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

Osteoporosis Clinical Trial

— BoneZone  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04608630
• Other study ID #: ANZIC-RC/NO001
• Status: Recruiting
• Phase: Phase 2
• Start date: July 15, 2021
• Est. completion date: May 2025

Study information

• Verified date: March 2023
• Source: Australian and New Zealand Intensive Care Research Centre
• Contact: Allison Bone
• Phone: +61 3 9903 0343
• Email: allison.bone[@]monash.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 450
• Est. completion date: May 2025
• Est. primary completion date: December 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Critical Illness
• Osteoporosis

Intervention

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.
• 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.
• 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.
• 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

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Sunshine Coast University Hospital	Birtinya	Queensland
Australia	The Wesley Hospital	Brisbane	Queensland
Australia	Barwon Health, University Hospital Geelong	Geelong	Victoria
Australia	Launceston General Hospital	Launceston	Tasmania
Australia	Alfred Health	Melbourne	Victoria
Australia	Austin Health	Melbourne	Victoria
Australia	Eastern Health - Box Hill Hospital	Melbourne	Victoria
Australia	Royal Melbourne Hospital	Melbourne	Victoria
Australia	St Vincents Hospital Melbourne	Melbourne	Victoria
Australia	Western Health - Footscray Hospital	Melbourne	Victoria
Australia	Western Health - Sunshine Hospital	Melbourne	Victoria
Australia	John Hunter Hospital	Newcastle	New South Wales
Australia	Fiona Stanley Hospital	Perth	Western Australia
Australia	St John of God Hospital Murdoch	Perth	Western Australia
Australia	St John of God Hospital Subiaco	Perth	Western Australia
Australia	Gold Coast University Hospital	Southport	Queensland
Australia	Blacktown Hospital	Sydney	New South Wales
Australia	Royal North Shore Hospital	Sydney	New South Wales
Australia	Royal Prince Alfred Hospital	Sydney	New South Wales
Australia	St Vincent's Health Sydney	Sydney	New South Wales
Australia	Wollongong Hospital, Illawarra Shoalhaven Health	Wollongong	New South Wales
New Zealand	Auckland City Hospital	Auckland

Sponsors (1)

Lead Sponsor	Collaborator
Australian and New Zealand Intensive Care Research Centre

Countries where clinical trial is conducted

Australia,  New Zealand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	Vertebral fracture	Incident vertebral fracture obtained during lateral BMD study	12 months
Secondary	Falls	Self-reported falls incidence and frequency	6 and 12 months
Secondary	Hospital readmission	All hospital readmissions within 12 months will be recorded	12 months
Secondary	Mortality	All deaths from enrolment to 12 months will be recorded	12 months
Secondary	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.
Secondary	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