OsteoporosisPhase 4NCT07281586
Step-down Therapy After Long-term Osteoporosis Treatment
A Phase 4 study testing zoledronate and Denosumab De-escalation in people with Osteoporosis, run by National Taiwan University Hospital at 1 site in Taiwan.
Trial summary
Maintaining bone mineral density (BMD) after discontinuing denosumab (Prolia) is a major clinical challenge, as rapid bone loss commonly occurs when treatment is stopped, especially after more than three years of use. Read more about this study
- Who is it for?
- Ages 50 to 85 years
- Conditions the study is for
- Osteoporosis
- What is being tested?
- zoledronate and Denosumab De-escalation
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 44 participants
- Where
- 1 siteTaiwan
- Study dates
- 1 Jan 2026to 31 Dec 2028
- 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 50 to 85 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Postmenopausal women aged ≥50 and ≤85 years with osteoporosis- or osteopenia-related fractures who have received denosumab (Prolia) continuously for at least 3 years, with no dosing interval exceeding 9 months; and men aged ≥50 and ≤85 years with osteoporosis- or osteopenia-related fractures who have received continuous denosumab (Prolia) therapy for at least 3 years, with dosing intervals not exceeding 9 months.
Who cannot join
- Secondary osteoporosis Metabolic bone diseases Active or prior malignancy Ongoing systemic glucocorticoid therapy Current use of hormone replacement therapy Use of any medications that affect bone metabolism Estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73 m² Known hypersensitivity to zoledronic acid Hypocalcemia Any other contraindications to zoledronic acid use
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Taiwan1 site, 1 recruiting
- Recruiting
National Taiwan University Hospital Yunlin Branch
Douliu, Taiwan, 640
Shau-Huai Fu, 0972655734, b90401045@gmail.com
About this study
Official title: Step-down Therapy After Long-term Osteoporosis Treatment: A Randomized Trial
Maintaining bone mineral density (BMD) after discontinuing denosumab (Prolia) is a major clinical challenge, as rapid bone loss commonly occurs when treatment is stopped, especially after more than three years of use. Standard sequential therapy with bisphosphonates such as zoledronic acid (Aclasta) often fails to fully prevent BMD decline, and most bone loss occurs within the first year, making effective suppression of the rebound effect essential.
This study investigates whether a de-escalation strategy-using half-dose denosumab (30 mg every six months) combined with sequential zoledronic acid-can better preserve lumbar spine BMD after long-term denosumab therapy. Eligible participants include postmenopausal women and men ≥50 years old with osteoporosis or osteopenia-related fractures who have received ≥3 years of denosumab.
Read more
The open-label trial applies stratified randomization based on denosumab duration (<4 years vs. ≥4 years), assigning 22 participants to each group.
Control group: standard therapy with one zoledronic acid infusion at the end of denosumab's effect and a second infusion one year later.
Intervention group: half-dose denosumab plus zoledronic acid at study entry, a second half-dose denosumab injection at six months, and a second zoledronic acid infusion at twelve months.
The study aims to determine whether this combined tapering-plus-bisphosphonate approach more effectively prevents lumbar spine BMD loss compared with conventional sequential therapy.
Read the detailed description
Effective maintenance of bone mineral density (BMD) after discontinuing denosumab (Prolia) remains a major clinical challenge. Although denosumab is highly effective in increasing BMD, patients frequently discontinue therapy due to issues such as adherence, comorbidities, or personal circumstances. This interruption can lead to rapid and profound bone loss, substantially increasing fracture risk. Current clinical consensus recommends follow-on bisphosphonate therapy-most commonly alendronate (Fosamax) or zoledronic acid (Aclasta)-after the pharmacologic effect of denosumab wears off. However, evidence indicates that in patients treated with denosumab for more than three years, conventional bisphosphonate transition alone is often insufficient to fully prevent post-discontinuation BMD decline. Importantly, most bone loss occurs within the first year after stopping denosumab, highlighting the urgent need for strategies that can suppress the rebound increase in bone turnover during this critical period.
