Senolytics to Improve Osteoporosis Therapy

Study Overview
=================
Brief Summary
-----------------
This randomised clinical trial aims to study osteoporosis as a disease of accelerated skeletal aging caused by the accumulation of senescent cells within the skeleton and investigate the effects and safety of senolytics and antioxidant therapy on bone.

Detailed Description
-----------------
Background, hypothesis, and aim: Evidence suggests that it is feasible to alleviate chronic age-related disorders by targeting the biology of aging. Recent studies implicate cellular senescence at the nexus of skeletal aging, suggesting that selectively eliminating senescent cells may emerge as a conceptually novel approach to manage the enormous problem of age-related bone loss. In addition, previous studies have demonstrated that antioxidants inhibit cellular senescence. The aim of this randomised clinical trial is to study osteoporosis as a disease of accelerated skeletal aging caused by accumulation of senescent cells within the skeleton and investigate the effects and safety of senolytics and antioxidant therapy on bone. The main trial endpoint is the percent change in circulating marker of bone resorption (CTX) measured at baseline and at week 21. Secondary endpoints are the changes in bone resorption marker tartrate resistant acid phosphatase (TRAcP) and bone formation markers (PINP, osteocalcin, and bone alkaline phosphatase) measured at baseline and at 21 weeks. Trial design: The study design is a randomised controlled open-label clinical trial. Study participants will be randomised 1:1:1 to one of three treatment groups, that will include either, a combination of 100 mg/d dasatinib (oral) for two consecutive days and 1.250 mg/d quercetin (oral) for three consecutive days followed by 25 days without treatment, with treatment being repeated every 4 weeks for a total of 20 weeks (i.e., 5 times), or treatment with 1 g nicotinamide riboside (NR) (oral) daily for 20 weeks, or no treatment for 20 weeks. Each participant will have a total of 7 to 10 visits at the clinical site. Blood samples will be obtained at all but one visit (2x20 ml each time). ECG will be performed at 6 visits for group 1 and at 2 visits for group 2 and 3. Scans will be performed at the first two and the last visit. Muscle-function tests will be performed at 2nd and last visit. Bone biopsies for RNA-sequencing (a technique indicating which of the genes encoded in our DNA that are active) will be collected in those that provide a separate consent and in up to 20 participants in each group (using block randomisation to ensure balanced distribution of sex and age, equaling a maximum of 60 biopsies.

Official Title
-----------------
SENolytics to Improve Osteoporosis Therapy: a Randomised Controlled Clinical Trial The SENIOR Trial

