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Vitamin D – to supplement or not to supplement - comment on Lancet article - Oct 2018

A study was published in the Lancet Diabetes & Endocrinology journal on Friday 5th October (Ref 1). It was entitled “Effects of vitamin D supplementation on musculoskeletal health: a systematic review, meta-analysis, and trial sequential analysis” and it was widely reported. Media headlines from the US to the UK reported “Vitamin D Supplements Don't Help Bone Health” (Refs 2 and 3).

See VitaminDWiki Vitamin D not help fractures and falls if not vitamin D deficient – meta-analysis Oct 2018

A UK researcher, Dr Zoë Harcombe, blogs every Monday about an academic paper from the previous week. This week she reviewed the Lancet vitamin D paper. Many of her posts are on open view, but this one is for her subscribers only (http://www.zoeharcombe.com/2018/10/vitamin-d-supplements/). She has kindly allowed me to share much of her article below:
The study
The study was led by Dr Mark Bolland with two co-authors. Dr Bolland has written previous papers finding no support for nutrient supplementation. He was the senior author on a paper in 2015, which concluded that increasing calcium intake (from dietary sources or by taking calcium supplements) “produces small increases in bone mass density, which are unlikely to lead to a clinically significant reduction in risk of fracture” (Ref 4). Dr Bolland was a co-author on a 2014 paper, which examined the effect of vitamin D supplements on bone mineral density (Ref 5). That paper concluded “Continuing widespread use of vitamin D for osteoporosis prevention in community-dwelling adults without specific risk factors for vitamin D deficiency seems to be inappropriate.”
This paper in the Lancet was a meta-analysis. A meta-analysis is a technique for taking all trials that meet certain criteria and pooling them together to see what the totality of the data show. It is generally considered to be the highest level of evidence that can be examined. The researchers identified 81 studies that met their criteria: 42 of these reported fractures, 37 reported falls and 41 reported bone mineral density. The 81 studies combined involved 53,537 participants.
The trials only involved adults over the age of 18. Two thirds of the trials involved people over the age of 65. The outcomes of interest were total or hip fractures, falls, or bone mineral density measured in key body areas (lumbar spine, total hip, femoral neck, total body or forearm). The primary endpoints were participants with at least one fracture, at least one hip fracture or at least one fall. The secondary endpoint was bone mineral density.
The study found that vitamin D had no effect on total fracture, hip fracture or falls. (i.e none of the relative risks achieved statistical significance). The trials were sub-grouped into: those that examined a vitamin D supplement group vs. a control group; those that compared a high vs. low dose vitamin D tablet; and those that were undertaken in a specific population (e.g. people with heart failure, diabetes, obesity etc). None of the sub groups achieved statistical significance either.

From surprise to not being surprised…
My first reaction to this paper was surprise. Leaving aside research on vitamin D and other conditions (heart disease, cancer, diabetes, depression etc), we know that vitamin D is an essential nutrient for bone health. We know that vitamin D deficiency can cause rickets. We know that the American Academy of Pediatrics was sufficiently concerned about rickets in American children that recommended vitamin D intakes were doubled in a 2008 publication (Ref 6). We know that not all areas of the globe allow sufficient access to sunshine all year round. We know that not everyone sunbathes even if the sun shines. We know that many millions of people take statins, which impair the process by which the body can make vitamin D following sun exposure. We know that approximately 200g of oily fish, or 39 eggs, are needed daily to deliver 15mcg of vitamin D and that not many people consume the former, let alone the latter. Surely, therefore, taking vitamin D supplements would help bone health?
My subsequent thoughts were that I should not be surprised. Would I expect fewer fractures and falls among those taking a vitamin D supplement in a trial? The answer was not necessarily – for a number of reasons. Has the meta-analysis examined the right trials to be able to dismiss the value of vitamin D supplementation? I’m not convinced that it has. This is not a fault of the meta-analysis. Do the ‘right trials’ to establish a definitive position on vitamin D supplementation even exist? I’m not convinced that they do…
I can think of five reasons immediately (more than one, or all, can apply), as to why the trials examined would not find positively for their particular vitamin D intervention:

  • 1) The people in the trials may have had adequate vitamin D levels at baseline – in which case a supplement would make little difference.
  • 2) The people in the trials may have been taking a supplement for too short a time – in which case a supplement would make little difference.
  • 3) The people in the trials may have been taking too low a dose for the supplement – in which case a supplement would make little difference.
  • 4) The people in the trials may not have been taking other nutrients that vitamin D works with – in which case a single supplement would make little difference.
  • 5) There may be other risk factors for fractures and falls that outweigh any benefit that can be achieved with a vitamin D supplement.