This study aims to investigate whether a dose-reduction (de-escalation) strategy-administering half-dose denosumab (30 mg every six months) combined with sequential zoledronic acid therapy-can better preserve lumbar spine BMD after long-term denosumab treatment. The target population includes (1) postmenopausal women with osteoporosis or osteopenia-associated fractures who have received at least three years of denosumab treatment, and (2) men aged ≥50 years with osteoporosis or osteopenia-associated fractures and ≥3 years of denosumab therapy.
The study uses an open-label, stratified randomized trial design. After enrollment, participants are stratified according to total duration of prior denosumab use: <4 years or ≥4 years. Within each stratum, participants are randomized into two groups, with 22 participants per group.
Control Group (Standard Sequential Therapy):
Participants receive conventional post-denosumab management. A single infusion of zoledronic acid is administered at the expected end of denosumab's pharmacologic effect, followed by a second zoledronic acid infusion one year later (±1 week).
Intervention Group (De-escalation + Bisphosphonate Strategy):
At study entry, participants receive a half-dose denosumab injection (expected duration of effect: six months) concurrently with one dose of zoledronic acid. Six months later (±1 week), participants receive a second half-dose denosumab injection. At twelve months after enrollment (±1 week), a second zoledronic acid infusion is administered.
This investigational regimen is designed to gradually taper denosumab exposure while simultaneously initiating bisphosphonate therapy to stabilize bone turnover. By providing partial RANKL inhibition during the early high-risk period and reinforcing mineralization with zoledronic acid, the study aims to determine whether this combined approach can more effectively mitigate the rebound effect and prevent lumbar spine BMD loss.
The results of this trial will help clarify whether a structured de-escalation plus bisphosphonate strategy offers superior protection compared with standard transition therapy in patients with long-term denosumab exposure.
- Conditions
- Osteoporosis
- Being tested
- zoledronate, Denosumab De-escalation
- Keywords
- long-term denosumab, zoledronate, half-dose denosumab, de-escalation strategy
- Medical subject headings
- Osteoporosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
zoledronateDrug
In the control arm, participants will receive zoledronate at trial entry, with a second dose administered at the start of the second year
zoledronateDrug
In the intervention arm, participants will receive zoledronate at trial entry, with a second dose administered at the start of the second year.
Denosumab De-escalationDrug
In the intervention arm, participants will receive a half-dose of denosumab at trial entry, followed by a second half-dose 6 months later during the first year.
| Study group | Role | What they receive |
|---|---|---|
| Control | Active comparator | Zoledronate is given 6 months after the final denosumab injection, with a second zoledronate infusion administered 18 months after the last denosumab dose. Receives: Drug: zoledronate |
| Denosumab De-escalation + Zoledronate | Experimental | Half-dose denosumab plus zoledronic acid at 6 months after the last denosumab dose, followed by a second half-dose denosumab injection at 12 months and a second zoledronic acid infusion at 18 months after the final denosumab dose. Receives: Drug: zoledronate; Drug: Denosumab De-escalation |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Lumbar Spine BMD Over 2 Years
Change in Lumbar Spine BMD Over 2 Years
Measured: 2 Years
Secondary outcomes (5)
Change in Total hip BMD Over 2 Years
Change in Total hip BMD Over 2 Years
Measured: 2 Years
Change in Femoral Neck BMD Over 2 Years
Change in Femoral Neck BMD Over 2 Years
Measured: 2 Years
Change in C-terminal telopeptide Over 2 Years
Change in C-terminal telopeptide over 2 years, which reflects the level of bone resorption, will be used to assess how bone turnover responds to the intervention throughout the study period.
Measured: 2 Years
Change in Procollagen Type I N-Propeptide Over 2 Years
Change in Procollagen Type I N-Propeptide over 2 years, which reflects the level of bone formation, will be used to assess how bone turnover responds to the intervention throughout the study period.
Measured: 2 Years
Incidence of clinical osteoporotic fracture
Incidence of clinical osteoporotic fracture
Measured: 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Dec 2025
- Study start1 Jan 2026 (estimated)
- Primary completion31 Dec 2028 (estimated)
- Study completion31 Dec 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for OsteoporosisStudies of the same condition, open and under way.
