Geriatric Medicine Gerontology A Review of Clinical Trials about Vitamin D Supplementation’s Effect on Physical Performance of Community Dwelling Oldest-Olds

Background: Although observational studies with community dwelling older adults demonstrate that low serum 25(OH)D (vitD) negatively impacts on the health, the effects of its supplementation are still controversial. The aim of this study is to review clinical trials that evaluated the effect of vitD supplementation on physical performance in community dwelling oldest old. Methods: A comprehensive search on electronic databases, including Pubmed, Medline, LILACS and Scielo was conducted. Eligible studies were clinical trials published between January 2015 and June 2021 in Portuguese, English and Spanish. The selected articles should meet the following inclusion criteria: Included elderlies aged 80 and over, independent, community-dwelling and of both sexes. Experimental studies with dependent elderly, institutionalized, hospitalized, diagnosed with dementia, acute and/or severe diseases were excluded. Results: Out of the 11533 articles from the literature search, 21 studies met the inclusion criteria. The results suggest that vitD supplementation alone in most studies does not improve physical performance, even in populations at higher risk (elderly people with insufficiency or deficiency of this vitamin, pre-frailty and frailty, functional impairment and advanced age). When combined with resistance exercise and with other nutrients that are also important for muscle health, there seems to be an improvement in physical tests. However, the heterogeneity of the studies carried out so far contribute to still contradictory results. Conclusion: Although vitD supplementation corresponds to a potential therapy to prevent physical decline in the elderly, studies with the Brazilian population will be needed to better clarify these effects in community dwelling oldest old.


Introduction
Worldwide low vitamin D status is emerging as a very common condition. It is estimated that more than one billion people are affected by this vitamin deficiency with a prevalence of 5.9% in the United States, 7.4% in Canada and 13% in Europe [1]. Even though Brazil has and elevated ultraviolet radiation vitamin D deficiency, which is defined as serum 25(OH)D (vitD) levels < 30 nmol/L or 12 ng/m, is still very prevalent. In São Paulo low serum concentrations range from 42% to 63% in the elderly [2,3].
Older adults are a risk group for vitD deficiency due to decreased skin capacity for pre-Vitamin D3 synthesis, reduced exposure to sunlight, increased adiposity, reduced consumption of major food sources, reduced intestinal absorption capacity and presence of comorbidities such as chronic kidney disease [4].
Vitamin D receptor (VDR) is expressed in different human tissues, which strengthens the hypothesis that VitD acts beyond its classical function of bone metabolism and calcium homeostasis, playing an important role in various systems [5]. In the central nervous system, for example, vitD seems to be associated Check for updates hospitalized, diagnosed with a specific health condition (dementia, acute or severe illnesses) and were in the immediate pre or postoperative period. Two articles analyzed different outcomes, but in the same population and with the same intervention, thus, they were considered as a single study.
The additional search of bibliographic references resulted in one clinical trial and two systematic reviews with only clinical trials published until 2016. Although one of the systematic reviews included a study with women who lived in nursing homes, all other clinical trials were carried out with community-dwelling elderly, therefore it was selected. These 3 studies added to the previous ones, resulted in 22 articles included in the current review (Table 1) .
Regarding the methodology and objective, all studies used cholecalciferol or vitamin D3 as main intervention and had as one of the aims evaluated the effect of this supplementation on physical performance. Ten clinical trials assessed the impact of cholecalciferol alone and nine mixed it with physical exercise and/or other nutrients. Rosendahl-Riise, et al. [16], in a systematic review of 15 clinical trials with healthy community dwelling older adults, demonstrated that vitamin D supplementation (different forms and dosages) with or without calcium did not result in improvement in muscle strength and mobility. Similarly, in the systematic review by Antoniak and Greig [18], an improvement in muscle strength assessed by handgrip strength occurred only when vitD supplementation was performed together with resistance exercise.
Cholecalciferol supplementation in vitamin D deficiency or insufficiency individuals had no beneficial effects on muscle mass [30] or strength and on Short Physical Performance Battery (SPPB) test [17,25,29]. While Ranathunga, et al. [25] at baseline found an association between low plasma VitD concentrations and poorer hand grip strength, after the supplementation this association was not significant, suggesting no effect of the intervention. In the study by Bislev,et al. [20], contrary to expectations, there was a significant 4% reduction in handgrip strength. On the other hand, at Rathmacher, et al.'s [33] clinical trial, supplementation with cholecalciferol, calcium and β-hydroxy-β-methylbutyrate (HMB) improved muscle strength and physical functionality even in participants not engaged in the exercise program. In Lee, et al.'s [27] study, cholecalciferol supplementation and resistance training enhanced muscle mass and reduced time to walk a standard course.
In sedentary elderly the combination of homebased resistance band training with daily intake of a supplement containing whey, dairy proteins, creatine, omega-3 fatty acids and cholecalciferol significantly improved maximal strength and appendicular and total lean mass [32]. In the study by Aoki, et al. [24] both with neurotransmitter synthesis and cell differentiation [6]. Vitamin D metabolites stimulate the proliferation and differentiation of muscle cells and influence the skeletal muscle contraction through calcium influx. In the elderly, this vitamin deficiency seems to be related to increased oxidative stress, negatively impacting on strength, balance and mobility [7][8][9].
Observational studies with community dwelling older adults have reported associations between vitD lower serum levels and poorer physical performance. Although vitD supplementation is proposed as a possible strategy to prevent or delay physical decline through its direct action on muscle fibers, the results of clinical trials that evaluated the effect of the supplementation in improving physical performance in elderlies are still inconsistent and controversial [1,10,11].

