Ostearthritis Biomarkers and Rehabilitation

NCT02964624 | Completed

• 1 other identifier: Osteoarthritis
• Study Type: interventional
• Target: 65
• Locations: 1 country
• Sites: 2

Brief 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.

Conditions

Osteoarthritis

Keywords

Osteoarthritis; biomarkers; HMGB1; knee

Outcome Measures

Primary Outcomes (1)

• Change from baseline to month 2 in Western Ontario and McMasters Universities Osteoarthritis (WOMAC) Index score

  Participants will answer the questionnaire WOMAC for the assessment of lower extremity pain, stiffness and physical function during daily activities. The WOMAC measures five items for pain (score range 0-20), two for stiffness (score range 0-8), and 17 for functional limitation (score range 0-68). For each item, the possible range of scores is therefore 0-100. Items are summed for each subscale, resulting in possible ranges as follows: pain=0-500, stiffness=0-200, physical function=0-1700. Most commonly, a total WOMAC score is created by summing the items for all three subscales. Higher scores on the WOMAC indicate worse pain, stiffness, and functional limitations. The collected data will be present through study completion, an average of 1 year.

  Baseline and 2 month

Secondary Outcomes (6)

• Change from baseline to month 2 in TUG test

  Baseline and 2 month

• Change from baseline to month 2 in VAS analysis.

  Baseline and 2 month

• Change from baseline in proinflammatory cytokines and biomarkers of cartilage breakdown in blood

  Baseline, 1 month and 2 month after RP

• Change from baseline to month 2 in Health-related quality of life (EuroQOL-5D, EQ-5D)

  Baseline and 2 month

• Change from baseline to month 2 in Radiographic knee osteoarthritis progression (joint space and KL score)

  Baseline and 2 month

Study Arms (1)

Rehabilitation

OTHER

The rehabilitation protocol will consist of three exercise session/week for eight weeks

Other: Rehabilitation

Interventions

Rehabilitation OTHER

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.

Rehabilitation

Eligibility Criteria

• Age: 45 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Women and men aged 45-65 years
• Clinical knee osteoarthritis according to the American College of Rheumatology Clinical Criteria
• Kellgren and Lawrence (KL) radiographic osteoarthritis grade 2 and 3 (mild to moderate radiographic osteoarthritis)

You may not qualify if:

• Severe knee osteoarthritis according to the KL classification (grade 4)
• Other known major musculoskeletal impairments in the lower extremities or the back or prostheses in any joint of the lower extremities
• Known serious coronary heart diseases or cancer
• Body mass index \>35
• Scheduled for surgery in any joint
• Persons who already perform sports related moderate physical activity more than two times a week
• History of knee replacement surgery or high tibial osteotomy;
• Any knee surgery or corticosteroid injections within the previous 6 months;
• Miss more than two rehabilitation sessions during the program or more than two consecutive sessions.

Sponsors & Collaborators

• Hospital Israelita Albert Einstein: lead
• Ohio State University: collaborator
• Federal University of São Paulo: collaborator

Study Sites (2)

Universidade Federal de Sao Paulo

São Paulo, São Paulo, 04022-001, Brazil

Location

Hospital Israelita Albert Einstein

São Paulo, São Paulo, 05652-000, Brazil

Location

Related Publications (14)

• Weinstein SL, Jacobs JJ, Goldberg MJ. Osteoarthritis of the knee. N Engl J Med. 2006 Jun 8;354(23):2508-9; author reply 2508-9. doi: 10.1056/NEJMc060815. No abstract available.

  PMID: 16760456 BACKGROUND

• Kapoor M, Martel-Pelletier J, Lajeunesse D, Pelletier JP, Fahmi H. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat Rev Rheumatol. 2011 Jan;7(1):33-42. doi: 10.1038/nrrheum.2010.196. Epub 2010 Nov 30.

  PMID: 21119608 BACKGROUND

• Cross M, Smith E, Hoy D, Nolte S, Ackerman I, Fransen M, Bridgett L, Williams S, Guillemin F, Hill CL, Laslett LL, Jones G, Cicuttini F, Osborne R, Vos T, Buchbinder R, Woolf A, March L. The global burden of hip and knee osteoarthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis. 2014 Jul;73(7):1323-30. doi: 10.1136/annrheumdis-2013-204763. Epub 2014 Feb 19.

  PMID: 24553908 BACKGROUND

• McAlindon TE, Bannuru RR, Sullivan MC, Arden NK, Berenbaum F, Bierma-Zeinstra SM, Hawker GA, Henrotin Y, Hunter DJ, Kawaguchi H, Kwoh K, Lohmander S, Rannou F, Roos EM, Underwood M. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage. 2014 Mar;22(3):363-88. doi: 10.1016/j.joca.2014.01.003. Epub 2014 Jan 24.

