Clinical trial NCT05328154: MAGnesium Effect With ANtiosteoporotic Drugs
Official title: Effects of the Combination of Magnesium Bisphosphonates Versus Bisphosphonates Alone on Bone Remodeling: Randomized Pilot Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Osteoporosis, Postmenopausal
Keywords: Osteoporosis
Magnesium
CTX
Bone remodeling
Lead sponsor: University Hospital, Clermont-Ferrand
Sponsor class: OTHER
First posted: 2022-04-14
Enrollment: 45
Sex: FEMALE
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Following the inclusion visit, patients will be assigned to one of the two groups (bisphosphonates alone or bisphosphonate associated with magnesium). Treatment assignment will follow a predefined randomization list and will be performed by a Clinical Research Associate who is totally independent from the protocol. The randomization list and a copy will be edited and given to the Clermont-Ferrand University Hospital Pharmacy and to the Rheumatology Department of the Gabriel Montpied University Hospital.
Primary purpose: TREATMENT

Brief summary: Randomized pilot clinical trial to demonstrate superiority of bisphosphonate-magnesium combination over bisphosphonates alone in postmenopausal osteoporosis in slowing bone remodeling as assessed by C-terminal telopeptide of bone collagen type 1 (CTX) dosage.

Detailed description: A pilot, randomized, controlled, open-label, single-center, two-parallel-arm clinical trial testing the addition of oral magnesium supplementation to prescribed drug therapy in the care setting. Category 1.

The primary objective of this randomized trial is to demonstrate the superiority of the combination of bisphosphonates and magnesium over bisphosphonates alone in postmenopausal osteoporosis, in terms of slowing bone remodeling, as assessed by the measurement of C-terminal telopeptides of type 1 bone collagen (CTX).

The secondary objectives are to study the impact of magnesium supplementation at 1 year on:

1. the evolution of other biological markers of bone remodeling (by creating a collection of biological samples) and bone densitometry on the following sites: spine, femoral neck, total femur,
2. the evolution of cardiovascular parameters,
3. the follow-up of the incidence of fractures,
4. the evolution of sarcopenia,
5. the evolution of quality of life and pain,
6. the genetic predisposition of osteoporosis including the confirmation of known genetic markers and the potential identification of new genetic variants involved (by creating a biobank),
7. the epigenetic biomarkers in the osteoporosis patient population (by creating a biobank),
8. the role of the microbiota in osteoporosis patients (by creating a biobank),
9. the occurrence of adverse events.

As part of their usual care and management, patients will be diagnosed with osteoporosis and prescribed bisphosphonates.

Patients will have 3 or 4 visits depending on which group they are randomized to: a first screening visit as part of routine care, which will take place in the Rheumatology Department of the Clermont-Ferrand University Hospital, then 2 visits for patients in the "bisphosphonates alone" group and 3 visits for patients in the "bisphosphonates associated with magnesium" group, which will take place in the Inserm 1405 Clinical Investigation Platform/Clinical Investigation Center (PIC/CIC) of the Clermont-Ferrand University Hospital.

Visit 0 - Screening visit and diagnosis of osteoporosis (1 month before day 0): Rheumatology Department

During this visit, the investigator physician will perform various examinations and tests usually performed as part of the patient's usual care and management in order to establish a diagnosis of osteoporosis.

These examinations are as follow:

* Bone densitometry less than one year using Dual X-ray Absorptiometry (DXA), either previously performed by the patient or prescribed at this consultation.
* Bone biological assessment, including the following tests: Complete Blood Count (CBC), platelets, C-Reactive Protein (CRP), urea, creatinine with CKD-EPI clearance calculation, liver enzymes (AST, ALT), serum calcium, serum calcium corrected by albumin, serum phosphorus, serum protein electrophoresis, Thyroid Stimulating Hormone (TSH), 25 OH vitamin D, serum CTX.

Some patients who require profile radiographs of the spine will have this examination added for the consultation, especially for the evaluation of vertebral fractures if the context justifies it. Other patients will also have these x-rays to calculate the abdominal aortic calcification score (Kauppila score).

Body composition will be requested during the bone densitometry evaluation on the DXA machine.

Once the diagnosis of osteoporosis is confirmed, the physician will propose to eligible patients to participate in this research protocol by explaining the objectives and the course of the study, and give them an information note.

