Further investigation revealed that compound 28 inhibited tumor growth in an orthotopic breast-tumor model without causing hypercalcemia which is the main side effect of secosteroidal VDR modulators.
Its pleotropic effect improves the bone remodeling initiated by osteoblast and alleviates the risk factors for vascular calcification with less hypercalcemia than vitamin D receptor analogs.
Two challenges that limit VDR agonist use clinically are hypercalcemia and the cooperation of VDR with ERG to hyper-induce the 1α,25-dihydroxyvitamin D3 metabolizing enzyme, CYP24A1, thus reducing VDR activity.
In conclusion, we have identified a unique VDR agonist compound with beneficial effects in mouse models of hyperparathyroidism and heart failure without inducing significant hypercalcemia.
Although the identification of mechanisms mediating VDR-regulated transcription has been one focus of recent research in the field, other topics of fundamental importance include the identification and functional significance of proteins involved in the metabolism of vitamin D. CYP2R1 has been identified as the most important 25-hydroxylase, and a critical role for CYP24A1 in humans was noted in studies showing that inactivating mutations in CYP24A1 are a probable cause of idiopathic infantile hypercalcemia.
The ingestion of excessive amounts of vitamin D<sub>3</sub> (or vitamin D<sub>2</sub>) results in hypercalcemia and hypercalciuria due to the formation of supraphysiological amounts of 25-hydroxyvitamin D [25(OH)D] that bind to the vitamin D receptor, albeit with lower affinity than the active form of the vitamin, 1,25(OH)<sub>2</sub>D, and the formation of 5,6-trans 25(OH)D, which binds to the vitamin D receptor more tightly than 25(OH)D. In patients with granulomatous disease such as sarcoidosis or tuberculosis and tumors such as lymphomas, hypercalcemia occurs as a result of the activity of ectopic 25(OH)D-1-hydroxylase (CYP27B1) expressed in macrophages or tumor cells and the formation of excessive amounts of 1,25(OH)<sub>2</sub>D.
Considering the selective anti-inflammatory effects of VDR agonists compared to glucocorticoids, sparing microbicidal functions, the fear of hypercalcemia as their only frequent side effect becomes a questionable reason for the lack of clinical studies.
We investigated the roles of the BsmI and TaqI VDR gene polymorphisms in the development of hypercalcemia in Turkish peritoneal dialysis (PD) patients.
From these results, we speculate that although the VDR gene polymorphism may affect the serum PTH level, it is not a risk factor for hypercalcemia in sarcoidosis.