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Under normal circumstances extrarenal sources of calcitriol probably constitutes a microendocrine system involved in cell differentiation and local intercellular communication with no influence on systemic calcium homeostasis. Under pathological conditions such as chronic renal failure, extrarenal sources have the potential to normalize serum calcitriol after adequate stimulation (such as, 25(OH)D administration). Extrarenal 1,25-(OH)2D3 synthesis is controlled by physiological levels of calcitriol. However, in sarcoidosis and other granulomatous diseases, 1,25-(OH)2D3 production by macrophages is deregulated, causing severe alterations in systemic calcium homeostasis.

In conclusion, a number vitamin D analogues have been developed that have very low calcemic activity but retain several other properties of 1,25-(OH)2D3, including the ability to differentiate leukemia and skin cells, to enhance the immune response, and to suppress parathyroid hormone levels. Although the mechanism of this selective activity is not yet clear, these analogues may provide new insights into the differences in action of 1,25-(OH)2D3 in various target tissues. Most importantly, the selective action of these analogues may be exploited for the treatment of diseases such as leukemia, psoriasis and hyperparathyroidism.