Smoking does not decrease response to monthly Vitamin D – RCT July 2020

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What factors modify the effect of monthly bolus dose vitamin D supplementation on 25-hydroxyvitamin D concentrations?

The Journal of Steroid Biochemistry and Molecular Biology, V 201, July 2020, https://doi.org/10.1016/j.jsbmb.2020.105687
Author links open overlay panelZhenqiang Wu a, Carlos A. Camargo Jr. b, Ian R. Reid c, Angela Beros a, John D. Sluyter a, Debbie Waayer a, Carlene M.M. Lawes a, Les Toop d, Kay-Tee Khaw e, Robert Scragg a

The increasing use of vitamin D supplements has stimulated interest in identifying factors that may modify the effect of supplementation on circulating 25-hydroxyvitamin D (25(OH)D) concentrations. Such information is of potential interest to researchers, clinicians and patients when deciding on bolus dose of vitamin D supplementation. We carried out a large randomized controlled trial of 5110 adults aged 50–84 years, of European/Other (84%), Polynesian (11%) and Asian (5%) ethnicity, to whom we gave a standard dose of vitamin D3 supplements (200,000 IU initially, then 100,000 IU monthly) which was taken with high adherence. All participants provided a baseline blood sample, and follow-up blood samples were collected at 6 months and annually for 3 years in a random sample of 441 participants, and also at 2 years in 413 participants enrolled in a bone density sub-study. Serum 25(OH)D was measured by LC/MSMS. Mixed model analyses were carried out on all 854 participants providing follow-up blood samples in multivariable models that included age, sex, ethnicity, body mass index (kg/m2), tobacco smoking, alcohol intake, physical activity, sun exposure, season, medical prescription of high-dose vitamin D3 (Cal.D.Forte tablets), asthma/COPD and the study treatment (vitamin D or placebo).
The adjusted mean difference in 25(OH)D in the follow-up points between vitamin D supplementation and placebo groups was inversely related (all p for interaction <0.05) to

• baseline 25(OH)D,
• BMI, and
• hours of sun exposure, and
• higher in females, elders,
• and those with high frequency of alcohol, medical prescription of vitamin D, and asthma/COPD.

The mean difference was not significantly related to

• ethnicity (p = 0.12),
• tobacco (p = 0.34), and
• vigorous activity (p = 0.33).

In summary, these data show that vitamin D status, BMI, sun exposure hours, sex and asthma/COPD modify the 25(OH)D response to vitamin D supplementation. By contrast, ethnicity, tobacco smoking, and vigorous activity do not.

Introduction
Vitamin D is a fat-soluble secosteroid and is an inactive prohormone. The active form of vitamin D is 1α, 25-dihydroxyvitamin D3, which acts as a classic hormone when it is released into the circulation [1]. By binding to the vitamin D receptor, it can regulate many functions, including cell proliferation, inflammation, antioxidant defenses and calcium homeostasis [1]. Vitamin D status is mainly ascertained through measurement of the total blood 25-dihydroxyvitamin D (25(OH)D) levels, which is the major circulating form of vitamin D and with a half-life of 2–3 weeks [2,3]. The main source of vitamin D is the synthesis of vitamin D3 in the skin by solar UV irradiation [4]. In adults, dietary sources only contribute about 5%–10 % of the requirement of vitamin D [4].

Although the optimal level of serum 25(OH)D is a topic of ongoing research, many researchers and organizations categorize a serum 25(OH)D level of less than 50 nmol/L as vitamin D deficiency [[[5], [6], [[7]]. Based on this definition, vitamin D deficiency is widespread across different locations around the world [5,8,9]. People with vitamin D deficiency can be brought above this specified level cheaply and easily with supplementation or food fortification [7,10,11]. Given it is more cost-effective to provide supplementation or fortify food with vitamin D than test 25(OH)D levels [12], it is useful to know whether there are differences in how people respond to vitamin D supplementation. This will help to ascertain if people with certain characteristics need more vitamin D supplements than others.

