Frailty in older people

Frailty in older people

European Geriatric Medicine 2 (2011) 344–355 Hot topic in geriatric medicine Frailty in older people T.E. Strandberg a,*, K.H. Pitka¨la¨ b, R.S. Til...

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European Geriatric Medicine 2 (2011) 344–355

Hot topic in geriatric medicine

Frailty in older people T.E. Strandberg a,*, K.H. Pitka¨la¨ b, R.S. Tilvis c a b c

Institute of Health Sciences/Geriatrics, University of Oulu, Oulu University Hospital, Unit of General Practice, and Oulu City Hospital, PO Box 5000, 90014 Oulun Yliopisto, Finland Helsinki University Central Hospital, Unit of General Practice, Helsinki, Finland Helsinki University Central Hospital, Clinics of Internal Medicine and Geriatrics, Helsinki, Finland



Article history: Received 10 August 2011 Accepted 12 August 2011 Available online 25 September 2011

Old age frailty has no consensus definition so far, but it is commonly operationalised as a physical phenotype consisting of weight loss, exhaustion, physical inactivity, slowness and weakness. Phenotypic frailty is characterised by reductions in the reserves of various organ systems and impaired stress tolerance, with increased risk of important endpoints: disability, morbidity and death. The development of sarcopenia is often a conspicuous characteristic, and cognitive decline is a frequent companion; frail individuals may also be obese. According to epidemiological studies, phenotypic frailty can be discerned in 5 to 10% of community-living older individuals, prefrailty even in 20 to 40%. To prevent deterioration and development of disability, prefrail and frail individuals should be recognised in time to target interventions in primary care. There is also an emerging interest in various specialties to recognise frailty to better adjust treatments and prevent complications. Multidomain and multisystem interventions are probably the best options for prevention and treatment, but at the moment best evidence is available from exercise. Various pharmacological treatments are being investigated for frailty components, but trial data are scarce so far. In advanced frailty, treatment is moved to appropriate geriatric palliative care. ß 2011 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved.

Keywords: Aged Frailty Pathogenesis Prevention Treatment

1. Introduction ‘‘The sixth age shifts Into the lean and slipper’d pantaloon, With spectacles on nose and pouch on side; His youthful hose, well sav’d, a world too wide For his shrunk shrank; and his big manly voice, Turning again toward childish treble, pipes And whistles in his sound.’’ William Shakespeare, As you like it; Act II, Scene VII. This review aims to summarise various aspects of frailty – a complex and fascinating syndrome in the epicenter of geriatric medicine [1–26]. A relatively new concept as a specific entity and so far mainly dealt with in the geriatric literature, frailty has been described as ‘‘a biologic syndrome of decreased reserve and resistance to stressors, resulting from cumulative declines across multiple physiologic systems and causing vulnerability to adverse outcomes’’ [6], or in shorter words, ‘‘an expression of the lack of adaptive capacity of the organism’’ [25]. This concept of frailty started to develop in the 1970s and 1980s [21] and it was mentioned in the American Medical Association White Paper on Elderly Health in 1990 [27]. Although frail older individuals have existed throughout history, frailty was not discerned from ‘‘normal’’ ageing, ‘‘primary’’ frailty from its

* Corresponding author. E-mail address: [email protected].fi (T.E. Strandberg).

consequences (disability, co-morbidity, cognitive disorders) [10], or from ‘‘secondary’’ frailty as a more direct consequence of diseases or trauma [28]. According to some views, both frailty and getting old are inherent components of the life course, a transition period or a ‘‘identity crisis’’ [29] – from robustness to approaching death. Therefore, it may even be seen as a dimension of medicalisation–‘‘disease mongering’’. Views on frailty intertwining with ageing through human history have been eloquently reviewed by Ferrucci et al. [30]. Frailty as something needing attention may also be a social phenomenon, consequence of modern society [22], which must take care of its weakest members without family support. In addition to these ‘‘philosophical’’ considerations, there is also controversy about the definition and operationalisation of frailty, and the reader is referred to in-depth reviews by Hogan et al. [9], the International Association of Nutrition and Aging (IANA) Task Force report [21], and the Canadian Initiative on Frailty and Aging [31]. As geriatricians, we consider the concept of frailty to give extra value and to need medical attention. Frailty has serious impact on older individuals, their families and society as a whole [10], and it should be recognised as a target for interventions [21]. Primary care physicians play a key role in the primary prevention, because the etiology probably involves life course disposition to adverse lifestyle: stress, physical inactivity, unhealthy nutrition, and negligence of chronic disease prevention [17]. Geriatricians are important in secondary prevention, for example, when an acute

1878-7649/$ – see front matter ß 2011 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved. doi:10.1016/j.eurger.2011.08.003

T.E. Strandberg et al. / European Geriatric Medicine 2 (2011) 344–355


Table 1 Dimensions of frailty research according to the Canadian Initiative of Frailty and Aging [29]. Dimension


Identification Prevalence

Operational diagnostic criteria, tools for screening, diagnostics and investigation Epidemiology among the community-living older people, effect of sex, age, ethnicity, effect of diagnostic criteria used Biological and physiologic determinants Which factors predict frailty and its associates Recognition in specialties outside geriatrics to ensure individualised care

