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

  • STATUS
    Recruiting
  • End date
    May 25, 2025
  • participants needed
    450
  • sponsor
    Australian and New Zealand Intensive Care Research Centre
Updated on 25 July 2021
denosumab
bone mineral density
zoledronic acid

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.

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 kappaligand, 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.

Details
Condition Osteopenia, Osteoporosis, Critical Illness, critically ill
Treatment Denosumab 60 MG/ML, Zoledronic Acid 5Mg/Bag 100Ml Inj, Sodium Chloride 0.9% Intravenous, Sodium Chloride 0.9% Injection, Sodium Chloride 0.9% Injection
Clinical Study IdentifierNCT04608630
SponsorAustralian and New Zealand Intensive Care Research Centre
Last Modified on25 July 2021

Eligibility

Yes No Not Sure

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
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