Sarcopenia: from clinical aspects to therapeutic possibilities

In recent years, with the increase in life expectancy and the increasing number of elderly people, sarcopenia has been recognized as a separate entity and a new field in geriatric medicine. The European Working Group on Sarcopenia in Older People defined sarcopenia as a syndrome characterized by progressive and generalized loss of skeletal muscle mass, strength and consequently muscle function, which carries with it an increased risk of falls, disability, loss of work ability and premature death. Sarcopenia in the elderly is being given major research focus in many countries, due to its great impact on morbidity, mortality and health care costs. Despite its clinical importance, sarcopenia is still underrecognized in daily clinical practice, in part due to the lack of available diagnostic tests and unique diagnostic criteria, as well as the lack of clear treatment guidelines. Diagnosing sarcopenia requires assessment of muscle mass, muscle strength and physical performance. The treatment of sarcopenia includes various non-pharmacological and pharmacological approaches, and is primarily focused on resistance and strength exercises, with simultaneous nutritional support.

INTRODUCTION

Sarcopenia is a syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength, and it represents the main determiner of increased risk of falls and fractures, decreased ability for performing everyday activities, cognitive decline, as well as the exacerbation of cardiovascular and respiratory diseases, which commonly leads to invalidity, loss of independence, and premature death [1],[2]. In its revised guidelines, from 2018, the European Working Group on Sarcopenia in Older People (EWGSOP2) added to the existing definition of sarcopenia the concept of reduced muscle function and its estimation, emphasizing that muscle strength, i.e., muscle function, is a better predictor of adverse events than muscle mass [3]. Also, the application of the defined algorithm and criteria for screening, diagnosing and determining the severity of sarcopenia is proposed within these guidelines. Early detection and treatment may prevent or alleviate some of the adverse outcomes of sarcopenia [4].

The prevalence of sarcopenia in older persons residing in nursing homes for the elderly is up to 29%, whereas the prevalence of sarcopenia in individuals residing in care facilities can reach up to 33% [4]. The coexistence of osteoporosis and sarcopenia has recently been designated as the syndrome osteosarcopenia. While osteoporosis is characterized by reduced bone mass and weakened bone microarchitecture, sarcopenia is characterized by loss of muscle mass, strength and function. Osteosarcopenia may encompass the existence of both of these characteristics at the same time. Frailty can be defined as a clinically manifest condition of increased sensitivity, with low grip strength, decreased energy of movement, low gait speed, and involuntary weight loss.

RISK FACTORS FOR THE DEVELOPMENT OF SARCOPENIA

The presence of certain risk factors influences the development of sarcopenia. These are listed below.

1. Lack of exercise and physical activity is believed to be one of the leading factors in the development of sarcopenia [5].
2. Hormonal and cytokine imbalance – decreased concentrations of the growth hormone, testosterone, thyroid hormones, and IGF (insulin-like growth factor), leads to the loss of muscle mass and strength, i.e., muscle wasting and weakness [6].
3. Inadequate food intake, decreased protein synthesis and regeneration, are characteristic of the elderly population with sarcopenia [7],[8],[9].
4. Motor unit remodeling – in sarcopenia, the number of motor neurons responsible for transmitting signals from the brain to the muscles, decreases [6].
5. Chronic systemic inflammation, which is a characteristic of ageing, through increased production of the tumor necrosis factor alpha, interleukin-6 (IL-6), C-reactive protein (CRP), and other inflammatory cytokines, leads to tissue damage and anabolic resistance, which is the main determiner of sarcopenia [10],[11].

CLASSIFICATION OF SARCOPENIA

Grading sarcopenia reflects the severity and gravity of the health status of an individual, and it assists the physician in selecting the mode of treatment and in defining realistic goals and expectations. Sarcopenia is classified as presarcopenia, sarcopenia in the narrow sense, and severe sarcopenia, i.e., primary and secondary sarcopenia.

Presarcopenia involves reduced muscle mass and may be diagnosed with muscle mass measurement techniques and through comparison with the standard population. Sarcopenia in the narrow sense involves reduced muscle mass, with the presence of one more criterion – decrease in muscle strength. Severe sarcopenia entails that all three criteria are present (reduced muscle mass, reduced strength, and reduced muscle function) [1].

Primary sarcopenia is exclusively associated to the ageing process, when all other causes are excluded with certainty. Secondary sarcopenia develops with at least one or more clear causes which are not exclusively connected with the ageing process, which may be sedentary lifestyle caused by disease (disability or immobility) or inadequate daily physical activity [12].

SARCOPENIA DIAGNOSTICS

Sarcopenia is most commonly suspected when symptoms are already present. Some of them are the following: feeling of muscle weakness, slackening, difficulty in performing everyday activities, frequent falls, and the subjective feeling of muscle wasting [3]. The EWGSOP2 proposes the Find-Assess-Confirm-Severity (FACS) algorithm for establishing the diagnosis of sarcopenia. The first step is screening for sarcopenia, most commonly with the Strength, assistance with walking, rising from a chair, climbing stairs, and falls (SARC-F) questionnaire. If sarcopenia is suspected, assessment of muscle strength is performed (for example, with hand-held dynamometry), upon which, if indicated, tests for the assessment of muscle quantity and quality (osteodensitometry, bioelectrical impedance analysis, computed tomography, magnetic resonance imaging) may be carried out. As a final step, a physical performance assessment test should be carried out, for the purpose of confirming the definitive diagnosis and determining the severity of sarcopenia (Figure 1) [13].

