Review Identifies Cellular Senescence and Clonal Hematopoiesis as Key Drivers of Skeletal Aging and Impaired Fracture Repair

A comprehensive review in Frontiers in Immunology establishes that skeletal fragility reflects biological aging of the bone-immune-hematopoietic system and identifies cellular senescence, clonal hematopoiesis, and failed inflammatory resolution as key targetable mechanisms for improving post-fracture repair.

Researchers from Shanghai University of Traditional Chinese Medicine and Fudan University published a structured review examining how systemic aging, clonal hematopoiesis of indeterminate potential (CHIP), and failed inflammatory resolution impair bone quality and delay fracture healing in older adults.

The authors synthesized evidence showing that DNMT3A mutations represent the strongest CHIP-associated skeletal driver in inflammatory bone loss models, whereas evidence for TET2 remains limited to systemic inflammation, and ASXL1 data are largely absent.

The review proposes an 'immune resilience' framework to describe the bone-repair system's capacity to transition from acute inflammation to resolution and remodeling, highlighting the role of persistent cellular senescence and dysfunctional macrophages in sustaining non-regenerative calluses.

Conventional fracture risk and post-fracture recovery predictions rely primarily on bone mineral density (BMD) and clinical risk factors, which fail to capture local bone marrow niche biology or tissue-repair capacity.

The paper highlights that cellular senescence is a local amplification mechanism of skeletal fragility; transient senescence supports early injury responses, but persistent senescent cell accumulation and SASP factors inhibit osteoblast differentiation and impede healing.

It outlines a critical translational bottleneck: peripheral blood biomarkers do not easily reflect highly compartmentalised callus and marrow microenvironments, necessitating local-to-peripheral calibration using single-cell and spatial transcriptomics.

The review identifies several geroscience pathways under development as candidates for treating skeletal aging, specifically selective senolytics, NLRP3 inhibitors, and specialized pro-resolving mediators (SPMs) such as maresin-1 and resolvin E1.

It highlights that future clinical trials of geroscience interventions must explicitly account for standard-of-care anti-osteoporosis therapies (e.g., bisphosphonates, denosumab), which act as biological modifiers of the bone niche.

The consensus recommendation to prioritize prospective fracture cohorts validating driver-specific and VAF-specific CHIP or phase-resolved immune trajectories could shape the entry criteria for orthopedic clinical trials.

The initiation of prospective fracture cohorts evaluating whether phase-resolved inflammatory trajectories and continuous VAF modeling of CHIP drivers explain variation in repair kinetics beyond conventional bone density and frailty measures.