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D. Sanchez-Rodriguez1,2,*, S. Piccard3,*, N. Dardenne4, D. Giet5, C. Annweiler6,7, S. Gillain3


1. WHO Collaborating Centre for Public Health aspects of musculo-skeletal health and aging, Division of Public Health, Epidemiology and Health Economics, University of Liège, Liège, Belgium; 2. Geriatrics Department, Rehabilitation Research Group, Hospital Del Mar Medical Research Institute (IMIM), Universitat Pompeu Fabra, Barcelona, Spain; 3. Geriatrics Department, Liège University Hospital, University of Liège, Liège, Belgium; 4. Public Health Department, Biostatistics, University of Liège, Liège, Belgium; 5. General Medicine Department, University of Liège, Liège, Belgium; 6. Department of Neurosciences and Aging, Division of Geriatric Medicine, Angers University Hospital; Angers University Memory Clinic; Research Center on Autonomy and Longevity; UPRES EA 4638, University of Angers, UNAM, Angers, France; 7. Robarts Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada; *Contributed equally.
Corresponding author: Dolores Sanchez-Rodriguez, MD PhD. WHO Collaborating Centre for Public Health aspects of musculo-skeletal health and aging, Division of Public Health, Epidemiology and Health Economics, University of Liège, Liège, Belgium, Tel: +32 493 43 27 50; Emails: dolores.sanchez@uliege.be

J Frailty Aging 2021;
Published online May 10, 2021, http://dx.doi.org/10.14283/jfa.2021.22



Introduction: The World Health Organization (WHO) has recently launched the term “intrinsic capacity”, defined as “the composite of all the physical and mental capacities of an individual”. Intrinsic capacity has a positive value towards healthy aging, and is constructed by five domains: cognition, vitality/nutrition, sensory, psychology, and mobility. ICOPE App and ICOPE Monitor are applications for the assessment (screening) of intrinsic capacity. Hypothesis: Intrinsic capacity assessed by the ICOPE Apps at baseline could be associated with the incidence of frailty, functional decline, and health outcomes during 1-year follow-up. Objectives: To assess the association between intrinsic capacity measured by the ICOPE Apps at baseline and the incidence of frailty in community-dwelling older adults during 1-year follow-up. Secondarily, to assess the association of intrinsic capacity and functional decline, mortality, pre-frailty, falls, institutionalization, and quality of life. Methods: Protocol for a cohort study of community-dwelling adults ≥65-year-old, with no other exclusion criteria than the inability to use the Apps or communicate by telephone/video-call for any reason (cognitive or limited access to telephone/video-call) OR being considered frail at baseline (defined as having a Rockwood’s clinical frailty scale, CFS score ≥4). Intrinsic capacity measured by the ICOPE Apps and CFS will be assessed at baseline, 4-, 8- and 12-month follow-up by telephone/video-call. Assuming a prevalence of frailty of 10.7%, and incidence of 13% (alpha-risk=0.05), 400 participants at 12-month end-point (relative precision=0.10) and 600 participants at baseline will be required. Results: Associations among the decrease in intrinsic capacity and higher risk of frailty, functional decline, and health adverse outcomes during 1-year follow-up are expected. Conclusions: ICOPE Apps might identify individuals at higher risk of frailty, functional decline, and health adverse outcomes. The implementation of the ICOPE Apps into clinical practice might help to deliver efficient person-centered care-plans, and benefit the healthcare systems.

Key words: ICOPE, intrinsic capacity, App, functional decline, older people, study protocol.



The World Health Organization aims at promoting initiatives focused on the preservation of individuals’ physical and mental capacities to achieve older ages in a good health status (healthy aging, defined as “the process of developing and maintaining the functional ability that enables well-being”) (1). Intrinsic capacity is a new term launched in the WHO in the plan of action 2016-2020 (1). The operational definition of “intrinsic capacity” is “the composite of all the physical and mental capacities of an individual” and is constructed by 5 domains: locomotion, vitality, sensory (vision and hearing), cognition, and psychological domain (2). Intrinsic capacity has a positive value, is focused on function, and switches the viewpoint from a negative paradigm of ageing (diseases, disability, frailty, etc.) towards the positive focus of a “healthy aging” (2,3).
The Integrated Care for Older People (ICOPE) program was launched by the WHO n. Global strategy and action plan on ageing and health in 2016 (4) and is focused on individuals’ comprehensive assessment and potential interventions on the 5 domains of intrinsic capacity (5, 6). In a second step, the strategy the WHO is aimed on providing evidence about trajectories of life (Normograms for Healthy Ageing Standards). The WHO plan of action scheduled for 2020-2030 would provide the continuity of this line of research (https://www.who.int/ageing/en/). The WHO guidelines on community-level interventions in integrated care have been recently launched, aimed at “Redesigning care for older people to preserve physical and mental capacity”, and involve the comprehensive assessment of the domains of intrinsic capacity (5, 6).
Two new technologies for the assessment of intrinsic capacity are available and capable to screen for individual’s intrinsic capacity (7, 8): The ICOPE application (App) has been developed by WHO and the ICOPE Monitor, has been developed as part of the INSPIRE program, an initiative from the Gérontopôle of Toulouse, which is a WHO Collaborating Center, in collaboration with the WHO and several partners from Toulouse (7, 8). The two Apps are already available free-of-charge in Apple or Android Store.
Frailty, defined as a “syndrome characterized by a clinical state in which there is an increase in an individual’s vulnerability for developing an increased dependency and/or mortality when exposed to a stressor” (9), is also a construct of several domains (10, 11). Despite frailty is a different construct, it would be expected that a decrease in intrinsic capacity, measured by the Apps is associated to the occurrence of frailty and functional decline, but these associations remain unexplored (3).
We hypothesize that intrinsic capacity, assessed by the ICOPE App and ICOPE Monitor at baseline, could identify individuals at higher risk of developing frailty, functional decline, and health adverse outcomes during 1-year follow-up. If these hypotheses are confirmed, ICOPE Apps could be incorporated into clinical practice in community-dwelling older people.
Objectives: Our primary objective is to assess the relationship between intrinsic capacity assessed with the ICOPE Apps (ICOPE App and ICOPE Monitor) at baseline and the incidence of frailty in community-dwelling older adults during 1-year follow up. Secondarily, to assess the association between intrinsic capacity measured by the ICOPE App and the ICOPE Monitor at baseline and the risk of functional decline, mortality, incidence of pre-frailty, falls, institutionalization, and loss of quality of life in this population during 1-year follow-up will be assessed.




