Ostearthritis Biomarkers and Rehabilitation
Condition: Osteoarthritis
MeSH terms: Osteoarthritis
Study type: Interventional

Summary: 
      Osteoarthritis (OA) is the most common type of degenerative joint disease. Furthermore,
      despite its incidence being amongst the highest in chronic diseases, effective biomarkers,
      diagnostic aids and imaging technology are not available to assist in the management of OA.
      Mounting evidence suggests that non-pharmacological treatment such as exercise/physical
      therapy may lower the risk for onset or progression of OA by mitigating inflammation.
      However, the mechanical unloading and overloading, as seen in disuse and overuse, lead to
      upregulation of several proinflammatory molecules and enhance tissue degradation, whereas,
      dynamic moderate mechanical loading exerts anti-inflammatory and anti-catabolic effects on
      articular cartilage by suppressing mediators of inflammation. However, the lack of robust
      biomarkers to measure the effectiveness of physical therapies, represent a critical gap in
      biotechnology, obliterating the progress in the optimal application of these therapies. Our
      central hypothesis is that the circulating levels of specific molecules could serve as robust
      biomarkers for quantitative measures of OA burden, prognosis, progression or treatment
      efficacy. The objective of this project is to identify and evaluate mediators that serve as
      biomarkers of OA progression and treatment. Recently, high mobility group box chromosomal
      protein 1 (HMGB-1) has been suggested to be markedly upregulated in OA. However, presently
      there are no inhibitors of HMGB1 that could be used therapeutically. Previous results showed
      that that gentle exercise is the only tool that can mitigate HMGB1 production by local and
      systemic macrophages, and thus inflammation. Serum concentration of HMGB1 will be evaluate as
      a biomarker in OA patients and relate it to the functional capacity of knee joints in OA
      patients after rehabilitation protocol (RP). The RP will consist of three rehabilitation
      session/week during eight weeks. The efficacy of a RP will be evaluated by functional scale
      Western Ontario & McMaster Universities Osteoarthritis (WOMAC), Scale for the measurement of
      health related quality of life using EuroQol five dimensions questionnaire (EuroQOL), Visual
      Analog Scale (VAS), and physical function tests. Besides all clinical assessment, serum
      levels of classical pro-inflammatory cytokines, hyaluronan and HMGB1 will be evaluated. A
      correlation of physical improvement after RP and serum biomarkers will be performed.
    

Detailed description: 
      Detailed Description:

      Methods/Design

        1. Participants after being textually and verbally informed about their rights, benefits
           and possible risks, objectives and methodologies of this study, all participants will
           sign a free and informed consent form.

        2. Study Design Prior to the rehabilitation protocol (RP), participants will perform one
           adaptation session to all the functional tests that will be applied to minimize learning
           bias. In the second session after 5 minutes warm up in a cycle ergometer (CEE), the Time
           Up and Go (TUG) test will be applied, followed by the isometric strength test. In the
           third day, after the same warm up, one repetition maximum testing will be conducted. At
           the end of the RP, all the tests will be repeated. Blood samples will be collected at
           baseline (day 0), 1 month (day 30 after RP) and at 2 months (day 60 after RP).

      2.1. Rehabilitation protocol (RP) The RP will consist of 3 exercise session/week for 8 weeks.
      Each session will begin with the evaluation of pain by the participants. If the pain is
      higher than four, an analgesic protocol (AP) containing ultra-sound, laser or transcutaneous
      electrical nerve stimulation (TENS) will be applied. After the AP, the participant will just
      execute the rehabilitation protocol if the pain decreased to or lower than four. Starting
      with a warm up exercise in a cycle ergometer (CEE), for 5 minutes at free cadence, then the
      intensity will be set at 90% of the intensity obtained during the incremental test (see item
      2.2a) and maintained for 10 min. Afterward, four sets (8-12 repetitions) of three different
      resistance exercises (RE) (leg press, knee extension and knee flexion) will be performed at
      70% of the load correspondent to 1RM test (see item 2.2b) with one minute interval between
      sets and exercises. During CEE Borg scale will be taken every two minutes and during RE the
      omnibus (OMNI) scale taken at the end of every set to monitor the intensity. At the end of
      the session, cool down global stretching exercises for inferior members will be performed and
      the VAS evaluated again. Ten seconds of tension for each stretching position targeting the
      hamstrings, quadriceps, gluteus maxim ums, gastrocnemius, thigh adductors and abductors.

      2.2. Rehabilitation intensity parameters.

        1. Cycle ergometer incremental test (CEEIT). After 5 minutes warm up at free cadence in a
           cycle ergometer, the intensity will be increased every 3 minutes until the participants
           register 11 to 13 in Borg scale which is consider a moderate intensity and to be
           correlated to blood lactate concentration threshold and anaerobic threshold,
           respectively .

        2. One repetition maximum. The test starts with a warm up of 5 to 10 repetitions with
           estimated moderate load (± 40-60% of 1RM). After 1 minute rest 3 to 5 repetitions are
           performed with higher load (±60-80% of 1RM) with 5 minutes rest. Then one attempt at
           estimated 1RM is given. If the participants fail to lift the load for two repetitions
           the test stops, otherwise after 5 minutes rest the load is increased and the test is
           performed again. Only five attempts per day are permitted to maintain the test reliable.

      Sample size calculation The estimation of sample size was determined on the basis of a
      greater improvement of subscale physical function of the WOMAC score, using G.Power 3.15
      software. Based on 10% expected difference between baseline measure and after RP and a
      standard deviation of 30 on physical function of WOMAC, 65 participants are needed with
      significance level of 0.05, and power of 80%.
    

Intervention name(s): Rehabilitation
Intervention type(s): Other
Intervention description(s): Protocol will consist of three exercise/week for eight weeks. Each session will begin with the evaluation of pain by the volunteer. Starting with a warm up exercise in a cycle ergometer (CEE), for 5 minutes at free cadence, then the intensity will be set at 90% of the intensity obtained during the incremental test and maintained for 10 min. Afterward, four sets of three different resistance exercises (RE) will be performed at 70% of the load correspondent to 1RM test with one minute interval between sets and exercises. During CEE Borg scale will be taken every two minutes and during RE the OMNI scale taken at the end of every set to monitor the intensity. At the end of the session, cool down global stretching exercises for inferior members will be performed and the VAS evaluated.
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Osteoarthritis; biomarkers; HMGB1; knee