Treatment With Zoledronic Acid Subsequent to Denosumab in Osteoporosis (ZOLARMAB)

February 3, 2021 updated by: Anne Sophie Sølling, Aarhus University Hospital
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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

61

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Denmark
      • Aarhus, Denmark, 8000
        • Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

46 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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
  • 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: 6-month group
Zoledronic 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.
Drug: Zoledronic Acid
Intravenous infusion of 5 mg zoledronic acid
Other Names:
  • Zoledronate
Active Comparator: 9-months group

Zoledronic 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.
Drug: Zoledronic Acid
Intravenous infusion of 5 mg zoledronic acid
Other Names:
  • Zoledronate
Active Comparator: Observation group

Zoledronic 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.
Drug: Zoledronic Acid
Intravenous infusion of 5 mg zoledronic acid
Other Names:
  • Zoledronate

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Change in lumbar spine BMD from baseline to 6 months after the zoledronic acid infusion.
baseline to 6 months after the zoledronic acid infusion
Number of Participants Who Fail to Maintain BMD
Time Frame: 2 years after the first ZOL treatment
Failure is defined as ≥ 3 % BMD loss at the lumbar spine
2 years after the first ZOL treatment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Changes in BMD From Baseline to One Year After the Zoledronic Acid Infusion.
Time Frame: 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.
from baseline to one year after the zoledronic acid infusion
Changes in BMD From Baseline to Two Years After the Zoledronic Acid Infusion.
Time Frame: 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.
from baseline to two years 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.
Time Frame: 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.
from baseline to one year after the zoledronic acid infusion.
Changes in p-CTX From Baseline to Six Months After the Zoledronic Acid Infusion.
Time Frame: from baseline to six months after the zoledronic acid infusion.
Changes in p-CTX from baseline to six months after the zoledronic acid infusion.
from baseline to six months after the zoledronic acid infusion.
Changes in p-CTX From Baseline to 12 Months After the Zoledronic Acid Infusion.
Time Frame: from baseline to 12 months after the zoledronic acid infusion.
Changes in p-CTX from baseline to 12 months after the zoledronic acid infusion.
from baseline to 12 months after the zoledronic acid infusion.
Morphometric Vertebral Fractures Assessed by Vertebral Fracture Assessment (VFA) One and Two Years After the Zoledronic Acid Infusion.
Time Frame: 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.
one and two years after the zoledronic acid infusion.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Aarhus University Hospital

Collaborators

University of Aarhus
Amgen

Investigators

  • Study Director: Bente L Langdahl, MD PhD DMSc, Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 13, 2017

Primary Completion (Actual)

August 1, 2020

Study Completion (Actual)

August 1, 2020

Study Registration Dates

First Submitted

March 13, 2017

First Submitted That Met QC Criteria

March 17, 2017

First Posted (Actual)

March 23, 2017

Study Record Updates

Last Update Posted (Actual)

February 21, 2021

Last Update Submitted That Met QC Criteria

February 3, 2021

Last Verified

February 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2015-005529-37

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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