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

Odense University Hospital

Status and phase: Enrolling; Phase 2

Conditions: Postmenopausal Women

Treatments: Drug: Everolimus (Afinitor®); Other: Football Fitness Concept

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT06789900

EU CT: 2023-508093-28-00

Details and patient eligibility

About

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.

Enrollment: 136 estimated patients

Sex: Female

Ages: 45 to 60 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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136 participants in 4 patient groups

Control group

No Intervention group

Description:

Participants will be asked to continue their life as usual with no specific recommendation

Football fitness group

Experimental group

Description:

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.

Treatment:

Other: Football Fitness Concept

Everolimus group

Experimental group

Description:

Participants will take an oral dose of everolimus 5 mg once a week for 24 weeks.

Treatment:

Drug: Everolimus (Afinitor®)

Everolimus and Football fitness group

Experimental group

Description:

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.

Treatment:

Other: Football Fitness Concept

Drug: Everolimus (Afinitor®)