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Vitamins- vit D

Primary Care Corner with Geoffrey Modest MD: Statin myopathy and vitamin D deficiency

1 May, 17 | by gmodest

by Dr Geoffrey Modest

A recent editorial provided reasonably convincing evidence that there is a relationship between low vitamin D levels and statin associated muscle symptoms, SAMS (see Glueck CJ. Atherosclerosis. 2017; 256: 125). See article for the references.

 

Details/summary of data:

— one study showed an inverse relationship between CK levels and vitamin D levels in patients on simvastatin, independent of symptoms

— a non-blinded study with high-dose vitamin D to normalize serum levels found that up to 95% of 134 patients with SAMS were free of muscle symptoms on reinstating statins, and this continued for up to 24 months later (the last time point measured)

— another trial of 150 patients with SAMS with a median vitamin D of 21ng/ml and given vitamin D supplements found that 87% were successfully able to restart their statins and remain symptom-free for 24 months

— a meta-analysis of 2420 patients documented that vitamin D levels tend to be lower in patients with SAMS; several other studies have confirmed that in patients with SAMS and low vitamin D levels, repleting the vitamin D levels leads to about 90% being able to tolerate rechallenge with statins

 

Commentary:

— SAMS is quite frequent, varies somewhat depending on the statin use/dose, but is reported in about 10% of patients.

— Myopathy is also a reasonably common symptom of vitamin D deficiency

— there are studies which suggest that even those with intolerable muscle symptoms from 3 or more statins, only 43% had muscle symptoms on rechallenge (and 27% had muscle symptoms only on placebo, 17% had symptoms to neither drug). ie, there is likely a pretty big placebo effect. Though the 90+% success rates with vitamin D noted above are a bit eye-popping.

— so, a provocative editorial. Clearly, especially in light of the potentially large placebo effect, and in light of the importance of statins in preventing clinical cardiovascular outcomes, there should be a well-designed randomized control trial to assess the true benefit of vitamin D repletion in those with SAMS who are vitamin D deficient. It is notable in several of the uncontrolled studies, increasing vitamin D even in patients with levels in the low 20 ng/ml range was effective, which is actually above what the Endocrine Society defines as deficient, <20 ng/ml. so, it makes sense in future RCTs to look at those patients who have SAMS and with 25-OH vitamin D levels <30 ng/ml or so to see if vitamin D supplementation helps, or perhaps in all-comers to see if there is a 25-OH vitamin D threshold.  The meta-analysis mentioned above found that the difference in vitamin D levels in those with and without SAMS was 28 vs 35 ng/ml.

 

Bottom line: statins are important for many patients, SAMS is common as is vitamin D deficiency, there are likely other benefits from vitamin D sufficiency anyway, vitamin D supplementation is pretty benign and inexpensive, so to me it seems reasonable at this point to try vitamin D supplementation in patients who are intolerant of statins because of SAMS, even if there baseline levels seem pretty good.

 

see here for an array of blogs on vitamin d.

 

Primary Care Corner with Geoffrey Modest MD: Vitamin D Decreases Acute Respiratory Illness

29 Mar, 17 | by EBM

By Dr. Geoffrey Modest

A recent meta-analysis found that vitamin D supplementation, especially in those who were quite deficient, led to lower risk of acute respiratory infections (see doi.org/10.1136/bmj.i6583).

Details:

  • 25 eligible RCTs were found, with a total of 10,933 patients, aged 0-95. The researchers were able to access individual participant data from the studies. Outcome data was obtained for those participants experiencing at least one acute respiratory tract infection. The trials were from 14 countries on 4 continents. All studies supplied oral vitamin D3 to those in the intervention arm. This was given as bolus doses every month to every 3 months in 7 studies, weekly doses in 3 studies, and daily doses in 12 studies. Study duration range from 7 weeks to 1.5 years.
  • Overall demographics: 50-50 male/female, 50% < 1yo/15% 1-16yo/28% 16-65yo/10% >65yo, 5% baseline 25(OH) level of <25 nmol/L, 33% >25 nmol/L, 62% not recorded

Results:

  • There was a 12% decreased risk of acute respiratory tract infections in those receiving vitamin D supplementation, adjusted OR 0.88 (0.81-0.96), p<0.001
  • The protective effect was seen in those receiving either daily or weekly vitamin D, without additional bolus doses (bolus was defined as at least 30,000 IUs), adjusted OR 0.81 (0.72-0.91), with number needed to treat =20, though there was no benefit in those receiving 1 or more bolus doses
  • In those on either daily or weekly vitamin D, there was differential benefit depending on the baseline 25-OH vitamin D level, with p=0.006 for the interaction:
    • If <25 nmol/L (equivalent to  10 ng/ml), 70% decrease, adjusted OR 0.30 (0.17-0.53)
    • ​If >25 nmol/L, 25% decrease, adjusted OR 0.75 (0.60-0.95)
  • There was no significant difference between the groups by daily dose of vitamin D (<20mg, equivalent to <800 IU; 20-50 mg, equivalent to 800-2000IU; >50 mg, equivalent to > 2000 IU), age, BMI, the presence of asthma or COPD, or having received influenza vaccination.
  • No serious adverse events in the vitamin D group, with 0.5% having hypercalcemia and 0.2% renal stones, though both events were evenly represented in the intervention and control arms.
  • The body of evidence contributing to these results was considered to be of high quality. And a review of the individual participant data from their included studies showed that the preponderance of them showed benefit from vitamin D therapy (i.e., it was not just a couple of large studies dominating the meta-analysis)
  • In differentiating acute respiratory illnesses, the significant benefit was in 11 studies for upper respiratory infections, with a 12% benefit limited to those on daily or weekly dosing [OR 0.88 (0.78-1.00), p=0.05], not in any of the other secondary outcomes they assessed (lower respiratory tract infections, use of antimicrobials, absence from school/work, serious adverse events)

