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Vitamin D, disease and therapeutic opportunities

Key Points

  • The discovery of the vitamin D endocrine system in 1970 sparked a new interest in the relationship between vitamin D and metabolic bone disease. In particular, the identification of the vitamin D receptor in tissues not related to calcium and bone has led to the investigation of vitamin D and its action in a number of other medical areas.

  • Many studies evaluating the effects of high-dose vitamin D in supplemental form in suppressing a wide range of diseases have been conducted, and many clinical investigators have interpreted that vitamin D does have a beneficial effect.

  • In metabolic bone disease, vitamin D cures rickets in children and osteomalacia in adults. However, in vitamin D-dependency type I and type II rickets, treatment with the vitamin D hormone, 1α,25-dihydroxyvitamin D3, offers more benefits. For osteoporosis, vitamin D does have a role; however, the development of oral vitamin D analogues that have anabolic properties would fulfil an unmet need.

  • Several vitamin D analogues have been marketed for the treatment of secondary hyperthyroidism associated with chronic renal failure, and are successful as they provide a wider therapeutic window compared with 1α,25-dihydroxyvitamin D3 and its synthetic precursor 1α-hydroxyvitamin D3. They have also proved successful in treating psoriasis.

  • Vitamin D and sunlight exposure has also been associated with various immune disorders (for example, multiple sclerosis and type 1 diabetes) and numerous cancers; however, the role of vitamin D-based therapies for these indications remains to be evaluated in large-scale studies.

  • Toxic effects of vitamin D and hypercalcaemia can occur when vitamin D is taken in doses above 25,000 IU per day (625 μg per day) or when the vitamin D endocrine system is dysregulated, such as in granuloma-forming disease or in various malignancies, such as Hodgkin's lymphoma.

  • Future development of vitamin D-based therapeutics will probably target specific aspects of vitamin D function, which will be aided by the identification of key specific genes responsible for the various functions of vitamin D.

  • It is likely that more efficacious vitamin D analogues selective for bone formation or resorption will be developed, and analogues selective for intestinal calcium absorption will also be developed. However, with the current status of knowledge, it seems that development of vitamin D analogues specific for components of the immune system is less promising.

Abstract

The discovery of the vitamin D endocrine system and a receptor for the hormonal form, 1α,25-dihydroxyvitamin D3, has brought a new understanding of the relationship between vitamin D and metabolic bone diseases, and has also established the functions of vitamin D beyond the skeleton. This has ushered in many investigations into the possible roles of vitamin D in autoimmune diseases, cardiovascular disorders, infectious diseases, cancers and granuloma-forming diseases. This article presents an evaluation of the possible roles of vitamin D in these diseases. The potential of vitamin D-based therapies in treating diseases for which the evidence is most compelling is also discussed.

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Figure 1: Pathway of native hormone or 1α,25-dihydroxyvitamin D3 production.
Figure 2: Depiction of 1α,25-dihydroxyvitamin D3 activities and target organs involved in maintaining plasma calcium homeostasis.
Figure 3: Vitamin D analogues for osteoporosis.
Figure 4: The link between the vitamin D and RAAS systems.

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Acknowledgements

This work was supported by a fund from the Wisconsin Alumni Research Foundation.

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Hector F. DeLuca is a founder of Deltanoid Pharmaceuticals, and Lori A. Plum is the Director of Research and Development at Deltanoid Pharmaceuticals, a company involved in the development of vitamin D analogues.

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Plum, L., DeLuca, H. Vitamin D, disease and therapeutic opportunities. Nat Rev Drug Discov 9, 941–955 (2010). https://doi.org/10.1038/nrd3318

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