A Randomized Controlled Trial Evaluating Methylsulfonylmethane Versus Placebo to Prevent Knee Pain in Military Initial Entry Trainees.
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.
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.
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.
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.
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.
Study-related materials were received from Bergstrom Nutrition, 1000 W 8th St, Vancouver, Washington, through an educational grant.
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(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|
|Date:||Oct 1, 2017|
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