Objective
The aim of this study is to review clinical trials that evaluated the effect of vitD supplementation on physical performance in community dwelling oldest old.

Methods
A comprehensive search on electronic databases, including Pubmed, Medline, LILACS and Scielo was conducted. Eligible studies were clinical trials published between January 2015 and June 2021 in Portuguese, English and Spanish. The following Mesh terms were used: Vitamina D and Idosos de 80 anos ou mais, Vitamina D and Idoso, Vitamina D and Anciano de 80 o más años, Vitamina D and Anciano, Vitamin D and aged, 80 and over, Vitamin D and aged.
The initial screening was carried out by the review of the title and abstract of each study. After identifying the ones of interest, they were independently analyzed by two researchers. The selected clinical trials should meet the following inclusion criteria: Performed with elderlies aged 80 and over, even if not exclusively, independent, community-dwelling and of both sexes. We also reviewed the references of the selected articles for the identification of relevant studies.
Experimental studies with dependent elderly, institutionalized, hospitalized, diagnosed with dementia, acute and/or severe diseases were excluded. The selected studies were read in full and reviewed in detail by the researchers. Any disagreement between the authors was resolved by consensus.

Results
A total of 11533 articles were identified through the database search. Of the 158 clinical trials originally identified 139 were excluded after full-text review because the intervention was performed with animals, the outcome evaluated was not related to the subject of interest, did not include individuals aged 80 years or over, participants were institutionalized, dependent, To examine the effects of vitamin D supplementation on neuroplasticity, serum brain-derived neurotrophic factor (BDNF) and muscle strength and function in older adults.
The participants were randomized to receive 2,000 IU/day of vitamin D3 or matched placebo for 10 weeks.
There was no effect of vitamin D on muscle power and function (Muscle strength, stair climbing power, TUG/Dynamic balance) Bauer, et al. 2015 [14] Participants (≥ 65 anos) were recruited from 18 study centers in 6 European countries. They were diagnosed with sarcopenic according to the following criteria: SPPB scores between 4 and 9, and a low skeletal muscle mass index (≤ 37% for men and ≤ 28% for women) (n = 380) To test the hypothesis that a specific oral nutritional supplement can result in improvements in measures of sarcopenia.

