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.