Background: A low vitamin D state and vitamin D deficiency is common in the elderly and has been correlated with various cardiovascular risk factors and events. Vitamin D deficiency has been demonstrated to play a major role in the pathogenesis of physical frailty and hypothesized to contribute to physical frailty through sarcopenia (the loss of skeletal muscle mass and function with aging). Sarcopenia has been shown to be a major contributor to morbidity in older adults. One possible mechanism for this association could be the effect of vitamin D on subclinical vascular function (vascular endothelial dysfunction; VED). Recent data highlight the role of increased inflammation and oxidative stress coexist in VED and sarcopenic modulated frailty which implicates chronic inflammation as a major component in the pathogenesis of frailty. Vitamin D supplementation has been shown to down-regulate mediators of Vascular Endothelial Dysfunction (VED) and correct the associated inflammatory status hence may be a simple strategy for the treatment and prevention of frailty.

Study objectives: The proposed research study is designed to investigate anti-inflammatory effects of vitamin D on physical frailty, sarcopenia and VED. The 2 main aims of the study are: 1) To establish a relationship between VED and sarcopenia-related physical frailty in a cohort of patient with cardiovascular conditions and 2) To investigate the effects of vitamin D supplementation in improving vascular endothelial function by correcting inflammatory and oxidative stress profiles and thus improve muscle tone in healthy working adults.

Method/design: The proposed study protocol will comprise of two inter-related study arms. The first arm of the study is aimed at addressing the first aim using a single-centred, prospective cross-sectional analytical design. This arm will also investigate the independent effects of vitamin D in the relationship of physical frailty and sarcopenia with VED. The second arm of the study will address the second aim. The second arm will adopt a pilot approach focusing on delineating the effects of down-regulation of inflammation-mediated pathways affecting muscle strength and function. In particular, the impact of vitamin D supplementation on Thrombospondin-1 (TSP-1; mediator of VED) and Tumor Growth Factor β1 (TGF-β1: modulator of inflammation) will be measured in healthy working adults.

Discussion: The hypothesis that vitamin D deficiency causes frailty via its inflammation related VED, which in turn leads to sarcopenia and physical frailty, will be explored. Novel frailty management strategies are essential to improve the quality of life of frail people and reduce the healthcare cost associated with frailty outcomes. The proposed research study will introduce a frailty management strategy via prevention/improvement of inflammatory status and early-stage subclinical CVD (VED) by simple and safe treatment strategy, vitamin D supplementation in older frail adults. The outcomes of the clinical intervention could be translated to better health outcomes by implementing frailty prevention/controlling strategy at early stages, before other CV complications occur by reducing the negative impact on patient’s quality of life and the healthcare systems, which will assist to reduce socioeconomic burden and improve quality of life of older people. This study will further investigate underlining mechanisms of association between vascular endothelial dysfunction and sarcopenia-related physical frailty. Positive outcome of the mechanistic study would provide baseline biomedical mechanistic insight for further studies to introduce new pharmacological interventions in frailty.

Clinical trial registration: This trial is registered in Australia New Zealand Clinical Trial Registry ACTRN12621000059864. The WHO Universal Trial Number (UTN): U1111-1254-3879.