Protein Turnover in the Osteoarthritic Knee


Rationale: Osteoarthritis (OA) of the knee is a common cause of pain and disability, especially in people over the age of 65. In the current health care system both conservative (e.g. intra-articular injections with corticosteroids) and surgical (total knee replacement, TKR) treatment are applied. Although frequently used, certain effects of these treatments on protein metabolism remain unclear. It is well known that maintenance of different tissues is determined by a dynamic balance between protein synthesis and breakdown rates, with temporary changes in either protein synthesis or breakdown allowing net protein accretion or loss. However, intra-articular injections with corticosteroids as a conservative treatment are thought to have several negative consequences thereby potentially affecting protein metabolism of different musculoskeletal tissues. In addition, though protein supplementation has shown to be an effective nutritional strategy in stimulating muscle protein synthesis, it remains unclear to what extent other musculoskeletal tissues are able to respond to dietary protein supplementation. Therefore, the current study assesses the impact of intra-articular corticosteroid injections and preoperative protein supplementation on protein synthesis in different musculoskeletal tissues of the knee.

Objective: To investigate the effect of preoperative protein supplementation and corticosteroid injections on Hoffa's fat pad, synovium, tendon, bone, muscle, ligament, menisci, and cartilage protein synthesis of the OA knee.

Study design: Randomized, parallel (three groups) study design. Each of the two intervention groups will be compared to the control group separately.

Study population: 36 adults (45-75 y) with OA of the knee undergoing TKR. Intervention: Intra-articular injection of betamethasone (2ml; 4mg/ml) and bupivacaine (8ml; 5mg/ml) or daily 40 g of pre-sleep protein two weeks before TKR, or no intervention.

Main study parameters/endpoints: Primary study parameters include protein synthesis rates and enrichments of Hoffa's fat pad, synovium, tendon, bone, muscle, ligament, menisci, and cartilage. Secondary parameters include whole-body protein synthesis, breakdown, oxidation, and net balance.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The risks involved in participating in this study are minimal. There are no potential effects known for the ingestion of protein. The corticosteroid injection is standard care in conservative treatment of osteoarthritis. Risks are small and limited to the knee itself, such as cartilage degeneration or joint destruction. Muscle biopsies and tissue collection will be performed during the surgical procedure.

Full Title of Study: “Protein Turnover in the Osteoarthritic Knee; the Impact of Preoperative Protein Intake and Intra-articular Corticosteroid Injections”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Basic Science
    • Masking: Single (Outcomes Assessor)
  • Study Primary Completion Date: December 31, 2020


  • Dietary Supplement: Preoperative protein supplementation
    • Daily 40 g of pre-sleep protein supplementation during 2-week preoperative period.
  • Drug: Preoperative intra-articular corticosteroid injection
    • Intra-articular injection of corticosteroid (combination of betamethasone and bupivacaine) 2 weeks before surgery.

Arms, Groups and Cohorts

  • No Intervention: Control group
    • Subjects in the control group will receive no intervention.
  • Experimental: Protein group
    • Subjects in the protein group will receive a daily 40 g pre-sleep protein supplement during the 2-week preoperative period.
  • Experimental: Corticosteroid group
    • Subjects in the corticosteroid group will receive a single intra-articular corticosteroid injection in the affected knee on the first day of the 2-week preoperative period.

Clinical Trial Outcome Measures

Primary Measures

  • Change in tissue-specific protein synthesis rates
    • Time Frame: Throughout the surgical procedure (stable isotope methodology) and during the 2-week preoperative period (D2O dosing methodology).
    • Fractional synthetic rates calculated based on tissue-free, plasma, and protein-bound tracer enrichments using stable isotope methodology and D2O dosing methodology.

Participating in This Clinical Trial

Inclusion Criteria

  • Written informed consent
  • Male and female patients scheduled for total knee arthroplasty
  • BMI between 18.5-30 kg/m2
  • Age 45 – 75 years
  • Mentally competent, as judged by the treating physician
  • Functioning gastrointestinal tract, eligible for oral protein supplementation

Exclusion Criteria

  • Corticosteroid injections less than 3 months prior to participation
  • Any medications know to affect protein metabolism (i.e. corticosteroids, non-steroidal anti-inflammatories, or prescription strength acne medications)
  • Lactose intolerance
  • Diabetes mellitus
  • Smoking
  • Alcohol abuse
  • Lateral menisectomy
  • Rheumatoid arthritis
  • Hypertension, blood pressure above 140/90 mmHg
  • Peripheral artery disease Fontaine III or IV
  • Pheynylketonuria
  • Surgical intervention in the past four weeks
  • Total parenteral nutrition at day of surgery
  • Neoadjuvant chemotherapy or radiotherapy
  • GFR <20 mL/min/1.73 m2
  • Osteoarthritis of the knee secondary to septic arthritis, osteonecrosis, fracture, OD, or malignant processes
  • Collagen disorders, e.g. Marfan and Ehler-Danlos
  • Any other medical condition that may interfere with the safety of the subjects or the outcome parameters, in the investigators judgement
  • Investigator's uncertainty about the willingness or ability of the subject to comply with the protocol instructions
  • Participation in any other studies involving investigational or marketed products concomitantly or within two weeks prior to entry into the study

Gender Eligibility: All

Minimum Age: 45 Years

Maximum Age: 75 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Maastricht University Medical Center
  • Provider of Information About this Clinical Study
    • Principal Investigator: Lex Verdijk, Assistant Professor – Maastricht University Medical Center
  • Overall Contact(s)
    • Joey Smeets, MSc, MD, +31651363946,

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