Bone Loss Prevention With Zoledronic Acid or Denosumab in Critically Ill Adults (BoneZone)

October 16, 2023 updated by: Australian and New Zealand Intensive Care Research Centre

Bone Loss Prevention With Zoledronic Acid or Denosumab in Critically Ill Adults - A Randomised Controlled Trial

The Bone Zone trial is a prospective, multi-centre, double-blind, phase II, randomised controlled trial evaluating the effect of denosumab or zoledronic acid compared to placebo on change in bone mineral density over one year in women aged 50 years or older and men aged 70 years or older requiring admission to intensive care for greater than 24 hours.

450 women aged 50 years or older and men aged 70 years or older, admitted to intensive care for greater than 24 hours will be recruited into the study from participating study centres.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Intensive care patients face health issues that extend beyond their critical illness. A specific area where critical illness may adversely affect the well-being of survivors is increased bone turnover during critical illness, and accelerated bone loss in subsequent years. Critical illness bone loss begins in the first days of critical illness, occurs in both men and women, and is greatest in post-menopausal women. Loss of bone mineral density is significantly greater at both the femur (-2+4.0% vs -0.7+1.1%, p=0.001) and spine (-2.9+4.1% vs -0.2+1.1%, p<0.001) in women in the year after critical illness compared to age-matched controls. One year after critical illness, 80% of women aged 50-years or greater are classified as osteoporotic or osteopaenic, compared to 71% of the approximately 3.7 million Australian women aged 50 year or greater. In the year after ICU admission a decrease in femur BMD of -1.52% (+ 2.85) is reported in men, which is significantly higher than age adjusted population controls (-0.42% + 1.13, diff -1.10% (95% CI -1.71 to -0.49, p<0.001). The annual incidence of first fracture in men aged 70 years and over is similar to the annual incidence of fracture in women aged 50 years and over. In addition, there is a dramatic increase in hip fractures as a proportion of all fracture's males aged 70 years and older in the general population. This population is most likely to suffer the major consequence of accelerated bone loss, fragility fracture, and the associated morbidity, loss of quality of life, and economic cost. Older women who survive critical illness have a significantly higher fragility fracture rate compared to community age-matched controls (Intensive Care Unit 4.33 vs control 2.81 per 100 patient years, adj HR 1.7 (95% CI 1.1-2.5), p=0.02).

Bone antiresorptive therapies are effective at reducing bone loss and decreasing fracture risk in non-critically ill populations. Zoledronic acid and denosumab represent antiresorptive agents with established efficacy in adults, and are potential target interventions able to be delivered during critical illness. Denosumab is a human monoclonal antibody directed against Receptor activator of nuclear factor kappa-Β ligand, a central stimulator of osteoclast activity, and is effective for prevention of fractures and bone loss in osteoporosis and malignancy. Zoledronic acid is a bisphosphonate class agent that binds to bone and suppresses bone resorption by entering osteoclasts and inhibiting the enzyme farnesyl pyrophosphate synthase, resulting in disruption of osteoclast attachment to bone surface. In addition to skeletal effects, there are possible mortality benefits associated with the use of antiresorptive medications in populations with increased bone loss.

There is currently insufficient high-quality evidence to support routine, early use of antiresorptive medications in critically ill adults. The Bone Zone trial is a phase III multi-centre randomised placebo-controlled trial of 450 women aged 50-years or greater and men aged 70-years or greater requiring intensive care admission for more than 2 calendar days, to determine the effect of denosumab or zoledronic acid on the prevention of bone loss in the year after critical illness.

