Wolff's law in action: a mechanism for early knee osteoarthritis.

There is growing interest in the role of bone in knee osteoarthritis. Bone is a dynamic organ, tightly regulated by a multitude of homeostatic controls, including genetic and environmental factors. One such key environmental regulator of periarticular bone is mechanical stimulation, which, according to Wolff's law, is a key determinant of bone properties. Wolff's law theorizes that repetitive loading of bone will cause adaptive responses enabling the bone to better cope with these loads. Despite being an adaptive response of bone, the remodeling process may inadvertently trigger maladaptive responses in other articular structures. Accumulating evidence at the knee suggests that expanding articular bone surface area is driven by mechanical stimulation and is a strong predictor of articular cartilage loss. Similarly, fractal analysis of bone architecture provides further clues that bone adaptation may have untoward consequences for joint health. This review hypothesizes that adaptations of periarticular bone in response to mechanical stimulation cause maladaptive responses in other articular structures that mediate the development of knee osteoarthritis. A potential disease paradigm to account for such a hypothesis is also proposed, and novel therapeutic targets that may have a bone-modifying effect, and therefore potentially a disease-modifying effect, are also explored.