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1. Introduction Vitamin D is the main hormone regulating calciumphosphate homeostasis and mineral bone metabolism.The discoverythat a variety of tissues can express vitamin D receptor (VDR) hasopened new ways of research related to vitamin D biological effectsand molecular pathways [1–3]. There is evidence that vitamin D isimplicated in the regulation of the immune system, thecardiovascular system, oncogenesis [4], and cognitive functions[5]. Loss of muscle mass and frailty are prevalent in many chronicdiseases such as chronic obstructive pulmonary disease, cardiacinsufficiency, cancer, and chronic kidney disease (CKD) [6].Vitamin D deficiency is indeed extremely frequent in the abovediseases. More than 3 decades ago, the clinical observation thatpatients with rickets and osteomalacia displayed proximal myopathysuggested a direct link between hypovitaminosis D and musclefunction [7]. Recent evidence has confirmed that vitamin D maymodulate muscle growth. In this review, we will specificallyaddress the effect of vitamin D on skeletal muscles and itsclinical implications, especially frailty and the risk of fall.

2. A Link between Vitamin D and Frailty? The term “frailty” isbecoming more and more popular in geriatric medicine. However, itsdefinition is vague. The Oxford dictionary defined it by “thecondition of being weak and delicate.” A more precise definition isgiven by Fried who defined frailty as “a biologic syndrome ofdecrease reserve and resistance to stressors that results fromcumulative declines across multiple physiologic systems and causesvulnerability to adverse outcomes [68].” Criteria of the frailphenotype have been described in order to translate the abovetheoretical definition into clinical indicators [68]. These are asfollows: unintentional weight loss, self-reported exhaustion,weakness (grip strength), slow walking speed, and low physicalactivity. According to these clinical criteria, 3 phenotypes havebeen identified: robust: 0 criteria; prefrail: between 1 and 2criteria; frail: 3 or more criteria. The majority of these criteriaare related to locomotion and physical strength. Thus, it looksreadily conceivable that hypovitaminosis D may lead to frailty,through negative effects on muscle strength and/or function. Theassociation between vitamin D status and frailty has been studiedin a number of observational studies. Data from an observationalstudy from Hirani et al. which included 1659 community-dwellingmen, with a 10% prevalence of frailty, showed that low vitamin Dlevels were independently associated with frailty [69]. A similarassociation was found by Tajar et al. in another cohort of elderlymen. Subjects with vitamin D levels <50 nmol/L had an odd ratioof 2,37 of being classified into the “frail” versus the “robust”phenotype [70]. Using data from the third National Health andNutrition Survey (NHANES), Wilhelm-Leen et al. found an associationbetween frailty and a low vitamin D status in both elderly men andwomen, with overall 4-fold increase in the odd ratio of frailty[71]. Vitamin D not only is associated with frailty but alsoappears to be associated with an increased risk to develop frailtyover time in women. In a prospective study including elderly women(age > 69 years), nonfrail women at baseline but displaying avitamin D level of less than 50 nmol/L hada higher risk of becomingfrail during the 4.5 years of followup than women with a higherlevel of vitamin D [72]. In a study from patients with cardiacinsufficiency, Boxer et al. found an association between lowvitamin D levels and the frail phenotype. In particular, vitamin Dlevels and the result of the 6-minute walking test were correlated[73]. In cardiac diseases, this functional test is known to predictsurvival [74]. Thus, low vitamin D is hypothesized to link withmortality in this setting. A prospective study including 4000individuals (1943 men and 2788 women, mean age: 70), followed up to12 years, indeed found a link between lower levels of vitamin D,frailty, and mortality. An assessment of vitamin D status and thephysical phenotype (robust/prefrail/frail) were performed atbaseline [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 torobust individuals with a high level of vitamin D. Thus, overall, aclear association between vitamin D level and frailty has beendemonstrated. Furthermore, interplays between vitamin D status,frailty, and mortality appear plausible. Whether vitamin Dsupplementation in frail subjects may reduce mortality ischallenging and needs to be investigated in the future.

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