The aging of the immune system leads to chronic inflammatory signaling, a consequence of the accumulation of forms of molecular damage and the maladative changes in cell behavior that occur in response to that damage. It is easy enough to point to the inflammation of aging and link it to accelerated onset and progression of all of the common age-related conditions, as sustained inflammation is indeed disruptive to tissue structure and function throughout the body. It is likely that there are also other, more subtle mechanisms involved in the relationship between immune aging and any specific age-related condition, however.
Osteoporosis (OP) is a systemic skeletal disorder characterized by decreased bone mineral density (BMD) and deteriorated bone microarchitecture, which leads to an increased risk of fragility fractures. Noticeably, the immune system has been recognized as a crucial regulator in bone metabolism. In recent years, osteoimmunology studies have shown that the immune system plays a key role in bone remodeling. The term “immunoporosis” was first proposed in 2018 to establish a novel field emphasizing the role of immune cells in OP pathogenesis.
Specifically, immunoporosis refers to the immunology of OP: it denotes the immune-driven mechanisms that underlie bone fragility, focusing on age-related alterations in innate and adaptive immune cells. These alterations drive chronic low-grade inflammation and enhance responsiveness to damage-associated molecular patterns (DAMPs) and other stress signals, thereby disrupting bone remodeling and resulting in increased bone resorption and reduced bone formation. For instance, activated T cells (e.g., Th17 and Treg), proinflammatory cytokines [e.g., interleukin (IL)-17, tumor necrosis factor-alpha (TNF-α), and receptor activator of nuclear factor-κB ligand (RANKL)], and innate immune cells (e.g., dendritic cells (DCs) and macrophages) may promote osteoclast formation and bone loss.
Traditional therapies for OP (e.g., bisphosphonates, denosumab, and PTH analogs) have shown immunomodulatory properties, indicating the clinical significance of this immunological pathway. Critically, aging can lead to immunosenescence, a phenomenon marked by reduced immune cell diversity, functional decline, and increased inflammatory cytokine production. It may further drive inflammaging, a state of persistent, low-grade systemic inflammation that further exacerbates bone resorption and impairs bone formation. Inflammaging and immunosenescence are now accepted as central contributors to aging-related bone loss.
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