Methylsulfonylmethane on Knee Laxity
Condition: Ligament Injury; Ligament; Laxity; Tendon Rupture; Tendon Injuries
MeSH terms: Wounds and Injuries; Rupture; Tendon Injuries
Study type: Interventional

Summary: 
      The proposed research will focus on determining the effect of methylsulfonylmethane (MSM) on
      knee laxity changes through the menstrual cycle in young active females.

      As an extension to recent discovery, that MSM reverses the negative effect of estrogen on
      engineered ligament function, the proposed work is designed to determine whether MSM can
      decrease the negative effect of estrogen on knee laxity in females.

      Ligament function is determined by the content and cross-linking of collagen, which is
      influenced by a milieu of biochemical and mechanical parameters. The greater the amount and
      cross-linking the greater the stiffness and strength of these connective tissues. In
      engineered ligaments it has been previously shown that the high levels of estrogen, normally
      present in the days before and after ovulation, can inhibit the cross-linking enzyme lysyl
      oxidase. This decrease in collagen cross-linking likely increases connective tissue laxity
      and contributes to observed 4-fold greater occurrence of anterior cruciate ligament (ACL)
      rupture in females. Conversely, MSM increases collagen cross-linking and recent work
      conducted by the Baar lab in engineered human ligaments treated with high estrogen
      demonstrated that MSM could completely reverse the effects of estrogen on ligament mechanics.

      The proposed research aims to advance this promising pre-clinical data and apply in a
      clinical trial. This research also proposes to quantify that knee laxity increases up to 5mm
      between the first day of menstruation and the day after ovulation and also that the magnitude
      of the increase in laxity is directly related to the magnitude of the change in estrogen.
      Importantly, a direct relationship between knee laxity and ACL rupture exists. For every
      1.3mm increase in anterior-posterior knee displacement, the odds of ACL rupture increase
      4-fold. Therefore, any treatment that decreases knee laxity could be expected to reduce ACL
      ruptures and have widespread application across the general active population and high-level
      athletics.
    

Detailed description: 
      Familiarization: Subjects would come to the Human Performance lab for a study orientation to
      be informed of the goals of the study, have anthropometric data collected (InBody770, In
      Body, Cerritos, CA) and familiarized with all testing and data collection tools. The purpose
      of this is to collect anthropometric data, review the study procedures and study
      requirements.

      Determination of menstruation date: After study familiarization instructions will be given to
      contact the research team and come back to the lab on the first day of menstruation to
      establish the individual study timeline. An ovulation kit will be provided. The ovulation kit
      would then be started at the end of the first reported menstrual cycle and be used daily
      until the 2-4 days of high estrogen (ovulation) are established.

      Baseline data: After menstruation date is established, for the first two months of the study,
      subjects would come to the lab on the first day of menstruation and the day after ovulation,
      have their knee laxity measured (GNRB dynamic laximeter, Prothia, Worcester, MA) and salivary
      analysis to determine estrogen levels. The first two months would determine normal changes in
      knee laxity and estrogen levels throughout the cycle within each subject.

      Intervention: Following the second ovulation testing day and once baseline values are
      established, subjects would be provided with 3 months of MSM or placebo control (rice flour)
      and instructed to take 2g each morning for the subsequent 3 months. Month 3 would serve as an
      MSM loading month and subjects would return to the laboratory throughout months 4 and 5 (day
      14 and first day of menstruation) for mechanical and estrogen testing.

      MSM or placebo treatments: The study will be a randomized double-blinded placebo-controlled
      trial. MSM or placebo capsules would be provided in a double blinded manner following the
      second mechanical test. Each individual would consume 2g of either the MSM or placebo control
      for the remainder of the study.

      Intervention Product and Preparation Intervention: MSM (OptiMSM®) is a pure, generally
      recognized as safe (GRAS) designated product. MSM can be found in small amounts in corn,
      tomatoes, tea, coffee, milk.

      Placebo: Rice flour is a commonly ingested food or additive. Intervention and placebo will be
      encapsulated in 1g vegetarian capsules (Hypromellose Capsule).

      Both intervention and placebo capsules are identically transparent with white powder inside.
      Capsules containers with 805 capsules (2g per day for each month plus extra) will be
      prepared, packaged by Bergstrom nutrition and transported with blinded code (A or B) so only
      individuals responsible for intervention and placebo preparation are removed from conducting
      the study and are off site (Vancouver, Washington).

      Product will be labelled by Bergstrom Nutrition. Subject ID and month (3, 4, or 5) will be
      filled in manually by University of California, Davis researcher upon randomization.

      Determination of knee laxity: Knee laxity will be determined using a GNRB dynamic laximeter
      following established protocols. Briefly, with the femur held in place, a controlled pressure
      will be applied to the calf. The pressure increases from 0 to 200 Newtons and a sensor
      measures kneecap displacement (laxity) in millimeters.

      Determination of estrogen levels: Salivary samples will be taken on the first day of
      menstruation and one day following ovulation for the 4 months of testing (month 1, 2, 4, 5).
      Estradiol levels in the saliva will be determined using the Estradiol Saliva ELISA kit (Rocky
      Mountain Diagnostics, CO) as per manufacturer's instructions.

      Data Collected:

        -  Record of menstrual cycle

        -  Salivary estradiol levels as described above

        -  Measurements of knee laxity
    

Intervention name(s): methylsulfonylmethane; Placebo
Intervention type(s): Dietary Supplement; Other
Intervention description(s): Subjects will be given 2 g/day methylsulfonylmethane.; Subjects will be given 2 g/day placebo (rice flour).
Other intervention name(s): MSM
Intervention MeSH terms: Dimethyl sulfone
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: double blinded randomized parallel design
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Supportive Care