gms | German Medical Science

Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2022)

25. - 28.10.2022, Berlin

The anti-diabetic drug Pramlintide protects from excessive bone resorption in ovariectomy-induced osteoporosis through the calcitonin receptor

Meeting Abstract

  • presenting/speaker Shan Jiang - Universitätsklinikum Hamburg-Eppendorf, Department of Trauma and Orthopedic Surgery, Hamburg, Germany
  • Judith Luisa Kokot - Universitätsklinikum Hamburg-Eppendorf, Department of Trauma and Orthopedic Surgery, Hamburg, Germany
  • Paul Richard Knapstein - Universitätsklinikum Hamburg-Eppendorf, Department of Trauma and Orthopedic Surgery, Hamburg, Germany
  • Antonia Donat - Universitätsklinikum Hamburg-Eppendorf, Department of Trauma and Orthopedic Surgery, Hamburg, Germany
  • Weixin Xie - Universitätsklinikum Hamburg-Eppendorf, Department of Trauma and Orthopedic Surgery, Hamburg, Germany
  • Anke Baranowsky - Universitätsklinikum Hamburg-Eppendorf, Department of Trauma and Orthopedic Surgery, Hamburg, Germany
  • Johannes Keller - Universitätsklinikum Hamburg-Eppendorf, Department of Trauma and Orthopedic Surgery, Hamburg, Germany

Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2022). Berlin, 25.-28.10.2022. Düsseldorf: German Medical Science GMS Publishing House; 2022. DocAB19-1033

doi: 10.3205/22dkou072, urn:nbn:de:0183-22dkou0725

Veröffentlicht: 25. Oktober 2022

© 2022 Jiang et al.
Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). Lizenz-Angaben siehe http://creativecommons.org/licenses/by/4.0/.


Gliederung

Text

Objectives: Pramlintide represents a synthetic analogue of pancreas-derived amylin and is used clinically for the treatment of type two diabetes. In synergy with Amylin, Pramlintide slows gastric emptying, promotes satiety, and inhibits glucagon secretion. It is now concluded that Amylin exerts most of its biologic effects through the calcitonin receptor (CTR), which, apart from metabolic active tissues, is also expressed in osteoclasts at high levels and functions as an essential regulator of bone turnover. This view, however, was challenged in a previous study, in which Amylin and CTR-deficient mice displayed opposing bone phenotypes and which suggested, that Amylin acts through a hitherto unidentified receptor other than CTR [1]. Based on these considerations, we first investigated whether Pramlintide is not only effective in the treatment of metabolic disorders, but also capable to limit bone resorption in osteoporosis, the most common bone disease worldwide. And second, our study aimed to answer the question whether CTR is indeed the key receptor mediating the effects of the Amylin analogue Pramlintide in bone metabolism.

Methods: Female WT and CTR-deficient mice were ovariectomized (OVX) at the age of 8 weeks and received daily Pramlintide and vehicle injection for 4 weeks post-surgery. Mice were sacrificed at the age of 16 weeks. Spine and femur were harvested for micro-CT and histological analyses. To investigate potential mechanisms in vitro, bone marrow-derived osteoblasts and osteoclasts were treated with vehicle or Pramlintide.

Results and conclusion: On a structural level, WT OVX mice displayed a significantly decreased bone mass with reduced trabecular number and thickness in both the axial skeleton and in long bones. OVX-induced bone loss was fully normalized in the spine and partially rescued in the distal femur upon daily Pramlintide treatment, whereas the beneficial effects of Pramlintide were completely abrogated in mice lacking the CTR globally. Performing cellular histomorphometry, WT OVX mice demonstrated significantly increased osteoclast parameters, which were normalized by Pramlintide treatment in a CTR-dependent manner. In contrast, osteoblast numbers were decreased in WT OVX mice and unaffected by Pramlintide treatment in mice of both genotypes. In line with these findings, Pramlintide did not affect osteoblast differentiation or extracellular matrix mineralization in vitro, whereas osteoclast formation was significantly inhibited by Pramlintide treatment throughout the entire course of differentiation. Our results provide the first evidence that Pramlintide is effective to prevent bone loss in OVX-induced osteoporosis. We show that Pramlintide functions as a potent inhibitor of osteoclastogenesis both in vivo and in vitro, which is mediated by the CTR. Together, these findings indicate that Pramlintide, in addition to its beneficial effects on glucose metabolism, may also preserve bone integrity in patients with type 2 diabetes and postmenopausal osteoporosis.


References

1.
Dacquin R, Davey RA, Laplace C, Levasseur R, Morris HA, Goldring SR, Gebre-Medhin S, Galson DL, Zajac JD, Karsenty G. Amylin inhibits bone resorption while the calcitonin receptor controls bone formation in vivo. J Cell Biol. 2004 Feb 16;164(4):509-14. DOI: 10.1083/jcb.200312135 Externer Link