If the patients are interested, the investigator physician will prescribe osteoporotic treatment to be started after the Visit 1: Day 0 inclusion visit.

Visit 1 - Inclusion visit (Day 0): PIC/CIC (2 hours)

During this visit, the physician will explain again the objectives and progress of the study with the different tests and questionnaires planned so that the patients can give their informed consent to participate.

During this visit, the following will be performed:

* A medical examination,
* A blood sample to measure magnesium levels and to obtain a collection of biological samples in order to:

  1. Evaluate bone biomarkers (osteocalcin, sclerostin, periostin, irisin, N-terminal propeptide of procollagen type 1 (P1NP), Dickkopf-related protein 1 (DKK1)),
  2. Characterize genetic predispositions of osteoporosis,
  3. Characterize epigenetic biomarkers in the osteoporosis patient population by microRNA analysis,
* A stool sample to obtain a biobank for subsequent microbiota analysis.
* A cardiovascular exploration based on the measurement of the increase in the diameter of the brachial artery (FMD, "Flow-Mediated Dilation"); measurement of the increase in digital volume (RHI, "Reactive Hyperemia Index") and measurement of the microcirculatory perfusion of the skin at the level of the hand (FLD, "Flow Laser Doppler"), and measurement of the stiffness of the main arteries (aorta) by the technique of Pulse Wave Velocity (PWV) measurement.
* Exploration of sarcopenia: the following questionnaires and tests will be performed: SARC-F (Strength, Assistance with walking, Rising from a chair, Climbing stars, and Falls), SPPB (Short Physical Performance Battery), the measurement of the muscular function and DXA with the measurement of the body composition.
* Pain exploration: Numerical Pain Scale (NPS), Brief Pain Inventory (BPI), and pain thresholds.
* Quality of life component questionnaires: Pittsburgh Sleep Quality Index (PSQI), the Hospital Anxiety and Depression scale (HADs) and the 36-Item Short Form Survey (SF-36).
* Randomization into two groups: a "bisphosphonates associated with magnesium" group, and a "bisphosphonates alone" group.
* Delivery of a daily follow-up diary to evaluate the average pain per day, the consumption of analgesics, and the occurrence of any adverse effects.

For the "bisphosphonates alone" group, this diary will be completed for the first month of taking bisphosphonates (Month 1) as well as for the last month before the end of study visit at one year (Month 12).

For the "bisphosphonates combined with magnesium" group, a diary will also be given to them for the first month of taking bisphosphonates and a second will be given to them at visit 2 which will cover the period of taking magnesium over the last 3 months preceding the end-of-study visit (Months 10 to 12).

Visit 2 only for patients in the bisphosphonate-magnesium arm (Day 0+9 months): PIC/CIC (15 minutes)

At this visit, 9 months after the start of the trial, a blood test will be performed to measure magnesium levels, and then patients will be given magnesium treatment to take daily for 3 months before their 1-year visit (during months 10, 11 and 12). Finally, they will be given a follow-up diary to evaluate the average pain per Numerical Pain Scale, the daily consumption of analgesics, and the occurrence of possible adverse effects.

→ In addition, for the patients in this group, a phone call will be made by the project team 6 weeks after the start of the magnesium treatment to ensure good tolerance and compliance with the magnesium intake.

Visit 3 - End of study visit at 1 year (Day 0+1 year): PIC/CIC (1h15)

During this visit, the following examinations, tests and questionnaires will be performed:

* A medical examination,
* A blood sample to measure magnesium levels, serum CTX and other biological bone markers (osteocalcin, sclerostin, periostin, irisin, P1NP, DKK1) and to perform microRNA analysis by collecting biological samples,
* A stool sample to study the microbiota (constitution of a collection of biological samples),
* A bone densitometry measurement (DXA),
* A cardiovascular exploration with FMD, RHI, FLD and PWV measurements and an estimation of the Kauppila score.
* Exploration of sarcopenia: questionnaires and tests SARC-F, SPPB, measurement of muscle function and body composition.
* Exploration of pain: NPS, BPI, and pain thresholds.
* Quality of life component questionnaires: PSQI, HADs and the SF-36. As part of routine care, patients will then be seen in a follow-up rheumatology consultation to confirm the indication for continuing treatment with biphosphonates, with a blood test identical to that performed during the pre-selection visit.

