Preclinical frailty assessments: Phenotype and frailty index identify frailty in different mice and are variably affected by chronic medications.

ABSTRACT

Use of different objective frailty assessment tools may improve understanding of the biology of frailty and allow evaluation of effects of interventions on frailty. Polypharmacy is associated with increased risk of frailty in epidemiologic studies, regardless of frailty definition, but the pathophysiology of the association is not well understood. This study aims to (1) assess and compare the prevalence of frailty from middle to old age following control, chronic polypharmacy or monotherapy treatment, when measured using the clinical frailty index assessment and the mouse frailty phenotype tools; and (2) to evaluate and compare the effects of chronic polypharmacy regimens with zero, low and high Drug Burden Index (DBI) and monotherapies from middle to old age on the rate of deficit accumulation on the frailty index, mean number of phenotype criteria, odds of being frail assessed by the frailty index or phenotype, and the time to onset of frailty assessed by the frailty index or phenotype. In a longitudinal study, middle-aged (12 months) male C57BL/6J(B6) mice were administered non medicated control feed and water, or therapeutic doses of different polypharmacy combinations or monotherapies in feed and/or water. Frailty assessments were performed at 12, 15, 18, 21 and 24 months. There was limited overlap between animals identified as frail using different frailty assessments. Polypharmacy has measurable and different effects on each frailty assessment. Long-term chronic administration of some polypharmacy and monotherapy therapeutic drug regimens increased the number of frailty deficits (clinical frailty index low DBI polypharmacy (15 and 21 months), high DBI polypharmacy (15-21 months), oxycodone (15-18 months), oxybutynin (15-18 months), citalopram (15-21 months) and metoprolol monotherapy (15 months) and modified frailty phenotype assessment (over the whole duration of treatment, low DBI polypharmacy (adjusted Risk Ratio(aRR) = 1.97, 95% confidence interval (CI) 1.43-2.72), high DBI polypharmacy (aRR = 1.88; 95% CI 1.36-2.60), oxybutynin (aRR = 1.48; 95% CI 1.01-2.16) and citalopram monotherapy (aRR = 1.96; 95% CI 1.41-2.74), p < 0.05) . The odds of developing frailty measured with the clinical frailty index increased with high DBI polypharmacy (adjusted odds ratio (aOR) = 3.13; 95% CI 1.01-9.66) and when measured with the frailty phenotype assessment increased with low DBI polypharmacy (aOR = 4.38, 95% CI 1.40-13.74), high DBI polypharmacy (aOR = 3.43; 95% CI 1.12-10.50) and citalopram monotherapy (aOR = 4.63; 95% CI 1.39-15.54)). No treatment affected time to frailty using either frailty assessment. Analysis of the number of deficits on the frailty index or number of positive criteria on the frailty phenotype allows analysis of rate of change and provides greater sensitivity, while the odds of being frail analysis provided a clinically relevant indicator of whether mice had greater chance of reaching a cut-off for becoming frail with medication exposure than without. Our results are consistent with clinical studies, demonstrating that certain polypharmacy regimens induce frailty, with different relationships observed when using different frailty assessments and analyses.