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

Intensive care patients face health issues that extend beyond their critical illness, including weakness, changes in quality of life, and an increase likelihood of disease and death. One area of post-ICU illness that may be preventable is fragility fracture. Fragility fractures occur due to weakening of bone, most commonly due to osteoporosis in postmenopausal women. Fragility fractures have devastating effects, resulting in hospitalisation, loss of independence and function, and increased likelihood of dying in the following year. Critical illness appears to increase the rate of bone loss, with studies showing an increased in markers of bone turnover, an accelerated loss of bone mass, and an increase in rate of fragility fractures, during and after critical illness. This is particularly evident in women, suggesting critically ill women face an extra injury to their bones at a time when they are already at risk. Medications that prevent or reduce bone loss have been extensively tested and shown to be effective in post-menopausal women, and other groups at risk of losing bone rapidly. This includes some types of cancer, and patients receiving therapies that cause bone loss. There is limited experience in using antiresorptive medications in critical illness, although some evidence suggests they may be effective at reducing bone turnover. Denosumab is a more recent antiresorptive medication that acts to prevent bone loss, and has been shown to be effective in large trials. It has not be used in critical illness, so we would like to perform a small study to ensure it is safe and effective in this group. Bisphosphonates, like Zoledronic Acid, have been used to treat critically ill patients with biochemical evidence of bone resorption, and shown to be associated with reduced mortality in retrospective studies of critically ill patients. Denosumab and Zolderonic Acid have side effects, including acute hypocalcaemia, flu like symptoms, osteonecrosis of the jaw, real impairment (zoledronic acid), change in immune function (denosumab), and post cessation bone loss (denosumab). Given these we plan to delay study drug administration until there is no active infection, and stable renal function. At the completion of this study we will examine the safety and effect of denosumab and zoledronic acid on bone turnover in postmenopausal critically ill women. If it appears safe and show signs of benefit, we will plan a larger study to assess effect on bone mass, fractures, and survival.