Key Points
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The pathogenesis of primary osteoporosis is complex and influenced by both environmental and genetic factors
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Oxidative stress, apoptosis, sex-steroid deficiency and macroautophagy are age-related risk factors that contribute to the pathogenesis of osteoporosis
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Lifestyle-related factors, such as inadequate intake of calcium and vitamin D, physical inactivity, smoking and excessive alcohol consumption are important risk factors for osteoporosis
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Mutations in several genes can cause different monogenic disorders characterized by decreased bone mineral density and increased bone fragility
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The contribution of genetic factors to polygenic osteoporosis is determined by the presence of variants in many genes, each with a small effect size
Abstract
Osteoporosis is a common disorder, affecting hundreds of millions of people worldwide, and characterized by decreased bone mineral density and increased fracture risk. Known nonheritable risk factors for primary osteoporosis include advanced age, sex-steroid deficiency and increased oxidative stress. Age is a nonmodifiable risk factor, but the influence of a person's lifestyle (diet and physical activity) on their bone structure and density is modifiable to some extent. Heritable factors influencing bone fragility can be monogenic or polygenic. Osteogenesis imperfecta, juvenile osteoporosis and syndromes of decreased bone density are discussed as examples of monogenic disorders associated with bone fragility. So far, the factors associated with polygenic osteoporosis have been investigated mainly in genome-wide association studies. However, epigenetic mechanisms also contribute to the heritability of polygenic osteoporosis. Identification of these heritable and nonheritable risk factors has already led to the discovery of therapeutic targets for osteoporosis, which emphasizes the importance of research into the pathogenetic mechanisms of osteoporosis. Accordingly, this article discusses the many heritable and nonheritable factors that contribute to the pathogenesis of primary osteoporosis. Although osteoporosis can also develop secondary to many other diseases or their treatment, a discussion of the factors that contribute only to secondary osteoporosis is beyond the scope of this Review.
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Change history
24 April 2015
In the version of this article initially published online, Figure 3 contained a typographical error (alchohol instead of alcohol). The error has been corrected for the print, HTML and PDF versions of the article.
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Acknowledgements
The authors' research is supported by grants G.0197.12N and G.0065.10N to W.V.H. from the Research Foundation—Flanders (FWO) and by the SYBIL (Systems biology for the functional validation of genetic determinants of skeletal diseases) project. SYBIL is funded by the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 602300 to W.V.H. In addition, E.B. holds a postdoctoral fellowship funded by the FWO.
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G.H. and E.B. contributed equally to this work. G.H. and E.B. researched the data for the article. All authors (G.H., E.B., W.V.H.) contributed substantially to discussions of the article content, writing the article, and review or editing of the manuscript before submission.
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Hendrickx, G., Boudin, E. & Van Hul, W. A look behind the scenes: the risk and pathogenesis of primary osteoporosis. Nat Rev Rheumatol 11, 462–474 (2015). https://doi.org/10.1038/nrrheum.2015.48
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DOI: https://doi.org/10.1038/nrrheum.2015.48
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Identification of kukoamine a as an anti-osteoporosis drug target using network pharmacology and experiment verification
Molecular Medicine (2023)
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Is the Citak classification of distal femur morphology age and gender dependent?
Archives of Orthopaedic and Trauma Surgery (2023)
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Therapeutic effects of isoquercetin on ovariectomy-induced osteoporosis in mice
Natural Products and Bioprospecting (2023)
