Acute Phase Reactions After Intravenous Infusion of Zoledronic Acid in Japanese Patients with Osteoporosis: Sub-analyses of the Phase III ZONE Study

Abstract

In a clinical trial involving Japanese patients with osteoporosis, post hoc analyses were performed to evaluate the incidence of acute phase reactions (APRs) after infusion of zoledronic acid (ZOL). The results highlighted differences in baseline factors between patients with vs without APRs. Changes in efficacy indicators such as bone turnover markers (BTMs) also showed significant differences. We, therefore, investigated the factors involved in the development of APRs in Japanese patients treated with a once-yearly intravenous infusion of ZOL 5 mg for 2 years by assessing the relation between APRs and efficacy. APRs reported in patients with primary osteoporosis from the ZONE study were analyzed post hoc. Baseline factors were compared in patients with vs without APRs, and changes in BTMs and bone mineral density (BMD) were also investigated. In the ZOL group, 51.2% (169/330) of patients developed APRs after the first infusion and 12.3% (33/268) after the second infusion. Comparison of baseline factors showed that patients without APRs in the ZOL group had a significantly higher neutrophil/lymphocyte ratio, lower serum levels of procollagen type I N-terminal propeptide, older age, and higher likelihood of prior bisphosphonate use vs patients with APRs. Patients with APRs showed significantly higher increases in total hip BMD at 6 and 12 months and larger reductions in BTMs vs patients without APRs. Patient profiles differed significantly between patients with vs without APRs, with APRs after the first infusion of ZOL being related to increases in total hip BMD and suppression of BTMs.This study is registered with ClinicalTrials.gov (identifier: NCT01522521; January 31, 2012).

Keywords: Acute phase reaction; Bone mineral density; Bone turnover marker; Osteoporosis; Zoledronic acid.

Conflict of interest statement

Masataka Shiraki has received consulting fees from Asahi Kasei Pharma, MSD, and Teijin Pharma and lecture fees from Astellas Pharma, Chugai Pharmaceutical, Daiichi-Sankyo, Eisai, Eli Lilly Japan, Ono Pharmaceutical, and Pfizer. Yasuhiro Takeuchi has received research grants and/or consulting fees from Amgen K.K., Eli Lilly Japan, Chugai Pharmaceutical, Teijin Pharma, Asahi Kasei Pharma, and Daiichi-Sankyo. Toshitsugu Sugimoto has received research grants from Astellas Pharma, Eisai, Ono Pharmaceutical, Daiichi-Sankyo, Chugai Pharmaceutical, and Eli Lilly Japan, and consulting and/or lecture fees from Asahi Kasei Pharma and Pfizer. Toshitaka Nakamura has received consulting fees from Asahi Kasei Pharma, Amgen, Chugai Pharmaceutical, Daiichi-Sankyo, Eli Lilly Japan, MSD, Taisho Toyama Pharmaceutical, and Teijin Pharma. Tatsuhiko Kuroda is an employee of Asahi Kasei Corporation. Satoshi Tanaka, Hiroaki Suzuki, and Kazuki Hiraishi are employees of Asahi Kasei Pharma Corporation.

© 2021. The Author(s).

Figures

Fig. 1

Percent changes from baseline in BTMs with or without APRs. a CTx, b P1NP, c TRACP-5b, and d BAP. *p < 0.05 between groups; values are mean ± SD. Solid line, closed circles: patients with APRs; dotted line, open circles: patients without APRs. APR acute phase reaction, BAP serum bone-specific alkaline phosphatase, BTM bone turnover marker, CTx serum C-terminal telopeptide of type I collagen degradation products, P1NP procollagen type I N-terminal propeptide, SD standard deviation, TRACP-5b tartrate-resistant acid phosphatase 5b

Fig. 2

Percent changes from baseline in BMD with or without APRs. a lumbar 2–4, b total hip, and c femoral neck BMD. Solid line, closed circles: patients with APRs; dotted line, open circles: patients without APRs. *p < 0.05 between groups; values are mean ± SD. APR acute phase reaction, BMD bone mineral density, SD standard deviation