, et al. Epidemiology of injuries associated with physical training among young men in the army. Med Sci Sports Exerc. 1993;25(2): 197-203. PMID: 8450721.

(14.) Kaufman KR, Brodine S, Shaffer R. Military training-related injuries: Surveillance, research, and prevention. Am J Prev Med. 2000;18(3):54-63. PMID: 10736541.

(15.) Knapik JJ, Bullock SH, Canada S, et al. Influence of an injury reduction program on injury and fitness outcomes among soldiers. Inj Prev. 2004;10(1):3742. PMID: 14760025.

(16.) Kim LS, Axelrod LJ, Howard P, et al. Efficacy of methylsulfonylmethane (MSM) in osteoarthritis pain of the knee: a pilot clinical trial. Osteoarthritis Cartilage. 2005;14:286-294. PMID: 16309928.

(17.) Pagonis TA, Givissis PA, Kritis AC, Christodoulou AC. The effect of methylsulfonylmethane on osteoarthritic large joints and mobility. Int J Orthop. 2014;23(l):19-24. Available at: http://www.ghrnet. org/index.php/ijo/article/view/745/862. Accessed August 1, 2017.

* Redesignated as the US Army Public Health Center in 2016.

CPT David J. Tennent, MC, USA

CPT Christina M. Hylden, MC, USA

MAJ Benjamin K. Kocher, SP, USA

James K. Aden, PhD

COL Anthony E. Johnson, MC, USA

CPT Tennent, CPT Ilylden, and MAJ Kocher are with the Department of Orthopaedics, San Antonio Military Medical Center, Joint Base San Antonio-Fort Sam Houston, Texas.

Dr Aden is with the US Army Institute of Surgical Research, Joint Base San Antonio-Fort Sam Houston, Texas.

COL Johnson is Chairman, Department of Orthopaedic Surgery, San Antonio Military Medical Center, Joint Base San Antonio-Fort Sam Houston, Texas.

Caption: CONSORT flow diagram.
Table 1. Initial demographics for all subjects.

                              MSM                Placebo

Age (years)             28 [+ or -] 6.9     26.4 [+ or -] 5.0
Height (m)              1.7 [+ or -] 0.1     1.7 [+ or -] 0.1
Weight (kg)            75.4 [+ or -] 13.7   74.9 [+ or -] 13.8
BMI                    24.9 [+ or -] 3.1    24.7 [+ or -] 3.1
Gender (male/female)         53/36                54/37

                       P value

Age (years)             .041
Height (m)              .722
Weight (kg)             .368
BMI                     .171
Gender (male/female)    .843

Table 2. Primary outcomes over 60 day treatment period comparing
MSM to placebo (values presented as mean [+ or -] SD).

                                     MSM

                   Baseline                 30 Day
KOOS
Pain          87.04 [+ or -] 2.78    84.60  [+ or -] 2.96
Symptom       83.07 [+ or -] 2.79    82.86 [+ or -] 2.96
ADL           92.79 [+ or -] 2.11    91.22 [+ or -] 2.27
Sport         79.21 [+ or -] 3.91    80.29 [+ or -] 4.17
QOL           77.39 [+ or -] 3.92    78.58 [+ or -] 4.09
POMS
Tension      14.01  [+ or -]  0.79   14.62 [+ or -] 0.86
Depression   16.03  [+ or -] 0.89    17.16 [+ or -] 0.98
Anger         14.80 [+ or -] 1.10    18.15 [+ or -] 1.21
Vigor         27.06 [+ or -] 1.31    25.43  [+ or -] 1.41
Fatigue       11.08 [+ or -] 0.87    13.70  [+ or -] 0.95
Confusion     11.60 [+ or -] 0.67    12.01  [+ or -] 0.72
Total Mood    58.37 [+ or -] 2.23    59.06  [+ or -] 2.44

                                    Placebo

                    60 Day                Baseline
KOOS
Pain         85.29 [+ or -] 3.69    87.96 [+ or -] 2.77
Symptom      83.02 [+ or -] 3.63    84.67 [+ or -] 2.78
ADL          91.56 [+ or -] 2.94    93.42  [+ or -] 2.10
Sport        80.12 [+ or -] 5.31    80.50 [+ or -] 3.88
QOL          78.47 [+ or -] 4.82    79.10 [+ or -] 3.90
POMS
Tension      13.21 [+ or -] 1.16    14.13 [+ or -] 2.78
Depression   16.47 [+ or -] 1.38    15.56 [+ or -] 0.88
Anger        15.75 [+ or -] 1.71    14.89  [+ or -] 0.55
Vigor        27.20 [+ or -] 1.85    25.19 [+ or -] 1.29
Fatigue      10.67 [+ or -] 1.29    11.31 [+ or -] 0.86
Confusion    11.00 [+ or -] 0.95    11.14 [+ or -] 0.66
Total Mood   59.75  [+ or -] 3.42   55.56 [+ or -] 2.19

