Treatment With Zoledronate Subsequent to Denosumab in Osteoporosis 2 (ZOLARMAB2)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Osteoporosis, Postmenopausal
• Intervention / Treatment: Drug: Zoledronate; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Aarhus, Denmark
    • Aarhus University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 36 years to 96 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 six 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 < -2.5 (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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: First part (year 1): groups 1+2; 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; zoledronate 5 mg
Active Comparator: First part (year 1): groups 3+4; 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; zoledronate 5 mg
Active Comparator: Second part (year 2-3): groups 1+3; Patients will receive yearly infusions of zoledronate 5 mg	Drug: Zoledronate; zoledronate 5 mg
Placebo Comparator: Second part (year 2-3): groups 2+4; Patients will receive yearly infusions of placebo.	Drug: Placebo; isotonic saline 100 mL

What is the study measuring?

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, 12, 18, 24 and 36 months

Collaborators and Investigators

• Sponsor: Aarhus University Hospital
• Investigators: Principal Investigator: Bente Langdahl, MD, Professor, DMSc, PhD, Aarhus University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): May 10, 2023
• Primary Completion (Estimated): February 1, 2027
• Study Completion (Estimated): February 1, 2027

Study Registration Dates

• First Submitted: November 29, 2022
• First Submitted That Met QC Criteria: December 15, 2022
• First Posted (Actual): December 16, 2022

Study Record Updates

• Last Update Posted (Estimated): October 2, 2025
• Last Update Submitted That Met QC Criteria: September 29, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Bone Diseases; Musculoskeletal Diseases; Metabolic Diseases; Bone Diseases, Metabolic; Osteoporosis; Nutritional and Metabolic Diseases; Osteoporosis, Postmenopausal; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Imidazoles; Organophosphorus Compounds; Organophosphonates; Diphosphonates; Zoledronic Acid
• Other Study ID Numbers: 01.12.2022

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No