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

Primary Purpose

Critical Illness, Osteoporosis

Status
Recruiting
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Denosumab 60 MG/ML
Zoledronic Acid 5Mg/Bag 100Ml Inj
Sodium Chloride 0.9% Intravenous
Sodium Chloride 0.9% Injection
Sponsored by
Australian and New Zealand Intensive Care Research Centre
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Critical Illness focused on measuring Intensive Care Unit, Osteoporosis, Bone densitometry, Zoledronic acid, Denosumab

Eligibility Criteria

50 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Female
  • Age ≥ 50 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, teriparatide within previous 2 years, or menopausal hormone therapy within previous 12-months or denosumab within previous 6 months)
  • Current fragility fracture of hip, spine, femur or forearm
  • Weight >120 kg or unable to undertake Bone Mineral Density for any reason
  • International Normalised Ratio > 3.0 or Platelet count < 30 10^9/L

Sites / Locations

  • John Hunter Hospital
  • St Vincent's Health SydneyRecruiting
  • Royal North Shore HospitalRecruiting
  • Blacktown Hospital
  • Royal Prince Alfred HospitalRecruiting
  • Wollongong Hospital, Illawarra Shoalhaven HealthRecruiting
  • Sunshine Coast University Hospital
  • The Wesley HospitalRecruiting
  • Gold Coast University HospitalRecruiting
  • Royal Adelaide HospitalRecruiting
  • Launceston General HospitalRecruiting
  • Barwon Health, University Hospital GeelongRecruiting
  • Alfred HealthRecruiting
  • Western Health - Footscray HospitalRecruiting
  • Western Health - Sunshine HospitalRecruiting
  • Royal Melbourne HospitalRecruiting
  • St Vincents Hospital MelbourneRecruiting
  • Austin HealthRecruiting
  • Eastern Health - Box Hill HospitalRecruiting
  • St John of God Hospital SubiacoRecruiting
  • Fiona Stanley HospitalRecruiting
  • St John of God Hospital MurdochRecruiting
  • Auckland City HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Active Comparator

Placebo Comparator

Arm Label

Denosumab

Zoledronic acid

Placebo

Arm Description

Patients allocated to the Denosumab arm will receive Denosumab 60mg in 1ml, administered via subcutaneous injection on Study Days 1 and 180.

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.

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Annualised change in lumbar spine bone mineral density for the year after Intensive Care discharge
Change in lumbar spine bone mineral densityT-score between baseline and 12 months
Clinical fragility fracture
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.
Vertebral fracture
Incident vertebral fracture obtained during lateral BMD study
Falls
Self-reported falls incidence and frequency
Hospital readmission
All hospital readmissions within 12 months will be recorded
Mortality
All deaths from enrolment to 12 months will be recorded
Change in quality of life
Quality of life will be measured using the European Quality of Life scale using a descriptive system scale from 1 to 5
Bone turnover outcomes (nested sub-study)
Change in the bone turnover markers serum collagen type 1 cross-linked c-telopeptide (CTX), and serum type 1 procollagen N-terminal propeptide (P1NP)

Full Information

First Posted
October 25, 2020
Last Updated
October 16, 2023
Sponsor
Australian and New Zealand Intensive Care Research Centre
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1. Study Identification

Unique Protocol Identification Number
NCT04608630
Brief Title
Bone Loss Prevention With Zoledronic Acid or Denosumab in Critically Ill Adults
Acronym
BoneZone
Official Title
Bone Loss Prevention With Zoledronic Acid or Denosumab in Critically Ill Adults - A Randomised Controlled Trial
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
July 15, 2021 (Actual)
Primary Completion Date
December 2023 (Anticipated)
Study Completion Date
May 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Australian and New Zealand Intensive Care Research Centre

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Critical Illness, Osteoporosis
Keywords
Intensive Care Unit, Osteoporosis, Bone densitometry, Zoledronic acid, Denosumab

