Abstract
Background
Global population aging has driven a marked rise in the co-prevalence of osteoporosis and cognitive impairment, and a bidirectional epidemiological association between the two conditions is now supported by multiple meta-analyses. The shared biological mechanisms underlying this comorbidity, however, remain incompletely defined, and the two disorders continue to be managed within largely separate clinical disciplines.
Aim and scope
This review consolidates existing evidence into an integrative immunopathological framework in which inflammaging—the chronic, low-grade, sterile systemic inflammatory state driven by senescent cells and their senescence-associated secretory phenotype (SASP)—is examined as a shared upstream driver that concurrently reconfigures skeletal remodeling and central neuroimmune dynamics through the bone–brain axis. We do not claim to identify novel molecular targets; rather, we synthesize an integrative perspective that has been treated in disciplinary silos.
Key mechanistic themes
At the molecular level, persistently elevated SASP-derived cytokines (IL-6, IL-1β, TNF-α) engage RANKL-dependent osteoclastogenesis in bone and prime microglial neuroinflammation in the central nervous system. Chronic NF-κB signaling and NLRP3 inflammasome activation, amplified in preclinical models by mitochondrial DNA release via the cGAS-STING axis, sustain this dual pathological output. Within the bone–brain axis, bone-derived endocrine signaling is remodeled during aging: osteocalcin (OCN) secretion declines, while osteocyte-derived sclerostin (SOST) rises and may antagonize Wnt/β-catenin signaling in both compartments. Blood–brain barrier disruption and peripheral immune-cell infiltration further amplify central neuroinflammation.
Balanced appraisal
We explicitly distinguish (i) conceptual hypotheses, (ii) preclinical (cellular and rodent) findings, and (iii) validated human data. Several widely cited mechanisms—including OCN–GPR158-mediated neuroprotection, cGAS-STING-driven neuroinflammation, and microbiome-based longevity signatures—rest predominantly on murine models or single cohorts and require independent human validation. Microglial responses in the aging brain reflect a heterogeneous state space rather than a uniform pro-inflammatory conversion.
Therapeutic implications
Candidate bone–brain dual-targeting interventions—senolytics (dasatinib plus quercetin), NLRP3 inhibitors, cGAS-STING blockade, GLP-1 receptor agonists, and microbiota-targeted strategies—are discussed with explicit reference to current evidence level, safety concerns, and translational limitations, rather than as established co-therapies. Dual-endpoint randomized trials enriched for elevated inflammaging biomarkers are needed before any of these agents can be positioned for clinical use in bone–brain comorbidity.
Conclusion
The inflammaging-centered framework advanced here provides a testable integrative pathophysiological perspective on bone–brain aging comorbidity and a rationale for interdisciplinary “bone–brain integrated” clinical evaluation in older adults, which we frame as an aspirational, hypothesis-generating model rather than an evidence-based standard of care.