Clinical trial NCT06789900: Everolimus and/or Exercise to Prevent Bone Loss in Postmenopausal Women
Official title: Targeting mTOR With Everolimus and/or Physical Training for Preventing Postmenopausal Bone Loss and Accelerated Skeletal Aging: The RapaLoad Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Postmenopausal Women
Keywords: Everolimus
Exercise
Football training session
postmenopausal women
bone loss
skeletal aging
Lead sponsor: Odense University Hospital
Sponsor class: OTHER
Collaborators: name: Institute of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark.
name: OPEN - Odense Patient data Explorative Network, The University of Southern Denmark, Odense, Denmark
name: Novo Nordisk A/S
First posted: 2025-01-23
Enrollment: 136
Sex: FEMALE
Minimum age (years): 45
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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 \&gt;-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.


Eligibility criteria: 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 \&lt;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 \&lt; 9.0 g/dl, Leukopenia - white blood cells (WBC) \&lt; 3,500/mm3, Neutropenia absolute neutrophil count \&lt; 2,000/mm3, or Platelet count - platelet count \&lt; 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 \&gt; 4.9 mmol/L and family history of dyslipidemia, Total cholesterol \&gt; 9.1 mmol/L, or triglycerides \&gt; 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 \&lt;-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

Primary outcomes:
measure: Procollagen type 1 N-terminal propeptide (P1NP)
timeFrame: Baseline and 24 weeks
Secondary outcomes:
measure: Bone resorption markers (CTX and TRAcP)
timeFrame: Baseline, week 2, week 4, week 12 and week 24
measure: Bone formation markers (Osteocalcin, bALP, P1NP (other time points))
timeFrame: Baseline, week 2, week 4, week 12 and week 24 (P1NP: week 2, week 4 and week 12)
measure: Bone mineral density (BMD)
timeFrame: Baseline, week 24
measure: Bone microarchitecture, mass and geometry
timeFrame: Baseline, week 24
measure: Muscle fitness and postural balances (test 1)
timeFrame: Baseline, week 24
measure: Muscle Fitness and postural balances (test 2)
timeFrame: Baseline, week 24
measure: Muscle fitness and postural balances (test 3)
timeFrame: Baseline, week 24
measure: Muscle fitness and postural balances (test 4)
timeFrame: Baseline, week 24
measure: Muscle fitness and postural balances (test 5)
timeFrame: Baseline, 24 weeks
measure: Muscle fitness and postural balances (test 6)
timeFrame: Baseline, week 24
measure: Muscle fitness and postural balances (test 7)
timeFrame: Baseline, week24
measure: Cardiopulmonary health (test 1)
timeFrame: Baseline, week 24
measure: Cardiopulmonary health (test 2)
timeFrame: Baseline, week 24
measure: Cardiopulmonary health (test 3)
timeFrame: Baseline, 24 weeks
measure: Cardiopulmonary health (test 4)
timeFrame: Baseline, week 24
measure: Cardiopulmonary health (test 5)
timeFrame: Baseline, week 24
measure: Metabolic health (test 1)
timeFrame: Baseline, week 24
measure: Metabolic health (test 2)
timeFrame: Baseline, week 24
measure: Metabolic health (test 3)
timeFrame: Baseline, week 24
measure: Metabolic health (test 4)
timeFrame: Baseline, week 24
Other outcomes:
measure: SF-12
timeFrame: Baseline, week 24
measure: SASP
timeFrame: Baseline, week 24
Locations:
city: Odense
country: Denmark
facility: Odense University Hospital
city: Odense
country: Denmark
facility: Odense University Hospital
Study officials:
affiliation: Odense University Hospital
name: Moustapha Kassem, DMSc, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Odense University Hospital
name: Florence Figeac, PhD
role: PRINCIPAL_INVESTIGATOR
References: