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

NCT05655013 | Active Not Recruiting Phase 4 DMC

• 1 other identifier: 01.12.2022
• Study Type: interventional
• Target: 200
• Locations: 1 country
• Sites: 1

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.

Conditions

Osteoporosis, Postmenopausal

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (10)

• Changes in total hip and femoral neck bone mineral density (BMD)

  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)

  After 12 and 36 months.

• Changes in carboxy-terminal collagen crosslinks (CTX) and procollagen type I N-terminal propeptide (PINP)

  After 3, 6, 12, 24 and 36 months.

• Morphometric vertebral fractures

  After 12 and 36 months.

• Serum RANKL/OPG, tartrate-resistant acid phosphatase type 5b (TRAcP-5b), sclerostin and Dickkopf-1 (Dkk-1)

  Baseline and after 1, 3, 6 and 12 months

Study Arms (4)

First part (year 1): groups 1+2

ACTIVE COMPARATOR

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

First part (year 1): groups 3+4

ACTIVE COMPARATOR

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

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

ACTIVE COMPARATOR

Patients will receive yearly infusions of zoledronate 5 mg

Drug: Zoledronate

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

PLACEBO COMPARATOR

Patients will receive yearly infusions of placebo.

Drug: Placebo

Interventions

Zoledronate DRUG

zoledronate 5 mg

First part (year 1): groups 1+2; First part (year 1): groups 3+4; Second part (year 2-3): groups 1+3

Placebo DRUG

isotonic saline 100 mL

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

Eligibility Criteria

• Age: 40 Years - 100 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Aarhus University Hospital: lead

Study Sites (1)

Aarhus University Hospital

Aarhus, Denmark

Location

MeSH Terms

Conditions

Osteoporosis, Postmenopausal

Interventions

Zoledronic Acid

Condition Hierarchy (Ancestors)

Osteoporosis; Bone Diseases, Metabolic; Bone Diseases; Musculoskeletal Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Diphosphonates; Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Bente Langdahl, MD, Professor, DMSc, PhD

  Aarhus University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD, Department of Endocrinology and Internal Medicine

Model Details: 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.

Study Record Dates

• First Submitted: November 29, 2022
• First Posted: December 16, 2022
• Study Start: May 10, 2023
• Primary Completion (Estimated): February 1, 2027
• Study Completion (Estimated): February 1, 2027
• Last Updated: October 2, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)