Glucocorticoid-Induced Osteoporosis

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.

Salvianolic acid B stimulates osteogenesis in dexamethasone-treated zebrafish larvae

“…Excessive Dex can evoke osteoporosis by depressing osteoblastic bone formation in humans and higher vertebrates. Excess GC also inhibits osteoblast differentiation and bone nodule formation in bone marrow stroma stem cells [1] , consistent with our previous studies [16] . Furthermore, previous reports indicate that GC induces the inhibition of osteogenesis in zebrafish larvae 21 , consistent with our present results.…”

“…This ultimately leads to osteoporosis characterized by the inhibition of bone formation, named glucocorticoid-induced osteoporosis (GIO) [1,2] . However, the underlying mechanisms of these deleterious effects caused by GC on skeletal tissue remain unclear, and there are also no ideal drugs and methods suitable for GIO.…”

Head-to-head comparisons of bisphosphonates and teriparatide in osteoporosis: a meta-analysis

“…As has been shown in numerous mouse models of GIO, an early phase of exaggerated osteoclast-mediated bone resorption is followed by a chronic phase of decreased osteoblastogenesis and reduced bone formation [4][5][6]. In contrast, estrogen deficiency-induced bone loss in PO has little effect on the osteoblast, being primarily associated with enhanced osteoclast formation and activity and reduced osteoclast apoptosis, resulting in large increases in bone resorption [7][8][9][10].…”

“…Glucocorticoid-induced osteoporosis (GIO) is the third most-common etiology of pathological bone loss (behind post-menopausal osteoporosis [PO] and bone loss due to aging), approaching 20% of all patients with osteoporosis [4]. As has been shown in numerous mouse models of GIO, an early phase of exaggerated osteoclast-mediated bone resorption is followed by a chronic phase of decreased osteoblastogenesis and reduced bone formation [4][5][6].…”

“…The latter include teriparatide, a recombinant human parathyroid hormone [rhPTH ] [3]. The mechanism underlying GIO favors PTH analogue therapy because chronic glucocorticoid use is primarily characterized by changes in osteoblast maturation, activity and survival [4].…”