Protocol for a prospective cohort study, designed to determine the incidence of frailty in community-dwelling older people during 1-year follow-up. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement (12) will be followed. Subjects who volunteer and meet eligibility criteria will be consecutively included.


The study will be conducted in Liège, a city located in the French-speaking region of Belgium. Volunteers will be recruited from 1) the Geriatric Department of the university hospital, 2) Outpatient clinics of primary care, and 3) Local press, television, and radio advertisements. In the first two options, the clinicians in the Geriatrics or primary care department that collaborate with the study, would identify a potential candidate and send an electronic mail with contact details to the personal from the study. In the third option, volunteers will receive instructions to proactively contact by telephone or electronic mail (e-mail) with the personal from the study. After receiving the e-mails, a telephone or video-call between the volunteer and the personal from the study will be scheduled in a maximum of 1 week. During the first interview, subjects will be assessed for eligibility, receive detailed information about the study, and sign electronically the informed consent by drawing their own signature in the screen of the mobile and forwarding it as an image. A printed copy of the informed consent with the signature in paper will be sent to volunteers’ homes by post mail afterward. Technical assistance in downloading the two Apps, signing the informed consent, the baseline assessment, and schedule next follow-up will be given during the first interview. The 4-, 8-, and 12-month follow-up will be conducted in a similar way. The Geriatric and primary care Department count with the technical devices and facilities to conduct the proposed test, and the Apps are free-of-charge (Apple /Android Store https://www.youtube.com/watch?v=gLva4ReV9KA). Data will be analysed at the Research Unit in Biostatistics, Public Health Department, University of Liege, Belgium. Table 1 summarizes study settings, variables, and timeline of the study.

Table 1
Variables, study settings, and timeline

a. Statistical analysis will be conducted at the Research Unit in Biostatistics, Public Health Department, University of Liege, Belgium; The sign “x” means test or probe performed and registered; the sign “-“means test not performed



Prospective cohort study of community-dwelling adults ≥65-year-old living at home, with no other exclusion criteria than the inability to use the ICOPE Apps or communicate by telephone/video-call for any reason (cognitive or limited access to technologies like telephone/video-call) OR being considered frail at baseline (defined as having a Rockwood’s clinical frailty scale, CFS score ≥4).
Intrinsic capacity assessment: Will be administered with the two Apps, the ICOPE App and the ICOPE Monitor.
ICOPE App: The screening by ICOPE App includes polar questions (yes/no) about the 5 domains of intrinsic capacity. Two results are possible: positive (probable decrease in intrinsic capacity) or negative (intrinsic capacity not decreased), as a total binary result of the 5 domains together. The App includes possibility to record the summary of the screening, download it in pdf, or send it by mail.
ICOPE Monitor: For the moment, ICOPE Monitor is equipped with ICOPE Step 1 (i.e. screening tool). ICOPE Monitor includes identification and informed consent of both the professional and the participant, detailed intrinsic capacity assessment of the 5 domains and reports the results obtained in each one of the 5 domains separately afterwards. The results obtained in the 5 domains are provided as a checklist: two results are possible for each one of the 5 domains: “right” or “wrong” in each domain. Updated advice for each domain and a link for further information is also provided. The App automatically schedules the date for the next 4-month follow-up and sends the informed consent by mail to the volunteer.
The results in the two Apps provide different approaches to IC. First, a global binary decision (IC decline or not) is directly provided by the ICOPE App (IC decline or not). Second, a binary decision of each one of the 5 domains per separate is provided directly by the ICOPE Monitor (each domain decreased or not); third, the binary decision obtained in the 5-domains could be combined as a score which might be just a count of IC declines, e.g. if we have 3 domains with decline among the 5 domains, the score would be 3/5. For purpose of this analysis, the second approach, a binary decision of each one of the 5 domains per separate provided directly by the ICOPE will be selected; the other two options would be studied as part of further secondary analysis.