Conditions
-----------------
Osteopenia, Osteoporosis

Intervention / Treatment
-----------------
* Drug: Dasatinib 100 Mg Oral Tablet
* Dietary Supplement: Quercetin 1.250 mg (oral)
* Dietary Supplement: Nicotinamide Riboside 1g (oral)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Men and women (menopause > 5 years and FSH and LH in the postmenopausal range) aged 60-90 years with increased fracture risk according to WHO 10 years absolute Fracture Risk Assessment Tool (FRAX) osteopenia (ICD10 DM858A) based on a T-score ≤ -2 to -2.5 at the total hip/femoral neck, or lumbar spine (FRAX score ranging from 10-70) osteopenia (ICD10 DM858A) based on a T-score < -1 to -2.5 and a fragility fracture at any time (excluding hip and vertebral fractures within the last 2 years) (FRAX ranging from 11-68) osteoporosis (ICD10 DM819) based on a T-score between >-3 and ≤ -2.5, which includes candidates suitable for conventional osteoporosis therapies, but who prefer to participate in the trial, despite being candidates for conventional osteoporosis therapy, or candidates which cannot be treated with conventional therapies due to contraindications. Ability to provide informed consent Exclusion Criteria: DXA of hip or spine not possible e.g., due to a prosthesis Inability to provide fasting blood samples Primary hyperparathyroidism Vitamin D deficiency (<50 nM) (re-test after substitution acceptable) Known disorders affecting bone metabolism, e.g., uncontrolled thyrotoxicosis, chronic kidney disease defined as eGFR <30 or liver dysfunction, rheumatism, celiac disease/malabsorption, hypogonadism, severe COPD, hypopituitarism, Cushing's disease, uncontrolled diabetes (HbA1c > 58 mmol/mol). Antiresorptive or bone anabolic drugs for the last 2 years (5 years if treated with zoledronic acid) Concomitant treatments known to influence bone metabolism e.g., glucocorticoids (systemic treatments), anabolic steroids, etc. Subjects taking the following other drugs if they cannot be held for at least 2 days before and during administration of D+Q: digoxin, lithium, all statins, repaglidine, bosentan, gemfibrozil, olmesartan, enalapril, valsartan, methotrexate, corticosteroids, eluxadoline, eltrombopag, nitroglycerin, pioglitazone, glyburide, enzalutamide, ezetimibe, colchicine, imatinib, cyclosporine, tacrolimus, sirolimus, carbamazepine, flecainide, phenytoin, phenobarbital, rifampicin, theophylline, warfarin, heparin, clopidogrel, celecoxib, desipramine, thioridazine, venlafaxine, tizanidine, atomoxetine, voriconazole, citalopram, diazepam, escitalopram, propranolol, clozapine, cyclobenzaprine, mexiletine, olanzapine, ondansetron Subjects taking medications that are sensitive to substrates or substrates with a narrow therapeutic range for CYP3A4, CYP2C8, CYP2C9, or CYP2D6 or strong inhibitors or inducers of CYP3A4 (e.g., cyclosporine, tacrolimus or sirolimus). If antifungals are necessary from an infectious disease perspective, then they will be allowed only if the levels are therapeutic. Subjects taking proton pump inhibitors and unwilling to discontinue therapy for two days before and during the study drug dosing periods. Anti-arrhythmic medications known to cause QTc prolongation Tyrosine kinase inhibitor therapy Subjects with an abnormal Complete Blood Count (clinically insignificant changes would be acceptable based on the judgement of the investigators) Subjects on antiplatelet agents (Clopidogrel; Dipyridamole + ASA; ASA, Ticagrelor; Prasugrel; Ticlopidine or other) who are unable or unwilling to reduce or hold therapy prior to and during the study drug dosing periods and collection of bone biopsies. Subjects may continue their previous regimen between study drug dosing periods. Known allergy to dasatinib, quercetin, or nicotinamide riboside Subjects taking the following antimicrobial agents: Aminoglycosides, Azole antifungals (fluconazole, miconazole, voriconazole, itraconazole), Macrolides (clarithromycin, erythromycin), antivirals (nelfinavir, indinavir, saquinavir, ritonavir, elbasvir/grazoprevir) Presence of any condition the Investigator believes would place the subject at risk or would preclude the subject from successfully completing all aspects of the trial e.g., heart failure, malignancy etc. QTc >470 msec Inability to take oral medication The study will exclude subjects with inability to speak and understand Danish and with inability to cooperate

Ages Eligible for Study
-----------------
Minimum Age: 60 Years
Maximum Age: 90 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dasatinib plus Quercetin (DQ)<br>Study participants will receive a combination of 100 mg/d dasatinib (oral) for two consecutive days and 1.250 mg/d quercetin (oral) for three consecutive days followed by 25 days without treatment, with treatment being repeated every 4 weeks for a total of 20 weeks (i.e., 5 times) | Drug: Dasatinib 100 Mg Oral Tablet<br>* Dasatinib tablets in blister packs of 10 tablets, from either: Sandoz, STADA Nordic, Zentiva or Bristol-Myers Squibb<br>* Other names: Sprycel;Dietary Supplement: Quercetin 1.250 mg (oral)<br>* five 200mg Quercetin Phytosome capsules, from Thorne<br>* Other names: Quercetin Phytosome;|
| Experimental: Nicotinamide Riboside (NR)<br>The participants will receive treatment with 1g Nicotinamide Riboside (oral) daily for 20 weeks | Dietary Supplement: Nicotinamide Riboside 1g (oral)<br>* four 250mg Nicotinamide Riboside Capsules, from Elysium Health<br>* Other names: NR;|
| No Intervention: Control<br>The participants in the Control group, will not receive any treatment for 20 weeks. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bone resorption marker CTX | Change in circulating marker of bone resorption C-terminal telopeptide of type I collagen (CTX) at 21 weeks. | Baseline, week 5, week 13, week 21 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bone resorption marker TRAcP | Change in circulating marker of bone resorption Tartrate Resistant Acid Phosphatase (TRAcP) at 21 weeks. | Baseline, week 5, week 13, week 21 | 
| Bone formation markers (PINP, osteocalcin, and bone alkaline phosphatase) | Change in circulating markers of bone formation (PINP, osteocalcin, and bone alkaline phosphatase) at 21 weeks. | Baseline, week 5, week 13, week 21 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Age related bone loss, Cellular senescence