The Journal of Nutrition, Health & Aging© Volume 12, Number 7, 2008

SARCOPENIA: DIAGNOSIS AND TREATMENT

SARCOPENIA: DIAGNOSIS AND TREATMENT J.E. MORLEY Division of Geriatric Medicine, Saint Louis University School of Medicine and GRECC, VA Medical Center St. Louis, Missouri. Contact: John E. Morley, M.B., B.Ch. Geriatric Medicine, Saint Louis University School of Medicine, 1402 S. Grand Blvd., M238, St. Louis, MO 63104, Email: [email protected]

In 1931, Critchley noted that with aging there was a loss of muscle mass which was most marked in the hands and feet (1). This age-related loss of muscle mass was called sarcopenia (from the Greek: sarx for flesh and penia for loss) by Irving Rosenberg (2). While originally sarcopenia was considered to be a generalized loss of muscle, it is now more conventionally used as a level of muscle loss substantially less than that seen in normal young persons, similar to the terms osteopenia and osteoporosis for bone (3). While it is recognized that the factors that cause strength loss are different from those producing muscle loss (4), sarcopenia usually results in a decline in strength and power leading to frailty and disability. The International Academy for Nutrition and Aging definition for frailty is strongly related to sarcopenia (Table 1) (5, 6). Table 1 The International Academy of Nutrition and Aging Screen for Frailty Fatigue Resistance (cannot climb 1 flight of stairs) Aerobic (cannot walk one block) Illnesses (more than 5) Loss of weight (greater than 5% in 1 year)

Sarcopenia is very common in older persons with a prevalence from 5 to 13% in persons aged 60 to 70 years and of 11 to 50% in persons over 80 years of age (5, 6, 7, 8, 9, 10, 11, 12). The large variability in prevalence is related to the differences in measurement and cut-offs used to define sarcopenia. Sarcopenia is approximately twice as common as frailty (13). In the United States, it can be estimated that there are roughly 3.6 million persons with frailty. Janssen et al. (14) utilized the NHANES data to demonstrate that sarcopenia was strongly associated with disability. They calculated that the total cost to the American Health System of sarcopenia was approximately $18.4 billion. Subsequently it has been recognized that persons who lose muscle, but remain obese, are at very high risk of disability and mortality (15). This condition is called “obese sarcopenia” or the “fat frail.” In addition, when muscle contains large amounts of fat as demonstrated by attenuation on magnetic resonance imaging, there is increased likelihood of poor outcomes (16). This condition is termed myosteatosis.

Received March 7, 2008 Accepted for publication March 17, 2008

452

Diagnosis The measurement of skeletal muscle mass is fraught with difficulty with al available methods having some drawbacks. The methods used to measure muscle mass are outlined in Table 2. Most studies measure appendicular muscle mass and correct this for height. About 75% of muscle mass is appendicular and approximately 60% of fat free mass is muscle. Table 2 Methods to Estimate Sarcopenia Approach

Problems

Cost

DEXA

Cannot distinguish muscle from organ protein Problem when abdominal fat is present

$$$

Bioelectrical Impedance

Problems with hydration status

$$

Anthropometry

Operator dependent Crude approximation

$

Urinary creatine/ Creatinine

Physical activity Non-muscle sources Renal clearance

$

CT or MRI

Cross-sectional

$$$$

Neutron Activation Cannot distinguish muscle from organ protein Limited availability

$$$

As already alluded to, aging is associated with changes in muscle composition and quality. With aging there is a decrease in both muscle fiber size and number. With aging, there is a greater loss of Type II fibers and an increase in hybrid type I and II fibers (17, 18). Changes in the muscle result in a slowing of twitch contraction time and a slowing of maximum shortening speed. For these reasons, it is important to measure muscle strength and power as well as mass. The Jamar dynamometer remains an excellent method for measuring upper arm strength in persons without arthritis. Lower limb strength and/or power can be obtained by measuring walking speed or stair climbing. The use of the Cybex and similar machines is useful for research, but requires expensive equipment and technical skill. Ultrasonic studies have shown that changes in tendons with alteration in pennation angles plays an important role in the ability to generate power (19). Electromyography can be used