Biological basis Risk factors Impact on the individual, relatives, and health services utilisation Prevention and management Social basis Environment and technology Health services Health and social policy

Interventions at population and individual levels

Dimensions marked bold are the scope of this review.

illness of an older individual has been successfully treated, but a possible downward spiral to disability should be avoided. All specialists treating older people need to recognise frailty as a vulnerable risk state, and clinic-friendly screening methods are needed. While we concur that the psychological and social dimensions of frailty should be taken into account [3,13,19,21], the focus in this review on frailty is mainly on the biological and clinical aspects. These are marked bold in Table 1, which presents the classification of the Canadian Initiative of Frailty and Aging ( [31]. 2. Diagnosis and classification As yet, frailty has not a precise, universal definition, and it is usually not considered a specific diagnosis. It is mentioned neither in the International Classification of Diseases (ICD)-10 nor in the Diagnostic and Statistical Manual of Mental Disorders (DSM)-V. The definition of old age frailty has been considered a complicated and demanding, albeit advocated challenge [13]. Frailty has been seen as a dynamic condition [16,21], a process [26], or a part of continuum, midway between robust independence and functional disability or predeath [5,24]. Professionals intuitively recognise frail older people as shrinked, sarcopenic, and slowly moving. This phenotype is beautifully described by the Finnish painter Helene Schjerfbeck in the self-portraits up to her ninth decade. Classification based on clinical judgment alone is not satisfactory for research purposes, and moreover, this slim and reduced stereotype is distorted by the common dissociation of thinness and frailty. The terms ‘‘fat-frail’’, or ‘‘sarcopenic obesity’’ [32–34] have emerged to describe individuals whose ‘‘frailty’’ is actually inside, muscle has been substituted and infiltrated (‘‘marmorised’’) by fat. Various definitions were recently discussed in the review by the I.A.N.A. Task Force [21]. Although no consensus was reached, it was clearly stated that frailty and disability should be separated–frailty per se is a predisability state. On the other direction, frailty it is not an inevitable part of ageing (vide infra) and may also be more or less reversible at least before disabilities develop – and disabilities

may also be reversible. Many older people with several diseases are not frail and never become frail [10], and the frailty phenotype may also be observed in people below 65 years [35]. Emerging data suggest that frailty is more than its parts, and is in a nonlinear fashion related to the number of abnormal physiological systems [26,36]. From the 1990s, various approaches with a whole array of unidimensional and multidimensional instruments have been presented to characterise frailty in a way, which would be practical for both research and clinic. The reader is referred to reviews for a detailed history [9,21,23], and this review is focused more on the recent approaches. Two main multidimensional approaches have evolved to operationalise frailty in the 2000s [21,23]. The quantitative ‘‘Index method’’ especially promoted by Rockwood et al., but also others [25,37–43], is based less on specific impairments and more on cumulative number of health deficits, which can be not only symptoms and signs but also diseases and disabilities. Of them, a frailty index (FI) is calculated. A prototype of the qualitative, rulesbased ‘‘Phenotypic method’’ has been formulated by Fried et al. [6,10,14]. Several specific symptoms and signs are defined, (Table 2) which together form a geriatric syndrome. In contrast to index method, phenotype may exclude the presence of disease and at least disability, and identification of phenotypic frailty can thus be used to prevent these consequences. The conceptual difference between phenotypic and index classification methods to define frailty is illustrated in Fig. 1. In order to expand the largely physical Fried phenotype to cognitive and mood domains, a ‘‘multi-domain phenotype’’ [21] has been suggested. Recently, also ‘‘hybrid’’ scales such as the Edmonton Frail Scale (EFS) [44] and the FRAIL scale [21] have been introduced for recognition of frailty, EFS including a social dimension as well. In the following, we describe more closely the index and especially the phenotypic methods, which have been most widely used in clinical and epidemiological studies. 2.1. Frailty index (FI) FI is usually calculated by dividing the number of deficits present by the number of deficits measured, whereupon it can vary

Table 2 General outline of structurised components of phenotypic frailty in the Cardiovascular Health Study [6]. Characteristic

Definition (often modified in subsequent studies according to available data)

Weight loss (unintentional) Weakness Poor endurance Slowness Low activity

Reduction > 10 lbs in prior year Grip strength (related to body mass index, gender) in lowest quintile ‘‘Exhaustion’’ based on self-report Walking time/15 feet (related to height, gender) in slowest quintile Males < 383 Kcals/week, Females < 270 Kcals/week. Lowest quintile

Positive for frailty phenotype:  3 criteria present. Intermediate or prefrail: 1 or 2 criteria present.