  PMID: 24462672 BACKGROUND

• Zhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD, Arden N, Bierma-Zeinstra S, Brandt KD, Croft P, Doherty M, Dougados M, Hochberg M, Hunter DJ, Kwoh K, Lohmander LS, Tugwell P. OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage. 2008 Feb;16(2):137-62. doi: 10.1016/j.joca.2007.12.013.

  PMID: 18279766 BACKGROUND

• Altman R, Asch E, Bloch D, Bole G, Borenstein D, Brandt K, Christy W, Cooke TD, Greenwald R, Hochberg M, et al. Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. Arthritis Rheum. 1986 Aug;29(8):1039-49. doi: 10.1002/art.1780290816.

  PMID: 3741515 BACKGROUND

• Hsueh MF, Onnerfjord P, Kraus VB. Biomarkers and proteomic analysis of osteoarthritis. Matrix Biol. 2014 Oct;39:56-66. doi: 10.1016/j.matbio.2014.08.012. Epub 2014 Aug 30.

  PMID: 25179675 BACKGROUND

• Kraus VB, Blanco FJ, Englund M, Henrotin Y, Lohmander LS, Losina E, Onnerfjord P, Persiani S. OARSI Clinical Trials Recommendations: Soluble biomarker assessments in clinical trials in osteoarthritis. Osteoarthritis Cartilage. 2015 May;23(5):686-97. doi: 10.1016/j.joca.2015.03.002.

  PMID: 25952342 BACKGROUND

• Terada C, Yoshida A, Nasu Y, Mori S, Tomono Y, Tanaka M, Takahashi HK, Nishibori M, Ozaki T, Nishida K. Gene expression and localization of high-mobility group box chromosomal protein-1 (HMGB-1)in human osteoarthritic cartilage. Acta Med Okayama. 2011 Dec;65(6):369-77. doi: 10.18926/AMO/47262.

  PMID: 22189477 BACKGROUND

• Hunt MA, Pollock CL, Kraus VB, Saxne T, Peters S, Huebner JL, Sayre EC, Cibere J. Relationships amongst osteoarthritis biomarkers, dynamic knee joint load, and exercise: results from a randomized controlled pilot study. BMC Musculoskelet Disord. 2013 Mar 27;14:115. doi: 10.1186/1471-2474-14-115.

  PMID: 23530976 BACKGROUND

• Andersson U, Harris HE. The role of HMGB1 in the pathogenesis of rheumatic disease. Biochim Biophys Acta. 2010 Jan-Feb;1799(1-2):141-8. doi: 10.1016/j.bbagrm.2009.11.003.

  PMID: 20123076 BACKGROUND

• Imamura M, Ezquerro F, Marcon Alfieri F, Vilas Boas L, Tozetto-Mendoza TR, Chen J, Ozcakar L, Arendt-Nielsen L, Rizzo Battistella L. Serum levels of proinflammatory cytokines in painful knee osteoarthritis and sensitization. Int J Inflam. 2015;2015:329792. doi: 10.1155/2015/329792. Epub 2015 Mar 2.

  PMID: 25821631 BACKGROUND

• Li ZC, Cheng GQ, Hu KZ, Li MQ, Zang WP, Dong YQ, Wang WL, Liu ZD. Correlation of synovial fluid HMGB-1 levels with radiographic severity of knee osteoarthritis. Clin Invest Med. 2011 Oct 1;34(5):E298. doi: 10.25011/cim.v34i5.15673.

  PMID: 21968272 BACKGROUND

• Campedelli RR, Jardim MRS, Antonioli E, de Oliveira FBD, Agarwal S, Ferretti M. Effect of simplified exercise program on quality of life, biomarkers, pain and muscle strength of individuals with knee osteoarthritis. Einstein (Sao Paulo). 2025 Dec 1;23:eAO1192. doi: 10.31744/einstein_journal/2025AO1192. eCollection 2025.

  PMID: 41379149 DERIVED

MeSH Terms

Conditions

Osteoarthritis

Interventions

Rehabilitation

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases

Intervention Hierarchy (Ancestors)

Aftercare; Continuity of Patient Care; Patient Care; Therapeutics; Health Services; Health Care Facilities Workforce and Services

Study Officials

• Mario Ferretti, PhD

  Hospital Israelita Albert Einstein

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 21, 2016
• First Posted: November 16, 2016
• Study Start: July 2, 2018
• Primary Completion: August 30, 2019
• Study Completion: December 30, 2019
• Last Updated: September 22, 2023

Record last verified: 2018-07

Locations

BR (2)