- More trials run by National Taiwan 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
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 44 participants (estimated)
Sponsor and investigators
- Lead sponsor
- National Taiwan University Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- National Taiwan University Hospital, Yun-Lin Branch
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07281586
- Sponsor's protocol ID
- 202412063MINE
- Status last verified
- Nov 2025
- First submitted
- 25 Nov 2025
- Last updated
- 15 Dec 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 15 Dec 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Step-down Therapy After Long-term Osteoporosis Treatment: A Randomized Trial
- ClinicalTrials.gov ID
- NCT07281586
- Acronym / sponsor ID
- 202412063MINE
- Conditions
- Osteoporosis
- Keywords
- long-term denosumab, zoledronate, half-dose denosumab, de-escalation strategy
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 44 participants (estimated)
- Lead sponsor
- National Taiwan University HospitalUniversity, hospital or other
- Collaborators
- National Taiwan University Hospital, Yun-Lin Branch
- Study start
- 1 Jan 2026 (estimated)
- Primary completion
- 31 Dec 2028 (estimated)
- Study completion
- 31 Dec 2028 (estimated)
- First posted
- 15 Dec 2025 (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.
Maintaining bone mineral density (BMD) after discontinuing denosumab (Prolia) is a major clinical challenge, as rapid bone loss commonly occurs when treatment is stopped, especially after more than three years of use. Standard sequential therapy with bisphosphonates such as zoledronic acid (Aclasta) often fails to fully prevent BMD decline, and most bone loss occurs within the first year, making effective suppression of the rebound effect essential.
This study investigates whether a de-escalation strategy-using half-dose denosumab (30 mg every six months) combined with sequential zoledronic acid-can better preserve lumbar spine BMD after long-term denosumab therapy. Eligible participants include postmenopausal women and men ≥50 years old with osteoporosis or osteopenia-related fractures who have received ≥3 years of denosumab.
The open-label trial applies stratified randomization based on denosumab duration (<4 years vs. ≥4 years), assigning 22 participants to each group.
Control group: standard therapy with one zoledronic acid infusion at the end of denosumab's effect and a second infusion one year later.
Intervention group: half-dose denosumab plus zoledronic acid at study entry, a second half-dose denosumab injection at six months, and a second zoledronic acid infusion at twelve months.
The study aims to determine whether this combined tapering-plus-bisphosphonate approach more effectively prevents lumbar spine BMD loss compared with conventional sequential therapy.
Detailed description
Effective maintenance of bone mineral density (BMD) after discontinuing denosumab (Prolia) remains a major clinical challenge. Although denosumab is highly effective in increasing BMD, patients frequently discontinue therapy due to issues such as adherence, comorbidities, or personal circumstances. This interruption can lead to rapid and profound bone loss, substantially increasing fracture risk. Current clinical consensus recommends follow-on bisphosphonate therapy-most commonly alendronate (Fosamax) or zoledronic acid (Aclasta)-after the pharmacologic effect of denosumab wears off. However, evidence indicates that in patients treated with denosumab for more than three years, conventional bisphosphonate transition alone is often insufficient to fully prevent post-discontinuation BMD decline. Importantly, most bone loss occurs within the first year after stopping denosumab, highlighting the urgent need for strategies that can suppress the rebound increase in bone turnover during this critical period.
This study aims to investigate whether a dose-reduction (de-escalation) strategy-administering half-dose denosumab (30 mg every six months) combined with sequential zoledronic acid therapy-can better preserve lumbar spine BMD after long-term denosumab treatment. The target population includes (1) postmenopausal women with osteoporosis or osteopenia-associated fractures who have received at least three years of denosumab treatment, and (2) men aged ≥50 years with osteoporosis or osteopenia-associated fractures and ≥3 years of denosumab therapy.
The study uses an open-label, stratified randomized trial design. After enrollment, participants are stratified according to total duration of prior denosumab use: <4 years or ≥4 years. Within each stratum, participants are randomized into two groups, with 22 participants per group.
