Persistent Flu-Like Symptoms in a Patient With Glaucoma and Osteoporosis
Prevention
Can an acute phase reaction to zoledronic acid be prevented? Bourke and colleagues reported that baseline calcium and/or vitamin D intake do not appear to affect rates of acute phase reaction in data pooled from 2 trials of zoledronic acid in postmenopausal women.14 However, patients receiving zoledronic acid had 25-hydroxyvitamin D values > 20 ng/mL 86% of the time, and values > 30 ng/mL 36% of the time. Bourke and colleagues suggest that “coadministration of calcium and vitamin D with zoledronate may not be necessary for individuals not at risk of marked vitamin D deficiency.”14 However, they did not prospectively test this hypothesis.
In our patient, vitamin D deficiency had been identified and treated, nearly achieving 30 ng/mL. The 2020 guidelines for postmenopausal osteoporosis recommend maintaining serum 25-hydroxyvitamin D levels 30 to 50 ng/mL, advising to supplement with vitamin D3 as needed.5 The 2012 guidelines for osteoporosis in men from the Endocrine Society suggest that men with low vitamin D levels receive vitamin D supplements to raise the level > 30 ng/ml.4
Oral analgesics have been studied for the prevention of adverse effects related to zoledronic acid. Initiating 650 mg acetaminophen 45 minutes before zoledronic acid infusion and then every 6 hours over the next 3 days has been shown to significantly reduce symptoms.15 Acetaminophen or ibuprofen given every 6 hours for 3 days (starting 4 hours after zoledronic acid infusion) has been shown to reduce fever and other symptoms.16
Statins have been shown in vitro to prevent bisphosphonate-induced γϐ T cell activation.17 This has led to studies with various statins, although none have yet shown benefit in vivo. A double-blind, randomized, placebo-controlled trial of postmenopausal women for fluvastatin (single dose of 40 mg or 3 doses of 40 mg, each 24 hours apart) did not prevent acute phase reaction symptoms, nor did it prevent zoledronic acid-induced cytokine release.17 Rosuvastatin 10 mg daily starting 5 days before zoledronic acid treatment and taken for a total of 11 days did not show any difference in fever or pain.18 A protocol for pravastatin has been disseminated, but no study results have been published yet.19
Prophylactic dexamethasone has also been studied. A randomized double-blind, placebo-controlled trial of oral dexamethasone 4 mg at the time of first infusion of zoledronic acid found no significant difference in temperature change or symptom score over the following 3 days.20 Chen and colleagues compared the efficacy of acetaminophen alone vs acetaminophen plus dexamethasone over several days.21 Acetaminophen 500 mg was given on the day of infusion and 4 times daily for 3 to 7 days for both groups, while dexamethasone 4 mg was given for 3 to 7 days. The dexamethasone group reported substantially lower incidence of any acute phase reaction symptoms (34% vs 67%, P = .003). A more recent study by Murdoch and colleagues comparing dexamethasone (4 mg daily for 3 days with the first dose 90 minutes before zoledronic acid infusion) with placebo found that the dexamethasone group had a statistically significant lower mean temperature change and acute phase reaction symptom score.22
