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Effect of etelcalcetide on parathyroid hormone secretion by primary hyperparathyroidism patient-derived primary parathyroid cells

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Abstract

Introduction

Etelcalcetide (Parsabiv®, AMG 416/ONO-5163) is a novel allosteric modulator for the calcium-sensing receptor approved for hemodialysis patients with secondary hyperparathyroidism of uremia. Etelcalcetide reduced parathyroid hormone levels in hemodialysis patients with secondary hyperparathyroidism of uremia in clinical studies. However, its direct effect on parathyroid hormone secretion in human parathyroid cells remains unknown. This study aimed to determine if etelcalcetide suppresses parathyroid hormone secretion by human parathyroid cells in vitro.

Materials and methods

We prepared primary cell cultures from human parathyroid tissue and determined calcium-sensing receptor expression levels by immunohistochemistry. Pathyroid tumors were removed from fourteen patients with primary hyperparathyrodism. Parathyroid tissue was dispersed with collagenase, resuspended in culture medium, incubated for 2 h with etelcalcetide and Ca2+, and the medium was then collected. Final etelcalcetide concentrations in the medium were 0.005–50 µmol/L. Levels of human parathyroid hormone in the medium were determined by enzyme-linked immunosorbent assay.

Results

In eight of the fourteen parathyroid cell cultures, extracellular Ca2+ reduced parathyroid hormone levels. In four of the eight parathyroid cell cultures which responded extracellular Ca2+, etelcalcetide reduced hormone secretion with the 50% effective concentrations of 0.57, 20.8, 0.42, and 0.57 µmol/L. Expression levels of the calcium-sensing receptor were significantly lower in primary hyperparathyroidism patient-derived parathyroid tissues compared with controls.

Conclusion

This is the first report that etelcalcetide directly reduced parathyroid hormone secretion from the primary cultured human parathyroid cells from patients with primary hyperparathyroidism. To verify this conclusion, further studies are needed using secondary hyperparathyroidism patient-derived parathyroid cells.

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Acknowledgements

We express our sincere gratitude to William W. Stark Jr., Audrey Hou, and Sunfa Cheng, MD, of Amgen Inc. (South San Francisco, CA, USA) for the collaborative research. We also thank our colleague Tamami Arai for preparing the manuscript and Chikara Honda for advise on statistical analysis.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Discovery Research Laboratories, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka, 618-8585, Japan

    Aiko Fujioka, Mikiyasu Taguchi, Yoshihiro Sugiura & Hiroyuki Yamada

  2. Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan

    Yasuo Imanishi, Ikue Kobayashi, Tomoe Hirakawa, Atsuto Inoue, Kazutsune Harada, Daichi Miyaoka, Noriyuki Hayashi, Masanori Emoto & Masaaki Inaba

  3. Research Promotion, Research Project Management Division, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka, 618-8585, Japan

    Atsuto Inoue

  4. EU/US Drug Development Division, Ono Pharma UK Ltd., MidCity Place, 71 High Holborn, London, WC1V 6EA, UK

    Kazutsune Harada

Authors
  1. Aiko Fujioka
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  2. Yasuo Imanishi
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  3. Ikue Kobayashi
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  6. Kazutsune Harada
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  7. Mikiyasu Taguchi
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  11. Noriyuki Hayashi
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  12. Masanori Emoto
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  13. Masaaki Inaba
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Contributions

AF designed the study and wrote the main manuscript. All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by AF, YI, IK, TH, AI, KH, MT, YS, HY, DM and NH. YI, AI, HY, ME and MI reviewed the manuscript critically for intellectual content. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Aiko Fujioka.

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Conflict of interest

AF, AI, KH, MT, YS, and HY are employees of Ono Pharmaceutical Co., Ltd.; YI, ME, and MI are on the speaker bureau for Ono Pharmaceutical Co., Ltd.; IK, TH, DM, and NH: none.

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Fujioka, A., Imanishi, Y., Kobayashi, I. et al. Effect of etelcalcetide on parathyroid hormone secretion by primary hyperparathyroidism patient-derived primary parathyroid cells. J Bone Miner Metab 39, 396–403 (2021). https://doi.org/10.1007/s00774-020-01158-2

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  • DOI: https://doi.org/10.1007/s00774-020-01158-2

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