Resistance Training and Rapamycin to Enhance Bone Formation in Postmenopausal Women
Trial statusRecruiting
Trial phasePhase 2
Trial typeInterventional
Biological sexFemale
Age60-75
SponsorOdense University Hospital
About this trial
The aim of the present clinical trial is to examine the effects of everolimus, resistance training, or their combination on bone and muscle health formation in elderly women aged 60-75 years. The main questions it aims to answer are:
Can rapamycin's analog (Everolimus), resistance training, or their combination, enhance bone formation and muscle functions in elderly women compared to non-treatment controls.
Participants will be randomized 1:1:1:1 to one of the following treatment regimens:
* Oral everolimus 5 mg once a week. * Oral placebo once a week. * Oral everolimus 5 mg once a week plus resistance training RT 1 hour, 3 times weekly. * Oral placebo once a week plus resistance training RT 1 hour, 3 times weekly.
During the study there will be a total of 5-7 visits, where the participants will undergo the following:
* Blood samles * DXA-, HRpQCT- (only Odense Universitetshospital) and MRI-scans * Muscle- and bone biopsies * Quality of life questionnaires * Testing of muscle funtion * Metabolic studies of muscle and bone protein turnover using labelling with deuturated water
Eligibility criteria
This trial accepts healthy volunteersQualifiers
Women aged 60-75 years old, any ethnicity.
Participants with T- score between < 1.0 and > -2.5 measured by DXA scan within 6 months of the first day of the study.
Adequate cognitive function to be able to give informed consent.
Disqualifiers
Osteoporosis and fracture history
Participants with osteoporosis (defined by DXA scan < 6 months old: low bone mass, T-score < -2.5 or hip fracture or clinical compression fracture of the spine).
History of low energy fractures within last 6 months. Health conditions limiting exercise
Health conditions that could limit walking and weightbearing exercise (for instance recent surgery, mobility limitation)
Trial design
Design model
Parallel
Treatments tested in this trial
Everolimus
DrugEverolimus 5 mg administered once weekly for 24 weeks
Placebo
DrugPlacebo administered once weekly for 24 weeks
Resistance training
Other interventionResistance training 3 times a week for 24 weeks
Treatment groups
148 Participants
are divided into 4 treatment groupsGroup A: EverolimusExperimental treatment 1 intervention
Group B: Everolimus and resistance trainingExperimental treatment 2 interventions
Group C: PlaceboPlacebo comparator 1 intervention
Group D: Placebo and resistance trainingPlacebo comparator 2 interventions
Trial outcomes
Primary outcomes
1
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
Time frame
From baseline to end of treatment at 24 weeksSecondary outcomes
1
Bone resorption markers
Change in bone resorption markers (C-terminal telopeptide of type 1 collagen (CTX) at baseline, 4, 12 and 24 weeks.
Time frame
From baseline to end of treatment 24 weeks2
BMD
Lumbar spine (L1-4), and total hip and femoral neck bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) at screening visit/baseline, and 24 weeks.
Time frame
From screening to end of treatment 24 weeks3
Bone mass
Bone mass at the distal radius and tibia measured using high-resolution peripheral quantitative computed tomography (HR-pQCT) at baseline, and 24 weeks.
Time frame
From baseline to end of treatment 24 weeks4
Bone microarchitecture
Bone microarchitecture at the distal radius and tibia measured using high-resolution peripheral quantitative computed tomography (HR-pQCT) at baseline, and 24 weeks.
Time frame
From baseline to end of treatment 24 weeksOther outcomes
1
Biomarkers of biological aging
Measurements of Biomarkers of biological aging in serum: senescence associated secretory phenotype (SASP), which reflect the whole-body burden of senescent cells at baseline and 24 weeks.
Time frame
From baseline to end of treatment 24 weeks2
Epigenetic clocks
Changes in biological age as determined by "epigenetic clocks" that estimate biological age based on DNA methylation pattern in a selected number of genes. Peripheral blood mononuclear cells (PBMCs) will be isolated from blood at baseline and 24 weeks. DNA will be obtained for DNA methylation evaluation and a fixed part of PBMCs will be used to determine cellular and molecular changes of bone resorbing cells (osteoclast).
Time frame
From baseline to end of treatment 24 weeks3
Bone changes
Two G8 bone biopsies will be obtained at the end of the trial to determine: (a) histomorphometric changes taking place at tissue levels (osteoblastic and osteoclastic activities), (b) global changes in gene expression taking place at tissue level by performing RNA-seq. (c) Spatial transcriptomics: measuring changes in gene expression at cellular levels, (d) r nanoindentation and spectroscopies to study bone strength and mineral properties (e) scanned with high resolution CT scanner for determining tissue-levels changes in microarchitecture
Time frame
At the end of the study 24 weeks4
Changes in bone stem cell characteristics and the composition of the cells
Bone marrow aspirates will be obtained to study changes in bone stem cell (called marrow stromal or mesenchymal stem cells, MSC) characteristics and the composition of the cells within the bone marrow cell population within each treatment arm. Following isolation of MSC, part of the cells will be prepared for single cell RNA-seq to determine changes in cellular composition of bone microenvironment and cellular senescence signature as an estimate of senescent cell burden and the rest will be store for further analysis of the cellular and molecular characteristics e.g. cell proliferation, cell differentiation, changes in metabolic activity. The bone marrow aspirate and bone biopsy samples will be exchanged between the two sites depending on the assays to be performed
Time frame
At the end of the study 24 weeksSponsors and contacts
Click on the lead sponsor to view all of their trials.
Odense University Hospital
Lead sponsor
Bispebjerg Hospital
Collaborator
Source ClinicalTrials.gov