T.E. Strandberg et al. / European Geriatric Medicine 2 (2011) 344–355



INDEX METHOD Measured health deficists and disabilities

Measured clinical items



Risk of further disability, comorbidity and death Fig. 1. Difference between phenotypic frailty and frailty index (FI). Phenotypic primary frailty may be distinct of disability and comorbidities, while frailty index counts deficits irrespective of their nature.

between 0 (no deficits) and 1 (maximal deficits). Consequently, if nine deficits exists out of 36, FI is 0.25. FIs have been calculated from various cohort studies in different countries using both clinical [38,39] (for example, the Clinical Frailty Scale from the Canadian Study of Health and Aging [CSHA]), and self-reported data (the National Population Health Survey of Canada (NPHS), indicating 22.7% of 65+ community-dwelling people to be frail (FI > 0.25) [25]. Also the Comprehensive Geriatric Assessment (CGA) can be used to calculate FIs [45]. These scales are multidimensional including – besides physical – also cognitive, psychological and/or social aspects affecting functionality, an example being the ‘‘Groningen Frailty Indicator’’. Although deficits measured vary in different studies, FIs have quite consistently predicted worsening health status, rate of institutionalisation, and death, especially when the number of measured deficits is > 30. Recently introduced ‘‘British FI’’ [46] has utilised exploratory factor analysis to compress various frailty indicators into a better metric than previous FIs. Nevertheless, before simpler indices are developed, the large number of information needed makes the FI approach less attractive in the clinic and especially in primary care. Also the inclusion of possible disabilities in the definition impairs the use of FI in prevention. 2.2. Frailty phenotype The essence of phenotype is that there is a as yet unidentified root cause(s) which gives rise to various clinically-measurable items or criteria. Of the phenotypic classifications, the criteria by Fried et al. [6] were initially on a relatively narrow basis (the Cardiovascular Health Study [CHS]). The criteria were then applied – with some modifications – on the prospective Women’s Health and Aging Study (WHAS) [14], and include the five items detailed in Table 2: (1) unintentional weight loss, (2) subjective exhaustion, (3) physical inactivity, (4) slowness, and (5) weakness. The presence of at least three criteria are taken to represent frailty, one to two criteria represent intermediate or ‘‘prefrail’’ status. The Fried criteria or their modifications have gained wide use in the 2000s (vide infra Epidemiology), and various aspects of the clinical validity of this phenotype have been tested. The classification has been verified to predict important endpoints, such as disability and death [6,14]. In the hands of other groups, the initial Fried criteria have often been

modified, depending on the data available, and even purely questionnaire-based criteria have been introduced and validated. [47,48]. In 2010, also a web calculator (SHARE Frailty Instrument, SHARE-FI), based on large European population datasets and using modified Fried criteria was introduced and validated [49]. This instrument has been intended for use in primary care. Although the Fried criteria are not particularly complex, even simpler (but still validated) phenotypic criteria have been sought after for everyday clinical practice. Fried criteria (and their extension with cognitive function, inflammatory status, subjective weakness and anorexia) may have subdimensions leading to a simpler set predicting disability [50]. Based on the Study of Osteoporotic Fractures (SOF) [51–53], a set of criteria has been presented consisting of three components: (1) chair-stand 5 times, (2) exhaustion, and (3) shrinking. The presence of all three criteria was taken to represent ‘‘frailty’’, and one or two criteria an intermediate or prefrail stage. Also a phenotype of frailty defined by the SOF criteria has been shown to predict important endpoints in both women [52] and men [53]. And even simpler criteria may be sufficient. Of the Fried phenotype components, shrinking, exhaustion and muscle weakness have been reported to be of less value [54], while slow gait speed (‘‘bradypedia’’) alone may be quick and inexpensive measure of frailty [55]. According to a recent, large analysis of cohort studies [56], gait speed, age and sex predicted at least survival as well as more complex variable combinations. With a course of 4 m, from a standing start and at usual pace, a cutoff speed around 0.8–1.0 m/s has been suggested [56]. An important criticism of the Fried phenotype has been the lack of cognitive and mood dimensions, which besides physical frailty are clearly important [15,21,57]. In the original study of the CHS population those with Mini Mental State Examination (MMSE) < 18 were excluded, but frailty was nevertheless associated with cognitive impairment [6]. In a study using extended Fried criteria, impaired cognitive function was consistently associated with slower walk speed, weaker grip and lower physical activity [50]. In the French Three-City study, inclusion of cognitive status improved the prognostic validity of frailty phenotype [57], and low MMSE score has been shown to predict frailty in older Mexican Americans [58], and conversely, physical frailty may predispose to cognitive decline [59].

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2.3. Which classification?

3. Comorbidity and disability

Despite satisfactory correlations between the two approaches, the index methods have predicted mortality better than the phenotypic classification [41,42]. It is understandable, because the index methods encompass comprehensively the geriatric essence of an older patient. On the other hand, the phenotype method may better recognise the biological nature of frailty not interfered with disease or disability – a biological syndrome with a pathophysiology of its own. Furthermore, the phenotypic method is simpler to use in clinic, and may be more sensitive to changes during follow-up. Of the phenotypic classifications the CHS (Fried) and SOF criteria have been compared in women [52], in the MOBILIZE Boston Study [60], and in the Osteoporotic Fractures in Men (MrOS) study [53], and found to be equal in predicting endpoints. In that situation, selection may be based on clinical utility. The magnitude and concordance of frailty using different methods has practical implications. This is reflected in the small study of van Iersel et al. [61]: among 125 geriatric patients the presence of frailty varied from 36 to 88% depending on the instrument used. In the MrOS study the prevalence of frailty using CHS or SOF criteria was quite similar (13–14%) and concordant in 71% of participants [53]. The prevalence differed more in the MOBILIZE Boston Study [60]: 10.0 and 4.2% of participants were frail according to the CHS and SOF criteria, respectively, and the agreement between the two was only moderate. In a situation where a consensus of a definite gold standard is lacking [21], and with scarce prospective studies comparing various methods to predict frailty [17], the clinician is left to define frailty with more or less pragmatic grounds. However, with the current research interest and several international databases, it is probable that both validated and clinic-friendly instruments will appear in the near future.

