Frailty Phenotype As Mediator Between Systemic Inflammation and Osteoporosis and Fracture Risks: A Prospective Study

Background: Systemic inflammation and frailty have been implicated in osteoporosis (OP) and fracture risks; however, existing evidence remains limited and inconclusive. This study aimed to assess the associations of systemic inflammation and frailty phenotype with incident OP and fracture and to evaluate the mediating role of frailty phenotype.

Methods: The present study analysed data from the UK Biobank, a comprehensive and representative dataset encompassing over 500 000 individuals from the general population. Baseline peripheral blood cell counts were employed to calculate the systemic inflammation markers, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII). Frailty phenotype was assessed using five criteria, defined as frail (≥3 items met), pre-frail (1-2 items met) and non-frail (0 items met). OP and fracture events were confirmed through participants' health-related records. Multivariable linear and Cox regression models were utilized, along with mediation analysis.

Results: Increased systemic inflammation was associated with increased risks of OP and fracture. The corresponding hazard ratios and 95% confidence intervals (CIs) for OP risk per standard deviation increase in the log-transformed NLR, PLR and SII were 1.113 (1.093-1.132), 1.098 (1.079-1.118) and 1.092 (1.073-1.111), and for fracture risk, they were 1.066 (1.051-1.082), 1.059 (1.044-1.075) and 1.073 (1.058-1.089), respectively. Compared with the non-frail individuals, the pre-frail and frail ones showed an elevated OP risk by 21.2% (95% CI: 16.5-26.2%) and 111.0% (95% CI: 98.1-124.8%), respectively, and an elevated fracture risk by 6.1% (95% CI: 2.8-9.5%) and 38.2% (95% CI: 30.7-46.2%), respectively. The systemic inflammation level demonstrated a positive association with frailty, with β (95% CI) of 0.034 (0.031-0.037), 0.026 (0.023-0.029) and 0.008 (0.005-0.011) in response to per standard deviation increment in log-transformed SII, NLR and PLR, respectively. The frailty phenotype mediated the association between systemic inflammation and OP/fracture risk. Subgroup and sensitivity analyses confirmed the robustness of these findings.

Conclusions: Systemic inflammation and frailty phenotype are independently linked to increased risks of OP and fracture. The frailty phenotype partially mediates the association between systemic inflammation and osteoporotic traits. These results highlight the significance of interventions targeting systemic inflammation and frailty in OP and fracture prevention and management.