Figure 1. Algorithm for screening and diagnosing sarcopenia based on the recommendations of the European Working Group on Sarcopenia in Older People (EWGSOP2); Find-Assess-Confirm-Severity – FACS)

SCREENING FOR SARCOPENIA

It is necessary to screen for sarcopenia, especially in patients over the age of 65 years. In clinical practice, this means that, when the patient reports some of the symptoms or signs of sarcopenia, (e.g., weakness, low gait speed, difficulty in rising from a chair, muscle wasting, weight loss), screening for sarcopenia should be performed. For the purpose of sarcopenia risk assessment, several tests are used, the most commonly applied being the SARC-F questionnaire. The SARC-F questionnaire is composed of five questions related to lifting and carrying weight, difficulties walking, rising from a chair, climbing stairs, as well as the frequency of falls. Each answer is scored from 0 to a maximum of 10 points. It is believed that the risk of sarcopenia is present when the score is higher than four points [14].

SARCOPENIA DIAGNOSIS

Upon screening, it is necessary to assess muscle mass, strength, and muscle performance. Clinically speaking, it is important to follow-up on the dynamics of these parameters by repeating measurements after certain periods of time. Which diagnostic method is to be chosen depends on numerous factors, such as validity, availability, price, level of technical equipment, the patient’s status, as well as the objective of the measurement (clinical or research purposes) [13],[19].

Methods for assessing muscle mass

Muscle mass may be indirectly assessed with different techniques and is defined as total skeletal muscle mass (TSM), as appendicular skeletal muscle mass (ASM), or as the surface area of the cross section of muscles belonging to certain muscle groups. Magnetic resonance imaging (MRI) and computed tomography (CT) are considered to be the golden standard for noninvasive muscle mass assessment, however, their use, due to limited availability and price, is mainly limited to specific clinical studies [15],[16].

Anthropometric measurements are relatively simple methods for assessing individual components of body composition, whereby measurements of human body dimensions (height, weight, skinfold thickness, body circumferences and diameters in certain reference points of particular regions of the body) and the use of appropriate equations, facilitate a simple method for obtaining data on body density, as well as the size of fat and lean body mass [16].

Computed tomography (CT) is a method which can be used to measure the quantity of abdominal visceral fat and to assess skeletal muscle mass, with particular focus on anatomical details, which is why it has a role in diagnosing sarcopenia [13].

Magnetic resonance imaging (MRI) is the most precise, albeit the least accessible method for assessing body composition, which is why it is most commonly used for measuring muscle mass in clinical studies. With the use of appropriate software, MRI provides precise data on the segment structure (fat, muscle, bone) of the studied body part [17].

Ultrasound (US) can also be used for determining body composition, i.e., for measuring the thickness of fatty and muscle tissue in patients. Ultrasonography can precisely measure the thickness of muscle and bone tissue, as efficiently as measuring the thickness of the subcutaneous and visceral fatty tissue. The procedure of ultrasonographic diagnostics is noninvasive and simple, however, its interpretation requires expertise and experience [18].

It is a known fact that dual-energy X-ray absorptiometry (DEXA) is clinically applied as the gold standard for establishing the diagnosis of osteopenia and osteoporosis. However, DEXA machines can also be used to assess body composition, at the level of the entire body or its individual parts, measuring three main components: mineral content of the bones, fat body mass, and lean body mass. By assessing parameters of sheer body mass without bones, such as appendicular sheer mass adjusted for body mass index (BMI) or height, it is possible to qualify patients with physiological muscle mass loss in relation to patients with a pathological loss. Because of its simplicity, availability, low cost, and low exposure to radiation, DEXA has been accepted as a noninvasive method for assessing muscle mass in all age groups [19].

Bioelectrical impedance analysis (BIA) is a simple, noninvasive, and relatively cheap method for estimating body composition, which is achieved by emitting an alternating electrical current of very low intensity, below the threshold of perception, and determining the resistance of the tissue when the current passes through the body. Newer devices provide an accuracy of measurement comparable with the gold standards for assessing body composition. This method can be used in very obese persons, as well as in immobile patients, while it is not recommended in persons with pacemakers, due to possible interference with its functioning [20].

Methods for measuring muscle strength

A hand-held dynamometer, which measures grip strength, is used for measuring muscle strength. Grip strength strongly correlates with the strength of the muscles of the lower extremities. A grip strength of less than 27 kg, for men, and less than 16 kg, for women, indicates a weakened muscle strength. Low grip strength is a strong indicator of poorer outcome, prolonged hospitalization, reduced quality of life, and premature death [21]. Due to the simplicity of the test, it is recommended that this test should be routinely administered in hospitalized patients as well as in everyday clinical practice. The chair stand test is used for assessing the strength of the proximal musculature of the legs and it measures the amount of time necessary for a patient to stand up five times in a row from the seated position without the use of the arms as support. This test requires strength and endurance. If more than 15 seconds are needed for a person to stand upright five times in a row from the seated position, this also indicates reduced muscle strength [13].