Outcome measures

Primary outcome measure: Incidence of frailty assessed by Rockwood’s clinical frailty scale (CFS) will be assessed at baseline, 4-, 8- and 12-month follow-up by telephone/video-call. An score <4 will indicate robustness, 4-6 pre-frailty status, and ≥ 6 frailty (10). Secondary outcome measures: Incidence of functional decline (assessed by Chair stand test (14, 15) and the loss of ≥20 points in Barthel index (16, 17), death (date), incidence of pre-frailty (assessed by CFS) (10), falls (number and date), institutionalization (date), and quality of life (EuroQol) (18) will be assessed at 4-, 8-, and 12-month follow-up by a telephone/video-call with the volunteer or a contact person.
Functional decline: Incidence of functional decline will be defined as 1) The loss of the capacity to raise from a chair within 14 seconds, measured by the chair stand test in the ICOPE Monitor (Chair stand test) (14, 15); or 2) The loss of at least one activity of daily living, defined as loss of ≥20 points in Barthel index (16, 17), administered by phone (19) at baseline, 4-, 8- and 12-month follow-up (16-20).
Death: Date of death will be recorded, reported by the contact person if the participant did not respond to the scheduled follow-up visit at 4-, 8-, and 12-month follow-up.
Pre-frailty: Incidence of pre-frailty will be assessed by CFS at baseline, 4-, 8- and 12-month follow-up by telephone/video-call. An score <4 will indicate robustness, 4-6 pre-frailty status, and ≥6 frailty (10).
Falls (number and date) will be recorded by the volunteers on a personal dairy book.
Institutionalization: Date of institutionalization will be reported by the contact person if the participant did not respond to the scheduled follow-up.
Quality of life will be measured by self-reported EuroQol (ranging from 0 -the worst possible health status- to 1 -the best possible health status-) (18) by telephone/video-call at baseline, 4-, 8-, and 12-month follow-up.
Covariate data collection: Demographic and clinical data will be collected during the telephone/video calls and used as covariates. Instrumental activities of daily living (IADL) (maximum score 8 points) will be recorded using the Lawton scale (21). The ratio of the total score obtained / total score of the applicable items will be used to avoid any discrimination based on usual housework distribution among couple as in Gillain et al., 2017. E.g. if one of the members of a couple does not usually perform an activity, that item will not account for that individual, then, the total score of the applicable items will be 7 instead of 8 (22).
Feasibility of the ICOPE App and ICOPE Monitor: Feasibility will be defined as “the state or degree of being easily or conveniently done” and explored by the Technological, Economical, Legal, Operational, Schedule (TELOS)-feasibility score, which assesses the potential of implementation of new systems, and considers them feasible if TELOS-feasibility score ≥3) (23). It will be administered to the geriatric and primary care practitioners who collaborate with the study.

Sample size calculation

Sample size has been calculated in terms of the ICOPE study primary objective: to identify incidence of frailty in community-dwelling older patients. Table 2 shows the sample size calculation determined by a power calculation based on the width of the confidence interval for a proportion and on the estimation of an incidence rate (24). Assuming a prevalence of frailty of 10.7% (25), an incidence of 13% (26) with an alpha risk of 0.05, we estimated that 400 participants at the 12-month end-point of the study would be necessary to meet a degree of certainness regarding the incidence (relative precision of 0.10) meaning a sample of 600 volunteers at baseline should be cover a potential large dropout regarding the characteristics of this study (observational, 1-year follow-up, potential frail people, unknown adherence rate to the follow-up).

Table 2
Sample size calculation according to the prevalence and expected incidence of frailty


Statistical plan

Descriptive analysis will be performed for each variable of the study. Qualitative variables will be described by absolute numbers and relative frequencies (%). Quantitative variables will be summarized by the use of means and standard deviation (SD) for symmetrical distribution or median and the interquartile deviation for asymmetrical distributions. Normality of variables will be checked graphically with histograms and quantile-quantile plots, and tested by the Shapiro-Wilk test. A transformation of the data might be performed, if needed.
The evolution of intrinsic capacity during the 1-year follow-up will be analyzed by Generalized Linear Mixte Model (GLMM). These models will be also used to study the evolution of outcomes measured every 4 months and the impact of covariates on these evolutions. Kaplan-Meier methods will be use to represent graphically the notion of time occurrence of frailty and mortality (4-month follow-up time will be used as notion of time).
For the outcomes with a precise date of event (frailty, mortality, falls, institutionalization), their association with intrinsic capacity will be analyzed by a joint model for longitudinal and time-to-event data (27); the same analysis might be performed for other variables of interest, if required. Indeed, on one hand, we want to analyze the evolution over time of covariates and on the other hand the effect of these covariates on the outcome. Multiple imputations methods would be applied to deal with missing data. The data will be processed using SAS 9.4 (©SAS Institute Inc., Cary, NC, USA) and R (version 3.5) (R Core Team) software packages. The level of statistical significance will be set as α = 5% (p < 0.05).


National and International research Ethics guidelines will be followed, including the 1964 Declaration of Helsinki and its further amendments, and the Committee on Publication Ethics (COPE) guidelines (28)(29). Data will be treated according to the law of data protection in Belgium and the Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 2016 on the protection of natural persons with regard to the processing of personal data (30). The approval of the Ethics Committee (Comité d’Ethique Hospitalo-Facultaire Universitaire de Liège) will be obtained. Written and oral information will be provided and informed consent will be signed electronically by all participants. The study has been registered at www.clinicaltrials.gov (NCT04413877 on June 2, 2020).



Our study will determine the associations among decrease in intrinsic capacity and the incidence of frailty, functional decline, and occurrence of health adverse outcomes in community-dwelling older people during 1-year follow-up. If these associations are observed in the study, the measurement of intrinsic capacity by new technologies would be ready to be implemented in clinical practice.
Several aspects of the study should be highlighted. First, it will include intrinsic capacity assessment (2). Indeed, even if the association of intrinsic capacity with mortality, functional decline, and falls was recently shown in older people in nursing homes (31), there is still very few data in community-dwelling population. The rationale to select intrinsic capacity, instead of using other syndromes or diseases, for example, sarcopenia, malnutrition, or dementia, is due to the multidimensional characteristics of older people, which require a global assessment. A single point of view might not be complete enough to take complex decisions in clinical practice.
Second, the study will provide evidence about the relationship between intrinsic capacity and frailty, which is a different multidimensional construct. Wide differences among frailty and intrinsic capacity have been pointed out, i.e. frailty is driven by deficits, while intrinsic capacity is driven by reserves; frailty is an approach towards treatment usually measured in clinical settings, while intrinsic capacity is an approach focused on function maintenance in the community setting; frailty has wide evidence about its prognosis capacity, while intrinsic capacity is quite new. It would be expected that intrinsic capacity, measured by the Apps is associated to the incidence of frailty, but this association remains unexplored and requires further studies (3).
Three different approaches of IC will be explored, in order to provide novel insight about how to deal with IC as variable, which is still an uncharted territory; for purpose of analysis, the approach that uses a binary decision of each one of the 5 domains per separate provided directly by the ICOPE will be selected, as it is effortless, obtained directly by the ICOPE Monitor, and provide insight to deliver potential therapeutic interventions. The other two options would be studied as part of further secondary analysis.
Mortality has been selected as clinically meaningful outcome of the study, as recommended by the Common data elements (CDE) and core outcome measures (COMs) in Frailty research consensus (32) and the Physical Frailty: ICFSR International Clinical Practice Guidelines for Identification and Management (33). Frailty has shown association with 2-fold higher all-cause mortality (HR 2.17, 95%CI 1.90-2.48) (34), including infectious diseases (HR 1.79, 95%CI 1.03-3.11) (34). Sample size calculation was based on a prevalence of frailty of 10.7% (25) and incidence 13%, (26)(35). Despite lower incidence rates (3.9%, 8%)(35–37), have been shown in other large cohorts, the highest one was selected for our sample size calculation to ensure the detection of frailty (11). Providing data about the relationship between intrinsic capacity and frailty will pave the path towards the change in the negative paradigm of aging, and a person-centred model focused on enhancing the 5 domains towards healthy aging (3).
Third, our study will include the use of new technologies by older people, which is an emerging field with promising results. Several projects on the use of technologies to support health status of older people are currently ongoing, e.g. the J48 supervised machine learning algorithm is identifies future fallers among otherwise healthy, independent older adults (38); eMIND is a randomized controlled trial that includes web-based multidomain interventions (39); and the ALLEGRO living lab is an experimental hospital-based room for the testing of devices by frail hospitalized older people (40). The International Network of Agencies for Health Technology Assessment (INAHTA) provides high quality evidence about new technologies to help health care suppliers and policy makers in their decisions. The Belgian Health Care Knowledge Centre (KCE) has recently joined the INAHTA in 2020 (41), which might be promising for this line of research.
Finally, some limitations related to the cohort design should be acknowledged. The inclusion of healthy community-dwelling older volunteers will be considered as a selection bias, as it has been previously reported in other cohorts of community-dwelling older people (42). The characteristics of voluntary older participants (motivation, involvement in self-care management, etc.) might differ from those who refused to get involved in a research study. Moreover, volunteers who are able to use online resources might be relatively younger at baseline, and their health status might be better than the population of the same age.
In summary, this study will apply the “Action-research philosophy” (43) to bridge the gap between research and clinical practice. It will provide evidence to implement the ICOPE App and ICOPE Monitor, deliver efficient person-centered care-plans, and benefit older adults, professionals, and the healthcare systems.


Funding: No funding has received to conduct this research
Conflicts of interest: Authors declare no conflict of interest
Authors’ contribution: DSR and SG conceived the manuscript; DSR, SP, ND, and SG wrote the manuscript; DSR and SG did literature review; ND calculated the sample size and wrote the statistical plan; DG, and CA corrected the manuscript. All co-authors read and approved the final version of the manuscript.



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Y. Rolland1, M. Cesari2, R.A. Fielding3, J.Y. Reginster4,5, B. Vellas7, A.J. Cruz-Jentoft6 and the ICFSR Task Force


1. Service de Médecine Interne et Gérontologie Clinique, Gérontopôle, CHU Toulouse, INSERM 1027, France; 2. IRCCS Istituti Clinici Scientifici Maugeri, University of Milan, Milan, Italy; 3. Tufts University, Boston, MA, USA; 4. Division of Epidemiology, Public Health and Health Economics, University of Liege, Liege, Belgium; 5. Chair for Biomarkers of Chronic Diseases, Biochemistry Department, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia; 6. Servicio de Geriatría, Hospital Universitario Ramón y Cajal (IRYCIS), Madrid, Spain; 7. Gerontopole, INSERM U1027, Alzheimer’s Disease Research and Clinical Center, Toulouse University Hospital, Toulouse, France
Corresponding author: Yves Rolland, Service de Médecine Interne et Gérontologie Clinique, Gérontopôle, CHU Toulouse, INSERM 1027, France, rolland.y@chu-toulouse.fr


