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Improved cholecalciferol nutrition in rats is noncalcemic, suppresses parathyroid hormone and increases responsiveness to 1, 25-dihydroxycholecalciferol. Vieth R, Milojevic S, Peltekova V. J Nutr. 2000 Mar;130(3):578-84. PMID: 10702588 We conclude suppression of 1,25(OH)(2)D and PTH, and higher renal VDR mRNA and 24-hydroxylase did not involve higher free 1,25(OH)(2)D concentration or a first pass effect at the gut. Thus, 25(OH)D or a metabolite other than 1,25(OH)(2)D is a physiological, transcriptionally and biochemically active, noncalcemic vitamin D metabolite. When viewed from a perspective that starts with higher vitamin D nutrition, the results indicate that low vitamin D nutrition may bring about a form of resistance to 1,25(OH)2D. This situation would explain why, in humans, nutritional rickets and osteomalacia are commonly associated with normal or increased levels of 1,25(OH)2D (Chesney et al. 1981Citation , Eastwood et al. 1979Citation , Garabedian et al. 1983Citation ,Rasmussen et al. 1980Citation )-these are not like the low hormone levels associated with any other endocrine-deficiency disorder. A connection between lower vitamin D nutrition and vitamin D resistance helps to explain why the supposedly inactive compound 25(OH)D is more relevant in diagnosing nutritional rickets than is the active hormone 1,25(OH)2D. If the features of improved vitamin D nutrition shown here were demonstrated for any newly synthesized compound, the compound would be classified as a noncalcemic 1,25(OH)2D analogue (Brown et al. 1989Citation , Finch et al. 1999Citation , Goff et al. 1993Citation , Koshizuka et al. 1999Citation ). Thus, we contend that 25(OH)D or a metabolite of it other than 1,25(OH)2D exists as a physiological and biologically-active noncalcemic vitamin D metabolite whose effects require further examination, particularly in relationship to studies involving the synthetic analogs of 1,25(OH)2D.

"I discussed in my last post how Dr Vieth has a model of tissue 1,25(OH)2D synthesis and degradation in which the level of active substance is pretty well independent of blood vitamin D level, provided the level is either rising or stable. I think it is also worth pointing out that he is talking, hypothetically, about tissue 1,25(OH)2D, not plasma level... As we know, almost nothing is known about tissue 1,25(OH)2D control. By Vieth's hypothesis tissue 1,25(OH)2D is OK so long as there is at least SOME vitamin D present in plasma and the level dose not vary too much. Obviously there is a level below which you can have as much of the enzyme for converting vitamin D to the active form as you like, if there is no vitamin D in your blood you can't make any 1,25(OH)2D in your tissues, or in your kidneys for export to your blood to control calcium levels. At the lower extremes we have rickets and osteomalacia. These are clear cut, unarguable markers of vitamin D deficiency, in the absence of confounding factors (there are a few)."

Serum levels of free 1,25-dihydroxyvitamin D in vitamin D toxicity. Pettifor JM, Bikle DD, Cavaleros M, Zachen D, Kamdar MC, Ross FP. Ann Intern Med. 1995 Apr 1;122(7):511-3. PMID: 7872586 CONCLUSIONS: Although the patients had normal or near-normal total 1,25-(OH)2D values, most patients had elevated free 1,25-(OH)2D levels. These findings suggest that elevated free 1,25-(OH)2D levels might play a role in the pathogenesis of hypercalcemia in vitamin D toxicity.

"Under year round UV exposure conditions (low latitudes, broken line, "High UV") there is no association between 25(OH)D and either prostate or pancreatic cancer. At high latitudes (Solid line, "Low UV") there is a positive association between blood levels of 25(OH)D and these cancers. The average year round levels of 25(OH)D actually tend to be higher in northern latitudes, higher than those where there is year-round solar UVB. Vieth explains that we know almost nothing about the enzymes controlling tissue 1,25(OH)2D levels and much of his discussion is extrapolated from renal enzyme activity."

