Relationship Between Changes in Serum Levels of Intact Parathyroid Hormone and Sclerostin After a Single Dose of Zoledronic Acid: Results of a Phase 1 Pharmacokinetic Study

Tatsuhiko Kuroda,Masataka Shiraki,Kazuki Hiraishi,Hiroaki Suzuki,Satoshi Tanaka,Toshitsugu Sugimoto,Toshitaka Nakamura

doi:10.1007/s00223-021-00900-w

Tatsuhiko Kuroda, Masataka Shiraki + Show 5 more

Open Access

https://doi.org/10.1007/s00223-021-00900-w

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Abstract

Although changes in serum sclerostin levels at 12 months after infusion of zoledronic acid have been reported, the changes in sclerostin levels at earlier time points are poorly understood. We reanalyzed the study data of a previous phase 1 pharmacokinetic study and investigated the correlation between changes in sclerostin levels and relevant factors in calcium metabolism. A total of 24 Japanese female subjects with primary postmenopausal osteoporosis were administered a single 4- or 5-mg dose of zoledronic acid. Serum and urine samples were collected on days 15, 29, 90, 180, and 365 after administration. Serum levels of calcium, phosphate, intact parathyroid hormone (iPTH), and sclerostin were measured. Levels of serum sclerostin were unchanged from baseline on days 15 and 29, but increased significantly on day 90, subsequently decreased significantly on day 180, and returned to baseline levels on day 365. A significant negative correlation was observed between changes in iPTH levels at early time points and sclerostin levels at later time points. This suggests that sclerostin was negatively regulated by iPTH, and the decrease in sclerostin may indicate the start of bone formation during later time points after zoledronic acid injection.

Highlights

Zoledronic acid is categorized as a nitrogen-containing bisphosphonate (BP) with an antiosteoclastic effect [1]
Decreases in serum calcium and phosphate were correlated with increases in intact parathyroid hormone (iPTH) at earlier time points after the injection of zoledronic acid
Increases in iPTH at earlier time points contributed to subsequent decreases in sclerostin

Summary

Introduction

Zoledronic acid is categorized as a nitrogen-containing bisphosphonate (BP) with an antiosteoclastic effect [1]. Injection of zoledronic acid 5 mg has been widely used for the treatment of osteoporosis [2]. Several studies have shown rapid decreases in bone resorption markers and subsequent decreases in bone formation markers after zoledronic acid infusion as a result of its antiosteoclastic effect [4, 5]. Sclerostin, a product of the SOST gene, has attracted attention, as it negatively regulates Wnt signaling and bone formation [7, 8]. Several clinical trials have demonstrated differences in the expression of sclerostin depending on the agents used in osteoporosis treatment [9,10,11,12]

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