Task Force members: Samuel Agus (Paris); Sandrine Andrieu (Toulouse, France); Mylène Aubertin-Leheudre (Montréal, Canada); Amos Baruch (South San Francisco, USA); Shalender Bhasin (Boston, USA); Louis Casteilla (Toulouse, France); Peggy Cawthon (San Francisco, USA) ; Manu Chakravarthy (Cambridge, USA); Rafael De Cabo (Baltimore, USA); Carla Delannoy (Vevey, Switzerland); Philipe De Souto Barreto (Toulouse, France) ; Waly Dioh (Paris, France); Luigi Ferrucci (Baltimore, USA); Françoise Forette (Paris, USA); Sophie Guyonnet (Toulouse); Joshua Hare (Miami) ; Darren Hwee (South San Francisco); Kala Kaspar (Vevey); Nathan LeBrasseur (Rochester, USA); Valérie Legrand (Nanterre, France); Roland Liblau (Toulouse, France); Yvette Luiking (Utrecht, The Netherland) ; Bradley Morgan (South San Francisco, USA) ; Eric Morgen (Richmond, USA); John Morley (St Louis, USA) ; Angelo Parini (Toulouse, USA); Suzette Pereira (Columbus, USA); Alfredo Ramirez (Cologne, USA); Leocadio Rodriguez Manas (Getafe (Madrid), Spain); Ricardo Rueda (Columbus, USA); Jorge Ruiz (Miami, USA); Peter Schüler (Langen, Germany); Alan Sinclair (London, United Kingdom); Nicolas Thevenet (Nanterre, France); Janneke Van Wijngaarden (Utrecht, The Netherlands); Bruno Vellas (Toulouse, France) ; José Viña (Valencia, Spain); Jeremy Walston (Baltimore, USA); Debra Waters (Dunedin, New Zealand)

J Frailty Aging 2021;in press
Published online February 7, 2021, http://dx.doi.org/10.14283/jfa.2021.4



Interactions among physiological pathways associated with osteoporosis and sarcopenia are thought to contribute to the onset of frailty. The International Conference on Frailty and Sarcopenia Research Task Force thus met in March 2020 to explore how emerging interventions to manage fracture and osteoporosis in older adults may reduce frailty, disability, morbidity, and mortality in the older population. Both pharmacological and non-pharmacological interventions (including nutritional intervention, exercise, and other lifestyle changes) were discussed, including nutritional intervention, exercise, and other lifestyle changes. Pharmacological treatments for osteoporosis include bone-forming and antiresorptive agents, which may optimally be used in sequential or combination regimens. Since similar mechanisms related to resorption underlie physiological changes in muscle and bone, these interventions may provide benefits beyond treating osteoporosis. Clinical trials to test these interventions, however, often exclude frail older persons because of comorbidities (such as mobility disability and cognitive impairment) or polypharmacy. The Task Force recommended that future clinical trials use harmonized protocols, including harmonized inclusion criteria and similar outcome measures; and that they test a range of multidomain therapies. They further advocated more high-quality research to develop interventions specifically for people who are frail and old. The ICOPE program recommended by WHO appears to be highly recommended to frail older adults with osteoporosis.

Key words: Frailty, osteoporosis, prevention, ICOPE.



All organisms show biologically driven declines in motor function as they age and these declines are closely linked to mortality (1, 2). In humans, these declines manifest as the frailty syndrome, which is defined by the overlapping characteristics of low physical activity, slowed motor performance, weakness, fatigue or exercise intolerance, and unintentional weight loss (3). Physiologically, frailty reflects a lowered resistance to stressors resulting from multi-systemic decline. Clinically, frailty is associated with diagnoses of sarcopenia, the age-related loss of muscle mass and strength, and osteoporosis, the loss of bone mass and the deterioration of bone tissue (4). When they occur together, the syndrome may be referred to as “osteosarcopenia” (5). Moreover, interactions between bone and muscle through multiple physiological pathways, including hormonal and inflammatory pathways, are thought to result in the frailty syndrome (6).
As it has done every year since 2014, the International Conference of Frailty and Sarcopenia Research (ICFSR) Task Force brought together researchers from academia and industry to discuss challenges and opportunities for managing frailty and sarcopenia. In 2020 the Task Force met in Toulouse, France, where it focused attention on emerging interventions to manage fracture and osteoporosis in frail older adults. This population group has often been excluded from recent osteoporosis drug trials due to comorbidities and polypharmacy, despite the fact that they may potentially benefit more from a treatment since they are more likely to have falls, fractures, disability and a poor prognosis.


