Are dietary supplements and nutraceuticals effective for musculoskeletal health and cognitive function? A scoping review

Abstract

Objective

The aim of our scoping review was to summarize the state of the art regarding micronutrients in order to identify which of them might effectively improve health status in the areas typically impaired in older people: bone, skeletal muscle, and cognitive function.

Design

Scoping review.

Methods

The Italian Study Group on Healthy Aging by Nutraceuticals and Dietary Supplements (HANDS) performed this scoping review, based on the following steps: doing a list of micronutrients related with musculoskeletal or cognitive functions, included in dietary supplements and nutraceuticals commercialized in Italy; planning a research on PubMed, according to an evidence-based approach, in order to the most relevant positive study for each micronutrient into each of the three areas involved (bone, skeletal muscle and cognitive function); identifying the micronutrients effective in maintaining or achieving an adequate health status in older people, specifying the effective and safe daily doses, according to the selected studies.

Results

In literature we found 12 relevant positive studies (1 international society guidelines/recommendations, 1 systematic review, 7 randomized controlled trials, and 3 prospective cohort studies). We showed that only 16 micronutrients resulted to have appropriate scientific evidences in terms of improving musculoskeletal health and/or cognitive function in older people: beta-alanine, calcium, creatine, fluorides, leucine, magnesium, omega-3 fatty acids, potassium, vitamin B6, vitamin B9, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K2, and zinc.

Conclusion

This scoping review showed that selected micronutrients in adequate doses might have an ancillary role in musculoskeletal health and cognitive functions in older people.

Introduction

In the early twentieth century, the level of knowledge concerning diseases typically due to dietary deficiency led to the hypothesis that there were substances (not yet discovered) probably included in small quantities in the diet, but essential for maintaining an optimal health status of farm animals and humans (1). In 1911, Casimir Funk, a Polish biochemist, affirmed that these micronutrients had an aminic nature and named them «vital amines» (2). Subsequently, Prof. Elmer McCollum performed a study on mice fed not only with the usual chow, but also with a butter fat and cod liver oil, with a consequent improvement of their health and survival suggesting that the supplementation contained an essential factor for the prevention of xerophthalmia and for the growth of mice (3). Based on the previous work of Funk, McCollum proposed to define these substances as «vitamins» (4).

Nowadays, it is well known that vitamins play a key role in the physiological regulation of the body. However, other micronutrients should be necessarily included in the diet, in particular in older people. Therefore, the growing interest in micronutrients intake led to an increasing need for a definition of dietary supplements.

The Dietary Supplement Health and Education Act (DSHEA) defined dietary supplements as products - not conventional foods - containing vitamins, minerals, amino acids, intended to supplement the diet by increasing the total daily intake of these substances (5). Previously, Stephen DeFelice had already introduced the term “nutraceutical” to define “food (or parts of a food) that provides medical or health benefits, including the prevention and/or treatment of a disease”. He coined this term from the fusion of the words “nutrition” and “pharmaceutical”, commonly used in marketing with no regulatory definition (6). More recently, nutraceuticals were defined as dietary supplements that include a concentrated form of a presumed bioactive substance, originally derived from a food, but present in a nonfood matrix, and used to maintain or improve health status in dosages exceeding those obtainable from conventional foods (7). However, there is no common agreement about using the term “nutraceutical” or “dietary supplement”, as resulting by searching for the term “Dietary supplements” in PubMed (using the MeSH mode), that automatically provides “nutraceutical” and “nutraceuticals” (8).

It was hypothesized that most of nutraceuticals have multiple physiological beneficial effects (9), being involved in several biological pathways to maintain a good health status. However, there is not a common agreement on the use of these substances, particularly concerning the adequate amount and safety. The modern diet of Western countries does not seem to lead to an adequate intake of micronutrients, as showed by recent data of US Centers for Disease Control and Prevention's National Health and Nutrition Examination Survey (NHANES) affirming that more than 25% of the US population had an insufficient intake of vitamins A, C, D and E, calcium, magnesium, and potassium in their diet (10).

Therefore, the market of dietary supplements has spread worldwide, as showed by US data, with a market estimated about $ 68 billion (11); also the Italian Society of Nutraceutical (SINut) registered an increase of 15-20% per year in sales in Italy (12). This continuous growth in the market might be due to advances in food technology and nutrition (13), and to the preference for production of nutraceuticals over drugs in pharmaceutical and biotechnological companies (14).