Placebo-Controlled Trial
The active group received a vitamin D and leucineenriched whey protein nutritional supplement to consume twice daily for 13 weeks. The control group received an iso-caloric control product to consume twice daily for the same period.
This 13-week intervention of a vitamin D and leucineenriched whey protein oral nutritional supplement resulted in improvements in appendicular muscle mass and in the chair-stand test. However handgrip strength and SPPB improved in both groups without significant between-group differences.
Bischoff-Ferrari, et al. 2016 [15] Home-dwelling men and women 70 years and older with a lowtrauma fall in the previous 12 months To determine the effectiveness of highdose vitamin D in lowering the risk of functional decline. Participants were randomized to receive either the intervention or an iso-caloric control product twice daily during 13 weeks. The intervention product contained per serving 20 g whey protein, 3 g total leucine, 9 g carbohydrates, 3 g fat, 800 IU vitamin D and a mixture of vitamins, minerals and fibers, and the iso-caloric control drink contained only carbohydrates, fat and some trace elements. Two clinical trials enrolled community-dwelling men and women 70 years and older with a prior fall and measured the impact of different concentrations of vitamin D3 supplement alone [15] or associated with omega-3 fatty acids and RE [31] in lowering the risk of functional decline. In both there was no difference on SPPB results after the intervention.
Physical performance also did not significantly improved with vitD supplement in older adults with 25(OH)D serum concentrations between 25-60 nmol/L [13] and in community-dwelling persons aged 60-80 years who had clinically relevant depressive symptoms and one or more functional limitations [26].
Gao, et al. [12] assessed in healthy postmenopausal women the effects of calcium, calcitriol and cholecalciferol supplementation on muscle strength. The participants that received calcitriol and calcium maintained the grip strength, while those supplemented with calcium alone or combined with cholecalciferol exhibited decreased grip strength at follow-up.