Visit 3 will be the last visit of the study.

Eligibility criteria: Inclusion Criteria:

* Women aged 50 years or older, with postmenopausal osteoporosis, fractured or not, requiring initiation of injectable bisphosphonate therapy as part of their care.
* Able to give informed consent to participate in the research.
* Affiliation to a Social Security system.

Exclusion Criteria:

* Initial densitometry more than one year old.
* Patient receiving a treatment or food supplement containing magnesium (Mg).
* Contra-indication to the administration of Mg: hypersensitivity to magnesium carbonate or to one of the excipients.
* Patients with a magnesium level \> 1.07 mmol/l.
* Patient with chronic renal failure, defined as creatinine clearance \< 35 mL/min estimated by Cockcroft-Gault or glomerular filtration rate \< 30 mL.min-1 estimated by CKD-EPI and taking into account which is more pejorative.
* Patient with a medical and/or surgical history deemed by the investigator or his representative to be incompatible with the trial.
* Patient under legal protection or deprived of liberty.
* Refusal to participate.

Primary outcomes:
measure: C-terminal telopeptides of collagen type 1 (CTX) dosage
timeFrame: Visit 0: Day 0-1 month
measure: C-terminal telopeptides of collagen type 1 (CTX) dosage
timeFrame: Visit 3: Day 0+1 year
Secondary outcomes:
measure: N-terminal propeptide of procollagen type 1 (P1NP) dosage
timeFrame: Visit 1: Day 0
measure: N-terminal propeptide of procollagen type 1 (P1NP) dosage
timeFrame: Visit 3: Day 0+1 year
measure: Osteocalcin dosage
timeFrame: Visit 1: Day 0
measure: Osteocalcin dosage
timeFrame: Visit 3: Day 0+1 year
measure: Sclerostin dosage
timeFrame: Visit 1: Day 0
measure: Sclerostin dosage
timeFrame: Visit 3: Day 0+1 year
measure: Periostin dosage
timeFrame: Visit 1: Day 0
measure: Periostin dosage
timeFrame: Visit 3: Day 0+1 year
measure: Irisin dosage
timeFrame: Visit 1: Day 0
measure: Irisin dosage
timeFrame: Visit 3: Day 0+1 year
measure: Dickkopf-related protein 1 (DKK1) dosage
timeFrame: Visit 1: Day 0
measure: Dickkopf-related protein 1 (DKK1) dosage
timeFrame: Visit 3: Day 0+1 year
measure: Magnesium (Mg) dosage
timeFrame: Visit 1: Day 0
measure: Magnesium (Mg) dosage
timeFrame: Visit 2: Day 0+9 months
measure: Magnesium (Mg) dosage
timeFrame: Visit 3: Day 0+1 year
measure: Evaluation of bone densitometric parameters (femoral neck)
timeFrame: Visit 0: Day 0-1 month
measure: Evaluation of bone densitometric parameters (femoral neck)
timeFrame: Visit 3: Day 0+1 year
measure: Evaluation of bone densitometric parameters (total femur)
timeFrame: Visit 0: Day 0-1 month
measure: Evaluation of bone densitometric parameters (total femur)
timeFrame: Visit 3: Day 0+1 year
measure: Evaluation of bone densitometric parameters (spine)
timeFrame: Visit 0: Day 0-1 month
measure: Evaluation of bone densitometric parameters (spine)
timeFrame: Visit 3: Day 0+1 year
measure: Endothelial dysfunction measured by FMD (Flow-Mediated Dilation)
timeFrame: Visit 1: Day 0
measure: Endothelial dysfunction measured by FMD (Flow-Mediated Dilation)
timeFrame: Visit 3: Day 0+1 year
measure: Measurement of digital volume increase by RHI (Reactive Hyperhemia Index), (Endo-PAT2000; Itamar Medical Ltd, Israel).
timeFrame: Visit 1: Day 0
measure: Measurement of digital volume increase by RHI (Reactive Hyperhemia Index), (Endo-PAT2000; Itamar Medical Ltd, Israel).
timeFrame: Visit 3: Day 0+1 year
measure: Microcirculation measurement by FLD (Flow Laser Doppler), PeriFlux® (Perimed)
timeFrame: Visit 1: Day 0