Commentary:

  • This meta-analysis basically found that in those patients who were quite vitamin D deficient, there was a pretty remarkable benefit to either daily or weekly vitamin D therapy in preventing acute respiratory infections (70% decrease), and specifically upper respiratory infections. There was also a 25% statistically significant decrease in acute respiratory infections in those with >25 nmol/L, though this was significantly less so than in the more deficient group. Although overall there was no benefit reported in those with 25(OH) vitamin D levels in the 25-50 nmol/L, 50-75 nmol/L or >75 nmol/L groups, they did not break this down by whether they were in the daily/weekly or bolus therapy groups (i.e., it is likely that as with the above analysis, there was benefit if these subgroups were limited to those on daily/weekly therapy. It would have been useful to see if there were a cutpoint of vitamin D level below which there was benefit from daily/weekly supplementation). And it does not appear that participants were randomized by their entry 25(OH) vitamin D levels in the individual studies in the meta-analysis.
  • This very low level of vitamin D deficiency (<25 nmol/L) is quite common in my practice (though I do work in Boston, a pretty high latitude, and with many patients with darker skin pigmentation and who are older, all 3 of which predispose to low vitamin D levels), and estimates are that around 6% (20 million) US adults are markedly vitamin D deficient (i.e. <10 ng/ml)
  • These conclusions are somewhat limited because of the small numbers of many racial or ethnic subgroups in the individual studies included in the meta-analysis
  • One pretty striking conclusion (and very unexpected to me) was that there would be such a difference between those given bolus supplements vs daily/weekly vitamin D. Other studies had suggested that giving the equivalent of about 800 IU/day, whether daily, monthly, or every 6 months, didn’t matter much, at least in terms of bone health. This data suggests that there may be a difference, at least for other outcomes.
  • Though I have not sent out any blogs on vitamin D for quite some time (see here for a slew of those blogs), there are some suggestive studies showing there are vitamin D receptors are all over the body (including the immune system, and also being associated with the induction of antimicrobial peptides and other antimicrobial chemicals such as reactive oxygen intermediates), observational studies of mortality benefit as well as benefit for specific autoimmune and other diseases, and even a study finding that vitamin D supplementation improves the response of patients with TB to medications (see  doi:10.1073/pnas.1200072109/-/DCSupplemental). Several newer studies have had some mixed results: some showing higher vitamin D levels are associated with decreased multiple sclerosis, better breast cancer survival, fewer relapses from ulcerative colitis, etc.; but some showing no benefit for pain in those with knee osteoarthritis, walking distance in those with heart failure; and several with contradictory results, e.g. for falls in the elderly, asthma in kids. A recent JAMA study (see Lappe J. JAMA. 2017; 317(12):1234) of 2303 healthy postmenopausal women >55yo in rural Nebraska found that vitamin D supplementation did not lead to decreased cancer (there are several other studies finding decreased breast, colon, and prostate cancer in those with higher vitamin D levels). But, despite the headline in Physician’s First Watch on 3/29/17 that “vitamin D supplements fail to prevent cancer in 4-year trial”, this trial looked at women who had a baseline 25-OH vitamin D level of 32.8 ng/ml (much higher than what is considered an adequate vitamin D level), were given 2000 IU of vitamin D and 1500 mg of calcium daily, and achieved a quite high vitamin D level of 43.9 ng/ml. So not so surprising that there was no benefit, since they were not even close to being vitamin D deficient.  Of note the 2011 Endocrine Society suggested that the cutpoint for vitamin D deficiency should be 20 ng/ml, though there are some suggestive data that it should be higher, at 30 ng/ml, though they felt that the data were not strong enough to push for this higher cutpoint (see doi: 10.1210/jc.2011-038). And even the 30 ng/dl cutpoint is lower than the mean in the Nebraska study!!

So, my general sense is that we probably should replete vitamin D levels (either more sun, if in the right latitudes and people are able, or by vitamin supplementation) in those who are deficient, since:

  • We do have vitamin D receptors all over our bodies for a likely evolutionary reason (and humans started off in climates where there was lots of sun)
  • There are lots of observational studies showing benefit for adequate vitamin D levels (though observational studies do not confer clear conclusions of benefit)
  • We should be careful about being too reductionist (i.e., there is not one magic bullet for health, but a constellation of healthful activities in concert, and this likely includes adequate vitamin D levels, either by adequate sun exposure or by taking supplements to increase vitamin D levels when the sun exposure is inadequate),
  • There seems to be very few adverse effects of vitamin D supplementation, including in the above Nebraska study where they achieved quite high vitamin D levels
  • And, unlike almost every other medical intervention, there is minimal cost, with potentially large benefit.

Primary Care Corner with Geoffrey Modest MD: calcium intake does not increase cardiovascular risk

13 Dec, 16 | by EBM

By Dr. Geoffrey Modest

A recent guideline from the National Osteoporosis Foundation and the American Society for Preventive Cardiology, with support from an independent evidence review team from Tufts University, determined that calcium supplementation, with or without vitamin D, had no relationship to cardiac health (for the recommendations see doi:10.7326/M16-1743; for the full document see doi:10.7326/M16-116).