Although frailty is commonly associated with various diseases and disabilities (and these are not separated in FIs), the concept of ‘‘primary’’ phenotypic frailty could be used as a distinction from comorbidity and disabilities [10,21]. This may help to better target research for prevention, therapy and rehabilitation [10]. In the CHS, phenotypic frailty without disability or clinical diseases was, however, distinguished in only a minority of all participants [6]. Moreover, the distinctions are unavoidably blurred, because also subclinical disease may alter balance and reserves and contribute to the frailty syndrome [10]. Sooner or later frailty is associated with development of comorbidities and disabilities [6], and the association may well be related to common pathology, for example, atherosclerosis. As a vicious circle, the presence of frailty further impairs comorbidities and disability. Clearly, more research is needed to disentangle – if ever possible – ageing, frailty, and comorbidities, especially cerebrovascular and other cardiovascular diseases and cognitive disorders [17,70]. Only this is the key to effective prevention, but it obviously requires better knowledge of epidemiology, etiology, and pathogenesis as well as systems biology approach in research [26].

2.4. Biomarkers Diagnostic accuracy is usually improved with specific biomarkers, routinely measurable with laboratory or imaging methods and indicating some physiologic state. None such exists for frailty thus far, although abnormal values of several laboratory variables are often seen in frail older people [20,36,62,63]. Ten such markers (HDL cholesterol, total/HDL cholesterol ratio, glycosylated hemoglobin, dehydroepiandrosterone sulfate (DHEAS), urinary cortisol, epinephrine and norepinephrine, fibrinogen, high-sensitive C-reactive protein and interleukin-6) together with blood pressure and waist-hip ratio were used to construct a summary score [63]. Among initially high-functioning people aged 70 to 79 years, each oneunit increase of this score was associated with a 10% increase in the risk of developing phenotypic frailty during a 3-year followup. Fried et al. used even a wider array of biomarkers and noted a nonlinear association with frailty [36]. These results are important, because they tie up clinical phenotype of frailty on one hand, and inflammatory, immunological, nutritional, metabolical, hormonal, and atherosclerotic aspects of frailty on the other [64]. Phenotypic frailty may also explain ‘‘old age paradoxes’’, i.e. a biomarker denoting worse prognosis in younger age is associated with a better prognosis in older populations. Examples are low serum alanine aminotransferase (ALT) concentration, which in older persons is associated with frailty and worse prognosis [65], and endogenously low serum cholesterol associated with worse prognosis among older patients [66,67]. This is contrasted with trial evidence of benefit of cholesterol-lowering treatment also in individuals aged 75 to 80 years [68,69].

4. Epidemiology Prevalence of frailty has varied widely depending on the definition and study populations. The majority of studies have used the phenotypic criteria of Fried (or their modifications), the use of which is thus no longer defined to one research group. Besides age, the prevalence increases with poorer socioeconomic status, associated deficits, disability, morbidities, and institutionalisation. Some general numbers are as follows [18]: in the community 3 to 7% of people aged 65 to 75 years, 20 to 26% of octogenarians, and up to one third of nonagenarians are frail. Prefrail status has been reported among 45% of people aged 65 years or over, and even in 37% of individuals aged 50–64 years [23]. Of all frail older people, 7% have no illness, one quarter have only one disease, and of persons aged 80 years and over, 20% have been assumed to be frail without specific medical conditions [18]. Recent and some older community studies of frailty in various populations [6,25,35,45,71–83] are listed in Table 3, more details can be found in the I.A.N.A. task force report [21]. 5. Etiology and pathogenesis Because etiology and pathogenesis of frailty based on FI (accumulation of deficits and diseases) are straightforward issues, the focus is here on phenotypic frailty. An interested reader is advised to study theoretical background ideas (e.g. ‘‘disuse syndrome’’, ‘‘allostatic load’’, etc.) in respective essays and reports [2,21,30,31,63,64,84,85]. In Fig. 2, we have adapted these ideas to very schematically illustrate the pathway of frailty and its divergence from ‘‘successful’’ ageing. The figure also aims to illustrate the nonlinear development of frailty, and the impact of intervening comorbidities or trauma. When a ‘‘critical mass’’ of dysregulation is reached, the likelihood of frailty greatly increases [11], as a constellation, not a specific disease [84]. Up to a certain point, frailty may also be reversible (green dotted lines) – if appropriate actions (primary or secondary prevention; vide infra) are taken [16,21,26] – but finally a ‘‘point of no return’’ is reached, if irreversible disabilities develop. This should be taken into account when considering prevention and treatment in later and end-stage frailty (see below) [28].


