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Pathogenesis of osteoporosis: concepts, conflicts, and prospects
Lawrence G. Raisz
Lawrence G. Raisz
Published December 1, 2005
Citation Information: J Clin Invest. 2005;115(12):3318-3325. https://doi.org/10.1172/JCI27071.
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Category: Science in Medicine

Pathogenesis of osteoporosis: concepts, conflicts, and prospects

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Abstract

Osteoporosis is a disorder in which loss of bone strength leads to fragility fractures. This review examines the fundamental pathogenetic mechanisms underlying this disorder, which include: (a) failure to achieve a skeleton of optimal strength during growth and development; (b) excessive bone resorption resulting in loss of bone mass and disruption of architecture; and (c) failure to replace lost bone due to defects in bone formation. Estrogen deficiency is known to play a critical role in the development of osteoporosis, while calcium and vitamin D deficiencies and secondary hyperparathyroidism also contribute. There are multiple mechanisms underlying the regulation of bone remodeling, and these involve not only the osteoblastic and osteoclastic cell lineages but also other marrow cells, in addition to the interaction of systemic hormones, local cytokines, growth factors, and transcription factors. Polymorphisms of a large number of genes have been associated with differences in bone mass and fragility. It is now possible to diagnose osteoporosis, assess fracture risk, and reduce that risk with antiresorptive or other available therapies. However, new and more effective approaches are likely to emerge from a better understanding of the regulators of bone cell function.

Authors

Lawrence G. Raisz

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Figure 3

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Interaction of the Wnt, BMP, and sclerostin pathways. Differentiation of...
Interaction of the Wnt, BMP, and sclerostin pathways. Differentiation of osteoblasts during both development and remodeling is dependent on the activity of both the Wnt and BMP pathways. Wnt signaling requires the interaction of the LRP5 and frizzled receptors (Frz) and can be inhibited by Dickkopf (DKK; an inhibitor of LRP5) and secreted frizzled-related protein (SFRP). Antagonists such as sclerostin can block both BMP and Wnt signaling. The mediator of the canonical Wnt pathway, β-catenin, can synergize with BMP2 to enhance osteoblast differentiation and bone formation. Consistent with these interactions are the findings that high bone mass can result both from activating mutations of the Wnt pathway and deletion of SOST, the gene encoding sclerostin.
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