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Lifestyle habits and insufficient sunlight exposure lead to a high prevalence of vitamin D hypovitaminosis, especially in the elderly. Recent studies suggest that in central Europe more than 50% of people over 60 years are not sufficiently supplied with vitamin D. Since vitamin D hypovitaminosis is associated with many diseases, such as Alzheimer’s disease (AD), vitamin D supplementation seems to be particularly useful for this vulnerable age population. Importantly, in addition to vitamin D, several analogues are known and used for different medical purposes. These vitamin D analogues differ not only in their pharmacokinetics and binding affinity to the vitamin D receptor, but also in their potential side effects. Here, we discuss these aspects, especially those of the commonly used vitamin D analogues alfacalcidol, paricalcitol, doxercalciferol, tacalcitol, calcipotriol, and eldecalcitol. In addition to their pleiotropic effects on mechanisms relevant to AD, potential effects of vitamin D analogues on comorbidities common in the context of geriatric diseases are summarized. AD is defined as a complex neurodegenerative disease of the central nervous system and is commonly represented in the elderly population. It is usually caused by extracellular accumulation of amyloidogenic plaques, consisting of amyloid (Aβ) peptides. Furthermore, the formation of intracellular neurofibrillary tangles involving hyperphosphorylated tau proteins contributes to the pathology of AD. In conclusion, this review emphasizes the importance of an adequate vitamin D supply and discusses the specifics of administering various vitamin D analogues compared with vitamin D in geriatric patients, especially those suffering from AD. Full article

Vitamin D presents a plethora of different functions that go beyond its role in skeletal homeostasis. It is an efficient endocrine regulator of the Renin–Angiotensin–Aldosterone System (RAAS) and erythropoiesis, exerts immunomodulatory effects, reduces the cardiovascular events and all-cause mortality. In Chronic Kidney Disease (CKD) patients, Vitamin D function is impaired; the renal hydrolyzation of its inactive form by the action of 1α-hydroxylase declines at the same pace of reduced nephron mass. Moreover, Vitamin D major carrier, the D-binding protein (DBP), is less represented due to Nephrotic Syndrome (NS), proteinuria, and the alteration of the cubilin–megalin–amnionless receptor complex in the renal proximal tubule. In Glomerulonephritis (GN), Vitamin D supplementation demonstrated to significantly reduce proteinuria and to slow kidney disease progression. It also has potent antiproliferative and immunomodulating functions, contributing to the inhibitions of kidney inflammation. Vitamin D preserves the structural integrity of the slit diaphragm guaranteeing protective effects on podocytes. Activated Vitamin D has been demonstrated to potentiate the antiproteinuric effect of RAAS inhibitors in IgA nephropathy and Lupus Nephritis, enforcing its role in the treatment of glomerulonephritis: calcitriol treatment, through Vitamin D receptor (VDR) action, can regulate the heparanase promoter activity and modulate the urokinase receptor (uPAR), guaranteeing podocyte preservation. It also controls the podocyte distribution by modulating mRNA synthesis and protein expression of nephrin and podocin. Maxalcalcitol is another promising alternative: it has about 1/600 affinity to vitamin D binding protein (DBP), compared to Calcitriol, overcoming the risk of hypercalcemia, hyperphosphatemia and calcifications, and it circulates principally in unbound form with easier availability for target tissues. Doxercalciferol, as well as paricalcitol, showed a lower incidence of hypercalcemia and hypercalciuria than Calcitriol. Paricalcitol demonstrated a significant role in suppressing RAAS genes expression: it significantly decreases angiotensinogen, renin, renin receptors, and vascular endothelial growth factor (VEGF) mRNA levels, thus reducing proteinuria and renal damage. The purpose of this article is to establish the Vitamin D role on immunomodulation, inflammatory and autoimmune processes in GN. Full article

Alzheimer’s disease (AD) is characterized by extracellular plaques in the brain, mainly consisting of amyloid-β (Aβ), as derived from sequential cleavage of the amyloid precursor protein. Epidemiological studies suggest a tight link between hypovitaminosis of the secosteroid vitamin D and AD. Besides decreased vitamin D level in AD patients, an effect of vitamin D on Aβ-homeostasis is discussed. However, the exact underlying mechanisms remain to be elucidated and nothing is known about the potential effect of vitamin D analogues. Here we systematically investigate the effect of vitamin D and therapeutically used analogues (maxacalcitol, calcipotriol, alfacalcidol, paricalcitol, doxercalciferol) on AD-relevant mechanisms. D₂ and D₃ analogues decreased Aβ-production and increased Aβ-degradation in neuroblastoma cells or vitamin D deficient mouse brains. Effects were mediated by affecting the Aβ-producing enzymes BACE1 and γ-secretase. A reduced secretase activity was accompanied by a decreased BACE1 protein level and nicastrin expression, an essential component of the γ-secretase. Vitamin D and analogues decreased β-secretase activity, not only in mouse brains with mild vitamin D hypovitaminosis, but also in non-deficient mouse brains. Our results further strengthen the link between AD and vitamin D, suggesting that supplementation of vitamin D or vitamin D analogues might have beneficial effects in AD prevention. Full article

Alfacalcidol (1α-hydroxyvitamin D₃) has been widely used since 1981 as a prodrug for calcitriol (1α,25-dihydroxyvitamin D₃) in the treatment of hypocalcemia, chronic renal failure, hypoparathyroidism and osteoporosis. More recently, doxercalciferol (1α-hydroxyvitamin D₂) has been used since 1999 as a prodrug for 1α,25-dihydroxyvitamin D₂ for the treatment of secondary hyperparathyroidism. Currently, six forms of vitamin D are known. They range from vitamin D₂ to vitamin D₇ and are distinguished by their differing side chains. Only vitamin D₂ and vitamin D₃ have been found to be biologically active based on the elucidation of activation pathways. Alfacalcidol and osteoporosis/doxercalciferol and secondary hyperparathyroidism are discussed, with a new look at old compounds including their practical syntheses. Full article