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Osteoarthritis (OA) appears to be a mechanically driven but chemically mediated disease process in which there is attempted (or aberrant) repair. Well established risk factors for OA include aging, obesity, gender, and, in selected subgroups, congenital anomalies. This review addresses less well established risk factors for OA that can impact joints through their effect on systemic metabolism rather than their contribution to local joint geometry and structure. These systemic risk factors include obesity; bone and bone density; nutrients, particularly those that function as antioxidants; and genetic factors. There is great opportunity for new prevention and intervention strategies as we expand our understanding of the role of these systemic risk factors.