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

Study Overview
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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.

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.

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

Conditions
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Critical Illness, Osteoporosis

Intervention / Treatment
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* Drug: Denosumab 60 MG/ML
* Drug: Zoledronic Acid 5Mg/Bag 100Ml Inj
* Drug: Sodium Chloride 0.9% Intravenous
* Drug: Sodium Chloride 0.9% Injection


Participation Criteria
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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

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Denosumab<br>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<br>* Patients allocated to the Denosumab arm will receive Denosumab 60mg in 1ml, administered via subcutaneous injection on Study Days 1 and 180.<br>* Other names: Xgeva;Drug: Sodium Chloride 0.9% Intravenous<br>* 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.<br>* Other names: Placebo;|
| Active Comparator: Zoledronic acid<br>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<br>* 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.<br>* Other names: Aclasta;Drug: Sodium Chloride 0.9% Injection<br>* 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<br>* Other names: Placebo;|
| Placebo Comparator: Placebo<br>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<br>* 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.<br>* Other names: Placebo;Drug: Sodium Chloride 0.9% Injection<br>* 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<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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 | Change in lumbar spine bone mineral densityT-score between baseline and 12 months | 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. | 6 and 12 months | 
| Vertebral fracture | Incident vertebral fracture obtained during lateral BMD study | 12 months | 
| Falls | Self-reported falls incidence and frequency | 6 and 12 months | 
| Hospital readmission | All hospital readmissions within 12 months will be recorded | 12 months | 
| Mortality | All deaths from enrolment to 12 months will be recorded | 12 months | 
| 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 | 0, 6 and 12 months. | 
| 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) | 0, Day 7, Day 28, 6 and 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Intensive Care Unit, Osteoporosis, Bone densitometry, Zoledronic acid, Denosumab