The Optimised Use of Romozosumab Study (OPTIMIST)

OPTIMIST is a two-year, randomised, active controlled, open-label, multicentre intervention trial. OPTIMIST includes 3 treatment groups each comprising combinations of romosozumab (ROMO) and zoledronate (ZOL) treatment used in standard doses (210 mg monthly (sc) and 5 mg yearly (iv), respectively). The study will investigate if it is possible to maximize the effect of romosozumab by giving it in 2 periods of 6 months interrupted by zoledronate for 12 months compared to romosozumab for 12 months uninterrupted followed by zoledronate for 12 months. The investigators will also evaluate if 6 months of romosozumab followed by 18 months of zoledronate is non-inferior to the standard regimen of romosozumab for 12 months followed by zoledronate for 12 months.

Recent clinical trials have demonstrated the benefit of bone anabolic treatment over no treatment or antiresorptive treatment in terms of increasing bone mineral density (BMD) and reducing fracture risk for patients with osteoporosis. However, the bone anabolic treatment is expensive and therefore restricted to a limited group of patients. This study is based on the hypothesis that treatment with romosozumab for 6 months, zoledronate for 12 months, and romosozumab for 6 months results in larger gains in bone mineral density than treatment regimens based on romosozumab treatment for 6 or 12 months followed by zoledronate for a total of 24 months of treatment due to reappearance of the bone anabolic effect of romosozumab upon retreatment. The OPTIMIST study is a two-year, randomised, active controlled, open-label, intervention trial. The study includes 270 postmenopausal women who will be randomised to 3 groups. Group 1 (n=90) will receive romosozumab for 12 months followed by zoledronate for 12 months. Group 2 (n=90) will receive romosozumab for 6 months followed by zoledronate for 12 months and romosozumab for 6 months. Group 3 (n=90 ) will receive romosozumab for 6 months followed by zoledronate for 18 months. The investigational drugs in this study are romosozumab 210 mg/2,34 mL and zoledronate 5 mg/100 mL This study will include 270 treatment naïve postmenopausal women. When inclusion and exclusion criteria have been reviewed, and the participant meets the requirements for study participation and continues to participate in the study, the patients will be randomized 1:1:1 Data will be registered in RedCAP (eCRF) and site monitoring assessed by the local Good Clinical Practice unit (GCP-unit). The patients will be recruited from the outpatient clinics and the Dual-Energy X-ray Absorptiometry (DXA) units to which patients are referred from their general practitioner or fracture liaison services (FLS) at: Department of Endocrinology, Odense University Hospital Department of Endocrinology and Internal Medicine, Aarhus University Hospital Department of Endocrinology, Køge Hospital Department of Endocrinology, Hvidovre Hospital Department of Endocrinology, Bispebjerg Hospital During the intervention phase, there will be obtained fasting blood test, high-resolution peripheral quantitative computed tomography (HR-pQCT),Oral Glucose Tolerance Test (OGTT), DXA, Vertebral fracture assessment (VFA) and biochemistry at different time stamps. From 105 patients there will be obtained bone marrow aspirates and performed jamshidi bone biopsies. The study will therefore show if it would be possible to treat twice as many patients for the same prize but also if the treatment for 12 months can be optimized. The knowledge about the optimal use of romosozumab will be included in an update of osteoporosis treatment guidelines. This will lead to optimized treatment of patients with severe osteoporosis.

90 patients 6 months of romosozumab followed by 12 months of zoledronate and lastly 6 months of romosozumab.

Changes in trabecular bone volume fraction (bone volume/tissue volume, BV/TV) and cortical porosity measured by high-resolution peripheral quantitative computed tomography (HR-pQCT)

Mean percent change in trabecular bone volume fraction and cortical porosity measured by HR-pQCT at the radius and tibia

Investigate the activation of bone remodelling and modelling-based bone formation by ROMO assessed by bone histology (jamshidi biopsy) at 1 (any group), 6 (any group), 18 (group 3), 19 (group 2) and 24 (group 2) months. Biopsies will be obtained from 15 participants at each timepoint. Investigate the depletion of osteoprogenitor cells during ROMO treatment assessed by molecular bone histology and single-nucleic transcriptomics.

Investigate the number and composition of osteoprogenitor cells in the bone marrow during the first and second romosozumab treatment.

Investigate the number and composition of osteoprogenitor cells in the bone marrow during the first and second romosozumab treatment. Bone marrow (BM) aspirates will be obtained by aspiration of the iliac crest (10-15 ml) during the jamshidi biopsy.

Change in oral Glucose tolerance test (OGTT) Data is collected by giving glucose and blood samples are taken afterward to determine the patients blood sugar (mmol/l) how quickly it is cleared from the blood

Change in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) calculated from fasting blood sugar (blood sample) and insulin levels (blood sample) by following equation: ([insulin (μU/ml)] × [fasting glucose (mmol/l)]/22,5)

Inclusion Criteria: Postmenopausal women (postmenopausal for at least two years) BMD T-score < -2.5 at lumbar spine, total hip, or femoral neck Osteoporotic fracture within the last 3 years at the spine, hip, pelvis, humerus or forearm after the age of 50 years. Exclusion Criteria: Osteoporosis treatment including hormone replacement therapy within the last 5 years Metabolic bone disease Known disorders affecting bone metabolism, e.g., uncontrolled thyrotoxicosis, liver dysfunction (baseline phosphatase higher than twice upper limit), rheumatism, severe COPD (chronic obstructive pulmonary disease), hypopituitarism, Cushing's disease Ongoing treatment with glucocorticoids (systemic) Estimated glomerular filtration rate (eGFR) < 35 mL/min Contraindications for zoledronate according to the Supplementary protection certificates (SPC) Contraindications for romosozumab according to the SPC For the subgroup with Jamshidi biopsies contraindications for local anaesthetics according to the SPC For the subgroup with Jamshidi biopsies contraindications for tetracycline or doxycykline according to the SPC