USPSTF issues draft recommendations on low-dose vitamin D and calcium for fracture prevention

http://www.huffingtonpost.com/ellen-sarver-dolgen/vitamin-d-calcium-supplements_b_3543283.html

The USPSTF today issued draft recommendations for effectiveness and potential harm of prescribing Vitamin D and Calcium in community dwelling men and pre-and post-menopausal women for the primary prevention of fractures.

Aging population, low bone mass and falls all contribute to a substantial health burden of fractures. Nearly 1 in 2 women older than 50 years of age will experience a fracture during her life time.

Currently, Vitamin D and Calcium supplementation are often advised for postmenopausal women to prevent fractures.

USPSTF recommendations on efficacy of Calcium and Vitamin D in preventing fractures are based on data from a total of 41,772 women across eight 8 RCTs with mean age between 53 to 80 years while for assessing the harm it reviewed the evidence from 9 RCTs with a total of 39,659 subjects, which also included 5,991 men.

The review of evidence concluded:

USPSTF found sufficient evidence to recommend against daily supplementation of 400 IU or less of vitamin D combined with 1,000 mg or less of calcium in prevention of fractures in postmenopausal women.

Evidence is also insufficient to make recommendations for greater than 400 IU of vitamin D and greater than 1000 mg of calcium supplementation in postmenopausal women.

At this time, there is insufficient evidence to determine the balance of benefits and harms of prescribing vitamin D and calcium supplementation, alone or combined, for the primary prevention of fractures in men and premenopausal women.

USPSTF found sufficient evidence that supplementation with vitamin D and calcium increases the incidence of kidney stones, although the magnitude of this harm was small.

This recommendation does not apply to persons living in institutional or nursing home care or with a history of osteoporotic fractures or those who are at increased risk for falls. It also does not apply to persons with a diagnosis of osteoporosis or vitamin D deficiency.

USPSTF recommends screening for osteoporosis in women aged 65 or older and in younger women if they have a high fracture risk. Evidence is insufficient to recommend for or against screening for vitamin D deficiency in asymptomatic adults.

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Vitamin D and Human Reproduction—Evolving perspectives

We are all well versed with the role of Vitamin D in maintaining calcium and phosphorus homeostasis and promoting bone mineralization. Its deficiency is linked to many chronic diseases of the cardiovascular and metabolic systems.

Evidence from animal and human studies suggests that vitamin D plays a very important role in human fertility and neonatal development. This steroid hormone has Vitamin D receptors (VDR) at multiple sites in the body including ovary, particularly the granulosa cells, endometrium and placenta.

It plays a very important role in ovarian steroidogenesis. [1] It deficiency contribute to development of insulin resistance and impaired glucose metabolism in patients with Polycystic Ovary Syndrome (PCOS). Therapeutic efficacy of supplementation with Vitamin D to improve insulin resistance, bring about ovulation and regularize menstruation in PCOs patients have been documented.[2] [3]

Observations also shows that lower 25(OH)D levels put women at higher risk of developing uterine fibroids, both in black and white ethnicities. In these women, the growth and size of the fibroid is also directly related to decreased levels of Vitamin D. Animal studies and human in vitro studies have shown the beneficial effect Vitamin D supplementation in inhibition of development and/or growth of uterine fibroids.[4] [5]

A recent study by Harris HR et al demonstrated that women within the highest quintile of Vitamin D blood values have one fourth the risk of developing endometriosis as compared to those in lowest quintile.[6]

It also plays a role in Body Mass Index (BMI) as per a recent meta-analysis, every 10% increase in BMI leads to 4% decrees in Vitamin D concentration.[7]

It’s role in male reproductive physiology is well documented by the fact that it’s level directly correlate with sperm motility and morphology.

As per Hill’s criteria a causal relationship between Vitamin D deficiency and negative outcome in IVF is explained but further research into knowing the magnitude of association is needed.[8]

A systemic review and meta-analysis by Lerchbaum E and Obermayer-Pietsch B published in Eur J Endocrinol May 1, 2012 concludes that Vitamin D plays an important role in Human reproduction and advocates the need of further research in therapeutic benefits of Vitamin D supplementation in such patients.  