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THE JOURNAL OF NUTRITION, HEALTH & AGING© to determine loss in motor units. It should be recognized that loss of executive function interacts with sarcopenia to produce falls – “the dual tasking” effect. The trigger to screen for sarcopenia should be a loss of muscle mass of 5% or greater over a year or less (20). Sarcopenia is one of the four major causes of weight loss (21). The other causes are anorexia (22, 23), cachexia (24) and dehydration (25). Loss of muscle mass leads to “masked” renal failure. This is important as renal failure is a common cause of cachexia (26). Differentiating the different causes of weight loss can be difficult as shown in Table 3. Table 3 Comparison of Sarcopenia, Cachexia and Anorexia

Weight loss Fat free mass Proteolysis Fat Mass Anorexia Cytokines

Sarcopenia

Cachexia

Anorexia

Mild Moderate Loss Increased Increased or Normal No Elevated or Normal

Severe Severe Loss Markedly Increased Marked Loss Yes Markedly Elevated

Moderate Mild Loss Normal Loss Yes Normal

Management The key to managing sarcopenia is physical activity coupled with adequate nutritional intake. At present, the only available drug therapy for sarcopenia is anabolic steroids. Numerous other drugs are at various stages of development (Table 4). Table 4 Management of Sarcopenia 1. 2.

Physical exercise – Aerobic/Resistant High protein supplement

3.

Anabolic steroids

4. 5. 6.

Selective Androgen Receptor Molecules (SARMs) Angiotensin Converting Enzyme Inhibitors Developmental

- casein - leucine - testosterone - nandrolone - ostarine - prindopril - antimyostatin - ghrelin agonists

Physical Activity Manini et al. (27) found that in 70 to 80 year olds high total energy expenditure leads to increased longevity. In this study, stair climbing was a major factor in producing increased total energy expenditure. Higher levels of physical activity attenuate the development of sarcopenia (28). When older persons undergo a period of enforced bed rest, they lose muscle at a greater rate than do young persons (29). Both aerobic and resistance exercise increase muscle mass and strength and decrease the rate of fat accumulation (30, 31, 32). Exercise decreases the rate of development of disability and frailty (33, 34). Spontaneous Physical Fun (SPF) is an important component of maintaining muscle mass. Spontaneous physical activity is 453

related to orexin levels in the hypothalamus of rodents (35). Older persons who get out of the house once a day do better than those who stay indoors (36). SPF includes stair climbing, walking, dancing and gardening. It needs to be done in combination with a regular exercise routine. Nutrition Low calorie and protein intake in older persons is associated with the development of frailty (37). Calories are essential for muscles to generate adequate energy. Thus, older persons with the physiological anorexia of aging or pathological causes of anorexia need to be aggressively treated to allow maintenance of an adequate calorie intake (38, 39, 40). Depression is a common, treatable cause of anorexia (41, 42, 43). Caloric supplements should be given between and not with meals (43a). The Recommended Daily Allowance of 0.8 g/kg body weight/daily of protein is insufficient to maintain nitrogen balance in older persons (44). To prevent sarcopenia older persons need between 1.2 to 1.5 g/kg daily. Essential amino acids such as leucine are not only building blocks but increase protein anabolism and decrease protein breakdown (45). There are now studies that demonstrate that creatine acts synergistically with resistance exercise to increase strength in older persons (46, 47). Anabolic Steroids Since 1889 when “Pud” Galvin, a pitcher for the Pittsburgh Steelers, used Brown-Sequard Elixir, sports persons have used anabolic steroids to improve performance. Total testosterone decreases by 1% per year and bioavailable testosterone by 2% per year from the age of 30 years in males (48, 49). Testosterone levels decrease rapidly from 20 to 45 years in women (50). A number of studies have shown that testosterone, even in eugonadal males, increased muscle mass (51, 52, 53). High doses of testosterone in hypogonadal older males increase strength (54, 55, 56) and improve physical performance (57). Testosterone increases muscle mass and strength by stimulating satellite cell production as well as muscle protein synthesis (58). Testosterone also increases muscle mass in postmenopausal women (50). Testosterone in combination with a caloric supplement decreased hospitalization in frail older men and women (59). Dehydroepiandrosterone (DHEA) levels decline steeply with aging and lower levels are associated with low muscle mass and strength in postmenopausal women (60). However, 50g of DHEA for a year failed to improve muscle mass or strength in males and females (61). Nandrolone, an injectable anabolic steroid, increases muscle mass and performance in older persons (62). It is similarly effective to increase muscle performance in patients with AIDS, COPD and renal failure (63, 64, 65). Recently, a number of selective androgen receptor molecules (SARMs) have been developed. These agents can be ingested orally and build muscle and promote bone. One of these agents

