Osteoporosis, PostmenopausalNCT03812367
Activity of Pre-Osteoclasts and Osteoclasts Over Time in Postmenopausal Women Treated With Denosumab or Zoledronic Acid
An observational study of Osteoporosis, Postmenopausal, run by University of California, Davis at 1 site in United States.
Trial summary
This study evaluates how patients treated with denosumab or zoledronic acid for osteoporosis may change the number of peripheral osteoclast precursors and osteoclast activity, and how that may be associated with changes in bone mass. Read more about this study
- Who is it for?
- Ages 50 years and older, women only
- Conditions the study is for
- Osteoporosis, Postmenopausal
- Type of treatment
- Injection or infusion
- How many people
- 0 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Jan 2019to 31 Dec 2021
- Phase
- Observational
- Are there results?
- None posted in the registry
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 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Study population: Women aged > 50 with diagnosis of osteoporosis.
Who may be able to join
- Women at least 50 years of age who are postmenopausal. Postmenopausal is defined as being amenorrheic for at a period of at least 12 months.
- Diagnosis of osteoporosis by T score of < -2.5 at either lumbar spine or the hip/femoral neck, or osteopenia that qualifies for treatment by FRAX calculation (10-year risk of hip fracture > 3% and/or major osteoporotic fracture of > 20%).
- 3a. Subjects who have had chronic treatment of denosumab (as defined as > 1 year [at least 3 6-monthly injections]) or zoledronic acid (defined as ≥ 2 years [at least 2 annual injections]) . Note: At the time of treatment initiation, subjects must have met criteria for on-label use (e.g. criterion 2 above).
- OR 3b. Subjects who are naïve to treatment with denosumab and/or zoledronic acid.
Who cannot join
- Renal insufficiency, with glomerular filtration rate (GFR) < 35 ml/min.
- Hypocalcemia within 6 months of study initiation.
- Known hypersensitivity to denosumab or zoledronic acid.
- Medications that could alter bone turnover including prednisone, anti-rheumatic medications, anti-metabolites (Cytoxan). Subjects who have been on stable doses of thyroid replacement or diabetes medications for more than 3 months are eligible.
- Evidence of untreated oral cavities or oral infections. Preventative dental exams should be performed before starting denosumab or zoledronic acid. Subjects must avoid invasive dental procedures during treatment with denosumab or zoledronic acid.
Trial locations and contacts
1 site in 1 country.
United States1 site
UC Davis Health, Center for Musculoskeletal Health
Sacramento, California, 95817
About this study
Official title: Prospective Study to Assess Changes in the Number and Activity of Pre-Osteoclasts and Osteoclasts Over Time in Postmenopausal Women Treated With Denosumab or Zoledronic Acid
This study evaluates how patients treated with denosumab or zoledronic acid for osteoporosis may change the number of peripheral osteoclast precursors and osteoclast activity, and how that may be associated with changes in bone mass.
Read the detailed description
Postmenopausal osteoporosis is the leading cause of low trauma fractures. At the time of menopause there is an uncoupling of bone turnover, with osteoclast mediated bone resorption increased more than bone formation, resulting in both loss of bone mass and architecture such that bone fractures with very little force.
Bisphosphonates are commonly used to treat postmenopausal osteoporosis, although the mechanisms of their action on bone are not completely understood. Gossiel and colleagues recently examined the effects of ibandronate, alendronate and risedronate on osteoclast precursor cells in a study of women (n=62) with postmenopausal osteoporosis. Fasting serum was collected at baseline and after 1 and 48 weeks of bisphosphonate treatment. Fluorescent-activated cell sorting (FACS)-Calibur was used to extract peripheral blood mononuclear cells (PBMC), and cells were stained for receptors of macrophage colony stimulating factor (M-CSFR) and tumor necrosis factor 2 (TNFR2), as well as adhesion molecules (CD11b and CD14). These cell surface antigens are important for osteoclast differentiation and activity. Osteoclast precursor cells were identified using flow cytometry to find cells that were dual positive (CD14+/M-CSFR+, CD14+/CD11b+, CD14+/TNFR2+). Results showed a significant (p<0.01) reduction in in expression of M-CSFR (53% decrease) and CD11b (49% decrease) after 48 weeks of treatment, suggesting that the action of bisphosphonates on mature osteoclasts may be mediated by reduction of osteoclast precursor cells.
