Clinical trial NCT04608630: Bone Loss Prevention With Zoledronic Acid or Denosumab in Critically Ill Adults
Official title: Bone Loss Prevention With Zoledronic Acid or Denosumab in Critically Ill Adults - A Randomised Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Critical Illness
Osteoporosis
Keywords: Intensive Care Unit
Osteoporosis
Bone densitometry
Zoledronic acid
Denosumab
Lead sponsor: Australian and New Zealand Intensive Care Research Centre
Sponsor class: OTHER
First posted: 2020-10-29
Enrollment: 450
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Annualised change in femoral neck bone mineral density for the year after Intensive Care discharge
timeFrame: 12 months
Secondary outcomes:
measure: Annualised change in lumbar spine bone mineral density for the year after Intensive Care discharge
timeFrame: 12 months
measure: Clinical fragility fracture
timeFrame: 6 and 12 months
measure: Vertebral fracture
timeFrame: 12 months
measure: Falls
timeFrame: 6 and 12 months
measure: Hospital readmission
timeFrame: 12 months
measure: Mortality
timeFrame: 12 months
measure: Change in quality of life
timeFrame: 0, 6 and 12 months.
measure: Bone turnover outcomes (nested sub-study)
timeFrame: Day 0, Day 7, 6 and 12 months
Other outcomes:
Locations:
city: Newcastle
country: Australia
facility: John Hunter Hospital
state: New South Wales
city: Sydney
country: Australia
facility: St Vincent's Health Sydney
state: New South Wales
city: Sydney
country: Australia
facility: Prince of Wales Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Blacktown Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Wollongong
country: Australia
facility: Wollongong Hospital, Illawarra Shoalhaven Health
state: New South Wales
city: Birtinya
country: Australia
facility: Sunshine Coast University Hospital
state: Queensland
city: Brisbane
country: Australia
facility: The Wesley Hospital
state: Queensland
city: Southport
country: Australia
facility: Gold Coast University Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Launceston
country: Australia
facility: Launceston General Hospital
state: Tasmania
city: Geelong
country: Australia
facility: Barwon Health, University Hospital Geelong
state: Victoria
city: Melbourne
country: Australia
facility: Alfred Health
state: Victoria
city: Melbourne
country: Australia
facility: Western Health - Footscray Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Western Health - Sunshine Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Melbourne
country: Australia
facility: St Vincents Hospital Melbourne
state: Victoria
city: Melbourne
country: Australia
facility: Austin Health
state: Victoria
city: Melbourne
country: Australia
facility: Eastern Health - Box Hill Hospital
state: Victoria
city: Perth
country: Australia
facility: St John of God Hospital Subiaco
state: Western Australia
city: Perth
country: Australia
facility: Fiona Stanley Hospital
state: Western Australia
city: Perth
country: Australia
facility: St John of God Hospital Murdoch
state: Western Australia
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Wellington
country: New Zealand
facility: Wellington Regional Hospital
Study officials:
affiliation: Barwon Health; ANZIC Research Centre
name: Neil Orford, A/Prof
role: STUDY_CHAIR
affiliation: St Vincent's Health Sydney
name: Priya Nair, A/Prof
role: STUDY_CHAIR
References: