Two days ago I called an elderly lady Mrs KS into my room. She had purple shoes. “Hi doc, I wanted to ask about my Vitamin D levels.” “Ok Mrs KS, what do you want to know?” She went on to describe her skin problems, headaches, muscle aches, dry eyes, abdominal pains, and a “strange pain that runs around my side and then up to my head”. Apparently she had been looking up vitamin D in a new book she bought online on a friends advice and was adamant that every one of these symptoms could be explained by her being vitamin D deficient.
So Vitamin D deficiency has been reported as a massive epidemic problem. It has the been reputed to be the cause of many things including cancers, fractures, headaches, weakness, fatigue, and possibly global warming (ok, I added that one…).
But how much of this is true? Who should I ACTUALLY be testing? And then even if I do test, will replacing it make any difference? How should I even replace it if I wanted to? Let’s look at the online evidence and available FOAM!
I have done my very best to keep this succinct but it is a big topic. I have put key points in big text.
Above is a link to the summary at the end by clicking and then scroll back through at your leisure if you wish. Enjoy!
Question – What is the physiology behind vitamin D and what does it do?
Orthobullets has a nice flow diagram on the physiology of Vitamin D and its relationship to the kidney, gut, and bone. It also shows the interplay with Ca/Ph/PTH. Good refresher! – Link
What about the non-classical effects of Vitamin D that are popping up everywhere eg. Immune system function? Here is a great series of pictures of different ways Vit D is used in the body. Worth a quick look, very interesting! – Link
The first scientific description of Vit D deficiency was in the 17th Century and was postulated to be the cause of Rickets. It wasn’t until 1920 that Sir Edward Mellanby devised a diet to show Vit D deficiency caused Rickets. Since the 1980’s the interest in Vitamin D has grown exponentially possibly due to our ability to sell it as a supplement and also ease of testing. – Link
Vitamin D has been reported to be involved in: Anaphylaxis, anaemia, anxiety, arthritis, atherosclerosis, autism, autoimmune diseases, bipolar disorder, brain damage, breast-tissue density, chronic fatigue, chronic pain, cognitive ability, colds, craniotabes, CRP levels, Crohn’s disease, Cystic Fibrosis etc etc etc…
In Australia, testing for Vitamin D has gone from 73,330 in 2002/03 to almost 3.5 million tests in 2011/12. Costs for these tests went from $2.6 million to $126.5 million (Australian Doctor Link).
Harvard School of Public Health explains where some of the excitement and controversies have began and its application to population health – Link
Question – So what DOES the evidence suggest for the array of medical conditions it is associated with?
There is a great starting summary article by MayoClinic Proceedings on the strength of evidence for different conditions for which Vitamin D deficiency may play a role. Very strong and good article – Link
Question – Is there an ‘all cause’ mortality risk for patient who are vitamin D deficient?
A large meta-analysis in 2007 from Archives of Internal Medicine including 18 trials with 57,311 patients showed a decreased relative risk for all cause mortality of 0.93 when patients given an average of 530 IU for 5.7 years. They suggest more studies are required however. – Link
All cause mortality confuses me however because it does not really give us much indication of how or why, just that it does?
$1,000,000 Question – Does Vitamin D replacement prevent fractures?
A 2009 Cochrane review involving 45 trials with 84, 585 participants on primary prevention of fractures in older people with Vitamin D, showed that taking Vitamin D alone was unlikely to prevent fracture. It did suggest that vitamin D with calcium may help prevent fractures in institutional care patients – Link
Conversely, NEJM published a meta-analysis on 11 trials with 31,022 persons in 2012 which suggested high dose vitamin D was somewhat favorable in the prevention of hip fracture and non vertebral fracture in persons 65yrs and older. BUT! This analysis has been panned by experts for incorrect interpretation of data, the use of calcium by some trials but not others, different levels of vitamin D etc etc. And finally, it was sponsored by DSM Nutritional Products! – Link
There are many other conflicting meta analyses like these ones so I will not bore you with them all. What does expert consensus say?
