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

• ClinicalTrials.gov Identifier: NCT04608630
• Recruitment Status: Recruiting
• First Posted: October 29, 2020
• Last Update Posted: July 20, 2021
• Sponsor: Australian and New Zealand Intensive Care Research Centre
• Information provided by (Responsible Party): Australian and New Zealand Intensive Care Research Centre

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 requiring admission to intensive care for greater than 24 hours.

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

Condition or disease	Intervention/treatment	Phase
Critical Illness; Osteoporosis	Drug: Denosumab 60 MG/ML; Drug: Zoledronic Acid 5Mg/Bag 100Ml Inj; Drug: Sodium Chloride 0.9% Intravenous; Drug: Sodium Chloride 0.9% Injection	Phase 2

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. 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 non-critically ill women, 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 women. The Bone Zone trial is a phase III multi-centre randomised placebo-controlled trial of 450 women aged 50-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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 450 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Bone Loss Prevention With Zoledronic Acid or Denosumab in Critically Ill Women - A Randomised Controlled Trial
• Actual Study Start Date: July 15, 2021
• Estimated Primary Completion Date: December 2023
• Estimated Study Completion Date: May 2025

Arms and Interventions

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: Zometa; Reclast; 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

Outcome Measures

Primary Outcome Measures :

1. 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

Secondary Outcome Measures :

1. 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
2. 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.
3. Vertebral fracture [ Time Frame: 12 months ]
   Incident vertebral fracture obtained during lateral BMD study
4. Falls [ Time Frame: 6 and 12 months ]
   Self-reported falls incidence and frequency
5. Hospital readmission [ Time Frame: 12 months ]
   All hospital readmissions within 12 months will be recorded
6. Mortality [ Time Frame: 12 months ]
   All deaths from enrolment to 12 months will be recorded
7. 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
8. 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)

Eligibility Criteria

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

Criteria

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 today
• 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:

• Active malignancy
• Metabolic bone disease
• Pregnancy
• Current estimated Glomerular Filtration Rate <30ml/min or receiving renal replacement therapy
• Known contraindication to denosumab or zoledronic acid
• Increased risk of osteonecrosis (poor dentition or oral hygiene, dental infection)
• Known 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 indication for anti-fracture therapy (known Bone Mineral Density T-score <-2.5 and/or known fragility fracture)
• 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

Contacts and Locations

Contacts

Contact: Allison Bone; +61 3 9903 0343; allison.bone@monash.edu

Contact: Tony Trapani; +61 3 9903 0343; tony.trapani@monash.edu

Locations

Australia, New South Wales

St Vincent's Health Sydney; Not yet recruiting

Sydney, New South Wales, Australia, 2010

Contact: Priya Nair, A/Prof

Australia, Victoria

Barwon Health, University Hospital Geelong; Recruiting

Geelong, Victoria, Australia, 3220

Contact: Neil Orford, A/Prof

Austin Health; Not yet recruiting

Melbourne, Victoria, Australia, 3084

Contact: Rinaldo Bellomo, Prof

Sponsors and Collaborators

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

More Information

• Responsible Party: Australian and New Zealand Intensive Care Research Centre
• ClinicalTrials.gov Identifier: NCT04608630
• Other Study ID Numbers: ANZIC-RC/NO001
• First Posted: October 29, 2020
• Last Update Posted: July 20, 2021
• Last Verified: July 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)
• Time Frame: As per the ANZIC Research Centre Data Sharing Policy
• Access Criteria: As per the ANZIC Research Centre Data Sharing Policy
• URL: https://www.monash.edu/__data/assets/pdf_file/0005/1098428/2017-10-05-ANZIC-RC-Terms-of-Ref.pdf

• 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

Keywords provided by Australian and New Zealand Intensive Care Research Centre:

Intensive Care Unit; Osteoporosis; Bone densitometry; Zoledronic acid; Denosumab

Additional relevant MeSH terms:

Osteoporosis; Critical Illness; Bone Diseases, Metabolic; Bone Diseases; Musculoskeletal Diseases; Metabolic Diseases; Disease Attributes; Pathologic Processes; Zoledronic Acid; Denosumab; Bone Density Conservation Agents; Physiological Effects of Drugs