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Glucocorticoid-Induced Osteoporosis

  • Chapter
Glucocorticoid Signaling

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 872))

Abstract

Osteoporosis is among the most devastating side effects of glucocorticoid (GC) therapy for the management of inflammatory and auto-immune diseases. Evidence from both humans and mice indicate deleterious skeletal effects within weeks of pharmacological GC administration, both related and unrelated to a decrease in bone mineral density (BMD). Osteoclast numbers and bone resorption are also rapidly increased, and together with osteoblast inactivation and decreased bone formation, these changes lead the fastest loss in BMD during the initial disease phase. Bone resorption then decreases to sub-physiological levels, but persistent and severe inhibition of bone formation leads to further bone loss and progressively increased fracture risk, up to an order of magnitude higher than that observed in untreated individuals. Bone forming osteoblasts are thus considered the main culprits in GC-induced osteoporosis (GIO). Accordingly, we focus this review primarily on deleterious effects on osteoblasts: inhibition of cell replication and function and acceleration of apoptosis. Mediating these adverse effects, GCs target pivotal regulatory mechanisms that govern osteoblast growth, differentiation and survival. Specifically, GCs inhibit growth factor pathways, including Insulin Growth Factors, Growth Hormone, Hepatocyte Growth/Scatter Factor and IL6-type cytokines. They also inhibit downstream kinases, including PI3-kinase and the MAP kinase ERK, the latter attributable in part to direct transcriptional stimulation of MAP kinase phosphatase 1. Most importantly, however, GCs inhibit the Wnt signaling pathway, which plays a pivotal role in osteoblast replication, function and survival. They transcriptionally stimulate expression of Wnt inhibitors of both the Dkk and Sfrp families, and they induce reactive oxygen species (ROS), which result in loss of ß-catenin to ROS-activated FoxO transcription factors. Identification of dissociated GCs, which would suppress the immune system without causing osteoporosis, is proving more challenging than initially thought, and GIO is currently managed by co-treatment with bisphosphonates or PTH. These drugs, however, are not ideally suited for GIO. Future therapeutic approaches may aim at GC targets such as those mentioned above, or newly identified targets including the Notch pathway, the AP-1/Il11 axis and the osteoblast master regulator RUNX2.

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Acknowledgements

We thank Gillian H. Little, Michael R. Stallcup (University of Southern California) and Tamas Röszer (University of Ulm) for insightful comments. BF, who holds the J. Harold and Edna L. LaBriola Chair in Genetic Orthopaedic Research, acknowledges support from the National Institutes of Health (RO1 DK071122). JT acknowledges support from Deutsche Forschungsgemeinschaft Immunbone (SPP 1468 Tu220/6-2 INST 40/492 SFB 1149, Collaborative Research Centre 1149) and from KaroBioScience Foundation.

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Authors and Affiliations

  1. Department of Orthopaedic Surgery, Keck School of Medicine, Institute for Genetic Medicine, University of Southern California, 2250 Alcazar Street, CSC-240, Los Angeles, CA, 90033, USA

    Baruch Frenkel D.M.D., Ph.D.

  2. Department of Biochemistry and Molecular Biology, Keck School of Medicine, Institute for Genetic Medicine, University of Southern California, 2250 Alcazar Street, CSC-240, Los Angeles, CA, 90033, USA

    Baruch Frenkel D.M.D., Ph.D.

  3. Department of Diabetes and Endocrinology, Eisenhower Medical Center, 39000 Bob Hope Drive, Rancho Mirage, CA, 92270, USA

    Wendy White M.D.

  4. Institute for Comparative Molecular Endocrinology, University of Ulm, Helmholtzstrasse 8/1, Ulm, D-89081, Germany

    Jan Tuckermann

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Correspondence to Baruch Frenkel D.M.D., Ph.D. .

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  1. Department of Nutritional Science & Toxicology, University of California Berkeley, Berkeley, California, USA

    Jen-Chywan Wang

  2. Division of Endocrinology Metabolism & Lipid Research, Department of Internal Medicine, Washington University School of Medicine Division of Endocrinology, St. Louis, Missouri, USA

    Charles Harris

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Frenkel, B., White, W., Tuckermann, J. (2015). Glucocorticoid-Induced Osteoporosis. In: Wang, JC., Harris, C. (eds) Glucocorticoid Signaling. Advances in Experimental Medicine and Biology, vol 872. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-2895-8_8

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