Acute Phase Reactions After Zoledronic Acid Infusion

Protective Role of 25-hydroxyvitamin D and Previous Oral Bisphosphonate Therapy

Chiara Crotti, MD; Nelson B. Watts, MD; Maria De Santis, MD, PhD; Angela Ceribelli, MD, PhD; Gianluigi Fabbriciani, MD; Francesca Cavaciocchi, PhD; Bianca Marasini, MD; Carlo Selmi, MD, PhD; Marco Massarotti, MD


Endocr Pract. 2018;24(5):405-410. 

In This Article


Patients and Study Design

We prospectively enrolled 153 consecutive patients (age 71 ± 8 years, mean ± SD; all Caucasian women visiting the Division of Rheumatology and Clinical Immunology at Humanitas Research Hospital between October 2008 and June 2011. All had postmenopausal OP, were eligible for the first treatment with ZOL, and signed informed consent forms. Exclusion criteria were the diagnosis of a systemic autoimmune disease or hematologic condition and ongoing treatment with corticosteroids, immunosuppressants, and/or biologic therapies. We recorded clinical and laboratory data for each subject and performed a retrospective analysis of parameters including serum levels of 25(OH)D (Diasorin Liaison platform immunoassay, Saluggia, Italy) and calcium and parathyroid hormone (PTH), assessed within 4 weeks before ZOL infusion at the same laboratory that participated in an external quality assurance program. Data included previous treatment with oral BPs (and duration), as well as time between oral BP cessation and first ZOL infusion. Because of their suggested (but not proven)[10–13] protective role against APR, statin use was recorded. Reference ranges were 8.5 to 10.5 mg/dL for serum calcium and 10 to 72 pg/mL for PTH. Baseline levels of 25(OH)D ≥30 and <30 ng/mL were considered adequate and inadequate, respectively.[14] The diagnosis of OP was based on internationally accepted densitometric, laboratory, and clinical criteria.[15,16]

ZOL was infused at the dose of 5 mg diluted 0.9% in 100 mL of saline solution given over 15 to 30 minutes. At the time of ZOL infusion, all patients were informed of the possible occurrence of APR and asked to record symptoms (fever, chills, flushes, fatigue, musculoskeletal symptoms, and malaise). They were advised to take acetaminophen (1 g orally every 6–8 hours) in case of APR and continue until symptom resolution; however, no patient took acetaminophen prior to infusion or APR onset. APR was defined as the occurrence of fever (body temperature >37°C) or the presence of at least 1 of the following: flu-like symptoms such as fatigue, malaise, bone/muscle pain, or headache occurring within 24 to 36 hours after ZOL infusion.[2]

Statistical Analysis

Continuous variables are expressed as means and SDs and compared between groups with the Mann-Whitney test or χ 2 test with Cornfield's approximation, as appropriate. Serum 25(OH)D levels and previous oral BP therapy were considered risk factors for the development of APR and analyzed with contingency tables (odds ratio [OR], confidence interval [CI]) and logistic regression analysis. Receiver operating characteristic (ROC) curves were generated to define sensitivity and specificity for APR associated with 25(OH)D insufficiency. All statistical procedures were carried out using Stata software version 13 (Stata Corp, College Station, TX), and differences among groups were considered significant when P<.05.