Recommendations:

  • calcium with or without vitamin D intake from food or supplements has no relationship (beneficial or harmful) with the risk for cardiovascular and cerebrovascular disease, mortality, or all-cause mortality in generally healthy adults at this time
  • Calcium intake should not exceed the National Academy of Medicine recommendations of 2000-2500 mg/d
  • Obtaining calcium from food is preferred to taking supplements
  • This recommendation is supported by a review of the human studies and is supported mechanistically and pathologically in animal studies on high-calcium diets (no biological mechanism supports the association between calcium intake and cardiovascular disease).

Commentary:

  • It is clear that calcium and vitamin D are necessary for adequate bone health. However several recent studies have questioned whether fractures were reduced by supplementation in older adults. There even have been reports that cardiovascular disease, including MIs and strokes, may be worse by supplementation (more below).
  • This review included 4 randomized controlled trials, one nested case-control study and 26 cohort studies.
  • Of note, very few studies looked at calcium intakes of greater than 1600 mg per day. One study that did do so, found that there was no increased cardiovascular disease (CVD) or mortality in those at the highest level of calcium by the combination of foods and supplements, but a somewhat increased risk in those on supplements only. However, for strokes there was a lower risk for all types of consumption.
  • There are several general concerns raised by all of these dietary studies:
    • They are usually dependent on dietary recall/food frequency questionnaires, often at only a few points in time, and dietary recall itself is not necessarily so accurate
    • It is really impossible in observational studies to isolate specific dietary ingredients or vitamins. Although analyses try to look at likely confounders, there are undoubtedly unanticipated ones (are those who have more calcium and vitamin D in their diet more likely to be health-conscious and also have a lower morbidity/mortality related to that? Or, contrarily, do those who are the least health-conscious take supplements to boost their calcium and vitamin D because they just heard on the news that this was important and might counteract their less healthy lifestyle?). It is interesting that in the one study with the highest levels of calcium intake, there was divergence between those who had calcium by foods versus supplements in terms of CVD and mortality. Perhaps those on supplements had generally less healthy diets? Or is there a fundamental physiologic difference between getting calcium from food versus pill (which appears to be different for CVD and stroke outcomes)??
    • The dietary studies themselves are often given equal weight, when some are better studies in others. For example, it is notable in the above that even the inconsistent association between calcium and/or vitamin D and CVD outcomes is more apparent in subgroup analyses than in the overall trials. And some showing lack of benefit for bone studied people with already adequate 25(OH)D levels to begin with (i.e. supplements might not do much more).
    • One cited concern is that increased calcium might lead to more vascular calcification. But this was derived from studies of persons with pretty severely impaired renal function on several meds, and not the general population.
    • As noted in prior blog (see http://blogs.bmj.com/ebm/2016/11/21/primary-care-with-geoffrey-modest-md-lessons-ive-learned-from-looking-at-the-medical-literature/ ), there are real concerns about the value of meta-analyses/systematic reviews. Of course, there also limitations of single trials, or the latest trial that makes it into the journals and popular press. This current study was a truly independent meta-analysis, conducted by a well-respected group, and the evaluation of the individual studies they included pretty impressively confirmed that calcium intake is safe, even up to the 2000 to 2500 mg per day range (but the studies are pretty limited on this, as noted above).
    • The current meta-analysis did raise pretty serious methodologic concerns about 2 recently published reports finding adverse cardiovascular outcomes with calcium supplementation with or without vitamin D
  • There is also some confusion in the medical literature about the benefits of vitamin D in terms of fall prevention (see http://blogs.bmj.com/ebm/2015/05/27/primary-care-corner-with-geoffrey-modest-md-vitamin-d-and-falls-in-the-elderly/ which critiques a recent study). The USPSTF most recent guidelines (prior to this study) still noted “that vitamin D supplementation is effective in preventing falls in community-dwelling adults aged 65 years or older who are at increased risk for falls”.

So, putting this all in perspective, I think that it is clear that bone health requires adequate vitamin d and calcium levels. Guidelines differ in their specific recommendations:

  • Some suggest achieving a 25(OH) vitamin d level of 20 ng/ml and some suggest 30 ng/ml.
    • The USPSTF in 2013 found insufficient evidence to recommend >400 IU vitamin D or >1000 mg of calcium (though it warns against supplementation with <= 300 IU vitamin D or <= 1000 mg calcium)
    • The Endocrine Society (see doi: 10.1210/jc.2011-0385) suggested checking 25(OH) vitamin d levels in people at high risk for deficiency, with deficiency defined as <20ng/ml (50nmol/L), and in general recommends:
      • For children <1yo, at least 400 IU/d; for 1-18 yo, at least 600 IU/d. but not enough reliable data to raise the 25(OH)D level to 30 ng/ml
      • For those 19-50yo, at least 600 IU/d, but might need 1500-2000 IU/d to achieve consistent levels >30 ng/ml
      • For those 50-70yo, at least 600 IU/d,but might need 1500-2000 IU/d to achieve consistent levels >30 ng/ml
      • For those >70yo: at least 800 IU/d. but might need 1500-2000 IU/d to achieve consistent level
      • For pregnant/lactating women, at least 600 IU/dbut might need 1500-2000 IU/d to achieve consistent levels >30 ng/ml
      • And more aggressive therapy (e.g. 2000IU/d) for those who are vitamin D deficient
  • For calcium, the NIH recommends (which is pretty similar to the Institute of Medicine):
    • Age 1-3: 700mg/d
    • 4-8 yo: 1000 mg/d
    • 9-19 yo 1300 mg/d
    • 31-70yo 1000 mg/d
    • But 51-70yo women and everyone >70yo: 1000 mg/d