Let’s look at each of these in turn:
1) Vitamin D levels at baseline
The measure commonly used to report vitamin D levels is Serum 25-Hydroxyvitamin D (25(OH)D). The US vitamin D factsheet reports that 25(OH)D levels of ≥50 nmol/L are generally considered adequate for bone and overall health in healthy individuals (those not suffering from osteomalacia). Levels between 30-50 nmol/L are generally considered INadequate. Levels below 30 are considered deficient (Ref 7).
This is by no means universally agreed upon. A ‘call to action’ was published in October 2015 by a number of vitamin D scientists arguing that blood levels of vitamin D should be 100-150 nmol/L (Ref 8). An article by Professor Tim Spector, barely a month earlier than the Lancet report, presented evidence that 30 nmol/L is “quite enough” (Ref 9).
Whatever levels are adequate or not, there can be no debate over the fact that the trials were not undertaken on people deficient in vitamin D to start with. Only 4 of the 81 trials were conducted on people with baseline levels below 25 nmol/L. Of the trials that reported baseline vitamin D levels, almost half involved participants with baseline levels above 50 nmol/L. The meta-analysis thus tells us nothing about the value of vitamin D supplementation in people with deficiency.
Interestingly, Dr Bolland submitted a paper with two colleagues in December 2017, which was finally published the day before the Lancet vitamin D study. This paper was an examination of “research waste.” This was defined as occurring when trials are conducted in the wrong populations. The example used was “Vitamin D deficient populations are most likely to benefit from vitamin D supplementation. We investigated waste attributable to randomised controlled trials (RCTs) of supplementation in populations that were not vitamin D deficient.” The paper concluded that “Up to 70% of RCTs of vitamin D with clinical endpoints, 71% of large completed RCTs, and 100% of ongoing large RCTs could be considered research waste because they studied cohorts that were not vitamin D deficient” (Ref 10).
Dr Bolland is aware of the limitations of studying vitamin D supplementation in the absence of deficiency and yet did not raise this as a limitation of the Lancet meta-analysis. On the contrary, the final sentence of the Lancet paper argued against the value of conducting trials of vitamin D supplementation in individuals with vitamin D deficiency “given the absence of effects of vitamin D seen in existing trials.”
2) The duration of the trial
55 out of 81 trials (68%) were less than, or equal to, a year long. Some were just a few weeks long. From the fracture meta-analysis, 60% of the intervention groups (43 out of 72) reported 10 or fewer incidents. Five had no fractures to report whatsoever. It is not possible to report that vitamin D made a difference when there was little to make a difference to!
There was no evidence presented that the trials, or the meta-analysis, took into account the time that it might take for vitamin D to make a difference. If someone had a fracture on day 1 of the trial, no intervention could have made a difference in that time. I have seen advice that a four month ‘run-in’ period would be needed before it could be expected that a supplement may have made a difference (the same applies to dietary trials, of course and yet I have never seen a run-in period for these either).
3) The dose taken
Although not statistically significant, the biggest difference in relative risk was observed in the pooling together of the four trials that compared a high vs. low dose of vitamin D. The incident rate in the high dose vitamin D group was 5% (20/401); it was 8.1% (32/394) in the low dose group. The number of incidents overall (52/795) was too low to achieve statistical significance. It may be the case that the general dose of vitamin D was too low to make a difference in the trials examined.
The dose may also have been too infrequent. Table 1 in the Lancet paper reported that only half of the trials involved a daily supplement for the intervention. The other half supplemented “intermittently”, whatever that was.
4) Other nutrients alongside
The nutrients vitamin D, calcium and phosphorus are the prime ones that work together for bone health (Ref 11). 25% of the trials included calcium supplementation; that means that 75% didn’t. There was no mention of phosphorus at all in the paper (and thus the titles of any of the trial papers). (Vitamin K2 is also a partner nutrient of relevance to vitamin D).
5) Other risk factors
The two main risk factors for fractures are sex and age (Ref 12). Males have more fractures than females when young (boys will be boys!) Females have a steady increase in fractures from the age of 50 onwards, experiencing up to triple the rate of men in the older age groups.
There are many reasons for women suffering more fractures than men: women tend to have smaller and thinner bones as a result of their smaller and thinner frames; women suffer bone nutrient depletion when they create (and give nutrients to) a baby; women suffer further bone deterioration when oestrogen levels drop at menopause.
The American bone health organisation reports major risk factors for fractures as: smoking (because of its impact on hormone levels); excessive alcohol (affects vitamin D metabolism and falls); steroids (can impair calcium absorption); chronic bowel diseases (such as Celiac, which can impair nutrient absorption) and diabetes (possibly via Celiac for type 1s) (Ref 13). Vitamin D deficiency, interestingly, was not reported as a risk factor – rather conditions that could impact vitamin D absorption were included. Could vitamin D be important for bone health but other factors more so, thus confounding results?

