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Review
. 2021 Apr 1;33(3):212-223.
doi: 10.4103/tcmj.tcmj_233_20. eCollection 2021 Jul-Sep.

The molecular etiology and treatment of glucocorticoid-induced osteoporosis

Cheng-Huan Peng  1   2   3 , Wen-Ying Lin  1 , Kuang-Ting Yeh  1   3 , Ing-Ho Chen  1   3 , Wen-Tien Wu  1   2   3 , Ming-Der Lin  2   4
Affiliations
Review

The molecular etiology and treatment of glucocorticoid-induced osteoporosis

Cheng-Huan Peng et al. Tzu Chi Med J. .

Abstract

Glucocorticoid-induced osteoporosis (GIOP) is the most common form of secondary osteoporosis, accounting for 20% of osteoporosis diagnoses. Using glucocorticoids for >6 months leads to osteoporosis in 50% of patients, resulting in an increased risk of fracture and death. Osteoblasts, osteocytes, and osteoclasts work together to maintain bone homeostasis. When bone formation and resorption are out of balance, abnormalities in bone structure or function may occur. Excess glucocorticoids disrupt the bone homeostasis by promoting osteoclast formation and prolonging osteoclasts' lifespan, leading to an increase in bone resorption. On the other hand, glucocorticoids inhibit osteoblasts' formation and facilitate apoptosis of osteoblasts and osteocytes, resulting in a reduction of bone formation. Several signaling pathways, signaling modulators, endocrines, and cytokines are involved in the molecular etiology of GIOP. Clinically, adults ≥40 years of age using glucocorticoids chronically with a high fracture risk are considered to have medical intervention. In addition to vitamin D and calcium tablet supplementations, the major therapeutic options approved for GIOP treatment include antiresorption drug bisphosphonates, parathyroid hormone N-terminal fragment teriparatide, and the monoclonal antibody denosumab. The selective estrogen receptor modulator can only be used under specific condition for postmenopausal women who have GIOP but fail to the regular GIOP treatment or have specific therapeutic contraindications. In this review, we focus on the molecular etiology of GIOP and the molecular pharmacology of the therapeutic drugs used for GIOP treatment.

Keywords: Bone remodeling; Glucocorticoid; Osteoblast; Osteoclast; Secondary osteoporosis.

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Conflict of interest statement

Dr. Ing-Ho Chen, an editorial board member at Tzu Chi Medical Journal, had no roles in the peer review process of or decision to publish this article. The other authors declared that they have no conflicts of interest.

Figures

Figure 1
Figure 1
Schematic representation of signaling pathways involved in bone remodeling and the formation of osteoblast and osteoclast. WNT, transforming growth factor-beta, bone morphogenetic protein, parathyroid hormone, and estrogen (e) are essential modulators of osteoblast and osteoclast formation. WNT and bone morphogenetic protein enhance the differentiation of osteoblasts. Bone morphogenetic protein, estrogen, and parathyroid hormone could indirectly regulate WNT activity by controlling the expression of Sost, and Dkk1 from osteoblasts and osteocytes. Transforming growth factor-beta enhances bone formation by suppressing the apoptosis of osteoblasts and osteocytes and enhancing the apoptosis of osteoclasts. Moreover, estrogen and WNT also suppress the apoptosis of osteoblasts and osteocytes. Blue lines indicate the effects of signaling molecules or the secreted proteins on the regulation of bone remodeling. Ligands are marked as yellow ovals. Signal modulators or the extracellular matrix proteins are marked as pink ovals. Endocrines are marked as green ovals
Figure 2
Figure 2
Schematic representation of the molecular etiology of glucocorticoid-induced osteoporosis and the effect of anti-osteoporotic drugs. Glucocorticoids (red) induce osteoporosis by inhibiting the differentiation of osteoblasts from mesenchymal stem cell, inducing apoptosis of osteoblasts and osteocytes, increasing the formation of osteoclasts, and prolonging the lifespan of osteoclasts. The effects of anti-osteoporotic drugs (green lines) such as bisphosphonates, teriparatide, denosumab, and raloxifene are indicated. Bisphosphonates inhibit the activity of osteoclast and induce its apoptosis. Bisphosphonates and the intermittent administration of teriparatide decrease the apoptosis of osteoblasts and osteocytes. Raloxifene, only used for postmenopausal women with glucocorticoid-induced osteoporosis, promotes bone formation by stimulating osteogenesis and suppressing osteoblast apoptosis and indirectly inhibits osteoclastogenesis by decreasing the expression of receptor activator of NF-κB ligand and increasing the expression of receptor activator of NF-κB ligand inhibitor osteoprotegerin. Denosumab inhibits osteoclastogenesis by neutralizing receptor activator of NF-κB ligand. Blue lines indicate the signaling affecting osteoclastogenesis
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