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SARCOPENIA: DIAGNOSIS AND TREATMENT is ostarine (66). Ostarine increased fat free mass and power as measured by stair climb in healthy older males and females with a mean age of 64.8 years (67). Vitamin D Low levels of vitamin D (less than 30 ng/ml) are associated with sarcopenia and declines in muscle strength (68, 69). Low vitamin D is an independent predictor of falls (70). Vitamin D replacement in persons with low levels increases strength and performance (71). Vitamin D levels fall longitudinally with age (72). Low vitamin D levels are particularly common in older persons residing in nursing homes (73, 74, 75). All older persons with sarcopenia should have vitamin D levels measured and, if low, vitamin D needs to be replaced. Growth Hormone In malnourished older persons growth hormone produces nitrogen retention and improves walking speed (76, 77). However, there is limited evidence that growth hormone can increase strength (78). For this reason, growth hormone is not recommended for the treatment of sarcopenia. Ghrelin is a hormone that is produced from the fundus of the stomach and causes increased appetite, growth hormone release and improved memory (79, 80). Ghrelin increased handgrip strength in patients with heart failure (81).

Conclusion Sarcopenia should be diagnosed by geriatricians. Diagnosis requires a DEXA measurement of fat free mass using the appendicular levels corrected for height squared. Ultrasound measurement of muscles and tendon angle may be an acceptable alternative. Basic treatment consists of aerobic and resistance exercise together with a high protein (leucine and creatine) supplement between meals. 25(OH) vitamin D levels should be measured and, if low, need to be aggressively replaced. A total or preferably free or bioavailable testosterone level should be obtained in males (96). If low, testosterone replacement at 100 mg a week intra-muscular is advised. In females nandrolone may be a reasonable alternative. A brachial/ankle Doppler should be obtained and if suggestive of peripheral vascular disease, the patient should be treated for atherosclerosis. This approach is summarized in Figure 1. Figure 1 Possible Approach to the Management of Sarcopenia

Angiotensin Converting Enzyme (ACE) Inhibitors There is epidemiological and animal studies supporting the use of ACE inhibitors for the treatment of sarcopenia (82, 83). Persons with the II ACE genotype have low ACE activity and better endurance performance in response to exercise training (84). Heart failure patients receiving an ACE inhibitor had improved exercise capacity (85). In a double blind controlled trial, 130 persons over 65 years of age received perindopril or placebo for 20 weeks (86). In this study perindopril increased walking distance by 31.4 meters. Other Factors High levels of cytokines, especially interleukin-6, result in a loss of muscle mass and decreased performance (87, 88, 89). There is however, no studies demonstrating that cytokine inhibitors improve muscle function. Myostatin inhibits muscle growth (90). Myostatin antibodies are in clinical trials to try and reverse sarcopenia. The metabolic syndrome and diabetes are associated with a decline in muscle strength, increased falls and hip fracture (91, 92, 93). Adequate control of diabetes and hypertriglyceridemia should be obtained in persons with sarcopenia. Loss of motor units is associated with loss of muscle mass and power (94). This may be due to declining ciliary neurotrophic factor levels with aging (95). Topiramate may improve nerve growth.

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