The “active aging” is one of the main targets of dietary supplements, as showed by the increasing sales of multivitamins, minerals, and vitamins B targeting this specific population (15). In addition, aging will represent an important issue for public health systems in the next years, because elderly population is continuously increasing, as showed by World Health Organization (WHO) demographics data, affirming that individuals aged ≥ 60 years will be the triple by the year 2050, with the sub-population aged over 85 years growing faster than all the others (16). Nowadays, in Italy people aged over 65 years represent more than 20% of the entire population and they are expected to exceed 32% by the next 30 years (17).

Aging is associated with an alteration of several physiological functions, including musculoskeletal performance, cognitive function, and bone loss. It is well known that age-related bone loss is associated with vitamin D deficiency (18), although recently it was hypothesized that even other vitamins and minerals might have a role in maintaining bone health (19) and contrasting the progressive age-related loss of muscle mass and strength in the elderly (20).

Furthermore, it was hypothesized that a significant role in progressive brain atrophy (21), in particular in mild cognitive impairment (MCI) (22., 23.), was played by an inadequate nutritional intake of vitamins B, suggesting that a supplementation with these elements might have beneficial effects on cognitive function in this population (24).

The main aim of this scoping review was to summarize the state of the art regarding the role of micronutrients, currently available in nutraceuticals or dietary supplements commercialized in Italy, in healthy aging, highlighting which of them, supported by Evidence-Based Medicine (EBM), might effectively improve biological and functional systems typically involved in functional deterioration of elderly people: bone, skeletal muscle, and central nervous system (CNS).

Methods

In performing this scoping review we followed the model proposed by Egger et al. (25) The steps of our work, showed in Figure 1, were: (1) configuration of the Italian Study Group on Healthy Aging by Nutraceuticals and Dietary Supplements (HANDS): 1 specialist in orthopedics and rehabilitative medicine as coordinator, 13 collaborators, 5 physiatrists (2 of them having expertise in musculoskeletal rehabilitation, 1 in neurological rehabilitation, and 2 in geriatric rehabilitation), 2 rheumatologists, 1 geriatric endocrinologist, 1 endocrinologist specialized in Food Science and Human Nutrition, 1 geriatrician, 2 orthopedics, and 1 specialist in Epidemiology and Public Health; (2) doing a list of micronutrients selected by the “EU Register of nutrition and health claims made on foods” (26) that have a health relationship with musculoskeletal or cognitive functions, included in dietary supplements and nutraceuticals commercialized in Italy; (3) planning a research on PubMed (Public MedLine, run by the National Center of Biotechnology Information, NCBI, of the National Library of Medicine of Bethesda, USA) using as MeSH (Medical Subject Headings) terms the selected micronutrients; for each of them we added to the PubMed Search Builder the following terms: “bone”, “skeletal muscle”, and “central nervous system” / “brain” / “cognitive function”; (4) searching for all the studies and researches published in medical literature in the last 10 years (up to August 2015), including only those in English language and performed on older people. Studies written in languages other than English or performed on patients with chronic diseases and/or receiving any concomitant pharmacological treatment, as well as in vitro studies, basic researches, and animal studies were excluded from our scoping review; (5) identifying, after a methodological quality assessment, for each micronutrient into each area (bone, skeletal muscle and CNS) the most relevant positive study, according to EBM pyramid: meta-analysis, systematic review, randomized controlled trial (RCT), cohort study, case control study, case series, and case report. In case of some studies had the same level of methodological quality, we considered the most recent one. For each area involved, if international society guidelines/recommendations concerning the effectiveness of a micronutrient existed, these were considered as references; (6) selecting micronutrients effective in improving health status in one or more of the three areas impaired in older people (bone, skeletal muscle, and CNS) according to the relevant studies identified; (7) identifying the effective daily doses of micronutrients, established according to the selected studies; (8) identifying the adequate daily doses according to Recommended Daily Allowances (RDAs) and to tolerable upper intake levels (UL) for vitamins and minerals, established by the European Food Safety Authority in 2006 (27); (9) doing a list of the resulting micronutrients with the effective and safe daily doses that improve health status in one or more of the three areas (bone, skeletal muscle, and CNS) usually impaired in older people.

Figure 1.

Flow-chart of the study

Results

From the 65 micronutrients listed on “EU Register of nutrition and health claims made on foods” (26) we identified a list of 39 micronutrients available in dietary supplements and nutraceuticals commercialized in Italy having a health relationship with musculoskeletal or cognitive functions (see Table 1).

Table 1.

Micronutrients available in dietary supplements and nutraceuticals, commercialized in Italy, administered to older people in order to improve their physical functioning in three areas (bone, skeletal muscle, and cognitive function)

Beta-alanine

Biotin

Calcium

Choline

Coenzyme Q10

Copper

Creatine

Fluorides

Glutamine

Iodine

Iron

L-arginine

L-carnitine

L-tyrosine

Leucine

Magnesium

Manganese

Omega-3 fatty acids

Phenylalanine

Phosphorus

Potassium

Selenium

Sodium

Taurine

Thiocic acid

Tryptophan

Vitamin A

Vitamin B1 (thiamine)

Vitamin B2 (riboflavin)

Vitamin B3 (niacin)

Vitamin B5 (pantothenic acid)

Vitamin B6 (pyridoxal 5’-phosphate)

Vitamin B9 (folic acid)

Vitamin B12 (cobalamin)

Vitamin C (ascorbic acid)

Vitamin D

Vitamin E

Vitamin K2 (menaquinone-7, MK7)

Zinc

We reported in Table 2 relevant positive studies selected according to evidence-based approach for each micronutrient, identifying: 1 international society guidelines/recommendations, 1 systematic review, 7 RCTs, and 3 prospective cohort studies.

Table 2.

Relevant positive studies after a research for each micronutrient for each area (bone, skeletal muscle, and cognitive function), involved in elderly