Another review by Vanni et al published in the Reproductive Biology and Endocrinology, 2014 emphasizes the importance of supplementation of Vitamin D in IVF settings because consisting evidence documenting the increase incidence of gestational diabetes, IUGR, pre-eclampsia and preterm births in patients deficient in Vitamin D.[9]

The authors opine that although drastic improvements in reproductive failure may not be achieved solely by supplementing Vitamin D, but its addition to any fertility regimen is cheap, effective and without any side effects. It is easily correctable by simple oral supplementation.

Dosage up to 4000 IU is safe, without any side effects and effectively improve maternal vitamin D status. [10]

Results of double blind randomized trial entitled “Vitamin D during IVF” is still awaited.[11]

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[1]Anagnostis P, Karras S, Goulis DG: Vitamin D in human reproduction: a narrative review. Int J Clin Pract. 2013, 67 (3): 225-235

[2] Selimoglu H, Duran C, Kiyici S, Ersoy C, Guclu M, Ozkaya G, Tuncel E, Erturk E, Imamoglu S: The effect of vitamin D replacement therapy on insulin resistance and androgen levels in women with polycystic ovary syndrome. J Endocrinol Invest. 2010, 33 (4): 234-238.

[3] Wehr E, Pieber TR, Obermayer-Pietsch B: Effect of vitamin D3 treatment on glucose metabolism and menstrual frequency in polycystic ovary syndrome women: a pilot study. J Endocrinol Invest. 2011, 34 (10): 757-63.

[4] Bläuer M, Rovio PH, Ylikomi T, Heinonen PK: Vitamin D inhibits myometrial and leiomyoma cell proliferation in vitro. Fertil Steril. 2009, 91 (5): 1919-1925.

[5] Halder SK, Osteen KG, Al-Hendy A: Vitamin D3 inhibits expression and activities of matrix metalloproteinase-2 and −9 in human uterine fibroid cells. Hum Reprod. 2013, 28 (9): 2407-2416.

[6]  Harris HR, Chavarro JE, Malspeis S, Willett WC, Missmer SA: Dairy-food, calcium, magnesium, and vitamin D intake and endometriosis: a prospective cohort study. Am J Epidemiol. 2013, 177 (5): 420-430.

[7] Vimaleswaran KS, Berry DJ, Lu C, Tikkanen E, Pilz S, Kiraki LT, Cooper JD, Dastani Z, Li R, Houston DK, Wood AR, Michaëlsson K, Vandenput L, Zgaga L, Yerges-Armstrong LM, McCarthy MI, Dupuis J, Kaakinen M, Kleber ME, Jameson K, Arden N, Raitakari O, Viikari J, Lohman KK, Ferrucci L, Melhus H, Ingelsson E, Byberg L, Lind L, Lorentzon M, et al: Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts. PLoS Med. 2013, 10 (2): e1001383-

[8] Hill AB: The environment and disease: association or causation?. Proc R Soc Med. 1965, 58: 295-300.

[9] Aghajafari F, Nagulesapillai T, Ronksley PE, Tough SC, O’Beirne M, Rabi DM: Association between maternal serum 25-hydroxyvitamin D level and pregnancy and neonatal outcomes: systematic review and meta-analysis of observational studies. BMJ. 2013, 26 (346): f1169-

[10] Wagner CL, McNeil R, Johnson DD, Husley TC, Ebeling M, Robinson C, Hamilton SA, Hollis BW: Health characteristics and outcomes of two randomized vitamin D supplementation trials during pregnancy: a combined analysis. J Steroid Biochem Mol Biol. 2013, 136: 313-320.

[11] https://clinicaltrials.gov/ct2/show/NCT01019785

Multivitamin supplements ‘Is a waste of money’ for most women during pregnancy.

Multivitamins Courtesy Pixabay 

The drug market is flooded with myriad combinations of prenatal multivitamins and nearly all women are routinely prescribed these at prenatal visit to healthcare provider. It has long been claimed that taking a daily multi translate into better health for women and her unborn child.

Maternal deficiency of certain nutrients is linked with congenital malformations and poor pregnancy outcomes like preeclampsia, IUGR, skeletal deformities and neural tube defects.

This has given rise to billion-dollar pharma industry manufacturing and marketing products targeted at antenatal women and her baby. Globally the retail value sales of Prenatal Vitamin grew by 34% between 2008 and 2013 to reach its current market value of US$ 4.7 billion worldwide and is expected to rise continuously.[1]

According to the researchers, a typical prenatal Multi(MV) contains at least 20 different vitamins and minerals and sometimes the dose exceeds 100% RDS value. The average cost of daily prenatal MV is $20 per month.

A recent review[2]  published in British Medical Journal's Drug and Therapeutics Bulletin have refuted the need of Multivitamin supplements in pregnancy, the authors say “For most women who are planning to become pregnant or who are pregnant, complex multivitamin and mineral preparations promoted for use during pregnancy are unlikely to be needed and are an unnecessary expense.”

“The marketing of such products does not appear to be supported by evidence of improvement in child or maternal outcomes. Pregnant women may be vulnerable to messages about giving their baby the best start in life, regardless of cost,” the review further adds.

We found no evidence to recommend that all pregnant women should take prenatal multi-nutrient supplements beyond the nationally advised folic acid and vitamin D supplements, generic versions of which can be purchased relatively inexpensively," they say.

"Pregnancy multivitamins are a waste of money because most mothers-to-be do not need them, according to researchers," BBC News reports[3]

The researchers also looked at individual vitamins and supplements taken during pregnancy like Vitamin A, C, D and E, iron and folic acid. Strong evidence was only found in favor of supplementing Vitamin D and folic acid.

They have also cautioned against the excessive intake of Vitamin A which may be teratogenic to the fetus.

The researchers in this review have further confirmed the NICE guidelines:

• Folic acid (400 micrograms) should be taken when trying to conceive and for the first 12 weeks of pregnancy to protect against neural tube defects (NTD), such as spina bifida, in babies. 
• Folic acid dose is increased to 5 milligrams of folic acid a day where there is a family history of neural tube defects or where they have diabetes or have had a previous baby with a neural tube defect.
• 10 micrograms of vitamin D which equals 400 I.U each day throughout pregnancy that has to be continued while breastfeeding.

ACOG currently advises a pregnant woman to eat a well-balanced diet that includes foods from five groups: grains, fruits, vegetables, protein foods and dairy. Women who are pregnant requires extra folic acid and iron, which can be sourced from taking a prenatal Multivitamin but "a well-rounded diet should supply all of the other vitamins and minerals."[4]

Janet Fyle, from the Royal College of Midwives also dispelled the myth for eating for ‘two’ in pregnancy.

"We would also stress that there is no need for pregnant women to 'eat for two'."This is a myth, and all that is required is a normal balanced amount of food."

This news has angered the pharmaceutical industry, who are arguing that the prenatal vitamins are prescribed to fill in the gaps in the diet and not to cure any specific disease.

Two earlier studies and an expert editorial published in Annals of Internal Medicine have dispelled that myth too.  "The message is simple: Most supplements do not prevent chronic disease or death, their use is not justified, and they should be avoided," says the editorial, signed by two researchers from Johns Hopkins University in Baltimore, one British researcher and one of the journal's senior editors.[5]

The review may not be systematic, but it provides data supporting the current recommendation of NHS. The researchers also argue that most studies favoring Multivitamin supplementation in pregnancy are from developing countries, where women are deficient in many key nutrients. Hence, the same recommendation does not hold true for developed countries.

However, according to current evidence, eating a good balanced diet, along with folic acid and Vitamin D supplementation ensures the best possible outcome for pregnant woman and her unborn child.

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[1] http://blog.euromonitor.com/2014/05/optimizing-development-the-growing-paediatric-and-prenatal-supplements-market.html

[2] http://dtb.bmj.com/content/early/2016/07/11/dtb.2016.7.0414

[3] http://www.bbc.com/news/health-36765161

[4] http://www.acog.org/Patients/FAQs/Nutrition-During-Pregnancy#extra

[5] http://annals.org/article.aspx?articleid=1789253