Treatment with denosumab (a monoclonal antibody that blocks the ability of receptor activator of NFκB ligand [RANKL] to bind to its receptor RANK on the osteoclast surface and inhibits the maturation and activity of osteoclasts) has been found to increase bone mineral density (BMD) at the lumbar spine and hip in both postmenopausal women and elderly men with osteopenia. However, after denosumab is discontinued there can be a rapid loss of BMD and an increased incidence of vertebral fractures. Current data suggests that the incidence of vertebral fracrure increases to levels similar to placebo after denosumab discontinuation, and only the incidence of multiple vertebral fracture is higher after denosumab discontinuation compared with placebo discontinuation, though further research is needed. The increase in the observed bone loss may be from increased osteoclast maturation and activity, or an change in the number circulating monocytes (the precursors of osteoclasts) during the denosumab treatment.
- Conditions
- Osteoporosis, Postmenopausal
- Medical subject headings
- Osteoporosis, Postmenopausal
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Group 1 | The denosumab naïve group | |
| Group 2 | The zoledronic acid naïve group | |
| Group 3 | The chronic denosumab (> 1 year with at least 3 biannual injections) | |
| Group 4 | The chronic zoledronic acid (≥2 years with at least 2 annual injections) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percent change in osteoclast circulation
Percent change (%Δ) from baseline in number of circulating osteoclast precursor cells by FACS analysis
Measured: 1 month, 6 months, 12 months
Percent change in osteoclast maturation and activity
Percent change (%Δ) in osteoclast maturation and activity, as assessed by resorption on dentin slides and expression of genes critical for osteoclast differentiation
Measured: 1 month, 6 months, 12 months
Percent change in number of TRAP cells
Percent change (%Δ) from baseline in the number of tartrate-resistant acid phosphatase (TRAP)+cells with 3 or mor nuclei by in vitro maturation
Measured: 1 month, 6 months, 12 months
Percent change in bone mass density
Percent change (%Δ) from baseline in BMD at the total hip and lumbar spine
Measured: 1 month, 6 months, 12 months
Percent change in bone turnover markers
Percent change (% Δ) from baseline in bone turnover markers C-telopeptide of type 1 collagen (CTX) and procollagen type 1 propeptide (P1NP)
Measured: 1 month, 6 months, 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Jan 2019
- Study start1 Jan 2019
- Primary completion1 Jun 2021 (estimated)
- Study completion31 Dec 2021 (estimated)
Why it stopped: The Investigator decided not to pursue this study.
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 University of California, DavisThe 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
- Observational
- Observational model
- Case-control
- Time perspective
- Prospective
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of California, Davis
- Sponsor type
- University, hospital or other
- Collaborators
- Amgen
- Responsible party
- Sponsor
- Investigators
- Nancy Lane, MD, Principal investigator, University of California, Davis
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03812367
- Sponsor's protocol ID
- 1030286
- Status last verified
- Jun 2019
- First submitted
- 18 Jan 2019
- Last updated
- 14 Jun 2019
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 14 Jun 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Prospective Study to Assess Changes in the Number and Activity of Pre-Osteoclasts and Osteoclasts Over Time in Postmenopausal Women Treated With Denosumab or Zoledronic Acid
- ClinicalTrials.gov ID
- NCT03812367
- Acronym / sponsor ID
- 1030286
- Conditions
- Osteoporosis, Postmenopausal
- Study type
- Observational
- Recruitment status
- WithdrawnReason stopped: The Investigator decided not to pursue this study.
- Enrolment
- 0 participants (actual)
- Lead sponsor
- University of California, DavisUniversity, hospital or other
- Collaborators
- Amgen
- Study start
- 1 Jan 2019 (actual)
- Primary completion
- 1 Jun 2021 (estimated)
- Study completion
- 31 Dec 2021 (estimated)
- First posted
- 23 Jan 2019 (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.
This study evaluates how patients treated with denosumab or zoledronic acid for osteoporosis may change the number of peripheral osteoclast precursors and osteoclast activity, and how that may be associated with changes in bone mass.
Detailed description
Postmenopausal osteoporosis is the leading cause of low trauma fractures. At the time of menopause there is an uncoupling of bone turnover, with osteoclast mediated bone resorption increased more than bone formation, resulting in both loss of bone mass and architecture such that bone fractures with very little force.
Bisphosphonates are commonly used to treat postmenopausal osteoporosis, although the mechanisms of their action on bone are not completely understood. Gossiel and colleagues recently examined the effects of ibandronate, alendronate and risedronate on osteoclast precursor cells in a study of women (n=62) with postmenopausal osteoporosis. Fasting serum was collected at baseline and after 1 and 48 weeks of bisphosphonate treatment. Fluorescent-activated cell sorting (FACS)-Calibur was used to extract peripheral blood mononuclear cells (PBMC), and cells were stained for receptors of macrophage colony stimulating factor (M-CSFR) and tumor necrosis factor 2 (TNFR2), as well as adhesion molecules (CD11b and CD14). These cell surface antigens are important for osteoclast differentiation and activity. Osteoclast precursor cells were identified using flow cytometry to find cells that were dual positive (CD14+/M-CSFR+, CD14+/CD11b+, CD14+/TNFR2+). Results showed a significant (p<0.01) reduction in in expression of M-CSFR (53% decrease) and CD11b (49% decrease) after 48 weeks of treatment, suggesting that the action of bisphosphonates on mature osteoclasts may be mediated by reduction of osteoclast precursor cells.
