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OsteoporosisPhase 4ZOLARMABNCT03087851

Treatment With Zoledronic Acid Subsequent to Denosumab in Osteoporosis

A Phase 4 study testing Zoledronic Acid in people with Osteoporosis, run by Aarhus University Hospital at 1 site in Denmark.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

Denosumab is an antibody against receptor-activator of nuclear factor kappa-B ligand that prevents recruitment and differentiation of mature osteoclasts. Treatment markedly decrease bone resorption and fracture risk, and many patients will reach osteopenic bone mineral density (BMD) levels on treatment with denosumab. Read more about this study

Who is it for?
Ages 50 years and older
Conditions the study is for
Osteoporosis
What is being tested?
Zoledronic Acid
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
61 participants
Where
1 siteDenmark
Study dates
13 Mar 2017to 1 Aug 2020
Phase
Phase 4
Are there results?
Yes, posted in the registrySummary in the doctors' view

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
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Postmenopausal women (postmenopausal for at least two years)
  • Men above 50 years
  • Treatment for at least two years with denosumab
  • Last denosumab injection less than five months ago

Who cannot join

  • Low-energy vertebral fracture at any time
  • Low-energy hip fracture within the last 12 months
  • BMD T-score < -2,5 (lumbar spine, total hip or femoral neck)
  • Alendronate treatment for more than three years prior to denosumab treatment
  • Ongoing treatment with glucocorticoids
  • Metabolic bone disease
Show all 12Show fewer
  • Hormone replacement therapy
  • Cancer
  • Estimated glomerular filtration rate (eGFR) < 35 mL/min
  • Allergy to zoledronic acid
  • Hypocalcaemia
  • Contraindications for zoledronic acid according to the SPC

Trial locations and contacts

1 site in 1 country.

Denmark1 site
  • Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark

    Aarhus, 8000

Other trials in Denmark

About this study

Denosumab is an antibody against receptor-activator of nuclear factor kappa-B ligand that prevents recruitment and differentiation of mature osteoclasts. Treatment markedly decrease bone resorption and fracture risk, and many patients will reach osteopenic bone mineral density (BMD) levels on treatment with denosumab. The treatment effect on bone turnover and BMD has, however, been demonstrated to be reversible. This study will show if the bone mass can be maintained by administrating zoledronic acid and if timing of the first dose of zoledronic acid after last dose of denosumab matters.

Read the detailed description

Background: Denosumab is an antibody against receptor-activator of nuclear factor kappa-B ligand that prevents recruitment and differentiation of osteoclasts. Treatment decreases bone resorption and fracture risk. After discontinuation, however, bone resorption increases and the bone mass gained during 2 years of therapy is lost within 1 year. At present denosumab treatment is considered to be life-long.

Aim: To investigate if infusion of zoledronic acid can prevent increases in bone turnover and bone loss in patients previously treated with denosumab and if there is difference between infusing zoledronic acid at six or nine months after the last injection of denosumab or when bone turnover is increased.

Methods: A randomized open label, interventional study in 60 patients investigating if treatment with zoledronic acid prevents bone loss after denosumab treatment when administrated six or nine months after last injection of deno-sumab or when bone turnover is increased. Forty patients will be allocated to the two intervention groups and 20 patients will be followed without treatment for up to 12 months after the last denosumab treatment. The patients in the observation group and the nine months group will be monitored monthly and if s-carboxy-terminal collagen cross-links (s-CTX) increases above 1.26ug/l (50% above the normal range for postmenopausal women and elderly men) infusion of zoledronic acid will be administered. Furthermore, a DXA scan (lumbar spine and hip sites) will be performed after three months in the observation group. If BMD has decreased more than 5% at any site, infusion of zoledronic acid will be administered. Finally, if a patient in the 9 months group or the in the observation group suffers an osteoporotic clinical vertebral or hip fracture, infusion of zoledronic acid will be administered.

The patients will be monitored with DXA 6, 12 and 24 months after the infusion of zoledronic acid. Zoledronic acid will be re-administered if BMD has decreased more than 5% at the lumbar spine, total hip or femoral neck. If s-CTX in-creases above 1.26 ug/l during the 2nd year a second infusion of zoledronic acid will be administered.

