Treatment With Zoledronate Subsequent to Denosumab in Osteoporosis 2

Study Overview
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Brief Summary
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The aims of ZOLARMAB2 are fourfold. First, the investigators want to investigate if multiple infusions of zoledronate can prevent the rebound activation of bone turnover and the subsequent bone loss in patients previously treated with denosumab and if there is difference between infusing zoledronate at fixed time-points after the last injection of denosumab or when bone turnover is increased. Second, the investigators want to investigate if bone loss will resume after controlling the rebound activation of bone turnover during the first year after denosumab discontinuation and if this can be prevented by yearly infusions of zoledronate. Third, the investigators want to investigate the underlying pathophysiological mechanisms by investigating biochemical markers, osteoclast and osteoblast activation signals in the bone and bone marrow, and the pool of preosteoclasts/mature osteoclasts before and after treatment with zoledronate. Fourth, the investigators want to investigate the effect of denosumab discontinuation on muscle mass and muscle strength and on insulin sensitivity.

Detailed Description
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This study has two parts. The first part (year 1) is a randomized open label, interventional study in 200 postmenopausal women investigating if treatment with zoledronate prevents bone loss after denosumab treatment. Zoledronate will be administered as an infusion six months after the last injection of denosumab followed by zoledronate infusions 3 and 6 months thereafter (groups 3+4) or followed by zoledronate infusions when bone turnover is increased (p-carboxy-terminal collagen crosslinks (p-CTX) > 0.4 ug/l which corresponds to the upper 50 % of the normal range for premenopausal women) (groups 1+2). Fifty patients will be randomised to each group. The patients in groups 1+2 will be monitored and if (p-CTX) is above 0.4 ug/l at month 3 or 6 zoledronate will be administered. If a patient in groups 3+4 experiences an osteoporotic clinical vertebral or hip fracture, zoledronate will be administered irrespective of p-CTX. The second part is a 2-year randomised, double-blind, interventional study in the women completing part 1. Patients in groups 1+3 will receive yearly infusions of zoledronate 5 mg and patients in groups 2+4 will receive yearly infusions of placebo. The patients will be monitored with DXA of the hip and spine 3, 6, 12, 24, and 36 months after baseline. Zoledronate will be administered to the patients allocated to the placebo group during phase 2 if BMD decreases more than 5% at the lumbar spine, total hip or femoral neck after months 12.

Official Title
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Treatment With Zoledronate Subsequent to Denosumab in Osteoporosis 2

Conditions
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Osteoporosis, Postmenopausal

Intervention / Treatment
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* Drug: Zoledronate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Postmenopausal women (postmenopausal for at least two years) Age ≥ 40 years Treatment for at least two years with denosumab Last denosumab injection less than five months ago At least 2 lumbar vertebrae that can be evaluated by DXA Exclusion Criteria: Low-energy vertebral fracture within the last ten years Multiple low-energy vertebral fractures (> 3) at any time Low-energy hip fracture within the last 12 months BMD T-score < -2.0 (lumbar spine, total hip or femoral neck) Zoledronate treatment for more than three years prior to denosumab treatment within the last ten years Alendronate treatment for more than three years prior to denosumab treatment within the last five years or for more than five years within the last 10 the years Treatment with other bisphosphonates (risedronate, ibandronate) for more than three years prior to denosumab treatment within the last five years Diabetes Mellitus Ongoing treatment with systemic glucocorticoids Metabolic bone disease (for example osteogenesis imperfecta, Paget's disease of bone) Hormone replacement therapy Active cancer within the last 5 years with the exception of basal cell skin cancer Estimated glomerular filtration rate (eGFR) ≤ 35 mL/min Contraindications for zoledronate according to the SPC Unable to read and understand Danish Immobility