Associations of frailty with osteoporosis, fragility fracture, and malnutrition

Bone fragility caused by osteoporosis occurs commonly in older adults and results in increased risk of fragility fracture (7). A systematic review of worldwide studies estimated that 9 million osteoporotic fractures occurred in 2000, resulting in substantial disability, morbidity, and mortality (8). However, osteoporosis may not be diagnosed until an individual has experienced multiple fragility fractures; and studies show that after diagnosis, treatment for osteoporosis is not routinely given in older adults and adherence to medical regimens is poor (9).
One of the most common and disabling fractures sustained by older persons is hip fracture, which may result in long-term mobility impairment, reduced ability to care for oneself or participate in everyday activities, pain, anxiety, and depression (10). Nutrition plays an important role in bone health and sarcopenia (11, 12), and malnutrition is common in individuals with hip fracture (13). Sarcopenia is also associated with an increased rate fractures in older adults (14, 15).
Most patients with hip fracture complain of pain and resulting functional limitations six months after the fracture (16), which can lead to a vicious cycle of self-medication and mistrust of clinicians (17). Recovery from hip fracture may be delayed in the presence of sarcopenia (18), and hip fracture may be particularly disabling in individuals with frailty (19). Nearly 30 years ago, Marottoli and colleagues showed that physical function before the fracture predicts functional recovery (20). Comorbidities, fear of falling, and other age-related conditions may further exacerbate hip fracture and its associated functional consequences (21, 22). Moreover, individuals over age 80 years, in addition to meeting the frailty phenotype proposed by Fried and colleagues (i.e., weight loss, fatigue, slow gait speed, weakness, sedentary lifestyle), often live alone, and often experience cognitive decline (23); thus they need special management for frailty. However, frail older persons are often excluded from clinical trials of fragility fracture interventions, in part because of comorbidities, sarcopenia, cognitive impairment, and polypharmacy (24).
The substantial impact of fragility fractures on functioning in frail older persons thus requires dedicated and multidisciplinary care pathways, which have been shown to improve quality of life and physical function and limit excessive costs (25,26). Intensive interventions including exercise and physical therapy immediately following hip fracture is essential. Preventive strategies also need to be widely implemented, including early identification of those at risk, increased prescribing of bone loss prevention treatments, and the introduction of care models based on the comprehensive geriatric assessment and personalization of interventions. Recently multidisciplinary, evidence-based guidelines for the management of osteoporosis and fragility fractures have been published (27–29).
Given the association of poor nutrition with sarcopenia and frailty (30, 31), assessment of the nutritional status of older adults provides a potential pathway to interventions that could delay or prevent these disabling conditions of aging (32). The Mini Nutritional Assessment (MNA) is a tool designed to rapidly assess nutritional status though a series of simple measurements and brief questions (33). The MNA has been validated in frail older persons (34) and in community-dwelling older adults, demonstrating that frailty and malnutrition are distinct but related conditions (35–37).
Using the MNA short form (MNA-SF), investigators showed that poor nutrition in combination with frailty was associated with an increased prevalence and incidence of poor functional outcomes in the Singapore Longitudinal Aging Study (32). In cancer patients, a low MNA score combined with a high Groningen Frailty Index (GFI) score was associated with an increased mortality risk (38). MNA score has also been used as a prognostic factor of adverse outcomes after hip fracture (39). Yet while there is mounting evidence about the importance of stratifying research populations for frailty, impaired nutritional status at baseline has been associated with greater benefits from the interventions (40, 41). The new ESPEN guidelines on the treatment of malnutrition in older people include a section on hip fracture, with the recommendation to incorporate nutrition intervention into a multidisciplinary approach (42).
As a screening tool in outpatients, the MNA-SF has been shown to have a sensitivity of 71.2% and specificity of 92.8% (AUC 0.906) for the detection of frailty, and a 45.7% sensitivity and 78.3% specificity (AUC 0.687) for the detection of pre-frailty (43). In hospitalized patients, the MNA-SF predicted frailty with good sensitivity but only marginal specificity (44). There is no evidence that the MNA can be used as an outcome measure in trials.


Pharmacological treatment for osteoporosis, sarcopenia, and frailty

Better targeting of therapeutic interventions for the management of osteoporosis starts with diagnosis, identification of risk factors, and an assessment of fracture risk (45). The International Osteoporosis Foundation and European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis published guidance for the diagnosis and management of osteoporosis in 2013, and recently updated such guidance (46). Diagnostic criteria for sarcopenia have also been recommended by other different groups. The European Working Group on Sarcopenia in Older People (EWGSOP) published a definition in 2010 and updated it in 2019 based on a better understanding of the condition (47,48); and the ICFSR published guidelines on the management of sarcopenia in 2018 (49). In 2017, sarcopenia also was assigned a diagnostic code in the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) code book, indicating recognition of sarcopenia as a separately reportable disease condition for clinical practice and drug development (50).
A fracture may trigger a downward spiral of recurrent fractures known as the “fracture cascade” (51). A study in Iceland showed that the first fracture dramatically increases the risk of a subsequent fractures, particularly during the first year following the first event and regardless of the site of it. The authors concluded that treatment should be started immediately to prevent recurrence of the problem (52). Bone fragility, determined by assessing bone mineral density (BMD) at the hip or spine by DXA scan, is associated with high fracture risk (53), suggesting that restoring bone density may significantly reduce the risk of a second fracture. Low muscle strength and low physical function (sarcopenia) also increase the risk of injurious falls and fractures after a first hip fracture (54).
Several bone-forming drugs are clinically available, including anti-resorptive agents such as denosumab (55–57); romosozumab, a monoclonal antibody that both increases bone formation and inhibits bone resorption (58,59); anabolic agents such as teriparatide (60) and abaloparatide (61–63); biphosphonates such as alendronate and zoledronic acid (64); and myostatin inhibitors, which are also under research as potential drugs to treat sarcopenia (65, 66).
Optimal treatment of osteoporosis may require sequential or combination therapies, for example starting with a bone forming agent then add an antiresorptive agent for maintenance. For example, in the phase 2 FRActure study in postmenopausal woMen with ostEoporosis (FRAME), romosuzumab followed by denosumab reduced the risk of fracture in postmenopausal women (67). Other sequential regimens that have shown promise in lowering fracture risk and/or increasing bone density include romosozumab followed by alendronate (68), abaloparatide followed by alendronate (69,70), and combination denosumab/teriparatide followed by denosumab alone (71).