measure: Microcirculation measurement by FLD (Flow Laser Doppler), PeriFlux® (Perimed)
timeFrame: Visit 3: Day 0+1 year
measure: Sphygmocor CPV® (Atcor Medical) large artery stiffness measurement (PWV)
timeFrame: Visit 1: Day 0
measure: Sphygmocor CPV® (Atcor Medical) large artery stiffness measurement (PWV)
timeFrame: Visit 3: Day 0+1 year
measure: Evaluation of the Abdominal Aorta Calcification (AAC) (Kauppila score)
timeFrame: Visit 0: Day 0-1 month
measure: Evaluation of the Abdominal Aorta Calcification (AAC) (Kauppila score)
timeFrame: Visit 3: Day 0+1 year
measure: Strength, Assistance with walking, Rising from a chair, Climbing stairs, and Falls (SARC-F) questionnaire
timeFrame: Visit 1: Day 0
measure: Strength, Assistance with walking, Rising from a chair, Climbing stairs, and Falls (SARC-F) questionnaire
timeFrame: Visit 3: Day 0+1 year
measure: Short Physical Performance Battery (SPPB) Questionnaire
timeFrame: Visit 1: Day 0
measure: Short Physical Performance Battery (SPPB) Questionnaire
timeFrame: Visit 3: Day 0+1 year
measure: Evaluation of the muscular strength
timeFrame: Visit 1: Day 0
measure: Evaluation of the muscular strength
timeFrame: Visit 3: Day 0+1 year
measure: Body composition measurement on Dual energy X-ray Absorptiometry (DXA)
timeFrame: Visit 0: Day 0-1 month
measure: Body composition measurement on Dual energy X-ray Absorptiometry (DXA)
timeFrame: Visit 3: Day 0+1 year
measure: The Brief Pain Inventory Questionnaire (BPI)
timeFrame: Visit 1: Day 0
measure: The Brief Pain Inventory Questionnaire (BPI)
timeFrame: Visit 3: Day 0+1 year
measure: The Numerical Pain Scale
timeFrame: Visit 1: Day 0
measure: The Numerical Pain Scale
timeFrame: Visit 3: Day 0+1 year
measure: Measurement of the threshold of sensitivity and pain perception induced by a thermal stimulus (hot and cold) at the Pathway - Médoc®.
timeFrame: Visit 1: Day 0
measure: Measurement of the threshold of sensitivity and pain perception induced by a thermal stimulus (hot and cold) at the Pathway - Médoc®.
timeFrame: Visit 3: Day 0+1 year
measure: Central sensitization tests, measurement of the Conditioned Pain Modulation (CPM) effect
timeFrame: Visit 1: Day 0
measure: Central sensitization tests, measurement of the Conditioned Pain Modulation (CPM) effect
timeFrame: Visit 3: Day 0+1 year
measure: The Pittsburgh Sleep Quality Index (PSQI)
timeFrame: Visit 1: Day 0
measure: The Pittsburgh Sleep Quality Index (PSQI)
timeFrame: Visit 3: Day 0+1 year
measure: The 36-Item Short Form Survey (SF-36)
timeFrame: Visit 1: Day 0
measure: The 36-Item Short Form Survey (SF-36)
timeFrame: Visit 3: Day 0+1 year
measure: The Hospital Anxiety and Depression Scale (HAD)
timeFrame: Visit 1: Day 0
measure: The Hospital Anxiety and Depression Scale (HAD)
timeFrame: Visit 3: Day 0+1 year
measure: Distribution of gene polymorphisms using OpenArray technology
timeFrame: Visit 1: Day 0
measure: MicroRNA analysis using OpenArray technology will be performed on 48 patients
timeFrame: Visit 1: Day 0
measure: MicroRNA analysis using OpenArray technology will be performed on 48 patients
timeFrame: Visit 3: Day 0+1 year
measure: Study of the microbiota will be performed on 48 patients
timeFrame: Visit 1: Day 0
measure: Study of the microbiota will be performed on 48 patients
timeFrame: Visit 3: Day 0+1 year
Other outcomes:
Locations:
city: Clermont-Ferrand
country: France
facility: CHU clermont-ferrand
Study officials:
affiliation: University Hospital, Clermont-Ferrand
name: Marie-Eva PICKERING
role: PRINCIPAL_INVESTIGATOR
References: