Why Does Bone Remodel, What Happens When It Doesn't, and How Can We Use This to Change Our Therapeutic Mindset?

Bone remodeling serves both long‐term metabolic as well as mechanical needs. Within the mechanical realm, remodeling helps to renew the bone matrix to prevent the tissue from aging to the point at which its mechanical properties are compromised, and skeletal fragility is increased. It is now well known that severely suppressing bone remodeling is as detrimental to skeletal health as is the rapid bone remodeling found in conditions such as osteoporosis or Paget's Disease. Failure to remodel bone can result in excessive microdamage burden, accumulation of advanced glycation end products (AGEs), and hypermineralization. Microdamage, left unrepaired, reduces the residual strength and stiffness of bone, and can lead to stress fractures. Hypermineralization and accumulation of AGEs cause tissue brittleness, which reduce bone toughness and increase the risk for fracture. Many current treatments for postmenopausal, glucocorticoid‐induced and age‐related osteoporosis prevent bone loss by suppressing bone remodeling, reducing the risk for some kinds of fractures (eg hip fractures), but this has negative effects on tissue material properties that may increase the risk for other types of fractures (stress fractures and atypical femoral fractures). Knowing this, investigations have begun into how to alter the physical properties of bone matrix without manipulating the activity of osteoclasts or osteoblasts. These cell independent approaches rely on moving bone water from compartments in which it is freely flowing, to those in which it is tightly bound, within the interface between the collagen and the mineral. Increasing bound water allows the collagen and mineral to slide at their interfaces, reducing stresses when bone is loaded, and delaying both the initiation of microcracks and the ultimate fracture of the bone. Agents that increase water content of bone, and move water between compartments, have been tested both ex vivo, and in living animal models. They have been shown to increase toughness in bone that is devoid of living cells. These agents have also been shown in diabetic animal models to reduce the skeletal fragility that is associated with Type II diabetes, a case in which fragility is not related to bone mass but only to the deterioration of matrix material properties consequent to AGE accumulation. These treatments offer the opportunity to reduce risk for fracture without manipulating cell activity. Given the importance of a vital and viable remodeling system to bone health, these new approaches promise an approach to reduce fracture risk without negative side effects associated with suppressing remodeling, and can be applied to cases of skeletal fragility that are not caused by aberrations of the remodeling system.