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Completed

NCT Number: NCT03051984

Skeletal Muscle Atrophy and Dysfunction Following Total Knee Arthroplasty

Total knee replacement, or arthroplasty, is the final clinical intervention available to relieve pain and functional limitations related to advanced stage knee osteoarthritis. Despite its beneficial effects, the early post-surgical period is characterized by the erosion of lower extremity muscle size and strength that cause further disability and slow functional recovery. While the detrimental effects of this period on muscle are widely recognized, the mechanisms underlying these adaptations are poorly understood and there are currently no widely-accepted clinical interventions to counter them

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Key information

Age range

50 year–75 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

University of Vermont College of Medicine

Burlington, Vermont, 05405, United States

About this study

Total knee arthroplasty (TKA) is currently the most common elective surgery in the US and will increase in frequency nearly five-fold by 2030 to 3.5 million surgeries annually. This surgery is most prevalent among older adults with advanced knee osteoarthritis (OA) and its increase is explained primarily by growth in this population. Although TKA reliably reduces joint pain, it fails to correct objectively-measured functional disability due, in part, to dramatic declines in lower-extremity neuromuscular function during the early, postsurgical period. These deficits are never fully remediated, remaining for years after surgery and contributing to persistent disability. Despite these detrimental effects of TKA, the fundamental skeletal muscle adaptations that occur in the early, post-surgical period are poorly defined and understudied and there is currently no widely-accepted, evidence-based intervention to counter these changes. To address this clinical problem, the investigators goals in this application are to define the skeletal muscle structural and functional adaptations following TKA at the whole body, tissue, cellular, organellar and molecular levels in humans in an effort to identify factors contributing to functional disability and to assess the utility of neuromuscular electrical stimulation (NMES) to counter post-surgical muscle adaptations at these same anatomic levels. We hypothesize that TKA fails to remediate physical disability in patients, in part, because of the profound skeletal muscle myofilament and mitochondrial loss and dysfunction that develops during the early, post-surgical period. Moreover, the investigators posit that NMES will improve functional recovery following TKA by countering these early skeletal muscle adaptations. To test this model, the investigators will evaluate participants with knee OA prior to and following TKA for skeletal muscle structure and function at multiple anatomic levels, with patients randomized to receive NMES or sham control intervention during the first 5 weeks post-surgery.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • symptomatic, primary knee osteoarthritis (OA)
  • being considered for total knee arthroplasty

Exclusion criteria

  • knee OA secondary to inflammatory/autoimmune disease
  • untreated/uncontrolled hypertension, diabetes or thyroid disease
  • chronic heart failure, actively-treated malignancy, exercise-limiting peripheral vascular disease, stroke or neuromuscular disease
  • body mass index >38 kg/m2
  • lower extremity blood clot or known coagulopathies
  • implanted pacemaker/ICD

Treatment and study plan

Neuromuscular Electrical Stimulation

Device

NMES will be conducted on the quadriceps of the operative leg using a portable stimulation device, starting within 48-72 hrs of surgery. The operative leg will be immobilized at a neutral angle (~30º), with electrodes affixed to the anterior surface of the thigh. Symmetrical, biphasic pulses (400 µs duration at 50 Hz) will be used, with a duty cycle of 25% (10 s on, 30 s off), with patient-selected stimulation intensity to cause visible contractions below pain threshold. NMES sessions will occur 5 d/week, twice daily for 45 min (5 min warm-up) for 5 wks.

Other names: NMES

Primary outcomes

  1. Cross-sectional Area (CSA) of Muscle Fibers

    Time frame: Baseline and 5-weeks post-TKA surgery

    CSA of skeletal muscle fibers via myosin heavy chain (MHC) immunohistochemistry

  2. Intermyofibrillar Mitochondrial Content

    Time frame: Baseline and 5-weeks post-TKA surgery

    Fractional area of intermyofibrillar (IMF) mitochondria via electron microscopy

  3. Maximal Calcium-activated Tension Single Muscle Fiber Tension

    Time frame: Baseline and 5-weeks post-TKA surgery

    Tension (force per unit muscle fiber cross-sectional area) from segments of chemically-skinned single human muscle fibers assessed under maximal calcium-activated condition, with muscle fiber type determined post-measurement by gel electrophoresis

Secondary outcomes

  1. Physical Activity Level

    Time frame: Baseline and 5-weeks post-TKA surgery

    Physical activity will be assessed by accelerometry.

  2. Quadriceps Muscle Cross-sectional Area

    Time frame: Baseline and 5-weeks post-TKA surgery

    Quadriceps muscle cross-sectional area will be assessed by computed tomography at the mid-thigh on both surgical and non-surgical non-surgical legs.

  3. Short Physical Performance Battery

    Time frame: Baseline and 5-weeks post-TKA surgery

    Physical functional assessment based on 2 lower extremity activities (5-time sit-to-stand, 4-m gait speed) and standing balance (side-side, tandem, semi-tandem) based on time or repetitions (0-4 score) with a minimum score of 0 and a maximal score of 12. Each activity is scored from 0 to 4 based on the level of performance (with higher values indicating better physical function and lower values indicating increasing levels of disability). The scores from the 3 activities are summed to give the total score, which is what is reported. Higher total score values indicate higher levels of physical function (more healthy), whereas lower values indicate increasing levels of physical disability/frailty.

  4. Knee Extensor Muscle Strength

    Time frame: Baseline and 5-weeks post-TKA surgery

    Knee extensor isometric peak torque assessed by dynamometry on the surgical leg.

  5. 30-second Sit-to-stand Test

    Time frame: Assessed at baseline and 5 weeks post-surgery

    Number of repetitions that an individual can complete the sit-to-stand transition in 30 seconds

Sponsors and collaborators

Lead sponsor

University of Vermont

Other

Collaborators

  • National Institute on Aging (NIA)

Registry information

Important dates

Study start
2017
Primary completion
2023
Study completion
2023
First posted
Feb 14, 2017
Registry last updated
Oct 2, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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