Everolimus and/or Exercise to Prevent Bone Loss in Postmenopausal Women (RapaLoad)

Targeting mTOR With Everolimus and/or Physical Training for Preventing Postmenopausal Bone Loss and Accelerated Skeletal Aging: The RapaLoad Study

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Postmenopausal Women
• Intervention / Treatment: Other: Football Fitness Concept; Drug: Everolimus (Afinitor®)

• Study Type: Interventional
• Enrollment (Actual): 136
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • Odense, Denmark, 5000
    • Odense University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control group; Participants will be asked to continue their life as usual with no specific recommendation
Experimental: Football fitness group; Participants will join structured hybrid exercise training via the "football fitness concept" 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: 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.	Other: Football 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
Experimental: Everolimus group; Participants will take an oral dose of everolimus 5 mg once a week for 24 weeks.	Drug: Everolimus (Afinitor®); Oral dose of everolimus 5 mg once a week for 24 weeks; Other Names: Football fitness session
Experimental: Everolimus and Football fitness group; Participants will join structured hybrid exercise training via the "football fitness concept" 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: 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 and take an oral dose of everolimus 5 mg once a week for 24 weeks.	Other: Football 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; Drug: Everolimus (Afinitor®); Oral dose of everolimus 5 mg once a week for 24 weeks; Other Names: Football fitness session

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Procollagen type 1 N-terminal propeptide (P1NP)	Percentage change in circulating levels of bone formation marker N-terminal fragment of procollagen type 1 (P1NP) at 24 weeks as compared with baseline	Baseline and 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bone resorption markers (CTX and TRAcP)	Change in circulating levels of bone resorption markers (C-terminal telopeptide of type 1 collagen (CTX) and Tartrate resistant acid phosphatase (TRAcP))	Baseline, week 2, week 4, week 12 and week 24
Bone formation markers (Osteocalcin, bALP, P1NP (other time points))	Change in circulating levels of bone formation markers (osteocalcin, and bone alkaline phosphatase) and additional time point for P1NP	Baseline, week 2, week 4, week 12 and week 24 (P1NP: week 2, week 4 and week 12)
Bone mineral density (BMD)	Lumbar spine (L1-4), and total hip and femoral neck bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA)	Baseline, week 24
Bone microarchitecture, mass and geometry	Bone microarchitecture at the distal radius and tibia assessed using high-resolution peripheral quantitative computed tomography (HR-pQCT)	Baseline, week 24
Muscle fitness and postural balances (test 1)	Y-balance test	Baseline, week 24
Muscle Fitness and postural balances (test 2)	Stork balance test	Baseline, week 24
Muscle fitness and postural balances (test 3)	Handgrip strength test	Baseline, week 24
Muscle fitness and postural balances (test 4)	leg strength test- knee extension and knee flexion tests	Baseline, week 24
Muscle fitness and postural balances (test 5)	Sit-to-stand chair test	Baseline, 24 weeks
Muscle fitness and postural balances (test 6)	stair climb test	Baseline, week 24
Muscle fitness and postural balances (test 7)	Counter Movement Jump test	Baseline, week24
Cardiopulmonary health (test 1)	Vo2 max (seismofit)	Baseline, week 24
Cardiopulmonary health (test 2)	Bicycle test with submaximal exercise (warm-up, submax HR and fat oxidation)	Baseline, week 24
Cardiopulmonary health (test 3)	5-s peak power test	Baseline, 24 weeks
Cardiopulmonary health (test 4)	maximal oxygen uptake test	Baseline, week 24
Cardiopulmonary health (test 5)	6-min walk test	Baseline, week 24
Metabolic health (test 1)	weight, lean and fat body mass by DXA scanning	Baseline, week 24
Metabolic health (test 2)	Fasting blood glucose	Baseline, week 24
Metabolic health (test 3)	Fasting insulin	Baseline, week 24
Metabolic health (test 4)	Lipid parameters	Baseline, week 24

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
SF-12	Quality of life questionnaire	Baseline, week 24
SASP	Serum levels of senescence associated secretory phenotype (SASP), which reflect the whole-body burden of senescent cells	Baseline, week 24

Collaborators and Investigators

• Sponsor: Odense University Hospital
• Collaborators: Novo Nordisk A/S; University of Southern Denmark; OPEN - Odense Patient data Explorative Network, The University of Southern Denmark, Odense, Denmark; Institute of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark.
• Investigators: Principal Investigator: Moustapha Kassem, DMSc, PhD, Odense University Hospital; Principal Investigator: Florence Figeac, PhD, Odense University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): October 14, 2024
• Primary Completion (Actual): March 1, 2026
• Study Completion (Estimated): October 1, 2026

Study Registration Dates

• First Submitted: November 27, 2024
• First Submitted That Met QC Criteria: January 22, 2025
• First Posted (Actual): January 23, 2025

Study Record Updates

• Last Update Posted (Actual): April 7, 2026
• Last Update Submitted That Met QC Criteria: April 1, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Exercise; Everolimus; postmenopausal women; bone loss; Football training session; skeletal aging
• Additional Relevant MeSH Terms: Bone Diseases; Musculoskeletal Diseases; Metabolic Diseases; Behavior; Nutritional and Metabolic Diseases; Bone Diseases, Metabolic; Motor Activity; Organic Chemicals; Macrolides; Lactones; Sirolimus; Everolimus
• Other Study ID Numbers: EU CT: 2023-508093-28-00

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: After completion of the project and irrespective of the outcomes, de-identified trial results will be published in peer-reviewed journals and www.clinicaltrials.gov. A summary of the clinical trial results will be presented in a language understandable to the layperson and made available in the EU database.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No