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

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ClinicalTrials.gov Identifier: NCT03087851
Recruitment Status : Active, not recruiting
First Posted : March 23, 2017
Last Update Posted : April 3, 2019
Sponsor:
Collaborators:
University of Aarhus
Amgen
Information provided by (Responsible Party):
Anne Sophie Sølling, Aarhus University Hospital

Brief 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 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.

Condition or disease Intervention/treatment Phase
Osteoporosis Drug: Zoledronic Acid Phase 4

Detailed Description:

Background: Denosumab is an antibody against receptor-activator of nuclear factor kappa-B ligand that prevents re-cruitment and differentiation of osteoclasts. Treatment decreases bone resorption and fracture risk. After discontinu-ation, 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 per-formed 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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Treatment With Zoledronic Acid Subsequent to Denosumab in Osteoporosis
Actual Study Start Date : March 13, 2017
Estimated Primary Completion Date : September 1, 2020
Estimated Study Completion Date : December 1, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Osteoporosis

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

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

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




Primary Outcome Measures :
  1. BMD lumbar spine [ Time Frame: 6 months ]
    Change in lumbar spine BMD from baseline to 6 months after the zoledronic acid infusion.

  2. BMD total hip, femoral neck and spine [ Time Frame: Two years ]
    The proportion of patients who fails to maintain BMD (total hip, femoral neck and spine). Failure is defined as ≥ 3 % BMD loss at the lumbar spine or ≥ 5 % BMD loss at the femoral neck or total hip.


Secondary Outcome Measures :
  1. BMD total hip and femoral neck [ Time Frame: One year ]
    Changes in total hip, femoral neck and lumbar spine BMD from baseline to one year after the zoledronic acid infusion.

  2. BMD total hip, femoral neck and lumbar spine [ Time Frame: Two years ]
    Changes in total hip, femoral neck and lumbar spine BMD from baseline to two years after the zoledronic acid infusion.

  3. Bone microarchitecture: Trabecular bone volume fraction and cortical porosity [ Time Frame: One year ]
    Changes in trabecular bone volume fraction and 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.

  4. Bone turnover markers: S-carboxy-terminal collagen crosslinks (CTX) and s-procollagen type I N-terminal propeptide (PINP) [ Time Frame: Six months ]
    Changes in CTX and PINP from baseline to six months after the zoledronic acid infusion.

  5. Bone turnover markers: S-carboxy-terminal collagen crosslinks (CTX) and s-procollagen type I N-terminal propeptide (PINP) [ Time Frame: One year ]
    Changes in CTX and PINP from baseline to 12 months after the zoledronic acid infusion.

  6. Morphometric vertebral fractures [ Time Frame: One and two years ]
    Morphometric vertebral fractures assessed by vertebral fracture assessment (VFA) one and two years after the zoledronic acid infusion.



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Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03087851


Locations
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Denmark
Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark
Aarhus, Denmark, 8000
Sponsors and Collaborators
Aarhus University Hospital
University of Aarhus
Amgen
Investigators
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Study Director: Bente L Langdahl, MD PhD DMSc Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark

Publications:

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Responsible Party: Anne Sophie Sølling, MD, PhD student, Aarhus University Hospital
ClinicalTrials.gov Identifier: NCT03087851     History of Changes
Other Study ID Numbers: 2015-005529-37
First Posted: March 23, 2017    Key Record Dates
Last Update Posted: April 3, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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
Keywords provided by Anne Sophie Sølling, Aarhus University Hospital:
Denosumab
Bone turnover markers
Bone mineral density
Additional relevant MeSH terms:
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Osteoporosis
Bone Diseases, Metabolic
Bone Diseases
Musculoskeletal Diseases
Metabolic Diseases
Zoledronic Acid
Denosumab
Bone Density Conservation Agents
Physiological Effects of Drugs