There are important clinical considerations for interventions using high doses of calcitriol, calcitriol precursors or its analogs: (1) They are incapable of correcting underlying vitamin D deficiency, and (2) their induction of CYP24A1 expression may further reduce not only systemic levels of 25(OH)D for local calcitriol production, but also intracellular calcitriol for VDR activation (see Figure 1). The gene discussed is VDR; the disease is vitamin D deficiency.