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Part 1: 1-year randomized open label, interventional study in 200 postmenopausal women. Part 2: 2-year randomised, double-blind, interventional study in the women completing part 1.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: First part (year 1): groups 1+2<br>Zoledronate will be administered as an infusion six months after the last injection of denosumab followed by zoledronate infusions 3 and 6 months thereafter | Drug: Zoledronate<br>* zoledronate 5 mg<br>|
| Active Comparator: First part (year 1): groups 3+4<br>Zoledronate will be administered as an infusion six months after the last injection of denosumab followed by zoledronate infusions when bone turnover is increased (s-carboxy-terminal collagen crosslinks (p-CTX) > 0.4 ug/l which corresponds to the upper 50 % of the normal range for premenopausal women). | Drug: Zoledronate<br>* zoledronate 5 mg<br>|
| Active Comparator: Second part (year 2-3): groups 1+3<br>Patients will receive yearly infusions of zoledronate 5 mg | Drug: Zoledronate<br>* zoledronate 5 mg<br>|
| Placebo Comparator: Second part (year 2-3): groups 2+4<br>Patients will receive yearly infusions of placebo. | Drug: Placebo<br>* isotonic saline 100 mL<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in lumbar spine bone mineral density (BMD) | Change in lumbar spine BMD after 12 and 36 months. | After 12 and 36 months. | 
| The proportion of patients who fails to maintain bone mineral density (BMD) | The proportion of patients (%) with significant decrease in BMD (≥ 3 % BMD loss at the lumbar spine or ≥ 5 % BMD loss at the femoral neck or total hip) after 12 months. | After 12 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in total hip and femoral neck bone mineral density (BMD) | Changes in total hip and femoral neck BMD after 12 and 36 months. | After 12 and 36 months. | 
| 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 after 12 and 36 months. | After 12 and 36 months. | 
| Changes in carboxy-terminal collagen crosslinks (CTX) and procollagen type I N-terminal propeptide (PINP) | Changes in CTX and PINP after 3, 6, 12, 24 and 36 months. | After 3, 6, 12, 24 and 36 months. | 
| Morphometric vertebral fractures | Morphometric vertebral fractures assessed by vertebral fracture assessment (VFA) after 12 and 36 months or by spinal x-ray if clinical suspicion of vertebral fracture. | After 12 and 36 months. | 
| Serum RANKL/OPG, tartrate-resistant acid phosphatase type 5b (TRAcP-5b), sclerostin and Dickkopf-1 (Dkk-1) | Serum RANKL/OPG, tartrate-resistant acid phosphatase type 5b (TRAcP-5b), sclerostin and Dickkopf-1 (Dkk-1) at 0, 1, 3, 6 and 12 months | Baseline and after 1, 3, 6 and 12 months | 
| Molecular bone histology | Molecular bone histology of accumulating osteoclast activation sites and pre-osteoclasts as well as single-nucleus transcriptomics on jamshidi biopsies at baseline in a total of 100 patients from groups 1 and 2 and in up to 15 participants in groups 1 and 2 at month 3 with a strong rebound response (p-CTX > 0.6 ug/l). | Baseline and after 3 months | 
| Osteoclasts | Osteoclasts differentiation, fusion, function, and response to zoledronate in cultures derived from peripheral blood at baseline from groups 1 and 2. 30 patients will be recruited from each group, hence 60 patients. | Baseline | 
| Epigenetic marker analysis | Epigenetic marker analysis with special focus on genes involved in osteoclast activation, differentiation, fusion, function and response to ZOL. Samples collected at baseline from all participants. | Baseline | 
| Muscle mass and muscle strength | Muscle mass assessed by whole-body DXA and muscle strength assessed by handgrip strength and muscle strength over the knee and elbow joints. A total of 100 patients from groups 1 and 2 will be investigated at baseline month 3 and 12. | Baseline and after 3 and 12 months | 
| Insulin sensitivity | Insulin sensitivity assessed by Hb1Ac, HOMA-IR, OGTT and advanced glycation end products (AGEs). | Baseline and after 3 and 12 months |