USPSTF (US Preventative Services Task Force) 2013 – states the evidence is insufficient to assess the balance of benefits and harms for Vitamin D and calcium supplementation for primary prevention of fractures – Link
A 2013 position statement based upon Australian and NZ Bone and Mineral Society, Endocrine Society of Australia, and Osteoporosis Australia, discusses the benefits of Vitamin D replacement on preventing falls but emphasise that most trials have included adequate calcium replacement also. They state that “Vitamin D deficiency is an independent predictor of falls; improving vitamin D status reduces the risk of falls and fracture in the elderly.” – Link
Slight catch. Calcium supplementation has recently been getting some significant press about its possible role in increased Cardiovascular events. New RACGP red book has advised us to exercise caution with their use in postmenopausal women. If this is the case then that makes supplementation with calcium questionable, which then also makes studies with Vitamin D and Calcium replacement somewhat impotent? Brilliant summary of evidence from NPS 2013 – Link
So there seems to be some evidence for fracture prevention with calcium and Vitamin D – but a few problems with this. Everyone seems happy to agree however that Vitamin D deficiency can lead to falls. Does it?
Question – Does Vitamin D deficiency play a role in falls?
Vitamin D is thought to help prevent falls through its role in muscle activation. Low levels of vitamin D have been implicated in lower limb weakness which can lead to falls. The biochemistry around this is discussed in this interesting article in the Journal of Neuroengineering and Rehabilitation – 2010 – Link
An MJA 2012 position statement on Vitamin D and health in adults in Australian and New Zealand eloquently states: – Link
“Vitamin D deficiency is an independent predictor of falls in older people, and circulating 25-OHD levels < 60–75 nmol/L have been associated with lower-extremity muscle weakness and impaired balance, and accelerated losses in muscle mass, strength and physical function.”
A meta-analysis published in the BMJ 2009 supports this: – Link
“Supplemental vitamin D in a dose of 700-1000 IU a day reduced the risk of falling among older individuals (>65yo) 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.”
So the evidence for preventing falls through Vitamin D’s effects on muscle strength is there, and by extrapolation it seems, we are saying it reduces fractures. What about preventing Cancer?
Question – Which Cancers does Vitamin D deficiency play a role in?
“4yr RCT in postmenopausal women from rural Nebraska showed a 60% or greater reduction in all cancer risks” – Link
According to an amazing article in Zeitgeistaustralia.org (red flag?) they claim you can have even better than 77% benefit “.. you can easily have a greater reduction than 77% by taking premium Vit D supplements or high-quality calcium supplements” – Link
Ok. So for the sceptics among us (and me) lets see where the evidence is at for individual cancers.
Breast Cancer – Summary – There seems to be a tendency here towards a possible link between low levels of Vit D in serum and also dietary levels, to breast cancer. The jury is currently out at a tea break though – they will be back later.
A large meta-analysis by Breast Cancer Research and Treatment 2010 stated “… overall relative risk reduction of 0.91 for high vs low levels of Vit D and their association with breast cancer.” Higher serum calcium also decreased risk by 19%. They suggest vitamin D and calcium have a chemoprotective effect against breast cancer – Link
This is supported by a meta-analysis done in 2007 in JAMA which also showed “higher intakes of total calcium and vitamin D were moderately associated with a lower risk of premenopausal breast cancer.” This was not supported in postmenopausal women however – Link
Like all medical research, other articles state different outcomes.
“The one full-scale randomized, placebo-controlled trial (Iowa Women’s Health Study) evaluating calcium (1000 mg elemental calcium per day) and vitamin D supplementation (400 IU D3 per day) with 36,282 participants failed to demonstrate a supplement effect on lowering breast cancer incidence.” – Anticancer Agents Med Chem 2013 – Link, Link 2
Bowel Cancer – Evidence is unclear but there is a suggested link between low levels of Vit D and patients developing colon cancer.
“Daily supplementation of calcium with vitamin D for seven years had no effect on the incidence of colorectal cancer among postmenopausal women (Women’s Health Initiative – 36,282). The long latency associated with the development of colorectal cancer, along with the seven-year duration of the trial, may have contributed to this null finding.” – Only 400U daily was given to trial subjects however – NEJM 2006 – Link
“The evidence to date (5 studies on PubMed in 2007) suggests that daily intake of 1000–2000 IU/day of vitamin D3 could reduce the incidence of colorectal with minimal risk.” – American Journal of Preventative Medicine 2007 – Link
In a meta-analysis of 26,335 cases from 60 observational studies in Nutr Cancer 2009 showed – “…Vitamin D was associated with a nonsignificant 6% reduction in CRC risk. Higher consumption of milk/dairy products reduces the risk of colon cancer, and high calcium intake reduces the risk of CRC. Low vitamin D intake in the study populations may limit the ability to detect a protective effect if one exists.” – Link
Large study in 1996 of 89,448 female registered nurses (?interesting group – they work inside). “…These findings do not support a substantial inverse association between calcium intake and risk of colorectal cancer, but an inverse association between intake of total vitamin D level and risk of colorectal cancer was suggested.” – Journal of the National Cancer Institute – Link
Prostate Cancer – Studies in primary prevention of prostate cancer to date have been inconclusive and further tests are underway. Utilising high dose Vit D to assist treatment of Prostate Cancer is showing good promise.
There is better evidence however for treatment of prostate cancer with high doses of Vitamin D. Studies are ongoing.
Journal of Clinical Endocrinology and Metabolism 2009 – “Vitamin D3 might benefit prostate cancer (PCa) patients because prostate cells can locally synthesize the active hormone calcitriol. 66 patients Gleason 6 or 7 were given Oral vitamin D3 which raised prostate calcitriol levels (level 1 evidence) and modestly lowered both PSA and PTH.” – Link
Other cancers – Studies have not suggested a link between Vitamin D and rarer types of cancers. In fact high levels of Vitamin D is a risk factor for DEVELOPING pancreatic cancer.
“A 2010 analysis of data from 10 studies did not find any association of vitamin D levels and 6 less common types of cancer — endometrial, esophageal, gastric, kidney, non-Hodgkin lymphoma, and ovarian. And, people with the highest vitamin D levels seemed to have a higher, rather than lower, chance of developing pancreatic cancer. In one study, smokers with higher blood levels of vitamin D were 3 times more likely to develop pancreatic cancer than those with low levels.” – American Journal of Epidemiology 2010 – Link
Question – What about some other medical diseases?
Multiple Sclerosis (MS) – If your patient has MS and is vitamin D deficient there is increasingly good evidence of replacing this to prevent further plaques. As for primary prevention, we don’t know yet.
This link was initially suggested after it was recognised that MS occurred more commonly in countries further away from the equator.
Vit D has some evidence that it may help prevent MS but more study is required. It is discussed in this Lancet article – Link
Low levels of Vitamin D have also been associated with a worsening of MS with more demyelinating lesions on imaging – Link
Cardiovascular disease – The general consensus from the literature is that Vitamin D deficiency does seem to play a role in cardiovascular disease however the full effects of this and the benefits of replacing or correcting it are not yet established. New RCTs are currently underway but we will have to watch this space.
Vitamin D’s link to cardiovascular disease has been suggested but not yet verified through RCTs or good pathophysiological pathways. Previous studies have had problems with low Vitamin D often being also associated with hypertension, hypercholesterolaemia, obesity, glucose intolerance, and the metabolic syndrome – Circulation 2007 – Link
This is, however, still being debated. Nutrients 2013 discusses the possibility that low Vitamin D levels may be an independent risk factor for CVD – Link
“In epidemiological studies, low levels of 25(OH)D are associated with increased risk of CVD and mortality. Data from randomized controlled trials (RCTs) are sparse and have partially, but not consistently, shown some beneficial effects of vitamin D supplementation on cardiovascular risk factors (e.g. arterial hypertension).” – Clinical Endocrinology 2011 – Link
Systematic review in 2009 suggested more study is required with suggestion of benefit as adjunctive therapy for treating TB, influenza, and viral URTIs. I wouldn’t advertise this because the studies really are not great.
Endocrine Practice – 2009 – Link
Question – What about some of the claimed symptoms of Vitamin D deficiency?
Fatigue, headaches, and MSK pain – Possibly. There seems to be a high prevalence of Vit D deficiency in patients with these symptoms (single Scandanavian study).
572 patients who reported any of the above three symptoms by a GP were referred for Vit D deficiency. 58% of patients were found to be Vitamin D deficient – Link
Depression – Yes! ..ish Increasing evidence of this link
Molecular Psychiatry 2013 – “This large cohort study (n=2400) indicates that low levels of 25(OH)D were associated to the presence and severity of depressive disorder suggesting that hypovitaminosis D may represent an underlying biological vulnerability for depression.” – Link
My first thought however is could this be linked to Seasonal Affective Disorder and is Vitamin D deficiency another sign that these people do not see much sunlight?
