Benefits of Resistance Training in Early and Late Stages of Frailty and Sarcopenia: A Systematic Review and Meta-Analysis of Randomized Controlled Studies

1Life expectancy is the highest to date, and world aging has increased at a staggering rate. Despite the fact that people live longer than ever, human aging produces various syndromes that reduce their quality of life, contribute to their dependence, and increase public care costs. Prominent among these syndromes are sarcopenia and frailty. A recent estimate from 28 European countries suggests increments of 60–70% in the prevalence of sarcopenia by 2045, resulting in 12.9 to 22.3% of people over 65 years old being affected. Sarcopenia is generated by a severe loss of muscle mass as a consequence of diverse factors such as nutritional status, physical activity, genetic heritability, or hormonal changes. This fact, together with a decline in the tendon proprieties and neural patterns, results in a loss of muscular strength and mobility (i.e., functional status). Frailty, for its part, is an age-associated medical syndrome that embodies a high risk for falls, disability, hospitalization, and mortality among older adults. Frailty has been shown to increase health costs by up to ~5 times. Therefore, these age-related physical syndromes require the implementation of treatment aimed to reduce the public health costs, but above all, to attenuate the loss of quality of life among older adults suffering from them. Frailty can lead to common healthcare issues, such as decrease of strength, immobility, falls, undernutrition, incontinence, depression and anxiety. In addition to healthy lifestyle behaviours, frailty may be prevented and even reversed with proper exercise training. Among frail older adults, exercise is particularly important to maintain physical functioning and self-autonomy, reducing the risk of falls, acute hospital and care home admission.

2On this matter, supervised exercise is proposed as an effective strategy to treat sarcopenia and physical frailty. Chiefly, resistance training interventions might be particularly beneficial to delay and reduce the causes (e.g., loss of muscle mass) and consequences (e.g., loss of muscular strength or functionality) that both syndromes usually produce, even at early stages. Resistance training is defined as a strength training exercise with the use of progressive overload in which the muscles create the force against external load. Moreover, resistance training is the most effective exercise type intervention compared to endurance training or the whole-body vibration training and can improve physical function and physical performance in older adults. Resistance training as an essential component of a complete exercise program complements the commonly known positive effects of aerobic training on health and physical capacities. Previous research has been carried out on the effects of physical exercise interventions on frailty and/or sarcopenia, and of resistance training on frailty or sarcopenia. However, there is a knowledge gap when it comes to the effect of resistance training on muscular strength, physical performance, and body composition at early (prevention) and late (treatment) stages in both syndromes combined. Besides, little is known about the potential effect of resistance training as a preventive strategy to reduce the occurrence of these syndromes.

3Because of its potential, research examining resistance training effects on age-related physical syndromes is on the rise. Therefore, an update of the state of the art is required. This research aimed to systematically review the scientific evidence examining the effect of resistance training on muscular strength, physical function, and body composition of older adults diagnosed with pre-sarcopenia, sarcopenia, pre-frailty, or frailty. Moreover, to address this issue comprehensively, a meta-analysis was conducted to synthesize the outcomes of comparative studies. Based on the available literature, it was expected that older adults diagnosed with frailty or sarcopenia at both early and late stages would demonstrate improvement in handgrip strength, lower-limb strength, muscle mass, and functional performance after eight or more weeks of resistance training.

4The protocol of this investigation was pre-registered in the PROSPERO database (CRD42019138253). The present systematic review and meta-analysis were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.

5A search from the earliest record up to and including December 2020 was carried out using the following electronic databases: Medline, Scopus, Web of Science, and Cochrane Library. The search strategy combined terms related to the population (e.g., sarcopenia, frailty) and intervention (e.g., resistance training, strength training). Table A1 shows the full Boolean search syntax used in PubMed. The PubMed syntax was then adapted for the search in the Web of Science and Scopus. Additionally, the article’s reference lists were scanned to identify additional studies for inclusion in the present review. The titles and abstracts of the retrieved articles were individually evaluated for eligibility. Potentially eligible articles were retrieved for full text evaluation. If any disagreement occurred, a consensus meeting was held between all the reviewers to reach an agreement upon inclusion of the publication.

