Future Treatment Strategies for Delayed Bone Healing: An Osteoimmunologic Approach.

Bone is a remarkable organ because it retains the capacity to regenerate.1 When successful, the healing of a fractured bone results in complete reconstitution of form and function. However, the healing process itself is quite complex and thus prone to failure. Even today, .10% of fracture patients in industrialized countries experience delayed or compromised healing. A high percentage of these patients are elderly persons prone to fracture and compromised healing. Specific treatment options to prevent delayed bone healing in such patients are still unavailable. Currently, patient fracture fixation and treatment are widely managed without specialized concepts for the elderly or for individual patient immune profiles. Growing evidence on the interplay of the immune and skeletal systems during bone healing might offer new possibilities to identifypatientsat risk earlier and suggest new approaches aimed at personalized treatment, depending on the patient’s immune status. Our understanding of the process of regenerative healing has shown that bone repair is a postnatal process that recapitulates embryologic processes of skeletal development.2 Following injury, the healing process is initiated by an inflammatory reaction, with both the innate and adaptive systems as central mediators. The essential role of the immune system also has recently been recognized in all subsequent healing phases, catabolic and anabolic.3,4 The essential role of immune cells in bone healing predestined them as therapeutic targets. Because of the plethora of immune cells with differing functions during specific healing phases, the first priority was the definition of possible targets. Evaluation of immune cell composition in a small cohort of successfully healed versus delayed-healing patients (ranked by delayed return to full weight bearing and bone bridging, identified radiographically and on CT) revealed elevated levels of terminally differentiated CD81 T cells (TEMRA, or effector memory RA T cells ). This immune cell subpopulation negatively influenced the bone healing process through cytokines, delaying the osteogenic differentiation of mesenchymal stromal cells (in vitro).5 Depletion of CD81 T cells in a clinically relevant animal model led to a better healing outcome. The question is whether the adaptive immune system and its memory capacity is a naturally occurring compromise providing a strong defense against pathogens while simultaneously reducing the regenerative healing capacity, particularly because the immunologic memory is developed only in higher vertebrate organisms, and in these organisms, the regenerative capacity is lower—the opposite of that, for example, in a limb-regenerating newt. Aging significantly delays bone fracture healing, but the underlying mechanisms remain unknown. However, inflammaging (ie, chronic inflammation) has been proposed as underlying many of the changes associated with human aging.6 Using lethal irradiation followed by bone marrow transplantation, Katharina Schmidt-Bleek, PhD