I personally do suggest to patients that they consume a high calcium diet, but this is often limited by cultural or other circumstances (e.g., lactose intolerance). And, it is hard for those living in the Northeast to get adequate sunlight for adequate vitamin D levels (and I still shoot for 30 ng/mL as a target). So, though I would prefer all calcium and vitamin D coming from natural sources (diet, sunlight), most of my patients are on supplements. And usually taking 1 tablet of calcium 600mg combined with vitamin D 400IU twice a day is adequate (though I do have some high risk patients, including those with low Bone Mineral Density, who need 2000 IU of vitamin D/day). And I do check 25 (OH) vitamin D levels in those I think are at high risk (BMD, history of fragility fracture, medications, very limited outside sun exposure, etc.).

Primary Care Corner with Geoffrey Modest MD: Vitamin d and falls in the elderly???

27 May, 15 | by EBM

By: Dr. Geoffrey Modest

A recent article, which got some general press, looked at the utility of exercise and/or vitamin D in fall prevention in older women (see JAMA Intern Med. 2015;175(5):703-711). The backdrop here is that falls are common in the elderly, and 20% lead to injury requiring medical attention. A systematic review and meta-analysis documented the benefit of vitamin D (see J Clin Endocrinol Metab, October 2011, 96(10):2997–3006), finding that in 26 studies with 46K people (majority elderly women), vitamin D was associated with 14% decreased risk of falls (47% in those vitamin D deficient, 10% in those not deficient, and both statistically significant), and this was especially true in patients who had calcium co-administered with the vitamin D. The US Preventive Services Task Force (USPSTF) in 2012 “recommends exercise or physical therapy and vitamin D supplementation to prevent falls in community-dwelling adults aged 65 years or older who are at increased risk for falls”, a grade B recommendation.

Untitled

(LeBlanc & Chou, 2015)

Details of the new study:

–2-year double-blind, placebo controlled vitamin D and open exercise trial, with 409 home-dwelling women 70-80 years old in Finland who had at least 1 fall in previous year, did not use vitamin D supplements, and could exercise.
–median age 74, BMI 28, 25(OH) vit D level 27 ng/ml, PTH 5 pg/ml, MMSE 28, 45% with hypertension, 20% cardiovasc disease, 10% diabetes, 25-30% osteoarthritis, <5% depression
–4 groups: placebo without exercise, vitamin D 800 IU/d without exercise, placebo with exercise, and vitamin D 800 IU/d with exercise. exercise was group training 2x/week for first 12 months, then 1x/week, with alternating exercise classes (balance challenging, weight bearing, strengthening, agility, and functional exercises) and gym exercises (weight machines, free weights). Also there was a home-training program for 5-15 minutes on all the other days.
–primary outcome: monthly reported falls. secondary outcome: injurious falls, and the number of fallers and injured fallers
–results: in units of falls/100-person-years

–placebo without exercise: 118.2, but secondary outcome of injurious fall rate: 13.2
–vitamin D without exercise: 132.1, but secondary outcome of injurious fall rate: 12.9
–placebo and exercise: 120.7, but secondary outcome of injurious fall rate: 6.5
–placebo and vitamin D: 113.1, but secondary outcome of injurious fall rate: 5.0
–hazard ratios for injured fallers were significantly lower among exercisers, both with (HR 0.38) and without vitamin D (HR 0.47)
–vitamin D groups did maintain femoral neck bone mineral density and increased trabecular density slightly, vs small losses in the non-vitamin D groups
–exercise improved muscle strength and balance, and vitamin D added nothing to that
–adherence: 98.1% with pills and those on vitamin D had 25(OH) D levels increasing to 37.0 ng/ml at 24 months;72.8% for training sessions; 66.1% with home exercises
–adverse effects: no severe effects/injuries from training program, though 22 in training program and 1 not in program saw MD for musculoskeletal concerns.
their conclusions:
–rate of injurious falls and injured fallers more than halved with strength and balance training
–neither exercise nor vitamin D affected the rate of falls
–exercise improved physical functioning

So, this study raises several issues. Overall this was a group of quite healthy and quite fit women (both their baseline Short Physical Performance Battery and Mini Mential Status Exam were very close to the highest scores possible). But the devil is in the details. Despite headlines like “neither vitamin D nor exercise affects overall fall rates in older women” in Journal Watch, and their comment that “these results weaken speculation that vitamin D supplementation alone can prevent falls”, this trial was done in women who were not vitamin D deficient: the Endocrine Society in the US defines vitamin D deficiency as <20 ng/ml, and suggests maintenance vitamin D dosages of 1500-2000 IU/day in those who had been deficient– see doi: 10.1210/jc.2011-0385. The meta-analysis above cited has diagrams showing the difference in fall prevention in people who are vs are not vitamin D deficient, though I will append at the bottom a more recent analysis done by the editorialists (see JAMA Intern Med. 2015;175(5):712-713).