Induction of ovarian cancer cell apoptosis by 1,25-dihydroxyvitamin D3 through the down-regulation of telomerase. Jiang F, Bao J, Li P, Nicosia SV, Bai W. J Biol Chem. 2004 Dec 17;279(51):53213-21. Epub 2004 Oct 12. PMID: 15485861 doi: 10.1074/jbc.M410395200 Overall, the study suggests that the down-regulation of telomerase activity by 1,25(OH)2VD3 and the resulting cell death are important components of the response of OCa cells to 1,25(OH)2VD3-induced growth suppression. Progressive shortening of telomere associated with cell divisions limits the life span of normal cells and eventually leads to senescence. To become immortal, human cancers including OCa are invariably associated with activation of mechanism that maintains telomere length. Approximately 85-90% of cancers show reactivation of telomerase. The present study shows that telomerase in OCa cells is down-regulated by 1,25(OH)2VD3. Down-regulation of telomerase is due to decreased stability of hTERT mRNA rather than VDRE-mediated transcriptional repression through the putative VDRE present in the regulatory region of the hTERT gene. It is known that the inhibition of telomerase may lead to a phenotypic lag during which cells would continue to divide until the point at which the telomeres became critically short. This phenomenon may explain why the apoptotic induction by 1,25(OH)2VD3 needs the treatment for more than 6 days. As mentioned in the results, no detectable shortening of telomeric repeats was observed in parental OVCAR3 cells after 9 days of treatment with 1,25(OH)2VD3 (Fig. 4D). This is likely due to the fact that the short telomere (about 3 kb) in OVCAR3 cells is very close to the minimal length required for survival and that cells with detectably shorter telomere may have been selected against apoptosis. It has been shown that transformed human cells enter crisis once the terminal restriction fragment of the telomere reaches a length of about 4 kb. This is insufficient to protect chro

Serum vitamin D level after an annual intramuscular injection of ergocalciferol. Heikinheimo RJ, Haavisto MV, Harju EJ, Inkovaara JA, Kaarela RH, Kolho LA, Rajala SA. Calcif Tissue Int. 1991;49 Suppl:S87. PMID: 1933611 An annual intramuscular injection of ergocalciferol (150,000 IU) normalized low serum (25(OH)D concentrations in elderly people for 1 year. The treatment had a slight effect on serum 24,25(OH)2D levels but no effect on 1,25(OH)2D levels.

Serum levels of vitamin D metabolites and breast cancer risk in the prostate, lung, colorectal, and ovarian cancer screening trial. Freedman DM, Chang SC, Falk RT, Purdue MP, Huang WY, McCarty CA, Hollis BW, Graubard BI, Berg CD, Ziegler RG. Cancer Epidemiol Biomarkers Prev. 2008 Apr;17(4):889-94. Epub 2008 Apr 1. PMID: 18381472 doi: 10.1158/1055-9965.EPI-07-2594 In this prospective study of postmenopausal women, we did not observe an inverse association between circulating 25(OH)D or 1,25(OH)2D and breast cancer risk, although we cannot exclude an association in younger women or with long-term or earlier exposure

Association of vitamin D deficiency with heart failure and sudden cardiac death in a large cross-sectional study of patients referred for coronary angiography. Pilz S, März W, Wellnitz B, Seelhorst U, Fahrleitner-Pammer A, Dimai HP, Boehm BO, Dobnig H. J Clin Endocrinol Metab. 2008 Oct;93(10):3927-35. Epub 2008 Aug 5. PMID: 18682515 doi:10.1210/jc.2008-0784 Conclusions: Low levels of 25(OH)D and 1,25(OH)2D are associated with prevalent myocardial dysfunction, deaths due to heart failure and SCD. Interventional trials are warranted to elucidate whether vitamin D supplementation is useful for treatment and/or prevention of myocardial diseases.

Evidence for alteration of the vitamin D-endocrine system in obese subjects. Bell NH, Epstein S, Greene A, Shary J, Oexmann MJ, Shaw S. J Clin Invest. 1985 Jul;76(1):370-3. PMID: 2991340 The results provide evidence that alteration of the vitamin D-endocrine system in obese subjects is characterized by secondary hyperparathyroidism which is associated with enhanced renal tubular reabsorption of calcium and increased circulating 1,25(OH)2D. The reduction of serum 25-OHD in them is attributed to feedback inhibition of hepatic synthesis of the precursor by the increased serum 1,25(OH)2D.

"Jo vuonna 1981 Hope-Simpson yritti löytää vuodenajasta riippuvaa tekijää, joka selittäisi influenssan vuosittaisen vaihtelun. Tätä tekijää on siitä lähtien etsitty, mutta vasta nyt on huomattu, että tuo tekijä voisi olla D-vitamiinin puute (Cannell et al 2006). Suuri joukko nimekkäitä tutkijoita on päätynyt tähän tulokseen "Epidemiology and Infection" -lehden joulukuun 2006 numerossa. Influenssa esiintyy säännönmukaisesti talviaikaan kun aurinko pohjoisella pallonpuoliskolla on matalalla. Tropiikissa influenssaa esiintyy puolestaan sadekausina kun ihmiset ovat sisällä. Myös harvemmin eteläisellä pallonpuliskolla toistuvaan El Nino -ilmiöön ja sen mukanaan tuomiin sadekausiin liittyy influenssaepidemian esiintyminen. Seerumista mitattavan 25(OH)D-vitamiinin ja varsinaisen kudosten aktiivisen D-vitamiinin, 1,25(OH)2D:n, pitoisuudet laskevat pohjoisella pallonpuoliskolla talviaikaan ja eteläisellä pallonpuoliskolla sadekausina. Tummaihoisilla 1,25(OH)2D, pitoisuudet ovat pohjoisessa, esimerkiksi Euroopassa ja Pohjois-Amerikassa, erityisen matalia, koska heidän ihonsa ei kykene täällä tuottamaan riittävästi D-vitamiinia. Tiedetäänkin että Pohjois-Amerikassa afrikkalaislähtöiset tummaihoiset sairastuvat influenssaan valkoihoisia enemmän ja heidän kuolleisuutensa on suurempi. "

1,25(OH)2 vitamin d inhibits foam cell formation and suppresses macrophage cholesterol uptake in patients with type 2 diabetes mellitus. Oh J, Weng S, Felton SK, Bhandare S, Riek A, Butler B, Proctor BM, Petty M, Chen Z, Schechtman KB, Bernal-Mizrachi L, Bernal-Mizrachi C. Circulation. 2009 Aug 25;120(8):687-98. Epub 2009 Aug 10. PMID: 19667238 doi: 10.1161/CIRCULATIONAHA.109.856070 Conclusion- These results identify reduced vitamin D receptor signaling as a potential mechanism underlying increased foam cell formation and accelerated cardiovascular disease in diabetic subjects.

Vitamin D and intervention trials in prostate cancer: from theory to therapy. Schwartz GG. Ann Epidemiol. 2009 Feb;19(2):96-102. Epub 2008 Jul 10. PMID: 18619854 doi:10.1016/j.annepidem.2008.03.007 This suggests that whereas vitamin D (e.g., cholecalciferol) might prevent prostate cancer, existing prostate tumors likely would require treatment with 1,25(OH)(2)D and/or its analogs. The major obstacle to the use of 1,25(OH)(2)D in patients therapeutically is the risk of hypercalcemia. Several maneuvers to reduce this risk, including pulse dosing and the use of less calcemic 1,25(OH)(2)D analogs, have been explored in Phase I-III clinical trials. Once merely a promise, vitamin D-based therapies for prostate cancer may soon be medical practice.

Vitamin D receptor (VDR) gene polymorphisms and haplotypes, interactions with plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and prostate cancer risk. Mikhak B, Hunter DJ, Spiegelman D, Platz EA, Hollis BW, Giovannucci E. Prostate. 2007 Jun 15;67(9):911-23. PMID: 17440943 DOI: 10.1002/pros.20570 RESULTS No association was found between these SNPs or their associated haplotypes and all PC subtypes except that haplotype 2 (A-f-b) with Cdx2 A, Fok1 f, and Bsm1 b alleles and haplotype 3 (A-F-B) with Cdx2 A, Fok1 F and Bsm1 B alleles compared to the most common haplotype (A-F-b), were associated with reduced risk of aggressive PC (high stage or Gleason sum 7; P = 0.02), both with two alleles suspected of being low risk. Carriers of the variant Cdx2 A allele who were deficient in plasma 25-hydroxyvitamin D (15 ng/ml) compared to non-carriers with normal 25-hydroxyvitamin D, had a lower risk of total and poorly differentiated PCs (Gleason sum 7) (P for interaction = 0.02 and 0.04, respectively). Plasma 1,25-dihydroxyvitamin D deficiency (26 pg/ml) was associated with a threefold risk of poorly differentiated PC (P for interaction = 0.01) when comparing carriers of the Cdx2 A allele to non-carriers with normal 1,25-dihydroxyvitamin D. CONCLUSION In this population of men, none of the VDR polymorphisms studied was associated with susceptibility to PC. Carriers of the variant Cdx2 A allele with low plasma 25-hydroxyvitamin D may experience a reduction in risk of total and poorly differentiated prostate cancers compared to non-carriers with adequate 25-hydroxyvitamin D.

