Osteoporosis, PostmenopausalPhase 4NCT05655013
Treatment With Zoledronate Subsequent to Denosumab in Osteoporosis 2 (ZOLARMAB2)
A Phase 4 study testing Zoledronate in people with Osteoporosis, Postmenopausal, run by Aarhus University Hospital at 1 site in Denmark.
Trial 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… Read more about this study
- Who is it for?
- Ages 40 to 100 years, women only
- Conditions the study is for
- Osteoporosis, Postmenopausal
- What is being tested?
- Zoledronate
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 200 participants
- Where
- 1 siteDenmark
- Study dates
- 10 May 2023to 1 Feb 2027
- Phase
- Phase 4
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 to 100 years
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 16Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read more
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.
Read the 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
- Being tested
- Zoledronate, Placebo
- Medical subject headings
- Osteoporosis, Postmenopausal
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ZoledronateDrug
zoledronate 5 mg
PlaceboDrug
isotonic saline 100 mL
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: 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). Receives: Drug: Zoledronate |
| Second part (year 2-3): groups 1+3 | Active comparator | Patients will receive yearly infusions of zoledronate 5 mg Receives: Drug: Zoledronate |
| Second part (year 2-3): groups 2+4 | Placebo comparator | Patients will receive yearly infusions of placebo. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in lumbar spine bone mineral density (BMD)
Change in lumbar spine BMD after 12 and 36 months.
Measured: 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.
Measured: After 12 months.
Secondary outcomes (10)
Changes in total hip and femoral neck bone mineral density (BMD)
Changes in total hip and femoral neck BMD after 12 and 36 months.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Baseline and after 3 and 12 months
Insulin sensitivity
Insulin sensitivity assessed by Hb1Ac, HOMA-IR, OGTT and advanced glycation end products (AGEs).
Measured: Baseline and after 3, 12, 18, 24 and 36 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Dec 2022
- Study start10 May 2023
- Primary completion1 Feb 2027 (estimated)
- Study completion1 Feb 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Osteoporosis, PostmenopausalStudies of the same condition, open and under way.
- More trials run by Aarhus University HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- 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 blind
- Who is masked
- Participant, Investigator
- Enrolment
- 200 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Aarhus University Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Anne Sophie Sølling, Aarhus University Hospital
- Investigators
- Bente Langdahl, MD, Professor, DMSc, PhD, Principal investigator, Aarhus University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05655013
- Sponsor's protocol ID
- 01.12.2022
- Status last verified
- Sep 2025
- First submitted
- 29 Nov 2022
- Last updated
- 2 Oct 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 2 Oct 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Treatment With Zoledronate Subsequent to Denosumab in Osteoporosis 2 (ZOLARMAB2)
- ClinicalTrials.gov ID
- NCT05655013
- Acronym / sponsor ID
- 01.12.2022
- Conditions
- Osteoporosis, Postmenopausal
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 200 participants (estimated)
- Lead sponsor
- Aarhus University HospitalUniversity, hospital or other
- Study start
- 10 May 2023 (actual)
- Primary completion
- 1 Feb 2027 (estimated)
- Study completion
- 1 Feb 2027 (estimated)
- First posted
- 16 Dec 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 4
- 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.
| Arm | Type | Receives |
|---|---|---|
| First part (year 1): groups 1+2 | Active comparator | Drug: ZoledronateZoledronate will be administered as an infusion six months after the last injection of denosumab followed by zoledronate infusions 3 and 6 months thereafter |
| First part (year 1): groups 3+4 | Active comparator | Drug: ZoledronateZoledronate 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). |
| Second part (year 2-3): groups 1+3 | Active comparator | Drug: ZoledronatePatients will receive yearly infusions of zoledronate 5 mg |
| Second part (year 2-3): groups 2+4 | Placebo comparator | Drug: PlaceboPatients will receive yearly infusions of placebo. |
Who may qualify
- Ages
- 40 to 100 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (16 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Zoledronatezoledronate 5 mg | Drug | First part (year 1): groups 1+2, First part (year 1): groups 3+4, Second part (year 2-3): groups 1+3 |
| Placeboisotonic saline 100 mL | Drug | Second part (year 2-3): groups 2+4 |
Primary outcome
Change in lumbar spine bone mineral density (BMD)
Time frame: After 12 and 36 months.
Change in lumbar spine BMD after 12 and 36 months.
The proportion of patients who fails to maintain bone mineral density (BMD)
Time frame: After 12 months.
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.
10 secondary outcomes
Changes in total hip and femoral neck bone mineral density (BMD)
Time frame: 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)
Time frame: After 12 and 36 months.
Changes in carboxy-terminal collagen crosslinks (CTX) and procollagen type I N-terminal propeptide (PINP)
Time frame: After 3, 6, 12, 24 and 36 months.
Morphometric vertebral fractures
Time frame: After 12 and 36 months.
Serum RANKL/OPG, tartrate-resistant acid phosphatase type 5b (TRAcP-5b), sclerostin and Dickkopf-1 (Dkk-1)
Time frame: Baseline and after 1, 3, 6 and 12 months
Molecular bone histology
Time frame: Baseline and after 3 months
Osteoclasts
Time frame: Baseline
Epigenetic marker analysis
Time frame: Baseline
Muscle mass and muscle strength
Time frame: Baseline and after 3 and 12 months
Insulin sensitivity
Time frame: Baseline and after 3, 12, 18, 24 and 36 months
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Oct 2025.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Bente Langdahl, MD, Professor, DMSc, PhD principal investigator
Aarhus University Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Zoledronate in people with Osteoporosis, Postmenopausal, run by Aarhus University Hospital at 1 site in Denmark.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 2 Oct 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in lumbar spine bone mineral density (BMD) (time frame: After 12 and 36 months.). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Oct 2025.