The sarcopenia challenge in fracture prevention at older age Critical for the understanding and prevention of fractures at later age is their close relationship with sarcopenia (muscle

Nutritherapy seeks to prevent or correct disease by the use of nutritional supplements including vitamins, trace elements, or macronutrients. This chapter of the “Les Entretiens du Carla” reviews the potential of nutritherapy for the prevention or improvement of sarcopenia, which is the progressive reduction in muscle mass and muscle strength prevalent in late-life. It is critical that we review nutrients and their potential to maintain muscle mass and strength which ultimately will help minimize falls and fractures among the older population. Evidence from randomized-controlled trials will be reviewed for muscle mass as well as important sarcopeniarelated endpoints including lower extremity strength and function, as well as falls and fallrelated fractures. This chapter will focus on vitamin D as a compelling strategy with evidence for strength gain, fall and fracture prevention from double-blind randomized controlled trials. The other strategy discussed is increased protein intake although longer-term trials and evidence for clinically important endpoints are limited. Today, there is no consistent data on other micronutrients or macronutrients with an established potential to combat sarcopenia. Received May 18, 2009 Accepted for publication June 2, 2009 than 20% by the European older population (8, 9). A 1999 landmark publication in the Journal of the American Medical Association (JAMA) by LeBoff and colleagues documented a 50% prevalence of severe vitamin D deficiency among postmenopausal women admitted with acute hip fracture (serum 25(OH)D levels < 30 nmol/l)[10]. The authors suggested in 1999 that heightened awareness is necessary to ensure adequate vitamin D nutrition, especially as vitamin D deficiency is preventable. The high prevalence of severe vitamin D deficiency among hip fracture patients has been confirmed in the early and late nineties by several studies from Europe (11-19). According to Swiss data published in 2008, the prevalence of severe 25(OH)D deficiency is still significant and basically unchanged compared to earlier data with a more than 50% prevalence of severe deficiency among hip fracture patients admitted from home and a 75% prevalence of severe deficiency among those admitted from institutions (20). Notably, less than 10% of 222 hip fracture patients investigated had any dose of vitamin D supplementation upon admission to acute care (20). Most vulnerable to low vitamin D levels are older individuals (21, 22), individuals living in northern latitudes with prolonged winters (23, 24), obese individuals (25), and African Americans of all ages (26-28). Older individuals are at high risk of low vitamin D status because of the decreased production of vitamin D in the skin with age after sun exposure, which is 4-fold lower compared to younger adults (29). Furthermore, among older adults and within Europe lowest 25hydroxyvitamin D levels are measured in Southern Europe (30), which may be explained by sun avoidance and sun protection at older age. Finally, nutritional sources of vitamin D are rare and are mostly limited to fatty fish, such as salmon, which is not regularly consumed in 2 servings and each day (31). Additionally, food fortification with vitamin D is not practiced in Europe as it is in the US, although the small benefit of about 200 IU vitamin D through consumption of fortified milk or orange juice in the US is small and did not prevent a further decline in 25hydrocyvitamin D status among US adults as documented in the newest NHANES study (oral presentation of Prof. Bess Dawson-Hughes; IANA conference Boston 2007). Vitamin D: its role in muscle health In humans, four lines of evidence support a role of vitamin D in muscle health and the prevention of sarcopenia. First, proximal muscle weakness is a prominent feature of the clinical syndrome of vitamin D deficiency. Second, VDR is expressed in human muscle tissue, and VDR activation may promote de novo protein synthesis in muscle (32). Third, several observational studies suggest a positive association between 25hydroxyvitamin D and muscle strength or lower extremity function in older persons (33, 34). Finally, in several doubleblind randomized controlled trials, vitamin D supplementation increased muscle strength and balance (35, 36), and reduced the risk of falling in community-dwelling individuals (36-38), as well as in institutionalized individuals (35, 39). Notably, a study by Glerup and colleagues suggest that vitamin D deficiency may cause muscular impairment even before adverse effects on bone occur (40). Mice without the VDR develop a skeletal muscle phenotype with smaller and variable muscle fibers and persistence of immature muscle gene expression during adult life (41). These abnormalities persist after correction of systemic calcium metabolism by a rescue diet (42). Vitamin D: desirable vitamin D status for better function and lower risk of sarcopenia A dose-response relationship between vitamin D status and muscle health was examined in NHANES III including 4100 ambulatory adults age 60 years and older. Muscle function measured as the 8-foot walk test and the repeated sit-to-stand test was poorest in subjects with the lowest 25-hydroxyvitamin D (below 20 nmol/l) levels. Similar results were found in a Dutch cohort of older individuals (33). Notably, while from the smaller Dutch cohort a threshold of 50 nmol/l has been suggested for optimal function (33), a threshold beyond which function would not further improve was not identified in NHANES III even beyond the upper end of the reference range (> 100 nmol/l)[34] with a similar benefit by gender, level of physical activity, and calcium intake. With respect to sarcopenia, appendicular skeletal muscle mass was measured in the Dutch cohort among 331 older adults using dual-energy xray absorptiometry. After a 3-yr follow-up, and after adjustment for physical activity level, season of data collection, serum creatinine concentration, chronic disease, smoking, and body mass index, persons with low (<25 nmol/l) baseline 25hydroxyvitamin D levels were 2.14 (0.73-6.33, based on muscle mass) times more likely to experience sarcopenia, compared with those with higher (>50 nmol/l) levels. The associations were similar in men and women. Vitamin D: weakness / sarcopenia Muscle weakness is a prominent feature of the clinical syndrome of vitamin D deficiency. Clinical findings in vitamin D deficiency myopathy include proximal muscle weakness, diffuse muscle pain, and gait impairments such as waddling way of walking (43). The VDR is expressed in human muscle tissue (44), and vitamin D bound to its nuclear receptor in muscle tissue may lead to de novo protein synthesis (32, 45). One uncontrolled biopsy trial in postmenopausal women with osteoporosis documented a relative increase in the diameter and number of type II muscle fibers after a 3 month treatment with 1-alpha-calcidiol (32). These findings were confirmed by three recent double-blind RCTs with 800 IU vitamin D3 resulting in a 4-11% gain in lower extremity strength or function (35, 36), and an up to 28% improvement in body sway (36, 38) in older adults age 65+ between 2 to 12 month of treatment. VALIDATED TREATMENTS AND THERAPEUTIC PERSPECTIVES REGARDING NUTRITHERAPY The Journal of Nutrition, Health & Aging© Volume 13, Number 8, 2009