Effect of Zoledronic Acid or Denosumab on Bone Loss in Critically Ill Adults – A Randomised Controlled Trial

The three interventions to be examined in this trial is the subcutaneous administration of denosumab 60mg (Arm 1), intravenous administration of zoledronic acid 5mg (Arm 2) and placebo (0.9% sodium chloride (SC or IV) or 5% dextrose (IV only)) (Arm 3). Participants will be randomised to one arm of the trial. The first dose of trial drug will be administered when the patient is deemed to have recovered from their acute illness and is being considered for discharge from ICU in the next 24-48 hours or is in a chronic phase of critical illness. This day of trial drug administration is Day 0. Vitamin D supplementation: Following enrolment and randomisation, an intramuscular (IM) bolus supplement of 50,000 IU will be administered prior to trial drug administration. This will be followed by an oral (PO) daily dose of 1000 IU for the duration of the trial. If the baseline level is found to be 100 nmol/L, daily oral vitamin D supplementation will be ceased. At 6 months after enrolment patients will be asked to return to the hospital, at which time patients in the denosumab arm of the trial will receive another injection of this drug, while the other two groups will receive a placebo injection Denosumab: Formulation: 60mg in a single-use 1mL syringe Administration: subcutaneous injection administered in upper arm, upper thigh, or abdomen. Frequency: 6 monthly Zoledronic acid: Formulation: 5mg in 100mL bag of 0.9% sodium chloride or 5% dextrose Administration: intravenous infusion over at least 15 minutes Frequency: once only Following administration of the trial drug, monitoring for hypocalcaemia will occur 24-48 hours post trial drug and Day 7 post trial drug. The majority of patients will have intra-arterial and/or central venous vascular access, with regular blood gas measurement that include calcium performed. Hypocalcaemia is defined as ionized calcium <0.9 mmol/L, based on ICU protocols for treatment of hypocalcaemia in other settings, ie. citrate induced hypocalcaemia with the use of citrate for anticoagulation. Hypocalcaemia will be treated with parenteral calcium, as per hospital dosing and administration protocols, to maintain a target ionized calcium range of 0.9-1.1 mmol/L. The second dose of trial drug and/or placebo will be administered at 6 months. All sites will be monitored by the Bone Zone Project manager or delegate to ensure the trial intervention is delivered as described. At this time participant hospital records (including pathology reports, bone densitometry reports, medication charts, progress notes) will be reviewed. A subset of participants will be included in a nested bone turnover marker and pathology sub study. 50 participants from each arm will be included in the sub study. The first 50 participants from each arm who are enrolled at a participating site and provide consent to participate in the sub study will be included.