Effect of denosumab and zoledronic acid on bone turnover markers in critically ill women

INTERVENTION: The intervention to be examined in this trial is the subcutaneous administration of denosumab 60mg compared to placebo (0.9% saline). The first dose of study drug will be given on day 3 in ICU after vitamin D assessment has been completed and supplementation provided, and in the absence of untreated or new infection. The second dose of intervention or placebo will be administered at the 6‐month follow‐up, after vitamin D assessment and supplementation as indicated. The first dose of study drug will be administered by an ICU registered nurse as a subcutaneous injection on study day 3 in ICU. Denosumab: *Formulation: 60mg denosumab in a single‐use pre‐filled 1ml syringe *Administration: subcutaneous injection administered in upper arm, upper thigh, or abdomen. Following administration of the study drug in ICU, monitoring for hypocalcaemia will occur a minimum of twice daily for 48‐hours. The majority of patients will have intra‐arterial and/or central venous vascular access, with regular blood gas measurement that include calcium performed. If routine testing provides twice‐daily calcium additional testing will not be 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 study drug will be administered by a registered nurse as a subcutaneous injection at 6‐months post‐ICU discharge. CONDITION: Critical illness Osteoporosis PRIMARY OUTCOME: Change in the serum bone turnover marker collagen type 1 cross‐linked c‐telopeptide (CTX) measured using the automated Roche Modular Analytics E170 analyser. Serum collagen type 1 cross‐linked c‐telopeptide limit of detection was 10 ng/L with inter‐assay coefficient of variations (CVs) of 6.5% at 361 ng/L, 3.8% at 816 ng/L and 3.4% at 3304 ng/L (n = 10). ; Incidence of serious adverse events (severe hypocalcaemia, new infection, and osteonecrosis jaw, assessed through examination, review of laboratory results, and review of participant medical records) Mortality (ascertained through interrogation of hospital database and participant follow‐up) INCLUSION CRITERIA: 1. Admitted to ICU 2. Female 3. Age >50 years or postmenopausal (amenorrhea for greater than 6‐months or serum FSH >40mIU/L) or Age < 50 years with bilateral salpingo‐oopherectomy 4. Expected duration of mechanical ventilation > 24 hrs SECONDARY OUTCOME: Annualised change in lumbar‐spine BMD measured by DEXA scan Annualised change in proximal femur BMD measured by DEXA scan Change in CTX measured using the automated Roche Modular Analytics E170 analyser. Serum collagen type 1 cross‐linked c‐telopeptide limit of detection was 10 ng/L with inter‐assay coefficient of variations (CVs) of 6.5% at 361 ng/L, 3.8% at 816 ng/L and 3.4% at 3304 ng/L (n = 10). Change in serum bone resorption marker type 1 N‐terminal procollagen (P1NP) measured using the automated Roche Modular Analytics E170 analyser. Serum type 1 N‐terminal procollagen inter‐assay CVs were 4.9% at 73 microgram/L, 2.6% at 392 microgram/L, and 2.1% at 768 microgram/L (n = 10) with a limit of detection of 5 microgram/L. Change in serum bone resorption marker type 1 N‐terminal procollagen (P1NP) measured using the automated Roche Modular Analytics E170 analyser. Serum type 1 N‐terminal procollagen inter‐assay CVs were 4.9% at 73 microgramg/L, 2.6% at 392 microgramg/L, and 2.1% at 768 microgramg/L (n = 10) with a limit of detection of 5 microgramg/L. Fragility fracture (ascertained through interrogation of radiological database and participant electronic medical record)