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

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.

Conditions

• Postmenopausal Women

Interventions

DRUG

Everolimus (Afinitor®)

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

Sponsors & Collaborators

• Institute of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark.

  collaborator UNKNOWN

• OPEN - Odense Patient data Explorative Network, The University of Southern Denmark, Odense, Denmark

  collaborator UNKNOWN

• Novo Nordisk A/S

  collaborator INDUSTRY

• University of Southern Denmark

  collaborator OTHER

• Odense University Hospital

  lead OTHER

Principal Investigators

• Moustapha Kassem, DMSc, PhD · Odense University Hospital

• Florence Figeac, PhD · Odense University Hospital

Study Design

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

45 Years

Max Age

60 Years

Sex

FEMALE

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2024-10-14

Primary Completion

2026-03-01

Completion

2026-10-01

Countries

• Denmark

Study Locations