Bottom line: this study really does not add much overall. Giving vitamin D to healthy, fit 74 year old women (even though they did fall in the year prior to the study), who already have sufficient vitamin D levels — it is not so surprising that the added 800 IU didn’t do much. The exercise component does show value (as in other studies), though in this study it was not in falls overall but in injurious falls. So, I still would either check vitamin D levels/treat if low in elderly women, or just treat with vitamin D if the latitude and general assessment is that vitamin D deficiency is really common; I would also make sure that there is sufficient calcium in the diet or through supplements. And, of course, I would encourage balance and strengthening exercises.

Primary Care Corner with Geoffrey Modest MD: Non-cow’s milk and low vitamin D levels

26 Jan, 15 | by EBM

By: Dr. Geoffrey Modest 

No shocker here, but it turns out that non-vitamin D fortified non-cow’s milk (eg goat’s milk or plant-based milk such as soy, rice, almonds…) leads to lower 25-OH vit D levels in the blood. In this Canadian study, they looked at serum 25-OH in kids who were drinking non-cow’s milk (which is only voluntarily fortified with vit D and, if so, with no regulation of content) vs. those on fortified cow’s milk, by law required to have 40 IU vit D/100 ml (see DOI:10.1503/cmaj.140555​). Note that this was an observational study, not RCT — so there might be other confounders (eg, those on non-cow’s milk are on it for specific reasons which could also affect their vitamin D levels, or have other dietary changes in addition to non-cow’s milk).

320px-Soy_milk_(2)

Results:

–2268 children aged 1-6 yo, coming in for routine well-child visits, had dietary history and blood tests. of these, 1950 drank only cow’s milk, 146 only non-cow’s milk, 88 both, 109 neither. Also, 50-60% of each group were on vit D supplementation
–Non-cow’s milk consumption was associated with a 4.2 nmol/L (1.7 ng/ml) decrease in 25-OH vit D per 250 ml milk consumed, vs. those on cow’s milk (p=0.008), and there was a linear gradient in those consuming both, reflecting the amount of non-cow’s milk drunk
–Those drinking exclusively non-cow’s milk were at higher risk of 25-OH vit D levels below 50 nmol/L (20 ng/ml), 11% vs. 4.7% with odds ratio of 2.7 (1.6-4.7)
–And (also not a shocker), there was variation in 25-OH vit D levels depending on whether there was either vit d supplementation (which, unfortunately, they did not quantify) and having darker skin pigmentation.

So, no big surprises. I bring this up because of the increasing understanding of the role of vitamin D in health in general and especially in kids. For example, the American Association of Pediatrics just released a clinical report for clinicians entitled “Optimizing Bone Health in Children and Adolescents” (see here), which suggests that “Adequate vitamin D intake for infants younger than 1 year is 400 IU/d. The RDA is 600 IU for children 1 year and older”.​ And, since fortified cow’s milk has been shown in several studies to be the main dietary source of vitamin D in early childhood, it may be very important for us clinicians to be particularly attentive to kids drinking non-cow’s milk (which anecdotally I have found occasionally but increasingly in our inner-city community) as well as the quantity of fortified dairy products consumed. Of course, one concern in a Canadian study is the remarkable lack of good sunlight in those northern climes, making the issue there (and a lot of northern US) even more important. Another perhaps significant issue is that an old study found a remarkable discordance between the advertised supplementation on fortified milk and the actual content (see DOI: 10.1056/NEJM199204303261802​), with only 29% of 42 samples having between 80-120% of the advertise content.

Primary Care Corner with Geoffrey Modest MD: Vitamin D Screening Recommendations USPSTF

10 Dec, 14 | by EBM

By: Dr. Geoffrey Modest

The US Preventive Services Task Force just published their recommendation for vitamin D screening: “the current evidence is insufficient to assess the balance of benefits and harms of screening for vitamin D deficiency in asymptomatic adults”, which applies to community-dwelling, nonpregnant adults aged >18 yo seen in a primary care setting and without either signs/symptoms of vitamin D deficiency or conditions where vitamin D treatment is recommended (for review of recommendations, see here; for full systematic review, see either here or here). This recommendation is largely based on the fact that no study has directly evaluated clinical outcomes or harms comparing those screened for vitamin D deficiency or not. They note:

–There is no consensus about what the cutoff is for vitamin D deficiency. Some use <50 nmol/L (<20 ng/mL), others <75 nmol/L (<30 ng/mL), though they do note that some studies do show low levels are associated with increased risk for fractures, functional limitations, cancer (colorectal and others), diabetes, cardiovascular disease, cognitive decline, depression and death.

–There is no standard test used and there are some variations in results depending on the test done. One issue, for example, is that although African-Americans have lower 25(OH)D levels, they also have lower levels of vitamin D binding protein, therefore similar levels of bioavailable vitamin D)

–Data are lacking that there is clear benefit for screening of the general community-dwelling population. Current studies have found that there is no benefit in finding/treating vitamin D deficiency on cancer, diabetes, risk of death, risk of fractures in those not at high risk of fractures. Data are inadequate about other outcomes, such as psychosocial and physical functioning. Also, they did not find any studies on cardiovascular or immune diseases that met their inclusion criteria. They do note that there are some data that treatment of asymptomatic patients is adequate for a few limited outcomes. “Vitamin D treatment, with or without calcium, may be associated with decreased risk for mortality and falls in older or institutionalized adults”.

