Postmenopausal Women
Conditions
Keywords
Everolimus, Exercise, Football training session, postmenopausal women, bone loss, skeletal aging
Brief summary
It is estimated that women lose around 20-25% of bone mass during the 5-10 years period of postmenopausal transition, and menopause is considered a major risk factor for osteoporotic fragility fracture. Currently, there is no preventive strategy to counteract these changes, and hormone replacement therapy is not considered an attractive option for many women, because of concerns related to side effects. Rapamycin, through inhibition of mTOR (the mechanistic target of Rapamycin) has been demonstrated in many preclinical animal models to extend lifespan and healthspan. The most well-established mTOR inhibitors include rapamycin (sirolimus) and its analog (also referred as rapalog). Everolimus are FDA approved and have been used for many years at a high dose as an immunosuppressant and anti-cancer drug. Exercise training has been demonstrated to counteract age-related degenerative changes in several clinical studies. The aim of this randomized clinical trial is to test the effects of treatment with oral Everolimus, exercise, or their combination as a preventive strategy for impaired musculoskeletal function in healthy postmenopausal women. The trial will include 136 women aged 45-60 years with T-score >-3 and no history of hip, Colles' or symptomatic vertebral fractures within the last 6 months, randomized to 24 weeks of treatment with one of the following regimens: 1. control group getting general health advice, 2. Football fitness session group, physical training consisting of structured hybrid exercise training via the football fitness concept for 1hour, 2 times/ week 3. Everolimus group receiving an oral dosage of 5 mg everolimus once a week, (4) Everolimus and football fitness session group, consisting of structured hybrid exercise training via the football fitness concept for 1 hour, 2 times/week combined with oral everolimus 5 mg once a week. The primary outcome of this trial is percentage change in bone formation marker P1NP (Procollagen Type 1 propeptide) between baseline and week 24. Secondary outcomes include percentage changes in bone resorption marker CTX (cross-lined C-telopeptide of type 1 collagen), bone mineral density (BMD), bone structure as determined by high resolution CT-scanning, muscle function and postural balance. As exploratory endpoints, changes in biological age as determined by epigenetic clocks, levels of senescence-associated secretory phenotype (SASP) as an indicator of whole-body burden of senescent cells.
Interventions
Oral dose of everolimus 5 mg once a week for 24 weeks
OTHERFootball Fitness Concept
Structured hybrid exercise training via the football fitness concept organized as a super-vised group training at the University of Southern Denmark, Department of Sports Science and Clinical Biomechanics. Football Fitness concept is designed for participants with little prior experience with football and it is multifaceted training incorporating endurance training, high-intensity interval training (HIIT) and strength training. The training session lasts 60 minutes, and participants will receive two training sessions per week for 24 weeks. Each session is composed of 4 elements: a 15 min warm-up that includes strength and balance exercises, a 15 min period with technical pair-based drills, and a 30-min period with small-sided football drills
Sponsors
Institute of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark.
OPEN - Odense Patient data Explorative Network, The University of Southern Denmark, Odense, Denmark
Novo Nordisk A/S
Odense University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
45 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
* Postmenopausal women aged 45-60 years old as evidenced by measuring serum levels of LH and FSH and absence of menstruation for at least 1 year. * No history of low energy hip or vertebral fractures during the last 6 months. * Ability to provide informed consent.