Low vitamin d levels predict stroke in patients referred to coronary angiography. Pilz S, Dobnig H, Fischer JE, Wellnitz B, Seelhorst U, Boehm BO, März W. Stroke. 2008 Sep;39(9):2611-3. Epub 2008 Jul 17. PMID: 18635847 doi: 10.1161/STROKEAHA.107.513655 Conclusions- Low levels of 25(OH)D and 1,25(OH)2D are independently predictive for fatal strokes, suggesting that vitamin D supplementation is a promising approach in the prevention of strokes.

Measurement of vitamin D levels in inflammatory bowel disease patients reveals a subset of Crohn's disease patients with elevated 1,25-dihydroxyvitamin D and low bone mineral density. Abreu MT, Kantorovich V, Vasiliauskas EA, Gruntmanis U, Matuk R, Daigle K, Chen S, Zehnder D, Lin YC, Yang H, Hewison M, Adams JS. Gut. 2004 Aug;53(8):1129-36. PMID: 15247180 doi: 10.1136/gut.2003.036657. Conclusions: These data demonstrate that elevated 1,25(OH)2D is more common in CD than previously appreciated and is independently associated with low bone mineral density. The source of the active vitamin D may be the inflamed intestine. Treatment of the underlying inflammation may improve metabolic bone disease in this subgroup of patients.

Sweat gland epithelial and myoepithelial cells are vitamin D targets. Koike N, Stumpf WE. Exp Dermatol. 2007 Feb;16(2):94-7. PMID: 17222221 DOI: 10.1111/j.1600-0625.2006.00513.x Nuclear receptor binding of 1,25(OH)2-vitamin D3 (vitamin D) in skin keratinocytes of epidermis, hair sheaths and sebaceous glands was discovered through receptor microscopic autoradiography. Extended experiments with 3H-1,25(OH)2-vitamin D3 and its analog 3H-oxacalcitriol (OCT) now demonstrate nuclear receptor binding in sweat gland epithelium of secretory coils and ducts as well as in myoepithelial cells, as studied in paws of nude mice after i.v. injection. The results suggest genomic regulation of cell proliferation and differentiation, as well as of secretory and excretory functions, indicating potential therapies for impaired secretion as in hypohidrosis of aged and diseased skin.

Plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D and risk of incident ovarian cancer. Tworoger SS, Lee IM, Buring JE, Rosner B, Hollis BW, Hankinson SE. Cancer Epidemiol Biomarkers Prev. 2007 Apr;16(4):783-8. PMID: 17416771 doi: 10.1158/1055-9965.EPI-06-0981 Overall, our results do not suggest that plasma vitamin D levels are associated with risk of ovarian cancer. However, we observed significant associations in some subgroups, which should be evaluated further in other studies because increasing vitamin D intake is an easy preventive measure to adopt.

Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, Orav JE, Stuck AE, Theiler R, Wong JB, Egli A, Kiel DP, Henschkowski J. BMJ. 2009 Oct 1;339:b3692. doi: 10.1136/bmj.b3692. PMID: 19797342 doi: 10.1136/bmj.b3692 Conclusions Supplemental vitamin D in a dose of 700-1000 IU a day reduced the risk of falling among older individuals by 19% and to a similar degree as active forms of vitamin D. Doses of supplemental vitamin D of less than 700 IU or serum 25-hydroxyvitamin D concentrations of less than 60 nmol/l may not reduce the risk of falling among older individuals.

Barger-Lux MJ, Heaney RP, Dowell S, Chen TC, Holick MF. Vitamin D and its major metabolites: serum levels after graded oral dosing in healthy men.Osteoporos Int. 1998;8(3):222-30.PMID: 9797906 [PubMed - indexed for MEDLINE]

Low vitamin d levels predict stroke in patients referred to coronary angiography.\nPilz S, Dobnig H, Fischer JE, Wellnitz B, Seelhorst U, Boehm BO, März W.\nStroke. 2008 Sep;39(9):2611-3. Epub 2008 Jul 17.\nPMID: 18635847 \ndoi: 10.1161/STROKEAHA.107.513655