Methods for measuring physical performance

Physical performance is defined as objectively measured function of the entire body related to locomotion. This concept includes, not only muscles, but the central and peripheral system as well, including balance. Gait speed is believed to be a quick, safe, and highly reliable test for sarcopenia, and it is widely used in everyday practice. The common gait speed test is performed for a distance of four meters, whereby the gait speed is measured with a stopwatch, while a speed of less than 0.8 m/s indicates severe sarcopenia This test is recommended for evaluating physical performance in clinical practice [13].

A frequently applied method is the short physical performance battery (SPPB) test, which is used to assess balance, speed, gait, strength, and endurance of an individual. The maximum score is 12 points, while the score of ≤ 8 points indicates poor physical function [13],[22].

SARCOPENIA TREATMENT

Timely identification and treatment are key in improving outcomes in patients with sarcopenia. Potential strategies directed at increasing muscle mass and strength are calory and protein supplementation, physical activity, hormone therapy, and therapy specifically targeting the mechanisms causing sarcopenia [23].

Nutritional support and physical activity are the two most important interventions which are best carried out simultaneously [24]. The EWGSOP2 guidelines, from 2018, recommend physical activity as the first step in treating sarcopenia [25]. Resistance exercises are especially useful in the elderly [26],[27]. This type of training improves muscle mass, strength, and function, it stimulates neurological adaptation (intermuscular and intramuscular coordination), and also improves bone density and metabolic health [28]. Resistance training has a positive effect on the neuromuscular system, it increases the concentration of hormones and the speed of protein synthesis. Resistance and strength training have proven very successful in the prevention and treatment of sarcopenia. Strength exercises can increase physical mass, while endurance exercises can improve functional capacity [29]. Although there are numerous exercise programs used in everyday practice, there is a need for setting specific guidelines for patients with sarcopenia [13].

Sarcopenia requires a special dietary regimen, which involves the appropriate intake of proteins, vitamin D, antioxidants, and branched-chain amino acids [30],[31]. The recommended daily intake of proteins is 1 – 1.5 g/kg, while the optimal daily energy intake must not be below 35 kcal/kg, in order to preserve the necessary oxygen balance and reduce the proteolysis of skeletal muscles. Plant-based protein sources are better than animal-based proteins sources, as they contain proteins rich with branched-chain amino acids [32]. Supplementation with branched-chain amino acids, especially leucin and its metabolite beta‐hydroxy‐ beta‐methylbutyrate (HMB), may stimulate protein synthesis in muscles [33].

Vitamin D deficiency contributes to the rise in mortality, which is why daily supplementation of 600 – 1.000 IU of vitamin D is recommended. Daily vitamin D supplementation also contributes to the increase in strength and to the reduction in frailty in the elderly, thus facilitating physical activity and exercise [34],[35]. Increased oxidative stress and disturbance of antioxidant composition is a characteristic of ageing and chronic diseases, which is why it is necessary to consider the use of antioxidants in the treatment of sarcopenia [36]. A study from 2015 showed the benefits of omega-3 polyunsaturated fatty acids from fish oil, for the increase in muscle mass and strength [37].

Treatment with anabolic hormones, testosterone, and the growth hormone is not recommended in the treatment of sarcopenia. The growth hormone increases muscular protein synthesis and increases muscle mass; however, it does not lead to an increase in muscle strength and function. The inefficiency of this hormone is the consequence of the resistance of its effector, insulin-like growth factor-1 (IGF-1) in ageing muscles [38]. Testosterone or other anabolic steroids have also been tested. These hormones have a modest positive effect on muscle mass and strength and their use is limited, due to their harmful effects, such as the increased risk of prostate cancer and the overall increased risk of cardiovascular events [39].

New therapeutic modalities in the treatment of sarcopenia are still being investigated. Selective androgen receptor modulators (SARM) are particularly significant due to their selectivity in relation to tissue [40]. Other compounds being explored are myostatin, thalidomide, celecoxib, anabolic agents, such as ghrelin and its analogues, and MT-102. The above-mentioned agents are still being investigated in clinical studies and have not yet been approved for the treatment of sarcopenia [41].

CONCLUSION

As an entity, sarcopenia can be considered a geriatric syndrome. Sarcopenia in the elderly is connected to adverse health outcomes, such as falls, invalidity, inability to care for oneself, resulting in a reduced quality of life in the elderly, an increased number of hospital admissions, and premature death. Revised EWGSOP2 guidelines, from 2018, propose the application of the FACS algorithm with clearly defined criteria, for the purpose of establishing the diagnosis of sarcopenia. Combining resistance exercises with certain pharmacological compounds and dietary supplements may have a beneficial effect on the elderly, and in this way, prevent and decelerate the progression of sarcopenia. Raising awareness on the significance of sarcopenia is of great importance for achieving favorable outcomes in the treatment and follow-up of the geriatric population.