Discussion
Although evidence from cross-sectional and cohort studies suggests a negative correlation between serum VitD concentrations and physical performance in higher-risk populations, that is, elderly people with vitamin D insufficiency or deficiency, pre-frailty and frailty, functional impairment and 80 years or more, exercise and vitamin D supplementation independently improved physical function and increased muscle mass in community-dwelling elderly individuals, with no differences between the groups. Although Seino, et al. [23] had demonstrated that resistance exercise (RE) plus dairy protein and micronutrient supplementation (200 IU/day cholecalciferol) resulted in muscle mass gain, this did not further improve balance, walking speed (VM), Time Up and Go (TUG) and strength tests.
In pre-frail or frail elderly people, two studies [19,28] with cholecalciferol supplementation did not show a significant change in muscle strength and physical performance. Bray, et al. [21] combined calcium carbonate and vitamin D3 supplement and instead of the previous ones it showed a modest beneficial effect on SPPB and VM in frail individuals and those with insufficient vitamin D levels at baseline.
One study with sarcopenic older adults reported results of treatment combining vitamin D and leucineenriched whey protein supplement. Muscle mass and lower extremity function evaluated by the chairstand test improved, but handgrip strength and SPPB improved in both groups without significant betweengroup differences. Still, those with higher baseline VitD values and dietary protein intake had better results of appendicular muscle mass in response to the intervention [14,22]. Nilsson MI, et al. 2020 [32] Male cohort (≥ 65 years) representative of the North American aging community in general: individuals with low physical activity levels (sedentary), normal-to-high BMIs, and varying degrees of age-related muscle loss (n = 32) To test the utility of a five-ingredient proteinbased (Muscle5) in combination with low-intensity training for maintenance of skeletal muscle mass, strength, performance and muscle quality in sedentary, free-living elderly Double-blind, randomized, placebo-controlled trial.
Participants underwent twelve weeks of home-based resistance band training (3 d/ week), in combination with daily intake of a five-nutrient supplement containing whey, micellar casein, creatine, vitamin D and omega-3 fatty acids or an isocaloric/ isonitrogenous placebo containing collagen and sunflower oil In the intervention group appendicular and total lean mass, lean mass to fat ratios, maximal strength (handgrip and leg press), function (5-Times Sit-to-Stand time) and fast-twitch muscle fiber cross-sectional areas of the quadriceps muscle were significantly improved.
Likewise, vitD might act synergistically with other nutrients, stimulating muscle synthesis, probably through anabolic pathways induced by insulin and leucine. According to the results of the clinical trials included in this review, interventions vitD supplement combined with other nutrients that are also important for muscle health, such as amino acids, creatine and omega-3 fatty acids, may be an important strategy to maintain and improve physical performance [45].
The mechanisms through which VitD can influence muscle function are still unclear, however two pathways are considered of the most importance: the genomic genomic and the nongenomic pathway. In the genomic pathway, the binding of calcitriol to the VDR receptor on muscle cells would trigger a nuclear response resulting in the de novo protein synthesis. This protein appears to determine calcium absorption, phospholipid metabolism and muscle cell proliferation and differentiation [45]. The non-genomic effects of VitD are also mediated by VDR receptors. Through the activation of cell signaling pathways, there is a rapid influx of calcium from the sarcoplasmic reticulum, resulting in the prolongation of the relaxation phase of muscle contraction [36]. Another non-genomic action of vitD includes the release of arachidonic acid which modifies the fluidity and permeability of the cell membrane [45]. Furthermore, recent studies have shown that vitD deficiency appears to be associated with increased oxidative stress with consequent skeletal muscle atrophy [36].
Although observational studies show an inverse association between serum 25(OH)D levels and the risk of falls possibly due to reduced type II muscle fibers and proximal muscle atrophy observed in with vitamin D deficiency's elderlies, LeBoff, et al. [46] in a clinical trial with 25871 healthy community older adults demonstrated that vitamin D3 supplementation (2000 IU/day) for 5.3 years did not result in a reduced risk of falls, even in participants with baseline 25(OH) D levels < 30 nmol/L. Studies on the effects of vitamin D supplementation on falls in this population are still conflicting.
The present review showed that vitamin D supplementation alone is not associated with improved physical performance even in populations at higher risk, [34] the clinical trials included in our review did not identify an improvement at physical performance with cholecalciferol supplementation alone. A systematic review conducted by Rosendahl-Riise, et al. [16] found that in addition to no beneficial results on muscle strength, in some cases the TUG results worsened. Antoniak & Greig, et al.
[18] at a systematic review showed that despite the RE combined with cholecalciferol supplement resulted in an increased muscle strength, when performance was assessed using the SPPB and TUG there was no additional benefit beyond that attributed to physical training. Studies following these systematic reviews, also described in this article, confirmed that isolated calcitriol supplementation does not seem to improve physical performance, requiring its association with other interventions.
Functional limitations related with greater dependence to perform activities of daily living (ADL), increased mortality and health care costs can be assessed through physical performance [35][36][37]. The tests used by the articles included in this review were gait speed, sit to stand... handgrip strength, Time Up and Go (TUG) and the Short Physical Performance Battery (SPPB). These tests assess muscle strength and balance, with gait speed being directly correlated with morbidity and mortality; [8] the sit to stand test measures in addition to lower limb strength, balance and risk of falls; [38] the handgrip strength, although evaluates the strength of the upper limbs, has a good correlation with functional capacity and health outcomes; [36,39] the TUG corresponds to an important predictor of functional limitations as it assesses muscle strength and gait speed, [40] as well as the SPPB, which has a high level of sensitivity and reliability to measure changes in physical performance in older adults in the community [41].
The studies included in this review show that although there are several clinical trials with the aim of evaluating in community-dwelling elderly people the effect of cholecalciferol supplementation on physical performance, this correlation is yet to be proven. Questions about the type of supplementation (associated or not with other nutrients and with resistance exercise), dose, period and who in the older population would benefit from this intervention are still controversial. The heterogeneity of the studies carried out so far, with differences in designs, populations, duration and dose of the supplement, tests and thresholds for assessing physical performance have made it difficult to draw conclusions.
Resistance exercise training corresponds to one of the most effective non-pharmacological treatments to improve physical performance, nevertheless when this practice is associated with VitD supplementation, muscle synthesis and regeneration seem to be enhanced [42]. VitD seems to play an important role in myogenesis and however, when combined with resistance exercise and other nutrients also important for muscle health, this intervention can result in beneficial effects. It should be noted that all clinical trials included in our study are international, carried out with elderly people aged 80 years or more in a non-exclusive way and that most participants had basal concentrations of 25(OH)D corresponding to insufficiency.
In conclusion, to clarify the issues surrounding the role of vitamin D in improve physical performance in community dwelling oldest old, further Brazilian randomized controlled trials with communityindependent elderly with frailty, sarcopenia, age over 80 years and serum 25(OH)D concentrations below < 25 nmol/l will be needed. In addition, well-designed and well conducted studies assessing the short, medium and long term results of different forms of supplementation combined with resistance exercise and nutrients such as whey protein, casein, creatine, leucine and omega-3 on these populations should be implemented. Finally, it is important to emphasize that the method chosen to measure physical performance must enable an early screening of physical decline, resulting in the prevention of negative outcomes.

Conclusions
Vitamin D supplementation corresponds to a potential economic and safe adjuvant therapy to maintain the elderly's independence and autonomy, nevertheless, studies with the Brazilian population will be needed to clarify its effects on community dwelling oldest-olds.