	Bone			Skeletal muscle			Cognitive function
	Authors	Type of study	Methods and Results	Authors	Type of study	Methods and Results	Authors	Type of study	Methods and Results
Beta-alanine				del Favero S, et al. Ami-no Acids 2012(28)	Randomized controlled trial (RCT)	This RCT examining eighteen subjects (60-80 years) who had not engaged in any exercise programme for at least 1 year. The group that received 3.2 g of beta-alanine per day for 12 weeks had a significant improvement in the time-to-exhaustion in the limit of tolerance (TLIM) test (from 5.2 ± 1.9 min to 6.6 ± 1.7 min; p=0.05).
Calcium	Rizzoli R, et al. Maturi- tas 2014(29)	European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ES- CEO) recommendations	The ESCEO proposed optimized recommended nutrient intakes for calcium (1000 mg∕day), vitamin D (800 IU∕day) and proteins (1.0-1.2 g∕ kg body weight/day), and a regular physical exercise (3-5 times per week) for maintaining musculoskeletal health in postmenopausal women	Rizzoli R, et al. Maturitas 2014(29)	ESCEO recommendations	The ESCEO proposed optimized recommended nutrient intakes for calcium (1000 mg∕day), vitamin D (800 IU∕day) and proteins (1.0-1.2 g/kg body weight/day), and a regular physical exercise (3-5 times per week) for maintaining musculoskeletal health in postmenopausal women
Creatine				Aguiar AF, et al. Eur J Appl Physiol 2013 (30)	RCT	This RCT compared a group of older women who assumed 5 g of creatine per day combined with resistance training (RT) on the one-repetition maximum (1 RM) strength with a group that performed only a RT on the 1 RM strength. The study group experienced a greater (p <0.05) increase (Δ%) in training volume (+164.2), 1RM bench press (+5.1), knee extension (+3.9) and biceps curl (+8.8) performance, and gained significantly more fat-free mass (+3.2) and muscle mass (+2.8) than the control group.
Fluorides	Grey A, et al. J Clin Endocrinol Metab 2013 (31)	RCT	In this RCT, change in procollagen type 1 N propeptide (P1NP) was significantly greater in each of the fluoride 5 mg and fluoride 10 mg groups than the placebo group (P<0.04 and 0.005, respectively). At the end of the study, P1NP was increased by 7.5% and 14.8% in the 5 mg fluoride and 10 mg fluoride groups, respectively.
Leucine				Rizzoli R, et al. Maturitas 2014(29)	ESCEO recommendations	Leucine is a key anabolic amino acid that exerts a dose-response effect on muscle protein synthesis (32). The ESCEO recom-
	mends an intake of 2.0-2.5 g of leucine that should be beneficial to stimulate postprandial muscle protein synthesis, according to recent studies (33-34).
Magnesium	Orchard TS, et al. Am J Clin Nutr 2014(35)	Prospective cohort study	This prospective cohort study, including 73,684 postmenopausal women showed that who consumed > 422.5 mg Mg/day had a baseline hip BMD 3% higher (p <0.001) and whole body BMD 2% higher (P< 0.001) than women who consumed <206.5 mg Mg/day.
Omega-3 fatty acids				Ruxton CH, J Hum Nutr Diet. 2015(36)	Systematic review	This systematic review showed that increasing omega-3 fatty acids intake had a role in improving memory in elderly.
Potassium	Zhu K, et al. Osteoporos Int. 2009 (37)	Prospective cohort study	This prospective cohort study was conducted on 266 elderly women, with a mean potassium intake of 3008±899 mg∕ day. Assuming 80% of total potassium intake is excreted in urine, the highest quartile of potassium excretion in this study could be translated to a potassium intake of greater than 3676 mg per day.
Vitamin B6 (pyridoxal 5’ -phosphate)	Dai Z, et al. Osteoporos Int 2013 (19)	Prospective cohort study	This study examining 63,257 men and women showed a statistically significant inverse relationship between dietary pyridoxine intake and hip fracture risk among women (p= 0.002). Women in the highest quartile intake (0.78-1.76 mg/1,000 kcal/day) had a 22% reduction in hip fracture risk (HR 0.78, 95% CI 0.66-0.93).	Smith AD, et al. PLoS One 2010(24)	RCT	This double-blind controlled trial examined 271 subjects, aged over 70 years old with mild cognitive impairment, randomly divided into: a study group, treated with folic acid (vitamin B9) (0.8 mg/day), vitamin B12 (0.5 mg∕ day) and vitamin B6 (20 mg/day) and a placebo group. Treatment with B vitamins for 24 months significantly slowed the rate of brain atrophy. After adjustment for age, the rate of brain atrophy per year was 29.6% less in the study group (0.76%, 95% CI 0.63- 0.90) compared to the placebo group (1.08%, 95% CI 0.94-1.22, p = 0.001).
Vitamin B9 (folic acid)				Smithz AD, et al. PLoS One 2010(24)	RCT	This double-blind controlled trial examined 271 subjects, aged over 70 years old with mild cognitive impairment, randomly divided into: a study group, treated with folic acid (vitamin B9) (0.8 mg∕day), vitamin B12 (0.5 mg∕day) and vitamin B6 (20 mg∕d) and a placebo group. Treatment with B vitamins for 24 months significantly slowed the rate of brain atrophy. After adjustment for age, the rate of brain atrophy per year was 29.6% less in the study group (0.76%, 95% CI 0.63-0.90) compared to the placebo group (1.08%, 95% CI 0.94-1.22, p =0.001).
Vitamin B12 (cobalamin)				Smithz AD, et al. PLoS One 2010(24)	RCT	This double-blind controlled trial examined 271 subjects, aged over 70 years old with mild cognitive impairment, randomly divided into: a study group, treated with folic acid (vitamin B9) (0.8 mg∕day), vitamin B12 (0.5 mg∕ day) and vitamin B6 (20 mg∕day) and a placebo group. Treatment with B vitamins for 24 months significantly slowed the rate of brain atrophy. After adjustment for age, the rate of brain atrophy per year was 29.6% less in the study group (0.76%, 95% CI 0.63-0.90) compared to the placebo group (1.08%, 95% CI 0.94-1.22, p =0.001).
Vitamin C (ascorbic acid)	Ruiz-Ramos Μ, et al. J Nutr Health Aging 2010(38)	RCT	This RCT, conducted on 90 elderly subjects, showed a significantly lower decrease of lipope- roxides (LPO) (p<0.05), linked with hip bone loss, in the group that received 1,000 mg of ascorbic acid and 400 IU of alpha-tocopherol, than the placebo group for a 12-month period.
Vitamin D	Rizzoli R, et al. Maturitas 2014(29)	ESCEO recommendations	The ESCEO proposed Rizzoli R, et al. Maturi- optimized recommended tas 2014 (29) nutrient intakes for calcium (1000 mg/day), vitamin D (800 IU∕day) and proteins (1.0-1.2 g∕ kg body weight/day), and a regular physical exercise (3-5 times per week) for maintaining musculoskeletal health in postmenopausal women	ESCEO recommendations	The ESCEO proposed optimized recommended nutrient intakes for calcium (1000 mg/day), vitamin D (800 IU∕day) and proteins (1.0-1.2 g/kg body weight/day), and a regular physical exercise (3-5 times per week) for maintaining musculoskeletal health in postmenopausal women.
Vitamin E	Ruiz-Ramos Μ, et al. J Nutr Health Aging 2010(38)	RCT	This RCT, conducted on 90 elderly subjects, showed a significantly lower decrease of LPO (p<0.05), linked with hip bone loss, in the group that received 1,000 mg of ascorbic acid and 400 IU of alpha-tocopherol, than the placebo group for a 12-month period.
Vitamin K2 (menaquinone-7, MK7)	Knapen MH, et al.
Osteoporos Int 2013 (39)	RCT	In this RCT, 244 healthy postmenopausal women were randomly assigned to receive 180 μg MK-7 per day or placebo capsules. After a 3-year supplementation, MK-7 intake significantly improved bone health in the study group compared to the placebo one, after adjusting for age and BMI (p=0.023 for bone mineral content, BMC; ρ=0.014 for BMD). After adjusting for age, there was a statistically significant difference between the two groups in impact strength index (LSI) (p<0.05)and compression strength index (CSI) (p=0.022 after 2 years; p=0.075 after 3 years).
Zinc	Nielsen FH, et al. Br J Nutr 2011 (40)	RCT	In this RCT, 224 post-menopausal women with similar femoral neck (FN) T scores and BMI were randomly assigned to 2 groups of 112 each that were supplemented daily for 2 years with 600 mg Ca plus maize starch placebo or 600 mg Ca plus 2 mg Cu and 12 mg Zn. Results suggested that Zn supplementation might be beneficial to bone health in postmenopausal women with usual Zn intakes <8 mg/day but not in women consuming adequate amounts of Zn