My takeaway thoughts
Having given the paper much consideration, I moved from being surprised to not being surprised. The meta-analysis per se is robust. There can be no doubt that the totality of the evidence examined found that vitamin D supplementation had no effect on total fracture, hip fracture or falls. However, a meta-analysis is only as robust as the trials that it pools. The trials available have major flaws. The vast majority of them did not study participants for whom vitamin D might make a difference. (This can, conversely, be used as an argument that people who have adequate levels of vitamin D won’t reduce their risk of fractures if they take a supplement.) Few trials may have been long enough. The dose may not have been high enough or frequent enough and there are many other risk factors that could confound the vitamin D intake.

To supplement or not to supplement, therefore?
The governments that advise us that we need 10-15mcg of vitamin D daily also tell us to cover up and/or apply sunscreen the minute the sun shines. Those same governments tell us to take statins, which further impairs any chance that we have of making vitamin D from sunshine. Those same governments tell us that we only need oily fish 2-3 times a week and that we should avoid eggs and dairy products for their saturated fat content.
If you ignore government advice on sun exposure, statins and diet, you are probably safe to ignore government advice on vitamin D supplementation. If you heed government advice on sun exposure, statins and diet, you would be well advised to heed government advice on vitamin D supplementation, because you sure as anything aren’t going to get vitamin D from anywhere natural!
Dr Zoë Harcombe, PhD

http://www.zoeharcombe.com

References
Ref 1: https://www.thelancet.com/journals/landia/article/PIIS2213-8587(18)30265-1/fulltext
Ref 2: https://www.huffingtonpost.co.uk/entry/vitamin-d-supplements-dont-help-bone-health-study_uk_5bb72974e4b028e1fe3c968b
Ref 3: https://www.theguardian.com/society/2018/oct/04/vitamin-d-supplements-dont-help-bone-health-major-study-concludes
Ref 4: https://www.bmj.com/content/bmj/351/bmj.h4183.full.pdf
Ref 5: https://www.ncbi.nlm.nih.gov/pubmed/24119980
Ref 6: http://pediatrics.aappublications.org/content/122/5/1142.short
Ref 7: https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/
Ref 8: https://grassrootshealth.net/document/scientists-call-to-daction/
Ref 9: https://theconversation.com/amp/vitamin-d-a-pseudo-vitamin-for-a-pseudo-disease-101907
Ref 10: https://bmcmedresmethodol.biomedcentral.com/articles/10.1186/s12874-018-0555-1
Ref 11: https://www.ncbi.nlm.nih.gov/pubmed/7015957
Ref 12: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4890652/
Ref 13: https://americanbonehealth.org/what-you-should-know/fracture-risk-factors/

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