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

NCT ID: NCT05655013

Last Updated: 2025-10-02

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 200 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-05-10
• Study Completion Date: 2027-02-01

Brief Summary

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

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.

Conditions

Osteoporosis, Postmenopausal

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

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

Group Type: ACTIVE_COMPARATOR

Zoledronate

Intervention Type: DRUG

zoledronate 5 mg

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).

Group Type: ACTIVE_COMPARATOR

Zoledronate

Intervention Type: DRUG

zoledronate 5 mg

Second part (year 2-3): groups 1+3

Patients will receive yearly infusions of zoledronate 5 mg

Group Type: ACTIVE_COMPARATOR

Zoledronate

Intervention Type: DRUG

zoledronate 5 mg

Second part (year 2-3): groups 2+4

Patients will receive yearly infusions of placebo.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

isotonic saline 100 mL

Interventions

Zoledronate

zoledronate 5 mg

Intervention Type: DRUG

Placebo

isotonic saline 100 mL

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 40 Years
• Maximum Eligible Age: 100 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Aarhus University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Anne Sophie Sølling

MD, PhD, Department of Endocrinology and Internal Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Bente Langdahl, MD, Professor, DMSc, PhD

Role: PRINCIPAL_INVESTIGATOR

Aarhus University Hospital

Locations

Aarhus University Hospital

Aarhus, , Denmark

Countries

Denmark

Other Identifiers

01.12.2022

Identifier Type: -

Identifier Source: org_study_id