Denosumab for Prevention of Acute Onset Immobilization-Induced Alterations of Bone Turnover: A Randomized Controlled Trial

Abstract

Metabolic bone disease is a devastating condition in critically ill patients admitted to an intensive care unit (ICU). We investigated the effects of early administration of the antiresorptive drug denosumab on bone metabolism in previously healthy patients. 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 4 weeks thereafter. Changes in serum levels of bone formation markers and urinary calcium excretion were secondary outcome parameters. Regarding serum levels of CTX-1, changes over time averaged À0.45 ng/mL (95% confidence interval [CI] À0.72, À0.18) for the denosumab group and 0.29 ng/mL (95% CI À0.01, 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 À0.74 ng/mL (95% CI À1.14, À0.34; p = 0.002). The group difference in changes between baseline and secondary osteocalcin measurement averaged À5.60 ng/mL (95% CI À11.2, À0.04; p = 0.049). The group difference in averaged change between baseline and secondary measurement of 24-hour urine calcium excretion was significant (À1.77 mmol/L [95% CI À3.48, À0.06; p = 0.044]). No adverse events could be attributed to the study medication. The investigation proved that a single application of denosumab early after admission to an ICU prevents acute immobilization-associated increase in bone resorption among previously healthy individuals.

A pilot feasibility randomised controlled trial of bone antiresorptive agents on bone turnover markers in critically ill women

“…There is a clear rationale for systematically investigating the role of antiresorptive agents during critical illness. First, critical illness is associated with increased bone turnover, characterised by increased osteoclastic bone resorption, an increase in immature osteoblast number and activity, and reduced activity of mature osteoblasts, of the magnitude described in postmenopausal females or metabolic bone disease 9 , 10 , 19 , 20 . There is limited evidence describing the mechanism and cellular pathways associated with this relationship.…”

“…In contrast, serum osteocalcin, a protein released by osteoclasts and important in bone mineralisation, increased similarly in both groups. A recent randomised controlled trial of early administration of denosumab in 14 ventilated women and men with severe intracerebral haemorrhage, reported an 80% decrease in serum CTX over 4-weeks with denosumab, compared to a 56% increase with placebo 20 . Denosumab was associated with a significant decrease in serum osteocalcin compared to placebo, with no difference in the bone formation marker P1NP.…”

An update of the effects of vitamins D and C in critical illness

“…Interestingly, bisphosphonates have been shown to significantly improve survival in patients at particularly high risk of mortality ( 63 ). In cases of prolonged immobilization, antiresorptive substances such as bisphosphonates or denosumab could be tried as a case-by-case decision ( 64 ). The basic prerequisite for this is an adequate vitamin D level as well as sufficient calcium intake, otherwise severe hypocalcemia may occur.…”

Pathophysiology and Therapeutic Management of Bone Loss in Patients with Critical Illness

“…The sole study investigating the relationship between denosumab administration and bone loss in critically ill patients was carried out by an Austrian research group. Wadiura and colleagues conducted a phase II clinical trial involving 14 previously healthy patients admitted to the ICU [126]. The investigators used a randomized, double-blind, placebo-controlled, non-inferiority design to assess whether prophylactic administration of denosumab is effective at preventing changes in bone turnover caused by acute immobilization.…”