In Table 3 we described the effective daily doses of the 16 selected micronutrients that have been shown to improve health status in older people: beta-alanine, calcium, creatine, fluorides, leucine, magnesium, omega-3 fatty acids, potassium, vitamin B6, vitamin B9, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K2, and zinc.

Table 3.

Effective daily doses of selected micronutrients that improve health status in the three areas (bone, skeletal muscle, and cognitive function), impaired in elderly

	Bone	Skeletal muscle	Cognitive function
Beta-alanine		3,200 mg
Calcium	1,000 mg	1,000 mg
Creatine		5,000 mg
Fluorides	5-10 mg
Leucine		2,500 mg
Magnesium	> 422.5 mg
Omega-3 fatty acids			3,000 mg
Potassium	> 3,676 mg
Vitamin B6 (pyridoxal 5’-phosphate)	1.22 - 3.52 mg		20 mg
Vitamin B9 (folic acid)			400 μg
Vitamin B12 (cobalamin)			500 μg
Vitamin C (ascorbic acid)	1,000 mg
Vitamin D	20 μg	20 μg
Vitamin E (alpha-tocopherol)	360 mg
Vitamin K2 (menaquinone-7, MK7)	180μg
Zinc	12 mg

In Table 4 we showed the effective and safe daily doses of the 16 selected micronutrients that improve health status in one or more of the three areas (bone, skeletal muscle, and CNS), impaired in elderly people.

Table 4.