Study Type

Interventional

Enrollment (Estimated)

450

Phase

  • Phase 2

Contacts and Locations

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

Study Contact

Study Contact Backup

Study Locations

  • Australia
    • New South Wales
      • Newcastle, New South Wales, Australia, 2305
      • Sydney, New South Wales, Australia, 2065
      • Sydney, New South Wales, Australia, 2148
      • Sydney, New South Wales, Australia
      • Sydney, New South Wales, Australia, 2010
        • Recruiting
        • St Vincent's Health Sydney
        • Contact:
          • Priya Nair, A/Prof
      • Wollongong, New South Wales, Australia, 2525
        • Recruiting
        • Wollongong Hospital, Illawarra Shoalhaven Health
        • Contact:
        • Principal Investigator:
          • Ahmad Elgendy
    • Queensland
    • South Australia
      • Adelaide, South Australia, Australia, 5000
    • Tasmania
      • Launceston, Tasmania, Australia, 7250
    • Victoria
      • Geelong, Victoria, Australia, 3220
        • Recruiting
        • Barwon Health, University Hospital Geelong
        • Contact:
          • Neil Orford, A/Prof
      • Melbourne, Victoria, Australia, 3004
      • Melbourne, Victoria, Australia, 3021
      • Melbourne, Victoria, Australia, 3084
        • Recruiting
        • Austin Health
        • Contact:
          • Rinaldo Bellomo, Prof
      • Melbourne, Victoria, Australia, 3052
      • Melbourne, Victoria, Australia, 3065
      • Melbourne, Victoria, Australia, 3011
      • Melbourne, Victoria, Australia, 3128
    • Western Australia
      • Perth, Western Australia, Australia, 6150
      • Perth, Western Australia, Australia, 6008
      • Perth, Western Australia, Australia, 6150
  • New Zealand
      • Auckland, New Zealand, 1023

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

50 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Female age ≥ 50 years or male age ≥ 70 years
  • Has been in the Intensive Care Unit for 2 or more calendar days and is not expected to be discharged from the Intensive Care Unit on the second day
  • Has required Intensive Care Unit level support (i.e. intravenous vasoactive drugs, or invasive mechanical ventilation, or non-invasive ventilation or high flow nasal oxygen at Fraction inspired Oxygen ≥0.4 and/or gas flows ≥40L/m) for a minimum cumulative duration of 6 hours
  • Expected to survive the current hospital admission

Exclusion Criteria:

  • Cancer related metastatic bone disease or multiple myeloma
  • Paget's disease
  • Pregnancy
  • Current estimated Glomerular Filtration Rate <30ml/min or receiving renal replacement therapy
  • Known contraindication to denosumab or zoledronic acid
  • Obvious holes in teeth or broken teeth or dental or gum infection
  • Known untreated hypoparathyroidism
  • Current treatment with anti-fracture agent (bisphosphonate, strontium or teriparatide within previous 2 years, or menopausal hormone therapy or romosozumab within previous 12-months or denosumab within previous 6 months)
  • Current fragility fracture of hip, spine, femur or forearm
  • Exceeds weight limit for BMD scan at site or unable to undertake Bone Mineral Density for any reason
  • International Normalised Ratio > 3.0 or Platelet count < 30 10^9/L