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
450 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Denosumab
Arm Type
Active Comparator
Arm Description
Patients allocated to the Denosumab arm will receive Denosumab 60mg in 1ml, administered via subcutaneous injection on Study Days 1 and 180.
Arm Title
Zoledronic acid
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Denosumab 60 MG/ML
Other Intervention Name(s)
Prolia, Xgeva
Intervention Description
Patients allocated to the Denosumab arm will receive Denosumab 60mg in 1ml, administered via subcutaneous injection on Study Days 1 and 180.
Intervention Type
Drug
Intervention Name(s)
Zoledronic Acid 5Mg/Bag 100Ml Inj
Other Intervention Name(s)
Zometa, Reclast, Aclasta
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Sodium Chloride 0.9% Intravenous
Other Intervention Name(s)
Saline, Placebo
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Sodium Chloride 0.9% Injection
Other Intervention Name(s)
Saline, Placebo
Intervention Description
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
Primary Outcome Measure Information:
Title
Annualised change in femoral neck bone mineral density for the year after Intensive Care discharge
Description
Change in femoral neck bone mineral density T-score between baseline and 12 months
Time Frame
12 months
Secondary Outcome Measure Information:
Title
Annualised change in lumbar spine bone mineral density for the year after Intensive Care discharge
Description
Change in lumbar spine bone mineral densityT-score between baseline and 12 months
Time Frame
12 months
Title
Clinical fragility fracture
Description
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.
Time Frame
6 and 12 months
Title
Vertebral fracture
Description
Incident vertebral fracture obtained during lateral BMD study
Time Frame
12 months
Title
Falls
Description
Self-reported falls incidence and frequency
Time Frame
6 and 12 months
Title
Hospital readmission
Description
All hospital readmissions within 12 months will be recorded
Time Frame
12 months
Title
Mortality
Description
All deaths from enrolment to 12 months will be recorded
Time Frame
12 months
Title
Change in quality of life
Description
Quality of life will be measured using the European Quality of Life scale using a descriptive system scale from 1 to 5
Time Frame
0, 6 and 12 months.
Title
Bone turnover outcomes (nested sub-study)
Description
Change in the bone turnover markers serum collagen type 1 cross-linked c-telopeptide (CTX), and serum type 1 procollagen N-terminal propeptide (P1NP)
Time Frame
0, Day 7, Day 28, 6 and 12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Allison Bone
Phone
+61 3 9903 0343
Email
allison.bone@monash.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Tony Trapani
Phone
+61 3 9903 0343
Email
tony.trapani@monash.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Neil Orford, A/Prof
Organizational Affiliation
Barwon Health; ANZIC Research Centre
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Priya Nair, A/Prof
Organizational Affiliation
St Vincent's Health Sydney
Official's Role
Study Chair
Facility Information:
Facility Name
John Hunter Hospital
City
Newcastle
State/Province
New South Wales
ZIP/Postal Code
2305
Country
Australia
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Rakshit Panwar
Email
rakshit.panwar@health.nsw.gov.au
Facility Name
St Vincent's Health Sydney
City
Sydney
State/Province
New South Wales
ZIP/Postal Code
2010
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Priya Nair, A/Prof
Facility Name
Royal North Shore Hospital
City
Sydney
State/Province
New South Wales
ZIP/Postal Code
2065
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Elizabeth Yarad
Email
Elizabeth.Yarad@health.nsw.gov.au
Facility Name
Blacktown Hospital
City
Sydney
State/Province
New South Wales
ZIP/Postal Code
2148
Country
Australia
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Amr Elrakaiby
Email
amr.elrakaiby@nsw.gov.au
Facility Name
Royal Prince Alfred Hospital
City
Sydney
State/Province
New South Wales
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
David Gattas
Email
david.gattas@sydney.edu.au
Facility Name
Wollongong Hospital, Illawarra Shoalhaven Health
City
Wollongong
State/Province
New South Wales
ZIP/Postal Code
2525
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Wenli Geng
Phone
0242551355
Email
wenli.geng@health.nsw.gov.au
First Name & Middle Initial & Last Name & Degree
Ahmad Elgendy
Facility Name
Sunshine Coast University Hospital
City
Birtinya
State/Province
Queensland
ZIP/Postal Code
4575
Country
Australia
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Peter Garrett
Email
Peter.garrett@health.qld.gov.au
Facility Name
The Wesley Hospital
City
Brisbane
State/Province
Queensland
ZIP/Postal Code
4066
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Bala Venkatesh
Email
bvenkatesh@georgeinstitute.org.au
Facility Name
Gold Coast University Hospital
City
Southport
State/Province
Queensland
ZIP/Postal Code
4215
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
James Winearls
Email
James.Winearls@health.qld.gov.au
Facility Name
Royal Adelaide Hospital
City
Adelaide
State/Province
South Australia
ZIP/Postal Code
5000
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Mark Plummer
Email
Mark.Plummer@sa.gov.au
Facility Name
Launceston General Hospital
City
Launceston
State/Province
Tasmania
ZIP/Postal Code
7250
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Matthew Brain
Email
matt.brain@ths.tas.gov.au
Facility Name
Barwon Health, University Hospital Geelong
City
Geelong
State/Province
Victoria
ZIP/Postal Code
3220
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Neil Orford, A/Prof
Facility Name
Alfred Health
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3004
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Emma Martin
Email
E.Martin2@alfred.org.au
Facility Name
Western Health - Footscray Hospital
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3011
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Craig French
Email
Craig.French@wh.org.au
Facility Name
Western Health - Sunshine Hospital
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3021
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Craig French
Email
Craig.French@wh.org.au
Facility Name
Royal Melbourne Hospital
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3052
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Emily See
Email
emily.see@mh.org.au
Facility Name
St Vincents Hospital Melbourne
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3065
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jenny Holmes
Email
Jennifer.Holmes@svha.org.au
Facility Name
Austin Health
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3084
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Rinaldo Bellomo, Prof
Facility Name
Eastern Health - Box Hill Hospital
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3128
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Peter Chan
Email
Peter.Chan@easternhealth.org.au
Facility Name
St John of God Hospital Subiaco
City
Perth
State/Province
Western Australia
ZIP/Postal Code
6008
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ed Litton
Email
ed_litton@hotmail.com
Facility Name
Fiona Stanley Hospital
City
Perth
State/Province
Western Australia
ZIP/Postal Code
6150
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ed Litton
Email
ed.litton@health.wa.gov.au
Facility Name
St John of God Hospital Murdoch
City
Perth
State/Province
Western Australia
ZIP/Postal Code
6150
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Adrain Regli
Email
adrian.regli@health.wa.gov.au
Facility Name
Auckland City Hospital
City
Auckland
ZIP/Postal Code
1023
Country
New Zealand
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Shay McGuinness
Email
ShayMc@adhb.govt.nz

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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 URL
https://www.monash.edu/__data/assets/pdf_file/0005/1098428/2017-10-05-ANZIC-RC-Terms-of-Ref.pdf

Learn more about this trial

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

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