Control Group (Standard Sequential Therapy):
Participants receive conventional post-denosumab management. A single infusion of zoledronic acid is administered at the expected end of denosumab's pharmacologic effect, followed by a second zoledronic acid infusion one year later (±1 week).
Intervention Group (De-escalation + Bisphosphonate Strategy):
At study entry, participants receive a half-dose denosumab injection (expected duration of effect: six months) concurrently with one dose of zoledronic acid. Six months later (±1 week), participants receive a second half-dose denosumab injection. At twelve months after enrollment (±1 week), a second zoledronic acid infusion is administered.
This investigational regimen is designed to gradually taper denosumab exposure while simultaneously initiating bisphosphonate therapy to stabilize bone turnover. By providing partial RANKL inhibition during the early high-risk period and reinforcing mineralization with zoledronic acid, the study aims to determine whether this combined approach can more effectively mitigate the rebound effect and prevent lumbar spine BMD loss.
The results of this trial will help clarify whether a structured de-escalation plus bisphosphonate strategy offers superior protection compared with standard transition therapy in patients with long-term denosumab exposure.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Control | Active comparator | Drug: zoledronateZoledronate is given 6 months after the final denosumab injection, with a second zoledronate infusion administered 18 months after the last denosumab dose. |
| Denosumab De-escalation + Zoledronate | Experimental | Drug: zoledronate, Drug: Denosumab De-escalationHalf-dose denosumab plus zoledronic acid at 6 months after the last denosumab dose, followed by a second half-dose denosumab injection at 12 months and a second zoledronic acid infusion at 18 months after the final denosumab dose. |
Who may qualify
- Ages
- 50 to 85 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- Postmenopausal women aged ≥50 and ≤85 years with osteoporosis- or osteopenia-related fractures who have received denosumab (Prolia) continuously for at least 3 years, with no dosing interval exceeding 9 months; and men aged ≥50 and ≤85 years with osteoporosis- or osteopenia-related fractures who have received continuous denosumab (Prolia) therapy for at least 3 years, with dosing intervals not exceeding 9 months.
Key exclusion criteria (1 listed)
- Secondary osteoporosis Metabolic bone diseases Active or prior malignancy Ongoing systemic glucocorticoid therapy Current use of hormone replacement therapy Use of any medications that affect bone metabolism Estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73 m² Known hypersensitivity to zoledronic acid Hypocalcemia Any other contraindications to zoledronic acid use
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 |
|---|---|---|
| zoledronateIn the control arm, participants will receive zoledronate at trial entry, with a second dose administered at the start of the second year | Drug | Control |
| zoledronateIn the intervention arm, participants will receive zoledronate at trial entry, with a second dose administered at the start of the second year. | Drug | Denosumab De-escalation + Zoledronate |
| Denosumab De-escalationIn the intervention arm, participants will receive a half-dose of denosumab at trial entry, followed by a second half-dose 6 months later during the first year. | Drug | Denosumab De-escalation + Zoledronate |
Primary outcome
Change in Lumbar Spine BMD Over 2 Years
Time frame: 2 Years
Change in Lumbar Spine BMD Over 2 Years
5 secondary outcomes
Change in Total hip BMD Over 2 Years
Time frame: 2 Years
Change in Femoral Neck BMD Over 2 Years
Time frame: 2 Years
Change in C-terminal telopeptide Over 2 Years
Time frame: 2 Years
Change in Procollagen Type I N-Propeptide Over 2 Years
Time frame: 2 Years
Incidence of clinical osteoporotic fracture
Time frame: 2 years
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 15 Dec 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.
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 and Denosumab De-escalation in people with Osteoporosis, run by National Taiwan University Hospital at 1 site in Taiwan.
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 1 inclusion and 1 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: looking for participants now, as of the sponsor's last update on 15 Dec 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 Taiwan. 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. 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?
Contact Shau-Huai Fu, PhD (+886972655734, b90401045@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Lumbar Spine BMD Over 2 Years (time frame: 2 Years). 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 15 Dec 2025.