Topical Vitamin D Analogs Beyond Psoriasis: Pharmacological Mechanisms, Cutaneous Drug Delivery, and Clinical Evidence

Topical vitamin D analogs are well-established therapies for psoriasis, but their broader dermatologic potential increasingly depends not only on their biological activity but also on the ability of topical formulations to achieve effective and localized cutaneous delivery. This narrative review critically examines the emerging use of calcipotriol, tacalcitol, and calcitriol beyond psoriasis, with particular emphasis on formulation strategies, cutaneous drug delivery, and their relationship with clinical performance. Conventional topical dosage forms, including ointments, creams, and solutions, remain the principal delivery systems used in clinical studies. Their therapeutic performance is influenced by vehicle composition, skin-barrier integrity, local retention, application conditions, and the physi-cochemical properties of the vitamin D compound, which collectively determine cutaneous penetration, tolerability, and systemic exposure. Across the reviewed indications, formula-tions and treatment protocols vary considerably, contributing to heterogeneity in clinical outcomes. Vitiligo currently presents the strongest clinical evidence, particularly when topical vitamin D analogs are combined with narrowband ultraviolet B phototherapy, whereas encouraging results have been reported for morphea, acne vulgaris, and inherited ichthyoses. Evidence for atopic dermatitis, alopecia areata, and basal cell carcinoma re-mains limited or inconsistent. Beyond conventional vehicles, emerging delivery technolo-gies including liposomes, nanoemulsions, solid lipid nanoparticles, nanostructured lipid carriers, polymeric nanocarriers, hydrogels, and microneedle-assisted systems offer op-portunities to enhance skin targeting, improve local drug retention and reduce systemic exposure. However, evidence specifically evaluating these advanced systems for vitamin D analogs remains predominantly preclinical. Future research should integrate clinical evaluation with formulation optimization, cutaneous pharmacokinetics, and comparative delivery studies, as accumulating evidence suggests that formulation-dependent skin de-livery may be a critical determinant of therapeutic success beyond psoriasis.