Table 3 Epidemiological studies of frailty in the community. Country


Cardiovascular Health Study [6]



Women’s Health and Aging Study-I [14,71]



Precipitating Events Project [16]



Women’s Health Initiative Observational Study [72]



Invecchiare in Chianti Study [73]


Cawthon et al. [74] Women’s Health and Aging Study-II [75]


5993 420

Three-City Study [76]


Graham et al. [77]

Mexican Americans) Italy


Place of residence, and clinical status




Prevalence unless stated otherwise


65 and older

Fried [6]


Community, moderatelyseverely disabled Community

65 and older

Men and women Women



Modified Fried


Modified Fried (questionnaire-based)

Prevalence16%. Incidence 14% during 3 years



Modified Fried Fried

4% 7.5-year incidence 9%

Men and women Men and women Men and women Men and women

Modified Fried

9% of women, 4% of men



Chair-stand and walking speed Modified Fried

16% severely frail, 39% moderately frail 7% of women, 3% of men overall. Among 65 years or older: Of women: 21% frail, 43% prefrail. Of men: 12% frail, 42% prefrail Not applicable

Community, 6% of frail women had ADL disability Community

70 and older 65 to 79 years

65 years and older

Men and women Men Women


Community Community, not frail at baseline Community

65 years and older



65 and older



70 and over

Twelve European countries (not UK)



50 years and older

The Chinese longitudinal healthy longevity survey [79]



65 years and older

Men and women

Frailty index of 39 variables

Woo et al. [80]

Hong Kong

65 years and older


64-74 years

Frailty index and Fried Fried

Concord Health and Ageing in Men Project [82]




70 years or older

Men and women Men and women Men

Not applicable

Hertfordshire Cohort Study [81]

Community (22 provinces throughout China) All regions of Hong Kong Community

Modified Fried


Survey of Health and Living Status of the Elderly [83] Song et al. [25]



]dwelling Community

65 years or older





65 years or older

Men and women Men and women

Frailty 5%, prefrailty 40%. Larger in women 25% of women, 19% of men

The Treviso Longeva (TRELONG) Study [78] Survey of Health, Aging and Retirement in Europe (SHARE, 1. and 2. Wave) [35,45]

Fried: phenotypic definition [6]; FI: frailty index.

4000 638

65 and older 70–79 years

Men and women Women

FI of selfreported data

9% of women, 4% of men

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T.E. Strandberg et al. / European Geriatric Medicine 2 (2011) 344–355


infections. Subclinical vascular disease may be an important more distal etiologic factor for frailty [17,87]: Prestages of atherosclerosis are observed already in young people in developed societies [88], and midlife risk factors such as cholesterol and high blood pressure predict also cognitive disorders in late life [89]. Many questions are unanswered, for example, why some people shrink, while others stay obese with frailty (sarcopenic obesity), and there are probably several pathways to phenotypic frailty [50].



Loss of energy and reserves

Frailty Disability


“Point of no return”

5.2. Pathogenetic mechanisms

Death Age

Adapted from Bortz, JAGS 1993;41:1004-8 Bortz WM. J Geront 2002;57A:M283-M288

Fig. 2. Pathways toward frailty, disability and death. Excessive loss of energy and reserves bends ‘‘successful’’ ageing toward prefrail and frail status, which also can happen due to disease alone. Green dotted lines depict potential reversibility, which is more feasible in prefrailty, but is possible even in the disability stage.

5.1. Etiology Four main avenues have been considered important in the etiology of frailty [10]: (1) genetic (epigenetic) factors, (2) ageing, (3) lifestyle factors, and (4) subclinical disease and consequences of temporary illness and trauma. Also hormonal and inflammatory changes, mitochondria (reactive oxygen species [ROS]), as well as autonomic nerve system are important in the totality of burden predisposing to frailty. The regulatory systems are interconnected, and failure in one disturbs also others and lead to a ‘‘circle of frailty’’ [6,10], finally reaching a critical loss of control. More research is needed on disturbances in regulatory mechanisms leading to multisystem failure and loss of organ reserve. Frailty is disconnected from age, because it cannot be considered a normal ageing phenomenon (all old people do not get frail even within very long life-spans), although ageing increases susceptibility to it. In experimental animals, genetic mutations and caloric restriction, which prolong the life-span, may also postpone frailty [86]. In the end, lifestyle factors over the life course may have a great impact on the development of frailty in later life [17]. These factors include physical inactivity, dysnutrition (overnutrition in youth and midlife, malnutrition in old age), alcohol intake, obesity, metabolic syndrome and other cardiovascular risk factors, diabetes, and

Pathogenetic factors include development of impairments and low reserve in several organ systems such as gastrointestinal (anorexia, weight loss), muscles (sarcopenia/dynapenia), bones (osteopenia), circulation (vascular dysfunction, atherosclerosis), brain (cognition, exhaustion, fatigue), hormone (deficiencies), immune (inflammation) systems, and general ageing energetics [10,21,90]. Insight of their interplay has been collected from the Women’s Health and Aging Studies (WHAS) I and II, where impairments of hematologic, inflammatory, and endocrine systems, micronutrient deficiency, adiposity, and impaired fine motor speed were combined [36]. The central etiopathogenetic mechanisms leading to phenotypic frailty are presented in Fig. 3, which is by no means complete. Important clinical signs include old age anorexia and immobilisation/inactivity which can further accelerate sarcopenia, and in the presence of disease and inflammation lead to cachexia – an ultimate catabolic state. Comprehensive reviews have been recently published on anorexia/weight loss [91], sarcopenia/dynapenia [92–98], cachexia [98,99], and exhaustion/fatigue [100]. Also cognition and frailty are interrelated. Low MMSE score may be an early marker for future frailty risk [58] and physical frailty is associated with the risk of mild cognitive impairment (MCI) and cognitive decline in ageing [59]. 6. Clinical significance Important clinical consequences of frailty are depicted in Fig. 4. Frail older people are common in emergency departments even after mild precipitating events, or just because they are incapable to cope at home for unspecific reasons. Because frailty (and already prefrailty) predisposes to diseases and disability [6], and conversely

Genes, epigenetics, ageing, cumulative oxidative stress, lifestyle, vascular dysfunction and atherosclerosis, trauma



GH,ghrelin, insulin/IGF-1, thyroxine, intramuscular LPL

ANOREXIA -Physiologic (NO, CCK, ghrelin, leptin) -Lack of protein, energy

LOSS OF MUSCLE MASS -Protein catabolism, -fibre changes

HORMONES - Sex steroids, DHEAS

LOSS OF MUSCLE POWER - Fat accumulation, fiber and motor unit changes

Sarcopenia/dynapenia Exhaustion

Weight loss


Gait speed

Grip strength

Social support, health services and technology, adaptation CLINICAL FRAILTY Fig. 3. Etiologic and pathogenetic factors contributing to phenotypic frailty. CCK: cholecystokinin, DHEAS: dehydroepiandrosterone sulphate, GH: growth hormone, IGF: insulin-like growth factor, IL: interleukin, LPL: lipoprotein lipase, NO: nitric oxide.

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Frailty Mobility, balance, osteopenia

Falls, trauma


Dysfunction, Disability

Hospital care


nutrition – with supplements if needed – are logical general procedures. Short-term courses of specific treatments, such as anabolic agents, to hasten the convalescent period may be an option in the future, but rigorous trial evidence of benefits and harms is needed. 7.2. Primary prevention If the development of frailty is a life course issue [17], also prevention should start early, focusing mainly on lifestyle. To gather enough endpoints (incident frailty) in a reasonable time, it is probably practical to organise primary prevention studies among at-risk prefrail than nonfrail individuals. Incident frailty should also be considered as an important endpoint in, for example, cardiovascular, dietary, and exercise studies.

Death Fig. 4. Clinical consequences of frailty. Low reserves in frailty may lead to consequences per se or via illness and trauma with which frailty has a bidirectional relationship.

impairs their consequences and slows recovery from acute illnesses, the need for health and social care, as well as institutionalisation, is increased among frail older people [82]. A recent study analysed disability trajectories during the last year of life among individuals aged 70 years and older [101]. Frailty defined by the Fried criteria was both a common cause of death (28% of deaths, even if not considered in deaths resulting from cancer, dementia and organ failure). In addition, it was also a very heterogenous condition: Of frail individuals 14, 19, 15, and 25% had no disability, catastrophic, accelerating, or progressive disability, respectively, in the last year of life. However, 25% had already persistently severe disability, when their last year began. Because frail older persons are very sensitive to treatment complications, immobility and malnutrition, frailty should be recognised by all specialties [102–110]. These patients require extra care in order not to prolong their hospital stays unnecessarily. It is important to recognise frailty when considering the risk/ benefit of complicated and intensive treatments for example in cardiology [102,103], malignant diseases [104,105], surgery [106– 108], nephrology [109], and urology [110]. Besides the frailtyprecipitating properties of general ward conditions (immobility, undernutrition), frailty-provoking treatments of diseases such as prostate cancer [110] are receiving attention. The present downside is that although a variety of screening methods (see above) are available to recognise frailty, no consensus exists as yet, and the clinician is left to make his/her own choice. 7. Prevention and treatment 7.1. General outline There is a clear need to elucidate effective preventive and treatment modalities for frailty [11,17]. Being a relatively new concept without consensus definition, operationalisation of frailty as a predisability state is lacking in most older randomised trials. Besides defining baseline characteristics of study participants, future trials should use methods and endpoints which are practical and meaningful to clinicians and focus interventions on those most likely to benefit (not too well, not too sick). Both in primary and secondary prevention prompt treatment of diseases and trauma as well as elimination of iatrogenic factors which may precipitate or worsen frailty in old age is required (Fig. 2). During any intervening condition in old age, rapid and effective mobilisation, as well as protein and energy-rich

7.2.1. Lifestyle As long-term studies mature, they increasingly demonstrate the impact of midlife lifestyle on later life. Although no formal trials with operationalised frailty as endpoint exist, preemptive measures maintaining general health, such as physical activity, vascular-healthy diet, non-smoking, weight control, and moderation with alcohol probably have potential to prevent or postpone frailty as well [17]. In older people, risk of frailty has been associated with insulin resistance, hyperglycemia, abdominal obesity, and both very low or very high body mass index, and lower protein intake [33,83,111–114]. The effect of nutrition and body weight is, however, bidirectional: before old age it is important to prevent excess nutrition and obesity, in old age to prevent undernutrition, especially protein deficiency, and weight loss [91]. Smoking reduces life expectancy, but is also associated with worse health-related quality of life and frailty in old age [115,116]. 7.2.2. Drugs used for other purposes Many treatments conventionally used for other purposes, such as cardiovascular prevention, may also affect frailty risk. There is evidence that drugs affecting the renin-angiotensin-aldosterone (RAA) system also favourably affect body composition and prevent sarcopenia with several possible mechanisms [97,117,118]. In a randomised trial angiotensin convertase enzyme (ACE) inhibitor, perindopril improved physical function in patients with impairment of daily activities or physical function (no definition for frailty), but without heart failure [119]. On the other hand, in the large Women’s Health Initiative (WHI) study [120], no difference in incident frailty was observed between the users and non-users of these drugs. Statins are used by large numbers of older people, and myopathy being a well-known potential side effects of these drugs [121], this could predispose to frailty through inactivity. In clinical studies information on this has been inconsistent [122–125], and statin use was not associated with incident frailty in the WHI study [126] Raloxifene used for breast cancer may improve body composition (increase fat-free mass, no effect on muscle strength) [127]. On the contrary, androgen-deprivation therapy for prostate cancer may accelerate the development of frailty in vulnerable older men [110]. Similar studies do not exist for antiestrogen treatment of breast cancer. 7.2.3. Specific treatments Although promising research in frailty-related areas (sarcopenia, cachexia) is ongoing, there is no formal evidence on the efficacy of any pharmacologic therapy in the primary prevention of frailty. Therefore, the following merely aims to give the reader an idea of possible candidate treatments. Serum 25-hydroxyvitamin D level has been associated crosssectionally (but not longitudinally) with less frailty in older men

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[128]; and women and vitamin D supplementation is well known to prevent osteoporosis, ameliorate neuromuscular control, and possibly prevent falls, [129,130]. Also agents aimed at preserving muscle function and mass would be logically useful for prevention of frailty. These include hormone replacement therapy with estrogen/progesterone [131,132], or testosterone [133,134], selective androgen receptor modulators (SARMs) [135,136] and phytoestrogen (isoflavone) supplements [132] Although the growth hormone/insulin-like growth factor I (GH/IGH-I) axis [137] and its signalling pathways are involved in sarcopenia and osteopenia, their therapeutic use for frailty is controversial. Overall, the use of endocrine interventions has not been recommended [138]. Scattered studies are available of omega-3 fatty acids – which may be useful because of their antiinflammatory effects [139], and stimulation of muscle protein synthesis [140] – ghrelin mimetics [141], DHEAS [142], and creatine [97,143,144]. According to clinical trial registers, there are several ongoing studies in primary prevention combining various treatment modalities. 7.3. Secondary prevention Secondary prevention aims to improve prognosis and prevent or postpone the development of disability among already frail individuals. However, only a few studies have operationally defined frailty even for some criteria and sought to distinguish frailty from disability. In Table 4, we have compared evidence from various treatment modalities in unselected and defined frail populations. At the moment, best trial evidence in secondary prevention of frailty is available from exercise training. 7.3.1. Exercise Among older people with or without various impairments and disabilities systematic reviews [97,145–149] have found that exercise programs positively affect clinically important mobility and disability measures, such as activities of daily living (ADL), and instrumental activities of daily living (IADL). Of the exercise


modalities increase of strength and especially power (strength and speed) are important [97]. In defined frailty, there is suggestive evidence that long-lasting and high-intensive (but with gradual start) multicomponent exercise programs are needed, and single lower extremity strength training have no proven effect on clinically important endpoints such as disability [145,147–149]. 7.3.2. Nutrition In contrast, and despite lower frailty risk with higher protein intake in nonfrail women [115], no evidence was found for the effect of pure nutritional interventions on disability in frailty [146]. This is in accordance with a Cochrane review [150] which suggested that protein and energy supplementation in older people with malnutrition increased weight but did not affect functional performance. However, mortality was reduced in older people who were undernourished. 7.3.3. Specific treatments In addition, there are several pharmacological possibilities and strategies to treat individual aspects of frailty [28,91,92,99,151– 159]. To give the reader an idea of ongoing research, we have listed these in Table 4 according to phenotypic criteria, but emphasise that treatments are based on scattered and heterogenous studies with various endpoints and target groups. Thus far, there is weak evidence that any of these interventions targeted specifically on older people with frailty – defined by current criteria – would offer meaningful clinical benefits. For example, androgen replacement in men may increase lean body mass, but does not affect muscle function variables, whereupon the clinical significance is doubtful. There are promises, but rigorous and large treatment studies are clearly needed to find out the value of combinations and right timing. 7.3.4. Multidomain treatments Because frailty is a multifactorial state, it is intuitive that multidisciplinary (exercise, nutrition, cognitive stimulations, social activities, preventive primary care, and specific treatments

