New simulation model for bone formation markers in osteoporosis patients treated with once-weekly teriparatide.

Sakae Tanaka,Masataka Shiraki,Yasuhiro Takeuchi,Mitsuru Saito,John P Bilezikian,Toshitsugu Sugimoto,Tatsuhiko Kuroda,Toshitaka Nakamura,Taiji Adachi

doi:10.1038/boneres.2014.43

Abstract

Daily 20-μg and once-weekly 56.5-μg teriparatide (parathyroid hormone 1–34) treatment regimens increase bone mineral density (BMD) and prevent fractures, but changes in bone turnover markers differ between the two regimens. The aim of the present study was to explain changes in bone turnover markers using once-weekly teriparatide with a simulation model. Temporary increases in bone formation markers and subsequent decreases were observed during once-weekly teriparatide treatment for 72 weeks. These observations support the hypothesis that repeated weekly teriparatide administration stimulates bone remodeling, replacing old bone with new bone and leading to a reduction in the active remodeling surface. A simulation model was developed based on the iterative remodeling cycle that occurs on residual old bone. An increase in bone formation and a subsequent decrease were observed in the preliminary simulation. For each fitted time point, the predicted value was compared to the absolute values of the bone formation and resorption markers and lumbar BMD. The simulation model strongly matched actual changes in bone turnover markers and BMD. This simulation model indicates increased bone formation marker levels in the early stage and a subsequent decrease. It is therefore concluded that remodeling-based bone formation persisted during the entire treatment period with once-weekly teriparatide.

Highlights

The recent development of bone anabolic drugs has provided a novel option for preventing osteoporotic fractures
Clinical studies have demonstrated that teriparatide significantly increases bone mineral density (BMD) and reduces vertebral fracture incidence with both a daily 20-mg treatment regimen[1] and a once-weekly 56.5-mg treatment regimen.[2]
MATERIALS AND METHODS The simulation analyses were based on the results of the Teriparatide Once-Weekly Efficacy Research (TOWER) trial, which was a randomized, multicenter, double-blind, placebo-controlled trial conducted in Japan.[2]

Summary

Introduction

The recent development of bone anabolic drugs has provided a novel option for preventing osteoporotic fractures. Clinical studies have demonstrated that teriparatide (human parathyroid hormone 1–34) significantly increases bone mineral density (BMD) and reduces vertebral fracture incidence with both a daily 20-mg treatment regimen (relative risk reduction: 65%)[1] and a once-weekly 56.5-mg treatment regimen (relative risk reduction: 80%).[2] The fracture risk reduction is partially explained by changes in BMD3–6 and/or bone turnover markers.[7]. Exposure to teriparatide increases bone formation markers first (e.g., procollagen type I N-terminal propeptide (P1NP)), followed thereafter by an increase in bone resorption markers (e.g. crosslinked C-telopeptide of type I collagen (CTX)).[8] The early increase in bone formation with the use of daily teriparatide creates an ‘anabolic window’.9–10.

Objectives

Methods

Results

Conclusion