                    30 Day                 60 Day
KOOS
Pain         89.25 [+ or -] 2.87    90.44 [+ or -] 3.48
Symptom      85.60  [+ or -] 2.87   87.18  [+ or -] 3.41
ADL          94.33 [+ or -] 2.19    94.57 [+ or -] 2.73
Sport        82.50 [+ or -] 4.04    85.11 [+ or -] 4.99
QOL          82.50 [+ or -] 4.00    84.91 [+ or -] 4.60
POMS
Tension      14.81 [+ or -] 0.82     13.8 [+ or -] 1.07
Depression   17.84 [+ or -] 0.93    16.81  [+ or -] 1.26
Anger        17.35 [+ or -] 1.16    16.35 [+ or -] 1.56
Vigor        23.55 [+ or -] 1.36    25.87 [+ or -] 1.71
Fatigue      14.14 [+ or -] 0.91    10.69 [+ or -] 1.19
Confusion    11.97 [+ or -] 0.70    10.96 [+ or -] 0.88
Total Mood   56.53 [+ or -] 2.34    59.17 [+ or -] 3.13

             Significance Between Groups (P value)

             Baseline   30 Days   60 Days
KOOS
Pain          .6489     .0281 *   .0477 *
Symptom       .4273      .1944     .1023
ADL           .6757      .0543     .1420
Sport         .6476      .4564     .4564
QOL           .5460      .1801     .0586
POMS
Tension       .8248      .7579     .4635
Depression    .4637      .3207     .7217
Anger         .9055      .3493     .6117
Vigor        .0479 *     .0606     .3022
Fatigue       .7162      .5088     .918
Confusion     .3473      .9376     .9539
Total Mood    .0786      .1418     .8053

KOOS indicates Knee Osteoarthritis Outcome Score; ADL,
Function in Daily Living; QOL, Quality of Life.
POMS indicates Profile of Moods States.

* Significance set at P<.05 with a Bonferroni correction of 2.

Table 3. KOOS and POMS scores over study period (values
presented as mean [+ or -] SD).

                                   MSM

              Difference           P
              0-30 Days            value
KOOS
 Pain         2.44 [+ or -] 2.45   .0540
 Symptom      0.51 [+ or -] 1.95   .8617
 ADL          1.57 [+ or -] 2.09   .1438
 Sport        1.08 [+ or -] 3.65   .5622
 QOL          1.19 [+ or -] 2.80   .4068
POMS
 Tension      0.62 [+ or -] 0.45   .3494
 Depression   1.13 [+ or -] 0.58   .0512
 Anger        3.38 [+ or -] 0.72   .0001 *
 Vigor        1.62 [+ or -] 0.70   .0193 *
 Fatigue      2.62 [+ or -] 0.51   <.0001 *
 Confusion    0.41 [+ or -] 0.35   .2438
 Total Mood   0.69 [+ or -] 1.42   .6268

              Difference           P
              0-60 Days            value
KOOS
 Pain         1.75 [+ or -] 3.31   .3013
 Symptom      0.84 [+ or -] 3.15   .9742
 ADL          1.23 [+ or -] 2.81   .3920
 Sport        0.91 [+ or -] 4.90   .7168
 QOL          1.07 [+ or -] 3.78   .5780
POMS
 Tension      0.80 [+ or -] 0.60   .3494
 Depression   0.44 [+ or -] 0.76   .5612
 Anger        0.66 [+ or -] 0.95   .3138
 Vigor        0.14 [+ or -] 0.92   .8758
 Fatigue      0.41 [+ or -] 0.68   .5505
 Confusion    0.60 [+ or -] 0.47   .2026
 Total Mood   1.38 [+ or -] 1.87   .4622

                                   Placebo

              Difference           P
              0-30 Days            value
KOOS
 Pain         1.29 [+ or -] 2.39   .2899
 Symptom      0.93 [+ or -] 2.25   .4183
 ADL          0.91 [+ or -] 2.01   .3787
 Sport        2.01 [+ or -] 3.51   .2633
 QOL          3.41 [+ or -] 2.68   .0135 *
POMS
 Tension      0.72 [+ or -] 0.43   .1194
 Depression   2.28 [+ or -] 0.55   <.0001 *
 Anger        2.46 [+ or -] 0.69   <.0004 *
 Vigor        1.64 [+ or -] 0.66   .0137 *
 Fatigue      2.83 [+ or -] 0.49   <.0001 *
 Confusion    0.82 [+ or -] 0.34   .0148 *
 Total Mood   0.97 [+ or -] 1.36   .4799

              Difference           P
              0-60 Days            value
KOOS
 Pain         2.48 [+ or -] 3.09   .1161
 Symptom      2.51 [+ or -] 2.90   .0908
 ADL          1.15 [+ or -] 2.59   .3856
 Sport        4.61 [+ or -] 4.56   .049
 QOL          5.81 [+ or -] 3.51   .0013 *
POMS
 Tension      0.57 [+ or -] 0.55   .5470
 Depression   1.25 [+ or -] 0.70   .0763
 Anger        1.46 [+ or -] 0.87   .0960
 Vigor        0.68 [+ or -] 0.85   .4215
 Fatigue      0.61 [+ or -] 0.61   .3296
 Confusion    0.18 [+ or -] 0.43   .6724
 Total Mood   3.61 [+ or -] 1.72   .0379

KOOS indicates Knee Osteoarthritis Outcome Score; ADL, Function in
Daily Living; QOL, Quality of Life. POMS indicates Profile of Moods
States.

* Significance set at P<.05 with a Bonferoni correction of 2.
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Author:Tennent, David J.; Hylden, Christina M.; Kocher, Benjamin K.; Aden, James K.; Johnson, Anthony E.
Publication:U.S. Army Medical Department Journal
Article Type:Report
Date:Oct 1, 2017
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