Question – So, my patient with the purple shoes still wants to be tested. Which patients should I test?
Everyone? – Essentially no. At this time given the uncertainties around the best way to evaluate, what levels to treat at and to, and controversies around the benefits of vitamin D replacement in the general population, most health agencies are not advocating a screening program. An interesting public health discussion from America is in the American Family Physician 2013 – Link
High Risk – NPS highlights the “at risk” groups who may benefit from testing:
– People who are housebound, particularly those over 65 years or resident in aged care facilities – prevalence of up to 77% reported in Australian facilities
– People with naturally dark skin – prevalence of 44% among children from an east African background attending a Melbourne health clinic. Dark skinned persons require up to 4 times more sun exposure for same production of Vitamin D
– People who cover themselves for religious or cultural reasons – prevalence of 68% in Sydney study
– Pregnant Women? – They also mention Vitamin D deficiency in pregnancy. Studies have not made clear what the aims, targets, or best methods of replacement is for this group. American College of Obstetricians and Gynaecologists conclude evidence is insufficient to recommend screening. We do know that fetal vitamin D will relate to the mothers levels. RANZCOG keeps it nice and vague. They suggest testing those who are at high risk (as above) – Link
– Paediatric populations? – Good clinical practice guidelines from SA on testing for vitamin D deficiency in high risk paediatric populations and also how to treat. The risk groups are similar to those discussed in adults – Link
– Others – Patients on medications that can affect Vit D metabolism, malabsorption syndromes, have limited access to the sun, avoid the sun with high risk of skin cancer, and patients who ARE OBESE!? Umm… so we are going back to testing everyone again? I looked at the evidence for this recommendation and it is on studies <50 people. I am not impressed.
Question – So I send my patient for a Vitamin D test. How will I interpret the result?
NPS Medicinewise has a great summary article that discusses some of the limitations with Vitamin D deficiency definition and reference ranges, and problems with testing – 2011 – Link
“Generally, serum 25-OHD levels > 50 nmol/L are agreed to indicate vitamin D adequacy. However, there is ongoing debate about the optimal level of serum 25-OHD. People with 25-OHD levels < 25 nmol/L are at increased risk of rickets or osteomalacia and are truly deficient. They should receive supplements.”
But every lab reference range is different. Here are some examples from local pathology companies near me:
– Healthscope – (60-160 nmol/L) – Link
– Melbourne Pathology – (<50 Deficient, 50-75 Indeterminate, >75 Sufficient) – Link
– Labtestsonline (RCPS) – Gives a general figure of <50 is deficient – Link
The NHMRC demonstrates how complicated this issue is with a long wordy article here if you’re interested – Link. The bit I wanted was – “…recent position statement a Working Group of the Australian and New Zealand Bone and Mineral Society, the Endocrine Society of Australia and Osteoporosis Australia (2005) defined mild deficiency for adults as serum 25-OHD levels between 25 and 50nmol/L; moderate deficiency as between 12.5 and 25nmol/L and severe, below 12.5nmol/L”
So the actual reference range we are aiming for is uncertain. It seems most societies are comfortable that <50nmol/L is deficient to the point where we could try to increase it with supplementation/sun exposure. But luckily we can rely on the number from the lab. Can’t we? Oh o…
Now I am certainly no pathologist and get quite confused by discussions on different “chemistry kits” for lab tests. If you would like more detail about the different methods here is a good discussion paper – “Vitamin D Testing – What’s the Right Answer” from AACC – Link
Also, the basic problems are discussed in a Lancet Article 2012 on Vitamin D testing. “Snellman and colleagues measured serum samples from 204 patients in three different laboratories by use of different methods. The proportion of patients identified as vitamin D insufficient (<50 nmol/L) varied from 8% to 43%.” – Link
Finally, Australian Doctor ran an article on doctor frustration on inconsistent Vitamin D testing in 2011 – Link
Royal College of Pathologists Australia has a position statement on current (2013) testing for Vitamin D – Link
So in summary, most groups agree <50nmol/L is deficiency of Vitamin D. The different types of tests will yield different results. Using different pathology companies can also yield inconsistent results. So who should I treat?
Question – What guidelines are there for treatment of Vitamin D deficiency?
Therapeutic Guidelines 2013 recommend treating institutionalised or housebound people, and also women who cover for religious reasons, with supplementation. They recommend giving 1000 to 2000IU orally daily of cholecalciferol. They suggest aiming for a level >75nmol/L.