Effective and safe daily doses of selected micronutrients that improve health status in one or more of the three areas (bone, skeletal muscle, and cognitive function), impaired in elderly

Beta-alanine	3,200 mg
Calcium	1,000 mg
Creatine	5,000 mg
Fluorides	5 mg
Leucine	2,500 mg
Magnesium	420 mg
Omega-3 fatty acids	3,000 mg
Potassium	3,700 mg
Vitamin B6 (pyridoxal 5’-phosphate)	20 mg
Vitamin B9 (folic acid)	400μg
Vitamin B12 (cobalamin)	500μg
Vitamin C (ascorbic acid)	1,000 mg
Vitamin D	20 μg
Vitamin E (alpha-tocopherol)	360 mg
Vitamin K2 (menaquinone-7, MK7)	180μg
Zinc	12 mg

Discussion

Our scoping review showed a low amount of evidences supporting the use of micronutrients for healthy aging. In particular, 16 micronutrients resulted to have appropriate scientific evidence of their effectiveness in older people: beta-alanine, calcium, creatine, fluorides, leucine, magnesium, omega-3 fatty acids, potassium, vitamin B6, vitamin B9, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K2, and zinc.

Beta-alanine

It is well known that supplementation with beta-alanine might increase muscle carnosine content by 60–80% in healthy young adults, with an improvement in performing high-intensity exercise (41., 42., 43., 44.). A recent RCT investigated the effects of beta-alanine supplementation on exercise performance capacity and on muscle carnosine content in elderly, including 18 subjects, aged 60–80 years, who had not engaged in any exercise program for at least 1 year. The study group, that received 3.2 g of beta-alanine per day for 12 weeks, had a significant improvement in the time-to-exhaustion in the limit of tolerance (TLIM) test (from 5.2 ± 1.9 min to 6.6 ± 1.7 min; p=0.05), demonstrating that beta-alanine supplementation might improve skeletal muscle function in older people (28).

Calcium

Calcium plays a key role in the synthesis and formation of bone and is necessary in elderly for their increased dietary requirement of calcium, due to multiple factors, especially in osteoporotic patients (45). The European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) proposed optimized recommended nutrient intake for calcium (1,000 mg/day), vitamin D (800 IU/day) and proteins (1.0–1.2 g/kg body weight/day), and a regular physical exercise (3–5 times per week) for maintaining musculoskeletal health in postmenopausal women (29).

Creatine

Creatine supplementation was identified as a potent ergogenic in order to prevent the age-related loss of muscle mass and strength (46). A recent RCT compared a group of older women who assumed 5 g of creatine per day combined with resistance training (RT) on the one-repetition maximum (1RM) strength with a group that performed only a RT on the 1RM strength. The study group experienced a greater (p<0.05) increase (Δ%) in training volume (+164.2), 1RM bench press (+5.1), knee extension (+3.9) and biceps curl (+8.8) performance, and gained significantly more fat-free mass (+3.2) and muscle mass (+2.8) than the control group (30).

Fluorides

Elemental fluoride stimulates osteoblast growth (47), bone formation, increasing trabecular bone mineral density (BMD) (48). On the other hand, there is no agreement regarding the role of fluorides on bone tissue, as showed by a RCT that reported that fluorides did not improve cortical BMD and increased rates of fracture (49). It was hypothesized that fluorides increased the trabecular BMD but adversely affected the cortical BMD, causing an impairment of bone mineralization (50., 51.).

Recently, a 1-year double-blind, placebo-controlled trial, randomly allocated 180 osteopenic post-menopausal women to receive a daily tablet containing 2.5 mg, 5 mg, or 10 mg fluoride. The results of this study showed a change in procollagen type 1 N propeptide (P1NP) significantly greater in both fluoride 5 mg and fluoride 10 mg groups than the placebo group (P<0.04 and 0.005, respectively). At the end of the study, P1NP was increased by 7.5% in the 5 mg fluoride group and 14.8% in the 10 mg fluoride group, showing a stimulation of bone formation, although not high (31).

Leucine

Leucine is a key anabolic amino acid that exerts a dose-response effect on muscle protein synthesis (32). A recent meta-analysis, conducted by Komar et al. demonstrated that leucine supplementation exerted beneficial effects on body weight, body mass index (BMI), and lean body mass in elderly, in particular in subjects predisposed to sarcopenia (52).

The ESCEO recommends a daily intake of 2.0–2.5 g of leucine that should be beneficial to stimulate postprandial muscle protein synthesis, according to recent studies (29, 33., 34.).

Magnesium

In postmenopausal women low magnesium intake is correlated with more rapid bone loss and/or lower BMD (53., 54.).