Perspectives: Many patients will reach osteopenic BMD levels on treatment with denosumab, however the treatment effect on bone turnover and BMD has been demonstrated to be reversible and it is therefore important to find out if denosumab treatment can be discontinued and bone mass maintained by other measures. This study will show if the bone mass can be maintained by administrating zoledronic acid and if timing of the first dose of zoledronic acid after last dose of denosumab matters. If bone loss can be prevented by zoledronic acid expenses on otherwise life-long denosumab treatment can be saved and long-term side effects of denosumab (atypical femur fractures and osteone-crosis of the jaw) can be prevented.

Conditions
Osteoporosis
Being tested
Zoledronic Acid
Keywords
Denosumab, Bone turnover markers, Bone mineral density
Medical subject headings
Osteoporosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Zoledronic AcidDrug

    Also called Zoledronate

    Intravenous infusion of 5 mg zoledronic acid

Study groups in NCT03087851
Study groupRoleWhat they receive
6-month groupActive comparatorZoledronic acid will be administered at study day 0. If s-CTX increases above 1.26 ug/l or BMD decreases more than 5% at any site a second infusion of zoledronic acid will be administered.
Receives: Drug: Zoledronic Acid
9-months groupActive comparatorZoledronic acid will be administered depending on increase in s-CTX (above 1.26 ug/l) or the occurrence of an osteoporotic clinical vertebral or hip fracture, but no later than at month 3. If s-CTX increases above 1.26 ug/l or BMD decreases more than 5% at any site a second infusion of zoledronic acid will be administered.
Receives: Drug: Zoledronic Acid
Observation groupActive comparatorZoledronic acid will be administered depending on increase in s-CTX (above 1.26 ug/l), decrease in BMD (more than 5% at any site), or the occurrence of an osteoporotic clinical vertebral or hip fracture, but no later than at month 6. If s-CTX increases above 1.26 ug/l or BMD decreases more than 5% at any site a second infusion of zoledronic acid will be administered.
Receives: Drug: Zoledronic Acid

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change in Lumbar Spine BMD From Baseline to 6 Months After the Zoledronic Acid Infusion.

    Change in lumbar spine BMD from baseline to 6 months after the zoledronic acid infusion.

    Measured: baseline to 6 months after the zoledronic acid infusion

  2. Number of Participants Who Fail to Maintain BMD

    Failure is defined as ≥ 3 % BMD loss at the lumbar spine

    Measured: 2 years after the first ZOL treatment

Secondary outcomes (6)
  1. Changes in BMD From Baseline to One Year After the Zoledronic Acid Infusion.

    Changes in lumbar spine BMD from baseline to one year after the zoledronic acid infusion.

    Measured: from baseline to one year after the zoledronic acid infusion

  2. Changes in BMD From Baseline to Two Years After the Zoledronic Acid Infusion.

    Changes in lumbar spine BMD from baseline to two years after the zoledronic acid infusion.

    Measured: from baseline to two years after the zoledronic acid infusion.

  3. Changes in Cortical Porosity Measured by High-resolution Peripheral Quantitative Computed Tomography (HR-pQCT) Scan at the Radius and Tibia From Baseline to One Year After the Zoledronic Acid Infusion.

    Changes in cortical porosity measured by high-resolution peripheral quantitative computed tomography (HR-pQCT) scan at the radius and tibia from baseline to one year after the zoledronic acid infusion.

    Measured: from baseline to one year after the zoledronic acid infusion.

  4. Changes in p-CTX From Baseline to Six Months After the Zoledronic Acid Infusion.

    Changes in p-CTX from baseline to six months after the zoledronic acid infusion.

    Measured: from baseline to six months after the zoledronic acid infusion.

  5. Changes in p-CTX From Baseline to 12 Months After the Zoledronic Acid Infusion.

    Changes in p-CTX from baseline to 12 months after the zoledronic acid infusion.

    Measured: from baseline to 12 months after the zoledronic acid infusion.

  6. Morphometric Vertebral Fractures Assessed by Vertebral Fracture Assessment (VFA) One and Two Years After the Zoledronic Acid Infusion.

    Morphometric vertebral fractures assessed by vertebral fracture assessment (VFA) one and two years after the zoledronic acid infusion.