Treatment with denosumab (a monoclonal antibody that blocks the ability of receptor activator of NFκB ligand [RANKL] to bind to its receptor RANK on the osteoclast surface and inhibits the maturation and activity of osteoclasts) has been found to increase bone mineral density (BMD) at the lumbar spine and hip in both postmenopausal women and elderly men with osteopenia. However, after denosumab is discontinued there can be a rapid loss of BMD and an increased incidence of vertebral fractures. Current data suggests that the incidence of vertebral fracrure increases to levels similar to placebo after denosumab discontinuation, and only the incidence of multiple vertebral fracture is higher after denosumab discontinuation compared with placebo discontinuation, though further research is needed. The increase in the observed bone loss may be from increased osteoclast maturation and activity, or an change in the number circulating monocytes (the precursors of osteoclasts) during the denosumab treatment.
Study design
- Observational model
- Case-control
- Time perspective
- Prospective
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Group 1 | – | –The denosumab naïve group |
| Group 2 | – | –The zoledronic acid naïve group |
| Group 3 | – | –The chronic denosumab (> 1 year with at least 3 biannual injections) |
| Group 4 | – | –The chronic zoledronic acid (≥2 years with at least 2 annual injections) |
Who may qualify
- Ages
- 50 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Women aged > 50 with diagnosis of osteoporosis.
Key inclusion criteria (4 listed)
- Women at least 50 years of age who are postmenopausal. Postmenopausal is defined as being amenorrheic for at a period of at least 12 months.
- Diagnosis of osteoporosis by T score of < -2.5 at either lumbar spine or the hip/femoral neck, or osteopenia that qualifies for treatment by FRAX calculation (10-year risk of hip fracture > 3% and/or major osteoporotic fracture of > 20%).
- 3a. Subjects who have had chronic treatment of denosumab (as defined as > 1 year [at least 3 6-monthly injections]) or zoledronic acid (defined as ≥ 2 years [at least 2 annual injections]) . Note: At the time of treatment initiation, subjects must have met criteria for on-label use (e.g. criterion 2 above).
- OR 3b. Subjects who are naïve to treatment with denosumab and/or zoledronic acid.
Key exclusion criteria (5 listed)
- Renal insufficiency, with glomerular filtration rate (GFR) < 35 ml/min.
- Hypocalcemia within 6 months of study initiation.
- Known hypersensitivity to denosumab or zoledronic acid.
- Medications that could alter bone turnover including prednisone, anti-rheumatic medications, anti-metabolites (Cytoxan). Subjects who have been on stable doses of thyroid replacement or diabetes medications for more than 3 months are eligible.
- Evidence of untreated oral cavities or oral infections. Preventative dental exams should be performed before starting denosumab or zoledronic acid. Subjects must avoid invasive dental procedures during treatment with denosumab or zoledronic acid.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Percent change in osteoclast circulation
Time frame: 1 month, 6 months, 12 months
Percent change (%Δ) from baseline in number of circulating osteoclast precursor cells by FACS analysis
Percent change in osteoclast maturation and activity
Time frame: 1 month, 6 months, 12 months
Percent change (%Δ) in osteoclast maturation and activity, as assessed by resorption on dentin slides and expression of genes critical for osteoclast differentiation
Percent change in number of TRAP cells
Time frame: 1 month, 6 months, 12 months
Percent change (%Δ) from baseline in the number of tartrate-resistant acid phosphatase (TRAP)+cells with 3 or mor nuclei by in vitro maturation
Percent change in bone mass density
Time frame: 1 month, 6 months, 12 months
Percent change (%Δ) from baseline in BMD at the total hip and lumbar spine
Percent change in bone turnover markers
Time frame: 1 month, 6 months, 12 months
Percent change (% Δ) from baseline in bone turnover markers C-telopeptide of type 1 collagen (CTX) and procollagen type 1 propeptide (P1NP)
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Jun 2019.
- Individual participant dataSharing planned: Undecided
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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.
Nancy Lane, MD principal investigator
University of California, Davis
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Osteoporosis, Postmenopausal, run by University of California, Davis at 1 site in United States.
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 4 inclusion and 5 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: withdrawn, as of the sponsor's last update on 14 Jun 2019. 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 United States. 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.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
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?
Percent change in osteoclast circulation (time frame: 1 month, 6 months, 12 months). The study lists 5 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 14 Jun 2019.