Senolytics to Improve Osteoporosis Therapy

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 FractureRisk Assessment Tool (FRAX)

1. osteopenia (ICD10 DM858A) based on a T-score ≤ -2 to -2.5 at the totalhip/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 fragilityfracture at any time (excluding hip and vertebral fractures within the last 2years) (FRAX ranging from 11-68)

3. osteoporosis (ICD10 DM819) based on a T-score between >-3 and ≤ -2.5, whichincludes candidates suitable for conventional osteoporosis therapies, but whoprefer to participate in the trial, despite being candidates for conventionalosteoporosis therapy, or candidates which cannot be treated with conventionaltherapies 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, celiacdisease/malabsorption, hypogonadism, severe COPD, hypopituitarism, Cushing'sdisease, uncontrolled diabetes (HbA1c > 58 mmol/mol).

• Antiresorptive or bone anabolic drugs for the last 2 years (5 years if treated withzoledronic 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 daysbefore 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 anarrow therapeutic range for CYP3A4, CYP2C8, CYP2C9, or CYP2D6 or strong inhibitorsor inducers of CYP3A4 (e.g., cyclosporine, tacrolimus or sirolimus). If antifungalsare necessary from an infectious disease perspective, then they will be allowed onlyif the levels are therapeutic.

• Subjects taking proton pump inhibitors and unwilling to discontinue therapy for twodays 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 changeswould 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 holdtherapy prior to and during the study drug dosing periods and collection of bonebiopsies. Subjects may continue their previous regimen between study drug dosingperiods.

• Known allergy to dasatinib, quercetin, or nicotinamide riboside

• Subjects taking the following antimicrobial agents: Aminoglycosides, Azoleantifungals (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 riskor would preclude the subject from successfully completing all aspects of the triale.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 andwith inability to cooperate