6The eligibility criteria were: (1) participants included older individuals (≥65 years of age) with pre-frailty, frailty, pre-sarcopenia or sarcopenia but without comorbid conditions (e.g., diabetes, cancer, stroke, dementia, depression); (2) resistance training intervention lasted ≥ 8 weeks as this is the recommended minimum intervention duration to increase muscle strength and treat sarcopenia. Moreover, muscle hypertrophy is observed after 8 weeks with longer training periods supporting lasting effects; (3) at least one outcome of interest (muscular strength, body composition, gait speed, balance, agility) was reported before and after the training intervention; (4) randomized controlled trial as study design; (5) manuscript published in English (dissertations and conference proceedings were excluded). Studies including other interventions as controls (supplementation, home-based exercise, educational programs, or combined interventions) were included.

7The following variables from the included studies were extracted independently by two authors (KT and MS): (1) characteristics of the study (year of publication, geographical area) and the sample (size, gender, and age); (2) description of the program conducted by the training and control group; (3) main outcomes of interest; and (4) overall effect of the outcome of interest. For quantitative analyses (meta-analyses), authors collected the group size and mean differences of the outcomes of interest with a 95% confidence interval (CI) or standard deviation (SD) for both groups (intervention and control). All data were tabulated in an Excel spreadsheet (Microsoft Corporation, Redmond, WA, USA) predesigned for this review. Coding sheets were cross-checked between authors, while discussion and consensus resolved any discrepancies.

8As described in our PROSPERO protocol, we initially intended to use the GRADE scale as a widely recommended system for observational studies and randomized controlled trials. However, subsequent to the protocol registration, we decided to use the Physiotherapy Evidence Database (PEDro) scale to assess the methodological quality of included studies. PEDro provides an assessment of the quality of randomized controlled trials, especially in evidence-based physical-therapy. The PEDro scale has demonstrated reliability with score range from 0 to 11, where scores ≤ 3 represent poor study quality, scores of 4–5 indicate fair quality, and scores ≥ 6 represent good to excellent quality. This change to the protocol has been registered in PROSPERO.

9The effect sizes (ES) were calculated as the standardized mean differences between the resistance training group and the control group. Sub-group analyses were conducted to examine ES for early stages of sarcopenia and frailty. As traditional meta-regression methods do not allow for multiple dependent outcomes from the same study to be included in one analysis, we used a meta-analytic method for dealing with dependent effect sizes named robust variance estimation (RVE). RVE is a form of random-effects meta-regression for multilevel data structures, which allows for multiple effect sizes from the same study to be included in a meta-analysis, even when information on the covariance of these effect sizes is unavailable. Instead, RVE estimates the variance of meta-regression coefficient estimates using the observed residuals. It does not require distributional assumptions and does not make any requirements on the weights. A study was used as the clustering variable to account for correlated effects within studies. Observations were weighted by the inverse of the sampling variance. A sensitivity analysis using alternative correlational values to calculate the standard error revealed that the choice of correlational value did not impact the overall results of the meta-analysis. I2 was used to evaluate between-study heterogeneity. Values of I2 more than 25%, 50%, and 75% were selected to reflect low, moderate, and high heterogeneity, respectively. All analyses were performed using packages robumeta (version 2.0) and metafor (version 2.0-0) in R version 3.4.4 (The R Foundation for Statistical Computing, Vienna, Austria).

10The database search yielded 1468 articles. Of those, 155 full texts were retrieved, and 26 deemed eligible. As one study reported its results in two separate articles, 25 studies were included in this review, as shown in the PRISMA flow diagram (Figure 1).

11The methodological quality of the studies is detailed in Table 1. Since all the studies obtained the predefined minimum score of 6 points, they were all included in the qualitative and quantitative syntheses. The minimum, maximum, and mean scores of the quality analysis were 6, 11, and 8.76 (±1.26) points, respectively.