Baseline data of a recent prospective cohort study, including 73,684 postmenopausal women, showed that who consumed > 422.5 mg Mg/day had 3% higher hip BMD values (p <0.001) and 2% higher whole body BMD values (p < 0.001) than women who consumed <206.5 mg Mg/day (35).

Omega-3 fatty acids

It is well known that long chain omega-3 polyunsaturated fatty acids (docosahexaenoic acid, DHA, and eicosapentaenoic acid, EPA) are important for optimal brain function and mental health (55., 56.). A recent systematic review affirmed that increasing omega-3 fatty acids intake had a role in improving cognitive function in the elderly (36). A positive RCT, included in this systematic review and performed on 38 participants aged 51–72 years, compared the cognitive performance, assessed by tests measuring working memory (WM), between a group with a dietary supplementation of 3 g of omega-3 fatty acids (1,500 mg EPA, 1,050 mg DHA, and 450 mg of unspecified fatty acid) with a placebo group. Supplementation with omega-3 fatty acids compared with placebo resulted in better performance in the working memory test (p < 0.05) (57).

Potassium

It was hypothesized that potassium might have a beneficial role on bone tissue through the anions provided by its salts and through an anion-independent effect of potassium on excretion of calcium and bone metabolism (58).

This prospective cohort study was conducted on 266 elderly women, with a mean potassium intake of 3,008 ± 899 mg/day. Assuming that 80% of total potassium intake is excreted in urine, the highest quartile of potassium excretion in this study could be translated to a potassium intake greater than 3,676 mg per day (37).

Vitamin B6 (pyridoxal 5'-phosphate)

In the last years, it was investigated the role of B vitamins in maintaining bone health and prevention of fractures; in particular a recent prospective cohort study, conducted on 63,257 participants, showed a statistically significant inverse relationship between dietary vitamin B6 intake and hip fracture risk among women (p = 0.002). Women in the highest quartile intake (0.78-1.76 mg/1,000 kcal/day) had a 22% reduction in hip fracture risk (HR = 0.78; 95% CI : 0.66-0.93) (19). Furthermore, a recent RCT (better described in the next paragraph) showed its role in maintaining an adequate cognitive status (24).

B Vitamins group (Vitamin B6, B9, and B12)

Smith et al. performed a double-blind RCT (24), including 271 subjects with MCI aged over 70 years. They divided the sample in two groups: a group treated with vitamin B6 (pyridoxal 5'-phosphate) (20 mg/d), vitamin B9 (folic acid) (0.8 mg/d), and vitamin B12 (0.5 mg/d) and a placebo group. This RCT showed that a treatment with B vitamins for 24 months significantly slowed the rate of brain atrophy. After adjustment for age, the rate of brain atrophy per year was 29.6% less in the study group (0.76%, 95% CI 0.63–0.90) compared to the placebo group (1.08%, 95% CI 0.94–1.22, p = 0.001).

Vitamin C (ascorbic acid) and Vitamin E (alpha-tocopherol)

Recently, it was hypothesized an association between BMD and oxidative stress (59). Considering the known role of vitamins C and E as antioxidants (60), Ruiz-Ramos et al., performing a RCT on 90 elderly subjects, showed in the group that received 1,000 mg of ascorbic acid and 400 IU of alpha-tocopherol for a 12-month period a significantly lower decrease of lipoperoxides (LPO) (p<0.05), linked with hip bone loss, than the placebo group (38).

Vitamin D

It is well known the action of vitamin D on muscle tissue, exerted through long- and short-term mechanisms involving genomic pathway, inducing an increased synthesis of myosin and calcium-binding proteins (61), and non-genomic pathway, being involved in short-term regulation of calcium-mediated second messengers that influences the skeletal muscle contraction (fast response) (62., 63.), and in growth of skeletal muscle fibers (long-term response) (64., 65.).

Several studies showed the relationship between serum 25-hydroxyvitamin D3 [25(OH)D3] levels and muscle strength (66., 67., 68., 69., 70., 71.), although there is no agreement in literature (72).

Recently, ESCEO proposed optimized recommended nutrient intakes for calcium (1,000 mg/day), vitamin D (800 IU/day) and proteins (1.0–1.2 g/kg BW/day), and a regular physical exercise (3–5 times per week) for maintaining musculoskeletal health in postmenopausal women (29).