Patients with confirmed osteomalacia or rickets should receive 5000IU orally for 4 weeks and then 1000-2000 IU as long as required. Therapeutic guidelines don’t mention any other patient groups that I can find?
Australian Prescriber 2010 – Link – discusses treatment further. They suggest daily requirements are 800 – 1000IU but larger doses are needed if already deficient. If 15-25 nmol/L then 3000-5000IU daily for 6-12 weeks to replete stores followed by 1000-2000IU per day. Reassess at 3-4 mths – earlier than this and it will not be at steady state. If <15 nmol/L then MEGAdose therapy can be used (100,000 IU) (NB: annual boluses >500,000 IU have worsened falls/fracture risk).
Question – Are there any adverse effects of treatment?
Australian Prescriber 2010 explains – “Vitamin D toxicity can be caused by excess oral intake, but not by prolonged exposure to sunshine. No evidence of toxicity has been found in cholecalciferol doses up to 4000 IU daily. Even doses of 100 000 IU at more than three-monthly intervals have not been associated with toxicity. Vitamin D intoxication causes hypercalcaemia and can present with symptoms of anorexia, nausea, constipation and depression. Examination and investigations may demonstrate renal calculi, renal impairment and anaemia.” – Link
Merck Manual explains that the majority of symptoms from Vitamin D toxicity come from hypercalcaemia (bones, stones, groans etc). This generally will only occur with taking 50,000 IU daily for several months – Link
Question – How do we get appropriate amounts from the sun?
Great guidelines for this are from the Osteoporosis Australia website. They also have a great chart for sun exposure times depending on what part of the country you are in! – Link
Great patient information sheet from the RCH – Link
Question – Can we get enough Vitamin D from dietary sources?
Very few foods contain Vitamin D. Salmon, mackerel, and mushrooms exposed to UV light have the highest levels. WebMD talks about the dietary amounts of Vitamin D – Link
The only food fortified with Vitamin D in Australia is margarine!! If you suggest patients eat enough of this, you might want to have a look at my article on cholesterol and statin’s in preparation… 😉 – Link
NHMRC article on Vitamin D in Australia explains that accurate levels of dietary intake of Vitamin D in Australia are not available. It has been suggested that only ~10% of Vitamin D will come from the diet – Link
After looking through all this research, what will be my practice in regards to vitamin D testing, interpretation, and treatment?The difficulty with a substance like Vitamin D is it is cheap, accessible, has few side effects unless taken in mega doses (100,000+ IU daily), and the media has increased hype around its potential benefits. In regards to its potential benefits in the general population, there is suggestion, but no solid evidence, of different benefits on cancer prevention, cardiovascular protection, depression, and also other general aches and pains.But is suggested benefit enough for me to test everyone? Personally I think not at this stage and I will watch for more research.Who will I be suggesting a Vitamin D test to? I will suggest testing to patients at high risk of vitamin D deficiency as discussed above. I will particularly focus on patients over 65yo at risk of falls as there is good evidence that replacing this will benefit the patient. Also, given the potential benefits of Vitamin D and calcium on osteoporosis I will try and increase dietary calcium in these patients and supplement Vitamin D where levels are low up to 75 nmol/L.The difficulties arise in the patients who present asking me to test their Vitamin D levels. From a population health perspective I should offer them the test but make them pay privately. Patients may not like this and may just go find another doctor who will test them.If I do test them, I will use <50 nmol/L as my reference range. If they are just below this, I can talk about increasing their sun exposure to adequate levels (as per the charts above) while considering their skin cancer risk. I can then retest in 3 months.If they have very low levels (eg. 25 or less), I will suggest supplementation with 1000-2000IU per day and reassess in 3 mths. Lower than 12.5 or at very high risk of falls I will consider higher dose supplementation as above.
Well thank you everyone for reading! (If you managed to wade through the quagmire to here!)
Please lets have a great debate on this! Let me know what you do. Let me know how you deal with these requests.
How do you plan to investigate or prescribe in the future? Let me know and I am very keen for some different opinions.
Til the next Map (which will be shorter!)… Cheers, Doc Rob. @Robapark
PS: Check out the SEDS trial website and consider getting your patients enrolled through Assoc. Prof Robyn Lucas at http://www.sedsstudy.org/contact-us.html