Pharmacological Interventions

To date there is no clear evidence that pharmacological interventions improve or ameliorate frailty.

ACE inhibitors, targeting the renin-angiotensin-aldostrerone axis have been shown to have no effect on incident frailty in a cohort of older women (aged 65-79 years at baseline) followed up for 3 years [97]. However, a single randomised control trial of perindopril used over 20 weeks showed an improvement in 6 min walking distances in 130 older adults (mean age 79 years) with pre-existing mobility problems [98].

Vitamin D is a potential candidate for pharmacological management of frailty given its effects on skeletal muscle, osteoporosis, and falls prevention. However, studies to date have demonstrated conflicting results. Higher serum 25-hydroxyvitamin D levels are associated with a lower prevalence of frailty in older men and women in observational studies [99,100]. Vitamin D supplementation has been shown to improve functional performance in older fallers with low serum 25-hydroxyvitamin D [101], but a recent real world RCT of high dose vitamin D supplementation in older fallers with both reduced and normal serum 25-hydroxyvi- tamin D demonstrated no improvement in lower limb function and a surprising increase in falls at 6 and 12 months [102].

Testosterone supplementation as a pharmacological intervention has shown conflicting results. Older men with low plasma testosterone treated for 36 months with transdermal testosterone, showed a significant improvement in lean muscle mass, but this did not translate to improvements in function [103]. Similar results were seen in older men with low testosterone and frailty given transdermal testosterone for 12-24 months [104]. However, improvements in hand grip strength and timed walking were found in older men treated with intramuscular testosterone therapy [105]. A recent large RCT of 790 older men with low serum testosterone given transdermal testosterone for 12 months showed no benefit to walking distance or self-reported vitality [106] . The main concern with testosterone treatment is its potential for cardiovascular side effects.

Replacement of dehydroepiandrosterone (DHEA), a steroid precursor of testosterone is a plausible treatment as levels of DHEA fall with advancing age and lower levels are associated with mortality and frailty [107]. A meta-analysis from 25 trials (n = 1353) of DHEA treatment in older men concluded that DHEA had a small effect on body composition but was not able to demonstrate an effect on function at a mean follow-up of 36 months.

Reduced IGF-1 is associated with frailty components [108], but to date treatment with growth hormone in the somatopause (the age related reduction in circulating growth hormone) leads to adverse events and only a minimal change to body composition and no improvement in function [109].

Of interest, the TNF-a antagonist drugs and other biologicals that have been used to treat diseases such as rheumatoid arthritis show a positive effect on the systemic symptoms of these diseases such as weakness and fatigue [110,111]. Thesecouldbe considered components of frailty and as such merit further investigation in a frail population.

Clearly further high quality trials are needed to discover new treatments and a search of the National Library of Medicine clinical trials registration website in January 2016 identified 15 ongoing interventional trials with frailty as an outcome including important trials of multifactorial interventions [112].

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