    Measured: one and two years after the zoledronic acid infusion.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted23 Mar 2017
  2. Study start13 Mar 2017
  3. Primary completion1 Aug 2020
  4. Study completion1 Aug 2020

Resources

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
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
61 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03087851
Sponsor's protocol ID
2015-005529-37
Other IDs
2015
Acronym
ZOLARMAB
Status last verified
Feb 2021
First submitted
13 Mar 2017
Last updated
21 Feb 2021
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Lacey DL, Boyle WJ, Simonet WS, Kostenuik PJ, Dougall WC, Sullivan JK, San Martin J, Dansey R. Bench to bedside: elucidation of the OPG-RANK-RANKL pathway and the development of denosumab. Nat Rev Drug Discov. 2012 May;11(5):401-19. doi: 10.1038/nrd3705.

    PubMed 22543469
  • Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, Delmas P, Zoog HB, Austin M, Wang A, Kutilek S, Adami S, Zanchetta J, Libanati C, Siddhanti S, Christiansen C; FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009 Aug 20;361(8):756-65. doi: 10.1056/NEJMoa0809493. Epub 2009 Aug 11.

    PubMed 19671655
  • Miller PD, Bolognese MA, Lewiecki EM, McClung MR, Ding B, Austin M, Liu Y, San Martin J. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone. 2008 Aug;43(2):222-229. doi: 10.1016/j.bone.2008.04.007. Epub 2008 Apr 26.

    PubMed 18539106
  • Koldkjaer Solling AS, Harslof T, Kaal A, Rejnmark L, Langdahl B. Hypercalcemia after discontinuation of long-term denosumab treatment. Osteoporos Int. 2016 Jul;27(7):2383-2386. doi: 10.1007/s00198-016-3535-5. Epub 2016 Apr 20.

    PubMed 27098536
  • Aubry-Rozier B, Gonzalez-Rodriguez E, Stoll D, Lamy O. Severe spontaneous vertebral fractures after denosumab discontinuation: three case reports. Osteoporos Int. 2016 May;27(5):1923-5. doi: 10.1007/s00198-015-3380-y. Epub 2015 Oct 28.

    PubMed 26510845
  • Anastasilakis AD, Makras P. Multiple clinical vertebral fractures following denosumab discontinuation. Osteoporos Int. 2016 May;27(5):1929-30. doi: 10.1007/s00198-015-3459-5. Epub 2015 Dec 22. No abstract available.

    PubMed 26694593
  • Shane E, Burr D, Ebeling PR, Abrahamsen B, Adler RA, Brown TD, Cheung AM, Cosman F, Curtis JR, Dell R, Dempster D, Einhorn TA, Genant HK, Geusens P, Klaushofer K, Koval K, Lane JM, McKiernan F, McKinney R, Ng A, Nieves J, O'Keefe R, Papapoulos S, Sen HT, van der Meulen MC, Weinstein RS, Whyte M; American Society for Bone and Mineral Research. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2010 Nov;25(11):2267-94. doi: 10.1002/jbmr.253.

    PubMed 20842676
  • Solling AS, Harslof T, Langdahl B. Treatment With Zoledronate Subsequent to Denosumab in Osteoporosis: A 2-Year Randomized Study. J Bone Miner Res. 2021 Jul;36(7):1245-1254. doi: 10.1002/jbmr.4305. Epub 2021 Apr 20.

    PubMed 33813753
  • Solling AS, Harslof T, Langdahl B. Treatment with Zoledronate Subsequent to Denosumab in Osteoporosis: a Randomized Trial. J Bone Miner Res. 2020 Oct;35(10):1858-1870. doi: 10.1002/jbmr.4098. Epub 2020 Jul 12.

    PubMed 32459005

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Zoledronic Acid in people with Osteoporosis, 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 4 inclusion and 12 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: finished, as of the sponsor's last update on 21 Feb 2021. 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. 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?

Yes. Results are posted in the registry (first posted 14 Jan 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

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 BMD From Baseline to 6 Months After the Zoledronic Acid Infusion. (time frame: baseline to 6 months after the zoledronic acid infusion). 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?

On the ClinicalTrials.gov record for NCT03087851, which also lists 9 linked publications.

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 21 Feb 2021.

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