Denosumab for prevention of immobilization-induced alterations of bone turnover in patients admitted to a neurosurgical intensive care unit: a randomized controlled trial

Background: Metabolic bone disease is a devastating condition in critically ill patients admitted to an intensive care unit (ICU). We investigated the effects of the antiresorptive drug denosumab on bone metabolism in previously healthy patients. Methods: Fourteen patients with severe intracerebral or subarachnoid hemorrhage were included in a phase 2 trial. Within 72 hours after ICU admission, they were randomized in a 1:1 ratio to receive denosumab 60 mg or placebo subcutaneously. The primary endpoint was group differences in the percentage change of C-terminal telopeptide of type 1 collagen (CTX-1) levels in serum from denosumab/placebo application to four weeks thereafter. Changes in serum levels of bone formation markers and urinary calcium excretion were secondary outcome parameters. Results: Regarding serum levels of CTX-1, changes over time averaged -0.45 ng/ml (95%CI: -0.72, -0.18) for the denosumab group and +0.29 ng/ml (95%CI: -0.01, +0.58) for the placebo group. The primary endpoint, the group difference in changes between baseline and secondary measurement, adjusted for baseline serum levels and baseline neurological status, averaged -0.74 ng/ml (95%CI: -1.14, -0.34; p=0.002). The group difference in changes between baseline and secondary osteocalcin measurement averaged -5.60 ng/ml (95%CI: -11.2, -0.04; p=0.049). The group difference in averaged change between baseline and secondary measurement of 24-hour urine calcium excretion was significant (-1.77 mmol/l (95%CI: -3.48; -0.06; p=0.044). No adverse events could be attributed to the study medication. Conclusion: The investigation proved that a single application of denosumab early after admission to an ICU prevents any immobilization-associated increase in bone resorption among previously healthy individuals.