–Harms: evidence is pretty consistent that the harms of vitamin D supplementation are “small to none”, with no studies overall finding an increase in adverse events, hypercalcemia, kidney stones, or GI symptoms

–These recommendations only address screening for the general population, not those specific populations at high risk of falls, fractures, cardiovascular disease, or cancer without first determining 25(OH)-vitamin D levels.

A few points:

–This recommendation only addresses screening for vitamin D deficiency, not the need to have adequate vitamin D levels.

–This recommendation addresses only the general asymptomatic population, not those who are symptomatic or at high risk of vitamin D deficiency, and calls for “more research to determine vitamin D treatment effects in younger noninstitutionalized adults and to clarify the subpopulations that are most likely to benefit from treatment”.

–For example, these results may not apply to other populations: vitamin D treatment is associated with decreased risk of death (pooled RR 0.83, with CI 0.70-0.00) in older, institutionalized people, and is associated with lower rate of falls in institutionalized people

–There is pretty clear consensus that vitamin D is an important component of health, with the Institute of Medicine suggesting that adults aged 18-70 yo should take 600 IU of vitamin D and those >70yo should have 800 IU, and that this amount should be sufficient for 97.5% of the population. The US Endocrine Society clinical practice guideline on vitamin D deficiency (see doi: 10.1210/jc.2011-0385​) also suggested that vitamin D deficiency is remarkably common, and that the primary approach should be generalized supplementation, with testing for vitamin D deficiency in those at risk for deficiency and treating those deficient (<20 ng/mL). They recommend the same intake as the IOM, but comment that these levels may not be enough to raise 25(OH)D levels to 30 ng/mL and may not provide all of the nonskeletal health benefits (which are unproven).

–And I do think there is concern about the correct test to do — eg, the African-Americans who have low 25(OH)D​ but normal vitamin D binding protein levels, or that obese patients may have higher adipose tissue stores which may be bioavailable.

So, what does this all mean? Mostly that there is not enough evidence to screen the general population. It is pretty clear that vitamin D is important, and unlike other vitamins/minerals, is not naturally occurring in many foods, but is generated by UV light exposure. So, unlike other vitamins, where I tend to rant about eating healthfully instead of trying to supplement an individual ingredient here or there, vitamin D levels are an accident of one’s latitude. And there are vitamin D receptors throughout the body, including the immune system, with at least one article finding that those patients randomized to vitamin D supplementation who had active pulmonary tuberculosis had accelerated sputum conversion and improvement of several markers of TB-associated inflammatory responses — see here​ . So, perhaps it is correct that we should not be spending the money to check 25(OH)D levels in everyone and that we should just strongly recommend adherence to the supplementation guidelines of the Institute of Medicine —  with the only caveat being that there may be better adherence with vitamin D supplementation if the patient knows that they themselves are vitamin D deficient instead of just being told to drink more milk/orange juice/take supplements as one of many health different provider suggestions.

Primary Care Corner with Geoffrey Modest MD: New Vitamin D Articles

29 Apr, 14 | by EBM

vitamin D deficiency has been associated with many different medical conditions noted over the past decade, presumably related to there being vitamin d receptors on almost cell types in the body. in general, vitamin D supplementation has been shown to benefit rickets, fractures and falls (though recent meta-anal did not find consistent positive effect on bone density). there are also strong associations with multiple sclerosis, an array of autoimmune disorders, infections, cardiac disease, and cancer. there has been a slew of posts about vit d, some showing increased insulin sensitivity or improved lipids with vitamin d supplementation, one showing improved response to TB infection by antiTB drugs when simultaneously given vitamin D. the data on vitamin D and risk of non-skeletal diseases, however, is still unclear, and the 2011 endocrine society guidelines clearly recommend vitamin D only for the proven skeletal issues (see doi: 10.1210/jc.2011-0385)

one BMJ article was an umbrella review (systematic collection and eval of info from multiple systematic reviews and meta-analyses on all clinical outcomes assessed) was done of observational studies of associations between circulating vit D levels and clinical outcomes, along with meta-anal of RCTs on supplementation (see here). they assessed 107 reviews and 74 meta-anals, looking at 137 outcomes (!!). results:

–probable associations between high vit D concentrations or supplementation: decrease dental caries in kids, increased newborn birth weight at term, decreased PTH levels in patients with ESRD on dialysis (in contrast to previous reports, they did not find evidence that vitamin d by itself improves bone mineral density or reduces the risk of fracture of falls in older people).
–suggestive health benefits: decreased risk of colorectal ca, non-vertebral fx, cardiovasc dz, htn, ischemic stroke, cognition, depression (from cohort studies), BMI, metabolic syndrome, type 2 diabetes, SGA newborns, gestational diabetes
–no conclusion: a huge list, mostly everything except the above 2 categories (see their Table 6) also impressive associations in their Forest plot as figure 3 (though, these are all from observational studies!!); figure 4 (less impressive) is the RCT review, though most of which had very few participants, which pretty much reflects the “probable associations” point above.

another BMJ article looked at either 25OHD levels or vit D supplementation and cause-specific mortality (see here). results:

–primary prevention observational studies: bottom vs top 1/3 of 25OHD levels (median 25OHD level in was 20.7 ng/ml):

