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

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE2

Total Enrollment

450 participants

Study Classification

INTERVENTIONAL

Study Start Date

2021-07-15

Study Completion Date

2027-02-28

Brief Summary

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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.

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Detailed Description

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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.

Conditions

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Critical Illness Osteoporosis

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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Denosumab

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

Group Type ACTIVE_COMPARATOR

Denosumab 60 MG/ML

Intervention Type DRUG

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

Sodium Chloride 0.9% or 5% Dextrose Intravenous

Intervention Type DRUG

Patients allocated to the placebo arm and Denosumab arm will receive 0.9% Sodium Chloride or 5% Dextrose 100ml administered via intravenous infusion over at least 15 minutes on Day 1.

Zoledronic acid

Patients allocated to the Zoledronic acid arm will receive Zoledronic acid 5mg in 100ml 0.9% Sodium Chloride or 5% Dextrose, administered via intravenous infusion over at least 15 minutes on Study Day 1.

Group Type ACTIVE_COMPARATOR

Zoledronic Acid 5Mg/Bag 100Ml Inj

Intervention Type DRUG

Patients allocated to the Zoledronic acid arm will receive Zoledronic acid 5mg in 100ml 0.9% Sodium Chloride or 5% Dextrose, administered via intravenous infusion over at least 15 minutes on Study Day 1.

Sodium Chloride 0.9% Injection

Intervention Type DRUG

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

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 or 5% Dextrose administered via intravenous infusion over at least 15 minutes on Day 1.

Group Type PLACEBO_COMPARATOR

Sodium Chloride 0.9% or 5% Dextrose Intravenous

Intervention Type DRUG

Patients allocated to the placebo arm and Denosumab arm will receive 0.9% Sodium Chloride or 5% Dextrose 100ml administered via intravenous infusion over at least 15 minutes on Day 1.

Sodium Chloride 0.9% Injection

Intervention Type DRUG

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

Interventions

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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.

Intervention Type 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 or 5% Dextrose, administered via intravenous infusion over at least 15 minutes on Study Day 1.

Intervention Type DRUG

Sodium Chloride 0.9% or 5% Dextrose Intravenous

Patients allocated to the placebo arm and Denosumab arm will receive 0.9% Sodium Chloride or 5% Dextrose 100ml administered via intravenous infusion over at least 15 minutes on Day 1.

Intervention Type 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

Intervention Type DRUG

Other Intervention Names

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Prolia Xgeva Zometa Reclast Aclasta Saline Placebo Saline Placebo

Eligibility Criteria

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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

Minimum Eligible Age

50 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Neil Orford, A/Prof

Role: STUDY_CHAIR

Barwon Health; ANZIC Research Centre

Priya Nair, A/Prof

Role: STUDY_CHAIR

St Vincent's Health Sydney

Locations

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John Hunter Hospital

Newcastle, New South Wales, Australia

Site Status RECRUITING

St Vincent's Health Sydney

Sydney, New South Wales, Australia

Site Status RECRUITING

Prince of Wales Hospital

Sydney, New South Wales, Australia

Site Status RECRUITING

Blacktown Hospital

Sydney, New South Wales, Australia

Site Status RECRUITING

Royal Prince Alfred Hospital

Sydney, New South Wales, Australia

Site Status RECRUITING

Wollongong Hospital, Illawarra Shoalhaven Health

Wollongong, New South Wales, Australia

Site Status RECRUITING

Sunshine Coast University Hospital

Birtinya, Queensland, Australia

Site Status RECRUITING

The Wesley Hospital

Brisbane, Queensland, Australia

Site Status RECRUITING

Gold Coast University Hospital

Southport, Queensland, Australia

Site Status RECRUITING

Royal Adelaide Hospital

Adelaide, South Australia, Australia

Site Status RECRUITING