However, the determinants of the 25(OH)D response to vitamin D supplementation have been reported to differ across studies [13,14]. A recent meta-analysis of 136 randomized controlled trials (RCTs) suggested that the higher dose of vitamin D supplements, higher baseline 25(OH)D levels and older age were significant predictors of higher achieved 25(OH)D levels after vitamin D supplementation [15]. A secondary analysis of a large RCT with 2187 older adults also revealed lower baseline 25(OH)D levels associated with larger increases in serum 25(OH)D levels in response to vitamin D supplementation, along with other associated factors include being female, optimal supplement adherence, winter season [16], but not age. In addition, a recent RCT with 133 menopausal women demonstrated that larger changes in serum 25(OH)D levels from vitamin D supplementation were associated with higher dose of vitamin D supplements, lower baseline 25(OH)D level, early spring season [17], but did not exam other possible predictors. As summarized by Mazahery and von Hurst [13], 3 out of 20 studies failed to show any significant association between baseline 25(OH)D levels and increases in serum 25(OH)D levels in response to vitamin D supplementation; 6 out of 15 studies failed to show any relationships between BMI and response to vitamin D supplements. These inconsistent results could be attributed to variations in participants, sample size, dose of vitamin D supplement, different types of vitamin D, adherence of vitamin D supplements, and methodological considerations (e.g. regression to the mean, uncontrolled confounders). In addition, other factors may modify the 25(OH)D response.

Given the mixed evidence and the possibility of other influencing factors, we investigated which modify the effect of a monthly large dose of vitamin D supplementation on serum 25(OH)D levels using a subsample of the large Vitamin D Assessment (ViDA) study in New Zealand. The large sample provided by the ViDA study enables variables, including lifestyle, to be investigated which have previously received little attention. It also provides an opportunity to resolve debate about some variables which may or may not affect changes in people’s circulating 25(OH)D concentrations from bolus dose vitamin D supplementation which is used clinically in some countries such as New Zealand.

Section snippets
Study design
We performed a longitudinal analysis of two subsamples of the ViDA study. The ViDA study recruited 5110 participants into a randomized, double-blinded, placebo-controlled trial to evaluate the effect of monthly large dose of vitamin D3 supplementation on a range of health outcomes, including cardiovascular disease, acute respiratory infection, falls and fractures. The study methods have been described in detail elsewhere [18]. In brief, adults aged 50–84 years were recruited mainly (97%) from. . . .

Study participants
From all 5110 participants of the ViDA study, a randomly selected annual sample of 441 participants (out of 518 invited) and a randomly selected bone density sample of 413 participants (out of 616 invited) were included in the current analysis. In total, 854 eligible participants with baseline plus one or more follow-up blood samples were randomized into vitamin D supplementation (n = 432) or placebo (n = 422) groups (Fig. 1). During the follow-up periods, not all the selected participants

Discussion
Given ongoing interest in identifying factors that may modify the effect of bolus dose vitamin D supplementation on circulating 25(OH)D levels, we investigated the longitudinal relationship between baseline factors and the difference in 25(OH)D levels between vitamin D supplementation and placebo groups in two subsamples of ViDA study participants with follow-up blood measures. In this community-based study of 854 eligible participants, the mean difference in 25(OH)D levels between vitamin D

Conclusion
In summary, in a subsample of the ViDA study with 854 older adults in New Zealand, we examined 13 baseline factors that could potentially modify the difference of 25(OH)D levels in response to bolus dose vitamin D supplementation. We confirmed that several demographic and physiological variables – such as age, sex, baseline 25(OH)D status, BMI, sun exposure hours and asthma/COPD – modify the effect of 25(OH)D levels in response to bolus dose vitamin D supplementation. By contrast, ethnicity, . . .

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16 studies cited this in Google Scholar as of April 2023

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Smoking decreases daily Vitamin D, but not non-daily?

Smoking reduces vitamin D - many studies
44 percent of successful RCTs in VitaminDWiki used non-daily dosing - Nov 2020

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VitaminDwiki – Better than Daily contains

33 items in BETTER THAN DAILY category

Non-daily (Bolus) is better:

1. Better compliance for everyone
   • Fewer opportunities to forget.
   • If happen to forget, just take the dose many days later
   • Fewer times to have to take a pill - for those who dislike doing so
2. Non-daily gets more vitamin D to the cells for the ~20% who have a poor Vitamin D Receptor
   • A high concentration gradient is one of 14+ ways to get past Vitamin D Receptor limitations
   • So, while 80% get no extra benefit from non-daily dosing, 20% will get an extra benefit

• Weekly Vitamin D better than daily – lower cost, less pill burden, perhaps 1.5X better response – meta-analysis Oct 2024
• Vitamin D given daily, weekly, or monthly has similar response (116 RCTs) – meta-analysis Aug 2023
• 44 percent of successful RCTs in VitaminDWiki used non-daily dosing - Nov 2020
• Monthly vitamin D dosing better for children than daily (again) - Oct 2023

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