Question

Please summarize these two passages from this article.

1. Introduction Vitamin D is the main hormone regulating calcium phosphate homeostasis and mineral bone metabolism.The discovery that a variety of tissues can express vitamin D receptor (VDR) has opened new ways of research related to vitamin D biological effects and molecular pathways [1–3]. There is evidence that vitamin D is implicated in the regulation of the immune system, the cardiovascular system, oncogenesis [4], and cognitive functions [5]. Loss of muscle mass and frailty are prevalent in many chronic diseases such as chronic obstructive pulmonary disease, cardiac insufficiency, cancer, and chronic kidney disease (CKD) [6]. Vitamin D deficiency is indeed extremely frequent in the above diseases. More than 3 decades ago, the clinical observation that patients with rickets and osteomalacia displayed proximal myopathy suggested a direct link between hypovitaminosis D and muscle function [7]. Recent evidence has confirmed that vitamin D may modulate muscle growth. In this review, we will specifically address the effect of vitamin D on skeletal muscles and its clinical implications, especially frailty and the risk of fall.

2. A Link between Vitamin D and Frailty? The term “frailty” is becoming more and more popular in geriatric medicine. However, its definition is vague. The Oxford dictionary defined it by “the condition of being weak and delicate.” A more precise definition is given by Fried who defined frailty as “a biologic syndrome of decrease reserve and resistance to stressors that results from cumulative declines across multiple physiologic systems and causes vulnerability to adverse outcomes [68].” Criteria of the frail phenotype have been described in order to translate the above theoretical definition into clinical indicators [68]. These are as follows: unintentional weight loss, self-reported exhaustion, weakness (grip strength), slow walking speed, and low physical activity. According to these clinical criteria, 3 phenotypes have been identified: robust: 0 criteria; prefrail: between 1 and 2 criteria; frail: 3 or more criteria. The majority of these criteria are related to locomotion and physical strength. Thus, it looks readily conceivable that hypovitaminosis D may lead to frailty, through negative effects on muscle strength and/or function. The association between vitamin D status and frailty has been studied in a number of observational studies. Data from an observational study from Hirani et al. which included 1659 community-dwelling men, with a 10% prevalence of frailty, showed that low vitamin D levels were independently associated with frailty [69]. A similar association was found by Tajar et al. in another cohort of elderly men. Subjects with vitamin D levels <50 nmol/L had an odd ratio of 2,37 of being classified into the “frail” versus the “robust” phenotype [70]. Using data from the third National Health and Nutrition Survey (NHANES), Wilhelm-Leen et al. found an association between frailty and a low vitamin D status in both elderly men and women, with overall 4-fold increase in the odd ratio of frailty [71]. Vitamin D not only is associated with frailty but also appears to be associated with an increased risk to develop frailty over time in women. In a prospective study including elderly women (age > 69 years), nonfrail women at baseline but displaying a vitamin D level of less than 50 nmol/L hada higher risk of becoming frail during the 4.5 years of followup than women with a higher level of vitamin D [72]. In a study from patients with cardiac insufficiency, Boxer et al. found an association between low vitamin D levels and the frail phenotype. In particular, vitamin D levels and the result of the 6-minute walking test were correlated [73]. In cardiac diseases, this functional test is known to predict survival [74]. Thus, low vitamin D is hypothesized to link with mortality in this setting. A prospective study including 4000 individuals (1943 men and 2788 women, mean age: 70), followed up to 12 years, indeed found a link between lower levels of vitamin D, frailty, and mortality. An assessment of vitamin D status and the physical phenotype (robust/prefrail/frail) were performed at baseline [75]. Mortality was positively associated with frailty. Frail individuals with a low vitamin D level were at increased risk (hazard ratio of 2.98) of death during the follow-up compared to robust individuals with a high level of vitamin D. Thus, overall, a clear association between vitamin D level and frailty has been demonstrated. Furthermore, interplays between vitamin D status, frailty, and mortality appear plausible. Whether vitamin D supplementation in frail subjects may reduce mortality is challenging and needs to be investigated in the future.

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Answer 1

Summary

Vitamin D is the key hormone of bone metabolism. However, the continual nature of vitamin D receptor suggests potential for multiple effects, that has led to new research exploring the effects of vitamin D on various tissues, specifically, in the skeletal muscle (1). In vitro studies have shown that calcitriol acts in myocytes through activation in the cell nucleus to promote cellular differentiation and proliferation (2). A presumed transmembrane receptor may be accountable for the effects leading to rapid influx of calcium within muscle cells. Hypovitaminosis D is consistently related with decrease in muscle function and performance and increase in disability (3). In contrast, vitamin D supplementation has been shown to improve muscle strength and gait especially in elderly patients (4). In spite of some disagreements in the clarification of meta-analysis, a compact risk of falls has been ascribed to vitamin D supplementation due to direct effects on muscle cells (5). This is why many authorities endorse vitamin D supplementation in the weak patient (6).

References

1.        Bikle DD. Structure and function of the vitamin D-binding proteins. In: Principles of Bone Biology. Elsevier; 2020. p. 713–37.

2.        Montenegro KR, Cruzat V, Carlessi R, Newsholme P. Mechanisms of vitamin D action in skeletal muscle. Nutr Res Rev. 2019;32(2):192–204.

3.        DeLuca GC, Kimball SM, Kolasinski J, Ramagopalan S V, Ebers GC. The role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol. 2013;39(5):458–84.

4.        Halfon M, Phan O, Teta D. Vitamin D: a review on its effects on muscle strength, the risk of fall, and frailty. Biomed Res Int. 2015;2015.

5.        Krishna SM. Vitamin D as A Protector of Arterial Health: Potential Role in Peripheral Arterial Disease Formation. Int J Mol Sci. 2019;20(19):4907.

6.        Peterlik M. Vitamin D insufficiency and chronic diseases: hype and reality. Food Funct. 2012;3(8):784–94.