–death from cardiovasc disease: RR 1.35 (1.13-1.61)
–death from cancer: RR 1.14 (1.01-1.29)
–death for non-vascular, non cancer:  RR 1.30 (1.07-1.59)
–all-cause mortality: RR 1.35 (1.22-1.49). there was a dose-response: as compared to people with 25OHD of 30, 21-29 with RR 1.07, 10-20 with RR 1.20, <10 with RR 1.50
–on subgroup analyses in observational studies, mortality higher in studies with lower baseline use of vitamin D supplements

–in RCTs, there were different RRs depending on type of vitamin D supplementation — all-cause mortality with vit D3 (cholecalciferol, from UVB radiation, supplement animal-derived) had RR 0.89 (0.80-0.99) and with vit D2 (ergocalciferol, plant-derived) RR=1.04 (0.97-1.11).
–with vit D2 supplementation, increased RR of mortality in studies with lower intervention doses and shorter average intervention periods. (this could be reverse causation: sicker patients, more likely to die sooner, may get less sun or take fewer supplements and therefore have lower 25OHD levels. also there is a report of patients finding decreased vit d with acute changes in systemic inflammatory response — eg see Am J Clin Nutr 2011;93:1006–11.

so, these studies confirm the many observational studies finding impressive associations between vitamin d levels and several clinical outcomes, including mortality.  but we really need good intervention studies to see if this pans out, or if potential confounders could explain the association (eg shared determinants, such as obesity, medical comorbidities or social status). Their figure 7, which looked at various subgroup analyses, showed a very consistent difference. but the studies do highlight risks, the most consistent being hypercalcemia, esp in the setting of chronic kidney disease.  there are ongoing RCT trials (eg VITAL trial of 26K men and women randomized to 2000 IU vit D3 assessing outcome of cancer, CAD, and stroke — due out in 2017). so, as with pretty much all nutritional studies, observational studies show positive effects of supplements, but the real proof needs big RCTs (though for vitamin d, i do think the observational data are pretty impressive, the basic physiology of having vitamin D receptors being everywhere, the limited data showing positive effects of vitamin D on immunologic function, and the low toxicity/cost of supplementation does make me check/treat low 25OHD levels, though will switch preferentially to D3 supplements given this last study).

geoff

Primary Care Corner with Geoffrey Modest MD: Vitamin D and lipids

8 Apr, 14 | by EBM

there are a plethora of articles on the potential benefits of vitamin d. as noted in many prior blogs, vitamin d receptors exist throughout the body. some vitamin d benefits are well-documented (bone, muscle, decrease in falls in elderly), some have small studies to support (improved response of TB to medications in those with adequate vitamin d levels, improved glucose tolerance), and many are epidemiologic studies (cancer — including prostate, breast, ovary; all-cause mortality; immunologic function and decrease in immunologic diseases — eg multiple sclerosis; heart disease,…) — for example, see doi: 10.1210/jc.2011-0385 for the endocrine society recommendations. the present article (see doi: 10.1097/gme.0000000000000188) supports a role in cholesterol profiles, from the Women’s Health Initiative calcium/vitamin D randomized trial. in brief,

–600 postmenopausal women (300 white, 200 African-American, 100 Latino) selected randomly from the Women’s Health Initiative CaD trial, randomized to elemental Ca 1,000 mg plus vit d 400IU/d vs placebo. 576 women with data to analyze: lipids assessed before and after the randomization. after 2 years:

–38% increase in 25OHD3 levels in those supplemented — 24.3 vs 18.2 ng/ml
–those on supplementation had 4.46 mg/dl decrease in LDL, nonsignif increase in HDL and nonsignif decrease in triglycerides (TG)
–those wtih higher 25OHD3 levels had higher HDL levels and lower LDL and TG. their figure discloses a linear relationship between increasing 25OHD3 levels on the range of 5-100 ng/ml and decreasing LDL as well as increasing HDL (dose-response curve), with a more complex relation with TG (decline begins around 15 ng/ml with linear decrease from that point to 100 ng/ml).

so, from this study the combo of ca/vit d helps lipids (though this is surrogate marker … really need to look at clinical events). unclear if vit d or calcium or combo is most beneficial. there are some data, for example, finding that calcium citrate by itself may have more beneficial lipid effect than calcium carbonate (used in this trial). one advantage of this study is that they looked at actual 25OHD3 levels achieved and lipid endpoints, instead of ecologic data based on general vitamin D supplementation and clinical results. and, in general, there was a clear, dose-response between the achieved vit D level and lipid markers. so, this study further supports either a strategy of checking 25OHD3 levels and supplementing when needed, or simply supplementing pretty much everyone in the northern climates….

geoff

Primary Care Corner with Geoffrey Modest MD: more vitamin d studies, including multiple sclerosis and dosing in infants

22 Jan, 14 | by EBM

several articles have come out over the past few months on vitamin d. there are a slew of them from before, including review articles (eg  N Engl J Med 2007;357:266-81) highlighting the vast array of possible important actions of vitamin D in immune function, cancer prevention, heart disease prevention, as well as the better documented effects in bone health and preventing falls in elderly. last year there was an article finding that obese adolescents with low vitamin D had improved insulin sensitivity on repleting vitamin D levels (see  doi: 10.3945/ajcn.112.050013). here are 3 more articles with more mixed results.

