RecruitingPhase 2NCT06789900

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

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

Sponsor

Odense University Hospital

Enrollment

136 participants

Start Date

Oct 14, 2024

Study Type

INTERVENTIONAL

Conditions

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.

Eligibility

Sex: FEMALEMin Age: 45 YearsMax Age: 60 Years

Inclusion Criteria3

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 Criteria18

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

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Interventions

DRUGEverolimus (Afinitor®)

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