Preventing frailty and its consequences through nutrition and exercise

The concept of frailty facilitates a better understanding of heterogeneity in the older population and promotes study of the aging process. It provides a possible target for preventive measures aimed at reducing the functional decline and the occurrence of negative events such as falls and fractures (72, 73). Frail patients present with weakness, fatigue, a sedentary lifestyle and mobility impairment. They may have anorexia and recent weight loss. All of these clinical signs increase the risk of falls and fractures. They are also accessible to interventions such as nutritional management and/or physical exercise (focused on strength training and balance), which reduce the risk of falling (74, 75).
Several mechanisms responsible for both growth and decline of muscles and bones are shared. It has been hypothesized that pharmacological, nutritional, and/or exercise-based interventions may also overlap and provide mutual/dual benefits (76). For example, both skeletal muscle and bone respond to treatment with androgens, and exercise is an essential element of treatment regimens for osteoporosis, sarcopenia, and frailty. Malnutrition plays an important role in the development of both sarcopenia and frailty (31). Decreased dietary protein intake has been shown to result in decreased lean muscle mass in the Health Aging and Body Composition (ABC) Study (77). The Vitality, Independence and Vigor Study (VIVE2) showed that a high protein, high vitamin D nutritional supplement added to a physical activity intervention led to improvements in muscle density and a loss of intermuscular fat in mobility-limited older adults (78), although these benefits seemed insufficient to improve functional measures such as gait speed (79). Other studies have shown that a combination of resistance exercise and increased protein intake prevented muscle wasting in older adults (80, 81).
Obesity is known to contribute to functional declines and frailty in older adults. Sarcopenia in combination with obesity – a condition known as sarcopenic obesity – increases the risk of functional decline through multiple synergistic pathways. Intervention strategies to combat sarcopenic obesity include weight reduction, calorie restriction, and exercise. Pharmacological strategies may also prove useful (82). Weight reduction through calorie restriction has been shown to have positive effects on longevity, yet it also may result in a loss of fat and lean mass and bone density (83,84). In a study of older frail obese adults, an intervention that combined weight loss and aerobic plus resistance exercise, Villareal and colleagues showed that in comparison to either approach alone, the combination resulted in greater physical function and aerobic capacity and attenuated the loss of bone mineral density (85, 86).
The mechanisms by which dietary changes and exercise influence muscle and bone provide clues that may help design better and more targeted intervention strategies. For example, evidence implicates age-related declines in muscle insulin-like growth factor 1 (IGF-1) in sarcopenia; and both exercise and injury increase IGF-1, IGF-1 receptors, and IGF-1 activated signaling pathways. Aging muscle may have less ability to synthesize IGF-1 or may be resistant to IGF-1, and aging may also be associated with attenuation of the ability of exercise to induce IGF-1 (87).
A small study of healthy older women fed with a low-protein diet for 10 weeks showed a decline in both muscle mass and IGF-1 (88). More than 20 years ago, Rizzoli and colleagues showed that protein supplementation in frail individuals post hip fracture restored levels of IGF-1 in the plasma and attenuated loss in bone mineral density compared to placebo (89). Supplementation with selenium and coenzyme Q10 have also been shown to increase levels of IGF-1 in older adults (90).
Skeletal muscle cells express the vitamin D receptor (VDR), and low levels of vitamin D have been associated with lower muscle strength, mobility impairments, and disability (91). In mobility-impaired older women, vitamin D supplementation increased VDR expression and improved skeletal muscle fiber size (92). However, another study in older adults with low baseline levels of serum 25(OH)D showed that while supplementation increased serum levels to more normal levels, there was no effect on lean mass, lower-extremity power, or strength (93).
Nutritional supplements that target inflammation have also been proposed as a strategy for improving muscle function in older adults. For example, omega-3 fatty acids derived from fish oil have also been shown to slow decline in muscle mass and function in older adults (94). However, a recent clinical trial, the ENabling Reduction of low-Grade Inflammation in SEniors (ENRGISE) Pilot study, which tested the efficacy of fish oil and the angiotensin receptor blocker losartan in older, mobility-impaired adults, showed no improvement of walking speed or serum level of the inflammatory marker IL-6 (95).
Demonstrating the efficacy of nutritional interventions is challenging for many reasons, including the difficulty of determining whether the baseline level of dietary intake is inadequate and capturing subtle effects of change from baseline. These challenges are exacerbated when nutritional interventions are superimposed on other interventions.


Designing clinical trials to target bone fracture in frail older adults

The burden of fracture is expected to increase worldwide as the population ages, yet few trials have assessed the benefit of treatments in the oldest old and even less in the frail population (96, 97). Thus, fracture prevention and optimizing bone health represent important public health goals. Interventions that target the frail population offer the potential for the greatest benefit, as was demonstrated in a study by Rolland and colleagues, which tested the ability of strontium ranelate to reduce vertebral fractures in osteoporotic women, independently of frailty status (98). Beyond pharmacological interventions, nutrition and exercise have been shown to act synergistically to improve bone and muscle health and thus should be incorporated into randomized clinical trials (99).
To increase the efficiency and maximizing learnings from clinical studies, sponsors and researchers should use harmonized protocols with similar outcome measures. The ICFSR Task Force suggested the following:

Possible Study Design

The placebo-controlled, parallel-arm, double-blind trial is the gold standard for assessing efficacy and effectiveness. Other elements of an optimal trial design include:
• A long run-in phase before initiating treatment, during which activity diaries could be monitored and dietary inadequacies or anemia corrected to ensure a stable baseline.
• 2 x 2 designs for studies testing multimodal approaches such as resistance exercise and/or combination of resistance and aerobic exercise and nutrition.
• Using assessment time points that have been harmonized with other studies to enable data pooling and meta-analyses of data.
• Use the gold standard of collecting falls incidence using monthly calendars.
• At least one-year of follow up. If studies aim to target bone fracture or prevent the progression from pre-sarcopenia to sarcopenia, long follow-up will be necessary.

Proposed Outcomes

• Primary outcome: fragility fractures at 24 months (hip and spine).
• Secondary outcomes:
o Physical performance and disability as measures of functional decline
o Injurious falls
o Patient-reported outcomes, including mobility assessments and quality of life
o Nursing home admissions
o Bone turnover biomarkers
o BMD assessment (hip and spine)
• Exploratory outcomes
o Cognitive function
o Comorbidities
o Survival

Note that Fragility fractures or injurious falls as the primary outcome will require a very large sample size. Benefit of pharmacological treatment has also needed a large sample size.