12In total, there were 2267 participants (1484 women). The mean age ranged from 62 to 98 years. The mean duration of resistance training programs was approximately 23 weeks (range 10–48 weeks), and the most common training frequency was 2–3 times per week (in 21 studies). Table 2 and Table 3 show the characteristics and the overall effect of the 25 studies included in the review. Table A2 presents the diagnostic criteria for frailty or sarcopenia with the prevalence of participants for each study.

13Meta-analysis showed significant changes in handgrip (ES = 0.51 [95% CI: 0.23 to 0.78], p = 0.001, Figure 2) and lower-limb strength (ES = 0.93 [95% CI: 0.64 to 1.22], p < 0.001, Figure 3) in favor of the resistance training group. Heterogeneity of the results around these outcomes was moderate for the handgrip (I2 = 68%) and high for the lower-limb strength (I2 = 77%). Sub-group analyses for early stages yielded positive but non-significant effects in handgrip (ES = 0.12 [95% CI: -0.13 to 0.36], I2 = 0%, p = 0.146, Figure 4) and lower-limb strength (ES = 0.35 [95% CI: −0.97 to 1.67], I2 = 52%, p = 0.372, Figure 5).

14Meta-analysis showed significant changes in favor of the resistance training group for the agility (ES = 0.78 [95% CI: 0.34 to 1.22], p = 0.003, Figure 6), balance (ES = 0.68 [95% CI: 0.23 to 1.13], p = 0.007, Figure 7), gait speed (ES = 0.75 [95% CI: 0.49 to 1.02], p < 0.001, Figure 8), and functional strength (ES = 0.76 [95% CI: 0.52 to 1.00], p < 0.001, Figure 9). Heterogeneity of the results around these outcomes was low for the functional strength (I2 = 48%), and high for the gait speed (I2 = 76%), postural stability (I2 = 82%), and agility (I2 = 78%). Sub-group analyses for early stages yielded positive but non-significant effects in agility (ES = 0.28 [95% CI: −0.47 to 1.03], I2 = 58%, p = 0.244, Figure 10) and balance (ES = 0.75 [95% CI: -0.45 to 1.94], I2 = 82%, p = 0.141, Figure 11), while benefits in gait speed (ES = 0.63 [95% CI: 0.22 to 1.04], I2 = 18%, p = 0.016, Figure 12), and functional strength (ES = 0.53 [95% CI: 0.31 to 0.76], I2 = 0%, p = 0.011, Figure 13) remained significant during early stages.

15Meta-analysis showed significant changes in fat mass (ES = 0.41 [95% CI: 0.23 to 0.59], p = 0.001, Figure 14) and muscle mass (ES = 0.29 [95% CI: 0.12 to 0.46], p = 0.002, Figure 15) and in favor of the resistance training group. Heterogeneity of the results around the body composition outcomes was very low for the fat mass (I2 = 18%) and moderate for the muscle mass (I2 = 54%). Sub-group analyses for early stages yielded positive but non-significant effects in fat mass (ES = 0.30 [95% CI: −4.32 to 4.92], I2 = 67%, p = 0.558, Figure 16) and muscle mass (ES = 0.25 [95% CI: −0.68 to 1.18], I2 = 69%, p = 0.458, Figure 17).

16This systematic review found that resistance training is a highly effective strategy to improve muscular strength, physical function, and body composition parameters in older adults with pre-frailty, frailty, pre-sarcopenia, or sarcopenia. Besides, resistance training during early stages had positive effects in all variables, being particularly effective in improving physical function. These findings reinforce the use of strength training interventions to delay and attenuate negative effects related to both physical syndromes.

