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Understanding vitamin D analogue studies

Posted on: February 29, 2012   by  Brant Cebulla

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Vitamin D, as we all know, is made in the skin, or can be taken as a supplement or found sparingly in foods. From there, it travels to the liver where the liver makes “blood vitamin D” [called calcidiol, or 25(OH)D]. From there, “blood vitamin D” travels two directions to complete two functions.

The first function is the endocrine function. “Blood vitamin D” is taken to the kidney and the kidney pumps “activated vitamin D” into the blood, and this hormonal “activated vitamin D” maintains calcium in the body. “Activated vitamin D” is called calcitriol or 1,25(OH)2D.

The second function is the autocrine function. “Blood vitamin D” is taken to cells all over the body; cells in the brain, the heart, the pancreas, the lungs and more. These cells produce “activated vitamin D” inside their own cells, and this intracellular “activated vitamin D” tells cells what to do. This autocrine function is what researchers are really excited about and why you hear about new discoveries in the news all the time.

Only in rare health conditions is the body not able to complete the endocrine and/ or autocrine functions with a sufficient supply of “blood vitamin D.” One of these rare conditions is chronic kidney failure (CKD), where the body’s kidneys simply cannot produce circulating “activated vitamin D” and maintain blood calcium for endocrine function. However the autocrine function works just fine still because “blood vitamin D” goes straight to the cells for production of “activated vitamin D,” not through the kidney.

When someone has chronic kidney failure, they are sometimes prescribed Zemplar, which is “activated vitamin D,” and it allows the person with CKD to still maintain calcium. These patients still need regular vitamin D however, to make sure they still have enough “blood vitamin D” to fulfill the autocrine function.

This fundamental understanding is important when we look at study designs, particularly in studies that use vitamin D analogues (forms of “activated vitamin D”). Fairly recently, a study came out that reported there was no benefit in vitamin D therapy for heart health in patients with CKD.

Ravi Thadhani, MD,et al. Vitamin D Therapy and Cardiac Structure and Function in Patients With Chronic Kidney Disease. JAMA February 15, 2012, Vol 307, No. 7, pp 637-742

You may have seen the media cover this story; again, claiming that vitamin D does not help. This study was a randomized controlled trail that used “activated vitamin D” for one group and placebo for the other group. But neither group actually received vitamin D to boost “blood vitamin D.”

In essence, they designed the study so that the “activated vitamin D” group could carry out endocrine function but not autocrine function, while the placebo group could carry out neither endocrine function nor autocrine function. If both groups cannot boost their autocrine function, then you would not expect to see better health outcomes in your trial. This is something we could have concluded prior to the investigators even completing the study.

The authors state:

“Given our results with an active vitamin D analog, it is unlikely that nutritional vitamin D supplementation (ergocalcfierol or cholecalciferol) of similar duration modifies LVH (left ventricular hypertrophy).”

As I have explained in this post, this thought process is fundamentally incorrect. In the 80s, this was the line of thinking, where researchers were really excited about the potential for “activated vitamin D” after they saw profound effects in test tubes. We know now, however, that organs all over the body prefer to make their own “activated vitamin D” with “blood vitamin D,” and for the most part, you cannot force feed organs “activated vitamin D” and expect results.

If you really wanted to test whether vitamin D helps with cardiac function in patients with CKD, you would have to administer two things. For ethical reasons, you have to administer a drug like Zemplar to all, to make sure both groups are making up for their kidney’s inability to produce circulating “activated vitamin D.” Then you administer vitamin D to half. The two groups would look like this:

  • Vitamin D daily + Zemplar
  • Placebo daily + Zemplar

That way the kidney gets what it needs in all the patients, and half the patients get vitamin D to see if the heart improves. If you want to see if vitamin D can help the heart in kidney failure patients, this is the only way to do it. Unfortunately, this study wasn’t designed properly, and this is something the media cannot assess.

In short, this study did not use vitamin D , it used Zemplar, and it is important for the media to clarify that this was a Zemplar study, not a vitamin D study.

6 Responses to Understanding vitamin D analogue studies

  1. Ian

    Thanks for this clear description and critique. I have provided a copy to my GP, who prescribed me Calcitriol for my vitamin D deficiency. (Blood calcium levels were normal).

  2. eelisabethpuur@gmail.com

    Is it possible to have a comment on these two, from Uro Today, I never herd of the site before, but you have to be a member to read
    One I was able to read, the other one not … don´t know why
    And one is about a vitamin D analog …

    The novel vitamin D analog ZK191784 inhibits prostate cancer cell invasion …
    UroToday – ‎29 feb 2012‎

    BACKGROUND: Low serum levels of 1,25(OH) 2 D 3 (1,25D), have been associated with aggressive biologic behavior of prostate cancer (PCa). In the present study, we examined the effects of 1,25D and its novel, low-calcemic analog ZK191784 (ZK) on matrix …

    http://www.urotoday.com/investigational-urology/vitamin-d-receptor-gene-variants-and-clinical-outcomes-after-androgen-deprivation-therapy-for-prostate-cancer-abstract.html

    Vitamin D receptor gene variants and clinical outcomes after androgen-deprivation therapy for prostate cancer – Abstract
    Tue, 28 February 2012