Potential Target Population

• Patients with low BMD, high rate of falls (such as ≥2 self-reported falls/year), and frailty.
• Inclusion criteria: ≥ 75 years old with osteoporosis defined by low BMD, FRAX, and/or history of osteoporotic fracture, and with frailty defined by variable proven predictive of falls (100). Patients in nursing homes and those with dementia should be included where possible.
• Exclusions: Projected life expectancy < 2 years or estimated glomerular filtration rate < 30 mL/min/1.73 m2, individuals who are bedridden or who have contraindications related to the drug being tested

Design of Interventions

Frailty is a complex syndrome requiring multidimensional interventions. Interventions should target two or more risk factors for falls. For example, polypharmacy and some specific medications have been associated with increase fracture risk (101, 102). The European Geriatric Medicine Society (EuGMS) Task and Finish group on Fall-Risk-Increasing Drugs (FRIDs) recently proposed practical recommendation and strategies to reduce the use of FRIDs (103). The increase risk of falls related to the use of psychotropics drugs (104), cardiovascular drugs (105) and other medications (106) is now well-known. As the field of geroscience continues to emerge, it may become possible to target aging itself (107). For example, cellular senescence represents a promising therapeutic paradigm for potentially preventing or even reversing age-related osteoporosis and simultaneously treating multiple aging comorbidities (108).
Multidomain interventions for preventing falls in older people living in the community typically include physical activity (strength and balance classes with walking practice), and deprescribing. A systematic review and meta-analysis concluded that such multidomain interventions may reduce the rate of falls and recurrent falls, although the impact on fracture reduction has not been clearly demonstrated (109).
To test an osteoporosis drug in combination with a multidomain intervention, four parallel groups are recommended: 1) osteoporosis drug alone, 2) multidomain intervention alone, 3) osteoporosis drug plus multidomain intervention, 4) placebo or active comparator.
The Multidomain Alzheimer’s Prevention Trial (MAPT) study is an example of a multidomain trial in frail older adults (110). This three-year, multicenter, randomized, placebo-controlled superiority trial enrolled community-dwelling persons aged 70 or older with spontaneous memory complaints, absence of dementia, and limitations in one instrumental activity of daily living or slow gait speed. They were randomly assigned to one of four groups: 1) a multidomain intervention comprising cognitive training, physical activity, and nutritional counseling plus omega-3 polyunsaturated fatty acids with a total daily dose of 800 mg docosahexaenoic acid and 225 mg eicosapentaenoic acid, 2) the multidomain intervention plus placebo, 3)omega-3 polyunsaturated fatty acids alone, or 4) placebo alone. The trial was registered with ClinicalTrials. gov (NCT00672685).


Conclusions and next steps

The ICFSR Task Force reached several conclusions. First, it recognized that the traditional care system is inadequate for dealing with complex health disorders of aging such as frailty, where multidisciplinarity is required (111, 112). Cognitive impairment is often associated with frailty and must be taken into consideration (113, 114). The links between frailty and cognition are now well described (115–117) and integrated care like the ICOPE program have to be promoted to prevent and treat fractures in frail older persons (118–121).
Second, the Task Force suggested that reducing fracture risk among older adults requires first intervening with a powerful agent to restore the strength of bone, and then switching to an anti-resorptive agent to maintain bone health. The need for treatment is especially true after a first major hip fracture. The high cost of many of these drugs imposes a barrier to such an approach and payers will require studies that document efficacy; yet fractures themselves are costly and health economics studies show that bone forming agents are cost-effective even over short time periods. Combination therapies were also recommended, not just for treating the bone but for other factors as well, particularly in individuals who are frail. Benefits of these drugs in frail populations with high risk of fracture, short life expectancy, and high risk of adverse events such as nursing home residents should be investigated. One problem is that these frail older adults often take many drugs due to co-morbidities, including cognitive impairment, undernutrition, depression, and loneliness, raising questions about the value of further adding drugs to treat osteoporosis versus decreasing drug consumption in frail older adults. Advances in the field of geroscience may help in the future to answer these questions by introducing new biomarkers and better targeted therapies (122–124).
Third, the Task Force noted that while pathophysiology of bone fracture is the same in frail and non-frail adults, the mechanisms that lead to bone fracture – poor balance, sarcopenia, poor physical performance, sedentary lifestyle, and poor nutritional status – differ. Given these differences, specific recommendations may be needed for interventions in people who are frail, for example by more routinely adopting multidimensional and comprehensive interventions (125). To develop these interventions, more studies are needed in people who are frail and old. In addition, high-quality research is needed to confirm the role of nutrition in reversing or preventing frailty and adverse outcomes in frail persons (126, 127). Moreover the ICOPE program developed by WHO appears to be most useful for the frail older adults with osteoporosis to maintain Intrinsic capacities, monitor functions with ICOPE MONITOR (119) and prevent further disabilities (Table 1).

Table 1
Screening Tool for the “Integrated Care for Older Persons” (ICOPE)


Acknowledgements: The authors thank Lisa J. Bain for assistance in the preparation of this manuscript.
Conflicts of interest: ACJ reports grants or personal fees from Fresenius Kabi, Abbott Nutrition, Nestlé, Nutricia, Sanofi, and Pfizer, all unrelated to the submitted article. MC is member of Advisory Board for Nestlé.
Ethical Standards: None
Open Access: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.



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