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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Science in Medicine

Pathogenesis of osteoporosis: concepts, conflicts, and prospects

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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Regulation of osteoclast formation and activity. In physiologic remodeli...
Regulation of osteoclast formation and activity. In physiologic remodeling, activation of bone resorption requires contact between cells of the osteoblast and osteoclast lineages. M-CSF, which may be either membrane bound or secreted, interacts with its receptor, c-fms, to stimulate differentiation and proliferation of hematopoietic progenitors, which then express RANK as preosteoclasts. Osteoclast differentiation and activity are stimulated by RANK/RANKL interaction, and this interaction can be blocked by soluble OPG. Bone-resorbing factors can also stimulate COX2 activity, which may amplify responses to RANKL and OPG by producing prostaglandins. In pathologic conditions, inflammatory and malignant cells can increase osteoclastogenesis by producing soluble or membrane-bound M-CSF and RANKL as well as PTH-related protein (PTHrP), cytokines, and prostaglandins.