Vitamin K2 (menaquinone-7, MK7)

A vitamin K deficiency is considered as an independent but modifiable risk factor for the development of osteoporosis and other age-related conditions (73).

A recent RCT was conducted on 244 healthy postmenopausal women, randomly assigned to receive 180 μg MK-7 per day or placebo capsules. After a 3-year supplementation, MK-7 intake significantly improved bone health in the study group compared to the placebo one, after adjusting for age and BMI (p=0.023 for bone mineral content, BMC; p=0.014 for BMD). Moreover when adjusting for age, there was a statistically significant difference in both impact strength index (ISI) (p<0.05) and compression strength index (CSI) (p=0.022 after 2 years; p=0.075 after 3 years) (39).

Zinc

The role of zinc in bone health is still not well defined. Recently, Nielsen et al. conducted a RCT on 224 post-menopausal women with similar femoral neck (FN) T-scores and BMI who were randomly assigned to 2 groups of 112 each that were supplemented daily for 2 years with 600 mg Ca plus maize starch placebo or 600 mg Ca plus 2 mg Cu and 12 mg Zn. The results indicated that Zn supplementation might exert beneficial effects on bone health in postmenopausal women with a daily Zn intake <8 mg/d but not in women consuming adequate amounts of this mineral (40).

Micronutrients and healthy aging

In our scoping review we showed only the data of positive relevant studies of the 16 selected micronutrients. However we examined the role of all the other 23 micronutrients that might have a health relationship with musculoskeletal and cognitive functions according to “EU Register of nutrition and health claims made on foods” (26).

As an example of the micronutrients excluded from our selection, we will show the negative relevant studies that prevent us to include sodium and vitamin A group.

Teucher et al. recently demonstrated in a randomized, repeat cross-over trial that efficiency of calcium absorption was higher after a period of moderately low calcium intake, but was unaffected by salt intake, because sodium was responsible for a significant change in bone calcium balance from positive to negative (74).

Furthermore, there is no common agreement on the relationship between vitamin A intake and risk of fracture; however, a recent meta-analysis showed that a high intake of vitamin A and retinol might increase risk of hip fracture and suggested that intake of beta-carotene (a provitamin A), that will be converted to retinol in blood, might be better than intake of retinol from meat, directly absorbed into blood after intake (75).

These are just some of the data that led us avoiding these micronutrients in our selection choosing those who were proven to be really effective in improving health status in older people.

In elderly, there is not only a progressive deterioration of cardiovascular system, but also cognitive and musculoskeletal impairments. Whereas it is well known the effectiveness of pharmacological approach to cardiovascular and immunological diseases, drugs for musculoskeletal and neurological disorders seemed to have limited scientific evidences. Therefore, the role of an alternative approach through dietary supplements and nutraceuticals might be promising in sustaining healthy aging (76).

Another interesting aspect that should be considered is that cognitive performance, often impaired in elderly, might be associated with dietary preferences and consequently with health status (77). As showed by NHANES more than a quarter of US population had an insufficient intake of vitamins and minerals in their diet (10).

An adequate dietary supplementation might improve health status in individuals with a lower-than-average amount of micronutrients (9), although there is not yet a common agreement regarding their role and their dosage regimens.

The reviewed nutraceuticals were not associated with an increase in significant adverse events, suggesting that good long-term safety and tolerance are not significant issues. Given the good safety profile of nutraceuticals, the marginal efficacy of conventional treatment, the high prevalence and rate of disability and the potential benefit of nutraceuticals in patients with osteoarthritis, a treatment trial in selected patients seems to be appropriate (78).

A limitation of our study was the assessment of only positive relevant studies; on the other hand this scoping review was the first study investigating the specific doses efficacious to improve musculoskeletal health and cognitive function in elderly.

Conclusion

Our scoping review shows that selected micronutrients in appropriate doses might have an ancillary role in musculoskeletal health and cognitive functions in older people. Therefore, we recommend that older people have an adequate nutrition or intake of nutraceuticals and/or dietary supplements, as supported by EBM, in order to maintain or achieve good health status.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Standards

This study is in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.