Exclusion criteria
* Diabetes (type 1 and 2) * Heart failure similar to NYHA Class IV * Primary hyperparathyroidism * Known disorders affecting bone metabolism, e.g., uncontrolled thyrotoxicosis, severe renal impairment (eGFR <20) or liver function (baseline phosphatase higher than twice upper limit (105 U/L)), active rheumatic diseases, celiac disease, severe chronic obstructive lung disease (COPD), hypopituitarism, or Cushing's disease. * Previous use of bone antiresorptive or bone anabolic drugs within the last 5 years. * Use of anabolic steroids in the previous year * Treatment with drugs known to affect cytochrome P450 3A due to its role in everolimus metabolism * History of coagulopathy or medical condition requiring long-term anticoagulation * Anemia - Hg < 9.0 g/dl, Leukopenia - white blood cells (WBC) < 3,500/mm3, Neutropenia absolute neutrophil count < 2,000/mm3, or Platelet count - platelet count < 125,000/mm3 * Patients with impaired wound healing or history of a chronic open wound * Scheduled for immunosuppressant therapy for transplant or scheduled to undergo chemotherapy or any other treatment for malignancy * Untreated dyslipidemia with LDL-c > 4.9 mmol/L and family history of dyslipidemia, Total cholesterol > 9.1 mmol/L, or triglycerides > 9.9 mmol/L * Any form of clinically relevant primary or secondary immune dysfunction or deficiency * Unstable ischemic heart disease * Bone mineral density (BMD) measured by DXA scanning with T-score <-3 * Known allergy to rapamycin or rapalogs * The study will exclude participants with inability to speak and understand Danish and with inability to cooperate or perform physical training. * Inability to give informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Procollagen type 1 N-terminal propeptide (P1NP) | Baseline and 24 weeks | Percentage change in circulating levels of bone formation marker N-terminal fragment of procollagen type 1 (P1NP) at 24 weeks as compared with baseline |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Bone resorption markers (CTX and TRAcP) | Baseline, week 2, week 4, week 12 and week 24 | Change in circulating levels of bone resorption markers (C-terminal telopeptide of type 1 collagen (CTX) and Tartrate resistant acid phosphatase (TRAcP)) |
| Bone formation markers (Osteocalcin, bALP, P1NP (other time points)) | Baseline, week 2, week 4, week 12 and week 24 (P1NP: week 2, week 4 and week 12) | Change in circulating levels of bone formation markers (osteocalcin, and bone alkaline phosphatase) and additional time point for P1NP |
| Bone mineral density (BMD) | Baseline, week 24 | Lumbar spine (L1-4), and total hip and femoral neck bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) |
| Bone microarchitecture, mass and geometry | Baseline, week 24 | Bone microarchitecture at the distal radius and tibia assessed using high-resolution peripheral quantitative computed tomography (HR-pQCT) |
| Muscle fitness and postural balances (test 1) | Baseline, week 24 | Y-balance test |
| Muscle Fitness and postural balances (test 2) | Baseline, week 24 | Stork balance test |
| Muscle fitness and postural balances (test 3) | Baseline, week 24 | Handgrip strength test |
| Muscle fitness and postural balances (test 4) | Baseline, week 24 | leg strength test- knee extension and knee flexion tests |
| Muscle fitness and postural balances (test 5) | Baseline, 24 weeks | Sit-to-stand chair test |
| Muscle fitness and postural balances (test 6) | Baseline, week 24 | stair climb test |
| Metabolic health (test 3) | Baseline, week 24 | Fasting insulin |
| Metabolic health (test 4) | Baseline, week 24 | Lipid parameters |
| Muscle fitness and postural balances (test 7) | Baseline, week24 | Counter Movement Jump test |
| Cardiopulmonary health (test 1) | Baseline, week 24 | Vo2 max (seismofit) |
| Cardiopulmonary health (test 2) | Baseline, week 24 | Bicycle test with submaximal exercise (warm-up, submax HR and fat oxidation) |
| Cardiopulmonary health (test 3) | Baseline, 24 weeks | 5-s peak power test |
| Cardiopulmonary health (test 4) | Baseline, week 24 | maximal oxygen uptake test |
| Cardiopulmonary health (test 5) | Baseline, week 24 | 6-min walk test |
| Metabolic health (test 1) | Baseline, week 24 | weight, lean and fat body mass by DXA scanning |
| Metabolic health (test 2) | Baseline, week 24 | Fasting blood glucose |
Other
| Measure | Time frame | Description |
|---|---|---|
| SASP | Baseline, week 24 | Serum levels of senescence associated secretory phenotype (SASP), which reflect the whole-body burden of senescent cells |
| SF-12 | Baseline, week 24 | Quality of life questionnaire |
Countries
Denmark
Contacts
Primary ContactSofie Damkjær, MD
Outcome results
None listed