ECE2020 Oral Communications Bone and Calcium (7 abstracts)
Loss of glucocorticoid rhythm induces an osteoporotic phenotype in mice
Elizabeth M Winter 1 , M Schilperoort 1 , J Kroon 1 , S Kooijman 1 , K Mletzko 2 , B Busse 2 , AM Pereira 1 , NM Appelman-Dijkstra 1 , N Bravenboer 1 , PCN Rensen 1 & OC Meijer 1
1Leiden University Medical Center, Department of Internal Medicine, Division of Endocrinology, Leiden, Netherlands; 2University Medical Center Hamburg-Eppendorf, Department of Osteology and Biomechanics (IOBM), Hamburg, Germany
Introduction: Glucocorticoid (GC)-induced osteoporosis is a widespread problem that is accompanied with increased fracture risk. Currently, it is unknown whether detrimental effects of GC therapy on bone are simply the consequence of supraphysiological GC doses, or whether absence of the endogenous GC rhythm also plays a role. In this study, we aimed to elucidate the importance of the presence of a diurnal corticosterone (CORT) rhythm, the primary GC in mice, for bone quality.
Methods & Results: We implanted female C57Bl/6J mice with slow-releasing corticosterone (CORT) pellets to blunt the rhythm in CORT levels without inducing hypercortisolism. Flattening of the CORT rhythm for 7 weeks reduced cortical and trabecular bone volume (−8%; P < 0.001 and −26%; P < 0.05, respectively), as determined by micro-CT analysis. Furthermore, tartrate-resistant acid phosphatase (TRAP) levels were increased (+42%; P < 0.01) while procollagen type 1 N-terminal propeptide (P1NP) levels were decreased (−37%; P < 0.001) in plasma of mice with a flattened CORT rhythm, indicative of a negative balance in bone remodeling. Double calcein labeling of bone in vivo revealed a reduced bone formation, as reflected by a reduced mineral apposition rate (−20%; P < 0.05), mineralizing surface per bone surface (−23%; P < 0.05) and bone formation rate per bone surface (−39%; P < 0.01). Collectively, these perturbations in bone turnover and structure decreased bone strength and stiffness (−15%; P < 0.01 and −11%; P < 0.01, respectively), as determined by mechanical testing.
Conclusion: We demonstrate for the first time that flattening of the GC rhythm results in an osteoporotic phenotype in mice. Our findings indicate that at least part of the fracture risk associated with GC therapy may be the consequence a disturbed GC rhythm, rather than an excess in GC dose alone. Thus, reintroduction of a trough and/or peak in GCs could be a promising novel strategy to prevent GC-induced osteoporosis.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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