    PURPOSE: Molecular epidemiology studies have shown that vitamin D receptor (VDR) gene polymorphisms are associated with prostate cancer risk.
    However, the prognostic value of these polymorphisms on clinical outcomes in prostate cancer patients receiving androgen-deprivation therapy (ADT) has not been determined.
    METHODS: We evaluated the association of five common VDR polymorphisms, ApaI, Tru9I, BsmI, FokI, and Cdx2, with clinicopathologic characteristics and clinical outcomes, including disease progression, prostate cancer-specific mortality, and all-cause mortality, in a cohort of 601 prostate cancer patients treated with ADT.
    RESULTS: Of the five VDR polymorphisms, FokI rs2228570 and BsmI rs1544410 were associated with Gleason score at diagnosis (P = 0.043) and prostate-specific antigen nadir following ADT (P = 0.023), respectively. The haplotype analysis revealed that the A-A-G (ApaI-Tru9I-BsmI) compared with C-G-G individuals were more likely to have high Gleason score (P = 0.050). However, none of these polymorphisms were significantly associated with disease progression and mortality after ADT.
    CONCLUSIONS: This is the largest study to date investigating the association of VDR polymorphisms and clinical outcomes in prostate cancer patients receiving ADT. Polymorphisms in the VDR gene might be associated with Gleason score, but these polymorphisms had no main effect on predicting response to ADT.
    Written by:
    Pao JB, Yang YP, Huang CN, Huang SP, Hour TC, Chang TY, Lan YH, Lu TL, Lee HZ, Juang SH, Huang CY, Bao BY. Are you the author?
    Department of Pharmacy, Yangming Branch, Taipei City Hospital, Taipei, Taiwan.
    Reference: World J Urol. 2011 Dec 23. [Epub ahead of print]
    PubMed Abstract
    PMID: 22193519
    UroToday.com Investigational Urology Section

    • Brant Cebulla

      These are studies that are a little beyond the realm of what we cover, so we don’t typically purchase access to these kinds of studies.

      Basically it is thought that activated vitamin D and all of its machinery have mechanisms in fighting/preventing cancer, so in both studies, the investigators are trying to hone in on this relationship.

  3. Davidclements

    I am a practicing internist.

    For those with Stage 3 (AKA Mild or first stage) chronic kidney disease (CKD), one standard of care (KDOQI guideline) is to measure the (25-OH) Vitamin D level and supplement to a level of 30 ng/mL. Another standard is to measure the Parathyroid hormone level (PTH), and if the level is over 70 nmol/L and the Vitamin D level is “adequate” (30 or more), to then prescribe some form of activated Vitamin D. Elevated PTH indicates excessive bone turnover which can lead to the bone disease of chronic kidney disease. The assumption is that if PTH is elevated the patient must have a deficiency of activated Vitamin D that can be treated only with activated Vitamin D. I observe our local renal specialists stopping the Vitamin D supplement when starting an activated Vitamin D supplement.

    My routine for treatment of elevated PTH is to supplement with Vitamin D3, first to a goal of 50 ng/mL, and if PTH is still elevated, a goal of closer to 100 ng/mL. My observation is that most of those Stage 3 CKD patients with elevated PTH can have their PTH levels suppressed to goal levels (less than 70 nmol/L) with Vitamin D alone. I rarely need to prescribe activated Vitamin D to meet the PTH goal. Sorry, no solid evidence, just repeated observation.

    If it can be proven that higher levels of Vitamin D dosing can suppress the PTH level adequately in these patients, the further question raised by the above post is whether there may some additional benefit to using Vitamin D rather than activated Vitamin D or in addition to activated Vitamin D. My personal bias for the moment is to use the more “natural” Vitamin D3 supplementation when possible, rather than activated Vitamin D.

    See standards of care at
    http://www.kidney.org/professionals/KDOQI/guidelines_bone/index.htm

  4. eelisabethpuur@gmail.com

    I still don´t get it, this thing about vitamin D-analogues. Look att this study,

    http://www.doctorslounge.com/index.php/news/pb/27376
    FRIDAY, March 9 (HealthDay News) — Vitamin D3 analogs modulate immunity in human psoriasis, inducing thymic stromal lymphopoietin (TSLP) and cathelicidin, according to a study published online March 2 in the British Journal of Dermatology.

    What do they compare? a topical of D3 and what? an injection, a tablet or what, dont understand. This makes me suspicious. I would also like to know the prise of the two studied, the D3 and the analogue …

    To determine whether vitamin D3 analogs also have immune modulating effects in human psoriasis, Emi Deguchi, M.D., and colleagues from Fukuoka University in Japan, examined cytokine levels in skin biopsies from psoriatic lesions from 10 patients not treated with vitamin D3 analogs and 10 patients treated with topical vitamin D3 analogs.

    The researchers found that, compared with samples from patients not treated with vitamin D3 analogs, samples from patients treated with vitamin D3 analogs had significantly higher levels of TSLP, thymus and activation-related chemokine, and C-C chemokine receptor type 4. Cathelicidin expression was also higher in these patients. Patients treated with vitamin D3 analogs had significantly lower levels of interleukin (IL)-12/IL-23 p40, IL-1α, IL-1β, and TNF-α.

    “Topical vitamin D3 analogs induced TSLP and cathelicidin in psoriatic lesion, resulting in suppression of IL-12/IL-23 p40, IL-1α, IL-1β, and TNF-α, thereby ameliorating psoriatic plaque,” Deguchi and colleagues conclude.

    • Brant Cebulla

      eelisabethpuur@gmail.com,

      It looks like they compared topical vitamin D3 analogue treatment to no treatment for human psoriasis. After measuring various markers for the disease, they saw improvement with topical vitamin D analogue. This makes sense because they were able to apply the activated vitamin D locally.

      Do you have any specific questions about this study?

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