Table 4 Possible treatment modalities for secondary prevention of frailty. Treatment

Overall evidence in unselected older people

Trial evidence from randomised controlled trials (RCT) in individuals with frailty defined at baseline

Exercise [97,145–149]

Exercise programs positively affect clinically important mobility and disability measures (activities of daily living (ADL), instrumental ADL (IADL)) among frail or disabled older persons both in community as well as in institutions. Increases weight, affects sarcopenia, and reduces mortality in undernourished older people, but does not affect functional performance. Combination with exercise needs more research

A few RCTs available, which suggest that long-lasting and high-intensive (with gradual start) multicomponent exercise programs are effective

Scattered evidence of effects on appetite, body composition and laboratory variables

No RCTs available

Scattered evidence of effect on body composition, muscle strength, physical function, and balance. Usually small studies, varied populations with possible disablities, and several inconsistent findings

One RCTs of testosterone in prefrail and frail men, and one RCT of DHEAS combined with exercise in frail women

Scattered evidence

No RCTs available

Nutrition [97,146,150]

Specific treatments for various frailty components Weight loss [91,99,151–153]: megestrol, dronabinol, cyproheptadine, oxoglutarate, ghrelin/ghrelin mimetics, mirtazapin, and other antidepressive drugs) Weakness (sarcopenia/dynapenia) [91,97,99,154–157]: testosterone, growth hormone, anabolic steroids (nandrolone), megestrol, selective androgen receptor modulators (SARMs), estrogen/progesterone, tibolone, vitamin D, dehydroepiandrosterone sulphate (DHEAS), atamestane, angiotensin converting enzyme (ACE) inhibitors, antimyostatin antibodies, branched chain amino acids (valine, leucine), creatine, carnitine Exhaustion [158,159]: antidepressive drugs, modafinil, dextroamphetamine, methylphenidate

No RCT evidence of pure nutritional interventions on disability in frailty


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in various combinations) and individualised approach would best serve secondary prevention. There is a definite need for such trials, and according to clinical trial registers, there are several ongoing studies combining exercise (also tai chi and yoga) and/or nutritional treatments with specific treatments such as vitamin D, testosterone, DHEAS, omega-3 fatty acids, or growth hormone. Also the optimal relationship between various treatment modalities such exercise and protein intake (timing, type, amount [97]) requires more research. One practical example of a multidisciplinary trial is the ongoing Frailty Intervention Trial (FIT) [160], whereupon frailty has been defined at baseline according to Fried criteria. This trial aims to target each frailty component on an individual basis, and uses physiotherapy, nutritional supplementation, psychological therapy, chronic disease management, as well as social engagement to achieve these aims. 7.4. Later and end stage frailty In later and end-stage frailty, prevention gives way to palliation and treatments follow the principles of adequate geriatric care. As with end-stage dementia, burdensome interventions should be avoided and the main goal is to ensure good quality of life and appropriate multidisciplinary care meeting complex medical, psychological and social needs, also those of caregivers. Treatment possibilities of end-stage frailty according to symptoms and depending on general condition have been reviewed [28].

8. Conclusions Recognition of frailty has extra value in recognition of vulnerable older people at high risk in various clinical settings, also in tertiary care. Procedures are largely dependent on timing. For primary prevention, frailty should be recognised already in its prefrail phase in order to prevent progression and observe special needs in stressful situations. This should happen in primary care and acute care hospitals. Most important means are exercise training (muscle power) and correction of nutritional state as well as treating possible underlying causes (temporary diseases or trauma) as effectively as possible. In secondary prevention, aimed to avoid disability and other consequences in already frail individuals, the most evidence-based intervention is long-lasting, intensive (with gradual start) multicomponent exercise. More research is needed especially of multidomain and multisystem as well as individualised treatments. In more advanced cases, procedures are increasingly moved to palliative direction. Pharmacological therapies – especially for sarcopenia/dynapenia, core features in frailty – are being developed, but evidence of their efficacy for frailty components is scarce at the moment.

9. Search strategy and selection criteria In this clinically-oriented review, we aimed to summarise and interpret the vast knowledge of frailty for the generalist. We searched (up to 31 January, 2011) the Cochrane Library, DARE, Medline, EMBASE, clinical trial registers (, WHO International Clinical Trials Registry Platform [ICTRP), Australian New Zealand Clinical Trials Registry [ANZCTR], and Cochrane Central register of Controlled Trials. We used the search terms ‘‘frailty’’ or ‘‘frail’’ in combination with the terms ‘‘aged’’ or ‘‘elderly’’. We also searched the reference lists of articles identified by this search strategy. In citing references, we aimed to focus on publications in the past 5 years (over half during 2008–2011), and review articles are cited to provide readers with more details.

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