17Muscular strength is considered the primary determinant of sarcopenia. To date, the handgrip evaluation represents the most common test used to measure this physical capacity due to its high affordability, portability, simplicity, and test-retest repeatability. Nevertheless, to obtain an overall indicator of strength, some investigations have suggested the need to complement this test with specific evaluations of the lower-limb muscles (e.g., isometric knee extension). The present study found that individuals suffering from (pre-) sarcopenia or (pre-) frailty significantly improved both handgrip (ES = 0.51, p = 0.001) and lower-limb (ES = 0.93, p < 0.001) strength after a training intervention based on resistance exercises. Indeed, except for one study in each analysis (handgrip and lower-limb), all investigations reported effects in favor of the resistance training group (Figure 2 and Figure 3). Moreover, specifically to lower-limb strength, our results revealed that these strength enhancements were detected both isometrically and dynamically.

18We found that all of the analyzed functional capacities were significantly improved by the implementation of a resistance training intervention (ES from 0.68 to 0.78). With the exception of one study for the agility and gait tasks (Figure 6 and Figure 8), and two investigations for the balance task (Figure 7), all studies found effects in favor of the resistance training group. Furthermore, all investigations reported superior effects for the resistance training group in relation to functional tasks (Figure 9). These findings could be strongly related to the significant lower-limb strength gains (Figure 3). Since the lower-limb muscles (e.g., knee extensors) are mainly responsible for actions such as chair rising or walking, the increment of strength in these structures could have been positively transferred into the physical function. In turn, these improvements in physical function can potentially reduce the dependency situation of older adults, thus increasing their quality of life and decreasing the public health costs.

19Our results revealed a positive effect of resistance training on the reduction of fat mass (ES = 0.41, p = 0.001, Figure 8) and increases in muscle mass (ES = 0.29, p = 0.002, Figure 9). Since the muscle mass can explain approximately 60–70% of strength capacity, these muscle mass enhancements are strongly related to the strength gains described above (Figure 2 and Figure 3). Similarly, the increases in muscle mass could have generated the decreases in fat mass as a result of the rise in the energy expenditure of the individuals. Together, these positive changes in body composition parameters could reduce the risk of other common diseases in older adults, such as metabolic syndrome.

20Generally, exercise interventions can decrease the prevalence of frailty and sarcopenia and are also effective in reducing the severity of these syndromes. Our results are consistent with previous studies supporting that resistance training is beneficial for the muscular strength and physical function in older adults with frailty or sarcopenia, but they do not combine both syndromes (sarcopenia and frailty) and if they do, they examine the effect of exercise overall. These new results support evidence that resistance training is the most effective exercise type of intervention to improve muscle strength and physical performance in older people compared to endurance training or whole-body vibration training. More specifically, it seems preferable to perform multi-component exercise programs combining a power-oriented resistance training regime with endurance and balance exercises.

21Great emphasis should also be placed on the issue of financial sustainability of healthcare. It has been observed that frailty and sarcopenia lead to the increase of public health costs. According to Bock et al., 2016 the mean total 3-month costs of frail participants in Saarland, Germany were € 3659 and non-frail older adults € 642, thus more than 80% of costs could be easily saved. For this reason, preventing, postponing or even reducing frailty could potentially decrease total healthcare costs in many countries.

22This study is not exempt from limitations. Firstly, except for the functional strength and fat mass, most of the meta-analyses indicated moderate to high levels of heterogeneity. This fact could be explained mainly by the different variables included in the quantitative analysis (i.e., clinical diversity), as well as by the different methodologies (e.g., volume, intensity, exercise, program duration) used in each study (i.e., methodological diversity). Secondly, although the mean duration of training interventions included in the present review (~20 weeks) allows us to suggest that resistance training is an effective short/medium-term strategy, more evidence including longer resistance training programs is needed to confirm the long-term benefits, in particular, whether they are effective for reducing prevalence of sarcopenia and frailty. Thirdly, future systematic reviews are encouraged to examine the effects of resistance training on other physiological parameters, such as the neural drive, muscle architecture, or tendon proprieties, among individuals with pre-sarcopenia, sarcopenia, pre-frailty, or frailty.

23Based on these results, resistance training should be considered as a highly effective preventive strategy to delay and attenuate the negative effects of sarcopenia and frailty in both early and late stages.