GlucocorticoidInduced Osteoporosis

Authors: Baruch Frenkel Wendy White Jan Tuckermann

Publish Date: 2015

Volume: , Issue: , Pages: 179-215

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Abstract

Osteoporosis is among the most devastating side effects of glucocorticoid GC therapy for the management of inflammatory and autoimmune 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 subphysiological 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 GCinduced 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 IL6type cytokines They also inhibit downstream kinases including PI3kinase 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 ßcatenin to ROSactivated 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 cotreatment 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 AP1/Il11 axis and the osteoblast master regulator RUNX2We 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 Tu220/62 INST 40/492 SFB 1149 Collaborative Research Centre 1149 and from KaroBioScience Foundation

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