Using senolytics to enhance osteoporosis treatment

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

This study is testing if a new combination treatment with dasatinib and quercetin can improve bone health in people with osteoporosis by targeting aging cells.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 120 (estimated)
• Ages: 60 Years to 90 Years
• Sex: All
• Sponsor: Odense University Hospital (Academic / other)
• Drugs / interventions: imatinib, dasatinib, methotrexate
• Locations: 1 site (Odense)
• Trial ID: NCT06018467 on ClinicalTrials.gov

What this trial studies

This randomized clinical trial investigates the role of senolytics and antioxidant therapy in treating osteoporosis, a condition linked to accelerated skeletal aging due to the accumulation of senescent cells. The study aims to evaluate the safety and efficacy of a combination treatment involving dasatinib and quercetin, administered in cycles over a 21-week period. Participants will be monitored for changes in bone resorption and formation markers to assess the impact of the interventions on bone health.

Who should consider this trial

Good fit: Ideal candidates are men and women aged 60-90 with osteopenia or osteoporosis and an increased fracture risk.

Not a fit: Patients with contraindications to conventional osteoporosis therapies or those who do not meet the inclusion criteria may not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could provide a novel treatment option for patients with osteoporosis, potentially improving bone health and reducing fracture risk.

How similar studies have performed: While the approach of targeting cellular senescence is relatively novel, preliminary studies have shown promise in similar contexts, suggesting potential for success.

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)

  1. 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)
  2. 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)
  3. 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

Where this trial is running

Odense

• Odense University Hospital — Odense, Denmark (Recruiting)

Study contacts

• Principal investigator: Moustapha Kassem, DMSc, PhD — Head of Research, Department of Endocrinology, Odense University Hospital
• Study coordinator: Shakespeare Jeromdesella, MD

Conditions Osteopenia, Osteoporosis; Age related bone loss; Cellular senescence