Design of a Multicenter, Randomized, Open Label, Parallel Group Study to Evaluate the Efficacy of Loxoprofen on Acute-Phase Reactions in Japanese Primary Osteoporosis Patients Treated with Zoledronic Acid

Abstract

Background/Purpose: The bisphosphonate zoledronic acid (ZOL) significantly increases bone mineral density and suppresses the incidence of fractures. However, ZOL causes acute‐phase responses (APRs) like other bisphosphonates.A very recent 2‐year phase III study (ZOledroNate treatment in Efficacy to osteoporosis; ZONE study) carried out in Japan has shown that the incidence rate of drug‐related adverse events (AEs) within 3 days after administration of ZOL was 57.4% and that of placebo was 11.7%, whereas APRs were reported in 31.6% of patients treated with ZOL in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial (HORIZON‐PFT). These results indicate that the incidence of APRs is higher in the Japanese populations, compared to other populations. And a sub‐analysis of the HORIZON‐PFT showed that the incidences of pyrexia and arthralgia in the Chinese population were higher than those in the multinational population, of which 14.2% were Asians. The highest risk of developing APRs was reported even in the non‐Japanese Asians and Pacific Islanders.These results indicate that the incidence of APRs is higher in the Asian populations, including Japanese, compared to non‐Asian populations. Previous studies have shown that APRs can be managed by treating patients with antipyretic and anti‐inflammatory drugs such as acetaminophen and ibuprofen. Methods: A total of 400 patients aged 60 or older were randomly allocated to a ZOL plus loxoprofen group (Z+L group) or ZOL group (Z group) on a 1:1 basis. After the treatment, patients were observed for 7 days, during which patients will record APRs for the first 3 days, and body temperature and drugs taken for 7 days. Primary endpoints are incidence of APRs and increase in body temperature, and secondary endpoints are relationship between prior treatment for osteoporosis in the past 3 years versus incidence of APRs, and that versus a change in body temperature.Results: APRs occurred at a rate of 34.4% in the Z+L group and 47.8% in the Z group (p =0.0109). And the incidence of APRs in patients with prior history of treatment with bisphosphonate is lower than that in naïve patients.Conclusion: Higher incidence of APRs was observed after zoledronic acid infusion in Japanese patients. However, the incidence of APRs decreased treating with loxoprofen after the zoledronic acid infusion, and less occurrence in patients with prior bisphosphonate use. The majority of APRs was also mild, and appeared to be transient.