Methods useful for vitamin D deficiency and related disorders
Methods for diagnosing, treating, and preventing catabolism-related vitamin D deficiency and related disorders, related compositions, apparatus and kits, are disclosed. A method involves measuring CYP24 expression and/or activity, or a proxy thereof such as FGF23 level, in a patient and correlating abnormally elevated CYP24 expression and/or activity with catabolism-related vitamin D deficiency or with susceptibility for catabolism-related vitamin D deficiency. In response to abnormally elevated CYP24 expression and/or activity, the method further includes administering a CYP24 inhibitor to the vitamin D deficient or at-risk patient, and preferably avoiding activation of the vitamin D binding receptor, such as by avoiding administration of active vitamin D compounds to such patients. Optionally, a vitamin D prohormone or prohormone can be administered.
1. A method of diagnosing and treating catabolism-related vitamin D deficiency or a susceptibility thereto in a patient having Chronic Kidney Disease, comprising:
requesting a test providing the results of a measurement, direct or indirect, of a patient's CYP24 expression and/or activity, wherein abnormally elevated CYP24 expression and/or activity indicates a susceptibility for catabolism-related vitamin D deficiency; and
administering an effective amount of a pharmaceutically acceptable formulation comprising a CYP24 inhibitor to the patient in response to abnormally elevated CYP24 expression and/or activity to treat or prevent catabolism-related vitamin D deficiency defined as a total serum level of 25-hydroxyvitamin D below 30 ng/mL.
2. The method of claim 1 , wherein said test comprises obtaining a tissue, blood or other bodily fluid, or cell sample from the patient and assaying the sample for a direct or indirect measure of CYP24 expression and/or activity.
3. The method of claim 1 , wherein, at the time of said measurement, the patient is not undergoing active vitamin D therapy.
4. The method according to claim 1 , wherein the patient does not have cancer.
5. The method according to claim 1 , further comprising requesting a test providing the results of the patient's 25-hydroxy vitamin D levels and treating vitamin D deficiency by administering the CYP24 inhibitor to a vitamin D deficient patient.
6. The method according to claim 5 , further comprising administering to the patient one or more of vitamin D prehormones, prohormones, and analogs of any of the foregoing.
7. The method of claim 6 , wherein said therapy comprises administration of a compound selected from cholecalciferol, ergocalciferol, 25-hydroxy vitamin D 2 , 25-hydroxyvitamin D 3 , and combinations thereof.
8. The method of claim 7 , wherein said therapy comprises administration of 25-hydroxyvitamin D 3 .
9. The method of claim 8 , wherein said therapy comprises administration of a therapeutically effective amount of 25-hydroxyvitamin D 3 to restore the patient's 25-hydroxy vitamin D levels to at least 30 ng/mL.
10. The method according to claim 1 , further comprising requesting a test providing the results of the patient's 25-hydroxyvitamin D levels and inhibiting and/or preventing vitamin D deficiency by administering the CYP24 inhibitor to a vitamin D replete patient.
11. The method according to claim 1 , wherein the Chronic Kidney Disease is Stage 1 or Stage 2.
12. The method according to claim 1 , wherein the Chronic Kidney Disease is Stage 3 or Stage 4.
13. The method according to claim 1 , wherein said patient has hyperparathyroidism.
14. The method according to claim 1 , wherein the patient's PTH level is above the target range for the patient's Stage of CKD.
15. The method according to claim 1 , wherein the patient has a deficiency in 1,25-dihydroxy vitamin D 3 .
16. The method according to claim 1 , further comprising avoiding active vitamin D therapy, or, if the patient is undergoing active vitamin D therapy then reducing the level of or omitting active vitamin D therapy.
17. The method according to claim 16 , further comprising administering the vitamin D prohormone 25-hydroxyvitamin D to the patient in an amount sufficient to increase 1,25-dihydroxy vitamin D levels.
18. The method according to claim 1 , wherein the CYP24 inhibitor is also a vitamin D receptor agonist.
19. The method according to claim 2 , wherein the test comprises assaying the concentration of one or more catabolic byproducts of CYP24 in serum or another bodily fluid as a measure of CYP24 activity.
20. The method according to claim 19 , wherein the test comprises assaying the concentration of one or more precursors to the one or more catabolic byproducts of CYP24 in serum or another bodily fluid and calculating a ratio of concentrations of one or more catabolic byproducts of CYP24 to serum concentrations of one or more corresponding precursors as an measure of CYP24 activity.
21. The method according to claim 20 , wherein the catabolic byproducts of CYP24 include one or both of 24,25-dihydroxyvitamin D and 1,24,25-trihydroxy vitamin D.
22. The method according to claim 20 , wherein the-assaying comprises measuring one or more ratios selected from the group consisting of 24,25-dihydroxyvitamin D to 25-hydroxy vitamin D and 1,24,25-trihydroxyvitamin D to 1,25-dihydroxy vitamin D.
23. The method according to claim 19 , wherein the catabolic byproducts of CYP24 include the 24-hydroxylated and/or 23-hydroxylated catabolic byproducts of one or more members selected from the group consisting of paricalcitol, doxercalciferol, 22-oxacalcitriol, dihydrotachysterol, and 26,26,26,27,27,27-hexafluorocalcitriol (falecalcitriol).
24. The method according to claim 19 , wherein the assaying follows acute or chronic administration of a CYP24 substrate.
25. The method according to claim 19 , wherein the test comprises assaying the concentration of one or more catabolic byproducts of CYP24 in serum.
26. The method according to claim 2 , wherein the assaying comprises measuring CYP24 mRNA in tissues, plasma, or cells.
27. The method according to claim 2 , wherein the assaying comprises measuring CYP24 protein in tissues, plasma, or cells.
28. The method according to claim 2 , wherein the assaying comprises measuring CYP24 enzymatic activity in tissues, plasma, or cells.
29. The method according to claim 2 , wherein the tissue or cell sample is selected from the group consisting of kidney tissue, liver tissue, parathyroid gland tissue, peripheral blood mononuclear cells, and buccal cells.
30. The method according to claim 1 , wherein the patient has abnormally elevated CYP24 expression and/or activity that is at least 2-fold increased over normal CYP24 expression and/or activity.
31. The method according to claim 1 , wherein the CYP24 inhibitor is a pure inhibitor of CYP24 or a dual-action CYP24 inhibitor/VDR agonist.