 

1. large meta-analysis of vitamin d supplementation and bone mineral density/BMD (see  doi.org/10.1016/S0140-6736(13)61647-5). included 23 studies (mean duration 2 yrs, 4082 people, 92% women, average age 59). mean baseline 25-OH vit D was <50 nmol/L (<20 ng/ml) in 8 studies. in general they found not much benefit from vit d supplementation, the only really significant one being in femoral neck BMD, specifically in those with the lowest baseline 25-OH vit D levels and in those supplemented with <800 as opposed to >=800 IU/d.

a couple of issues. there seem to be large individual variations in the physiologic effect of vit D deficiency, with only approx 50% having secondary hyperparathyroidism (none of the studies geared therapy to the hyperPTH group). and, somewhat surprisingly, in this meta-analysis the improvement in BMD was not in the highly cortical bone of the forearm, where hyper PTH has the most osteopenic effect and is the purported mechanism for osteopenia. the authors argue that vitamin D is mostly important for the maintenance of circulating calcium in a specific range, and in fact in high doses can stimulate osteoclastogenesis. it is important to keep in mind that BMD is a surrogate marker, which does not necessarily predict risk of fracture (BMD is a quantitative assessment of bone density, not a qualitative evaluation of its microstructure/strength, and there can be discordance — eg fluoride increases bone density but actually increases risk of fracture).

it is not easy to reconcile this meta-anal with others. i posted last year on a meta-anal in NEJM (see  DOI: 10.1056/NEJMoa1109617) which included 31K people (mean age 76 and 91% women) which found a nonsignificant 10% reduction in risk of hip fracture and a significant 7% reduction in risk of any nonvertebral fracture, with those in the highest vitamin D intake (median 800 IU) having a significant 30% reduction in risk of hip fracture and 14% reduction in risk of any non-vertebral fracture. this result was consistent across age groups, community-dwelling vs in an institution, baseline 25-OH vitD levels, and additional calcium intake, concluding that higher dose vitamin D (>=800IU/d) was “somewhat favorable in prevention of hip fracture and any nonvertebral fracture in persons 65 years of age or older”.

2. article in JAMA neurology looked at vitamin d status and progression of multiple sclerosis (see doi:10.1001/jamaneurol.2013.5993). this study was an intervention study looking at the efficacy of early vs delayed use of b-interferon in pts with clinically isolated syndrome (CIS) to assess progression to clinically definite MS (CDMS) or MS defined by clinical and MRI criteria (MDMS).  in this 5 yr study, they measured 25-OH vit d in the beginning and several points in the study. 400 pts. finding:

 

–average 25(OH)D following a CIS strongly associated with MS activity and progression (MRI and clinical) of MS over 4-5 years.

–those with serum 25(OH)D >50nmol/L (20 ng/ml) had 4x lower change in T2 lesion volume on MRI, 2-fold lower rate of brain atrophy, and lower disability on the Expanded Disability Status Scale (EDSS)

–and, the above findings were in a population on meds to decrease MS progression/relapse

 

there have been observational data that low vitamin D levels are associated with development of MS, thought to be related to the vitamin D effects on immune function (there are vit d receptors pretty much everywhere in the body, not just the bone and muscle).  i sent out an article 1-2 years ago which showed improved response to TB meds in a cohort also given vit d supplementation (see vit d and tb treatment pnas 2012 in dropbox, or doi:10.1073/pnas.1200072109/-/DCSupplemental).  but, the current study was an observational component of an intervention trial for b-interferon, and it is limited by inherent biases of observational studies (and those with higher vit D levels in the study tended to be younger, have lower BMI, lower number of T2 lesions on MRI, and higher brain volume when they presented with CIS, though the above results did control for age, sex, treatment time and T2 lesion score)). also almost all white. but at least they looked at patients with very early MS symptoms (independent of vitamin D levels) and looked at clinical/MRI progression. also, no ceiling effect was observed with vit D levels.

 

3. study done in montreal to assess different doses of vitamin d in breast-fed one-month olds and assess 25(OH)D levels at 3,6,9 and 12 months of age (seeJAMA. 2013;309(17):1785-1792). vitamin D3 doses were 400, 800, 1200, or 1600 units.  current recommendations are 400IU/d supplement in US and Canada, though some countries have higher recs (france and finland recommend ?1000IU/d).  results, assessing 2 different 25(OH)D goals:

 

–for the goal of 25(OH)D level >75mmol/L (30ng/ml): at 3 months, 55% in 400IU group, 81% with 800IU, 92% with 1200IU, 100% with 1600 IU.  But not sustained at 12 months in any group, with falloff proportional to dose: about 35% of those on 400IU/d up to 80% in those on 1600 IU/d

–for the goal of 25(OH)D level >50mmol/L (20ng/ml): essentially all achieved this goal at 3 months and at 12 months.

–bone mineral content and plasma PTH levels increased over time, while ionized calcium, and urinary calcium/creat ratios declined over time,  but no diff between groups in any of these measures

–of note, the 1600IU dosage was discontinued during the study because of 25(OH)D levels that were felt to be dangerously high.

 

so, all in all, seems reasonable to continue with the 400IU recommendation at this point, since by all of the markers noted including bone mineral content, this was as good as higher doses. the real clinical outcome, both for bone and non-bone benefits of vitamin D, will require longer term followup into later childhood. other issues include the applicability of the results of this study to kids of different ethnicities/skin pigmentation, or living at different latitudes.

 

so, overall, the data on vitamin D remains mixed. my sense, pending large intervention studies, is that there may well be important benefits to correcting vitamin D deficiency (decreased falls in elderly have been documented, but also effects on bone, immunologic function, potentially preventing cancer) outweigh the pretty much insignificant toxicity (except for patients on very high doses)

 

geoff

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