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: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Denosumab
Patients allocated to the Denosumab arm will receive Denosumab 60mg in 1ml, administered via subcutaneous injection on Study Days 1 and 180.
Drug: Denosumab 60 MG/ML
Patients allocated to the Denosumab arm will receive Denosumab 60mg in 1ml, administered via subcutaneous injection on Study Days 1 and 180.
Other Names:
  • Prolia
  • Xgeva
Drug: Sodium Chloride 0.9% Intravenous
Patients allocated to the placebo arm and Denosumab arm will receive 0.9% Sodium Chloride 100ml administered via intravenous infusion over at least 15 minutes on Day 1.
Other Names:
  • Saline
  • Placebo
Active Comparator: Zoledronic acid
Patients allocated to the Zoledronic acid arm will receive Zoledronic acid 5mg in 100ml 0.9% Sodium Chloride, administered via intravenous infusion over at least 15 minutes on Study Day 1.
Drug: Zoledronic Acid 5Mg/Bag 100Ml Inj
Patients allocated to the Zoledronic acid arm will receive Zoledronic acid 5mg in 100ml 0.9% Sodium Chloride, administered via intravenous infusion over at least 15 minutes on Study Day 1.
Other Names:
  • Reclast
  • Zometa
  • Aclasta
Drug: Sodium Chloride 0.9% Injection
Patients allocated to the placebo arm and Zoledronic acid arm will receive 0.9% Sodium Chloride 1ml administered via subcutaneous injection on Days 1 and Day 180
Other Names:
  • Saline
  • Placebo
Placebo Comparator: Placebo
Patients allocated to the placebo arm will receive 0.9% Sodium Chloride 1ml administered via subcutaneous injection on Days 1 and Day 180 and 0.9% Sodium Chloride 100ml administered via intravenous infusion over at least 15 minutes on Day 1.
Drug: Sodium Chloride 0.9% Intravenous
Patients allocated to the placebo arm and Denosumab arm will receive 0.9% Sodium Chloride 100ml administered via intravenous infusion over at least 15 minutes on Day 1.
Other Names:
  • Saline
  • Placebo
Drug: Sodium Chloride 0.9% Injection
Patients allocated to the placebo arm and Zoledronic acid arm will receive 0.9% Sodium Chloride 1ml administered via subcutaneous injection on Days 1 and Day 180
Other Names:
  • Saline
  • Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Annualised change in femoral neck bone mineral density for the year after Intensive Care discharge
Time Frame: 12 months
Change in femoral neck bone mineral density T-score between baseline and 12 months
12 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Annualised change in lumbar spine bone mineral density for the year after Intensive Care discharge
Time Frame: 12 months
Change in lumbar spine bone mineral densityT-score between baseline and 12 months
12 months
Clinical fragility fracture
Time Frame: 6 and 12 months
Self-reported incident clinical fractures obtained at follow-up visits. Information on the date, site, and circumstance of the fracture obtained by interview and X-ray report sought and confirmed by medical report.
6 and 12 months
Vertebral fracture
Time Frame: 12 months
Incident vertebral fracture obtained during lateral BMD study
12 months
Falls
Time Frame: 6 and 12 months
Self-reported falls incidence and frequency
6 and 12 months
Hospital readmission
Time Frame: 12 months
All hospital readmissions within 12 months will be recorded
12 months
Mortality
Time Frame: 12 months
All deaths from enrolment to 12 months will be recorded
12 months
Change in quality of life
Time Frame: 0, 6 and 12 months.
Quality of life will be measured using the European Quality of Life scale using a descriptive system scale from 1 to 5
0, 6 and 12 months.
Bone turnover outcomes (nested sub-study)
Time Frame: 0, Day 7, Day 28, 6 and 12 months
Change in the bone turnover markers serum collagen type 1 cross-linked c-telopeptide (CTX), and serum type 1 procollagen N-terminal propeptide (P1NP)
0, Day 7, Day 28, 6 and 12 months

Collaborators and Investigators

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

Sponsor

Australian and New Zealand Intensive Care Research Centre

Investigators

  • Study Chair: Neil Orford, A/Prof, Barwon Health; ANZIC Research Centre
  • Study Chair: Priya Nair, A/Prof, St Vincent's Health Sydney

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)

July 15, 2021

Primary Completion (Estimated)

December 1, 2023

Study Completion (Estimated)

May 1, 2025

Study Registration Dates

First Submitted

October 25, 2020

First Submitted That Met QC Criteria

October 25, 2020

First Posted (Actual)

October 29, 2020

Study Record Updates

Last Update Posted (Actual)

October 17, 2023

Last Update Submitted That Met QC Criteria

October 16, 2023

Last Verified

March 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ANZIC-RC/NO001

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

At the conclusion of the study, the study management committee will consider requests from researchers who provide a methodologically sound scientific proposal as per the Data Sharing Policy set out in the ANZIC Research Centre Terms of Reference.

IPD Sharing Time Frame

As per the ANZIC Research Centre Data Sharing Policy

IPD Sharing Access Criteria

As per the ANZIC Research Centre Data Sharing Policy

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

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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