In this article, the author looks at complications and issues caused by vitamin D deficiency in women
Dr Andrew Blann  PhD FRCPath FRCPE Blood Science Solutions, Birmingham, UK


Interest in vitamin D has been growing over the past 10 years, and is often seen by some as a necessary nutritional supplement to the diet. This article aims to provide an objective assessment of this vitamin, and its place in women’s health.

Vitamin D is the collective term for a small number of fat-soluble steroid hormones needed for the intestinal absorption of calcium, magnesium and phosphates, and without which blood levels of these chemicals will fall. The expression of the vitamin D receptor on many tissues points to a broad role in physiology, and therefore, potentially, in pathology. Nevertheless, interest in vitamin D follows from its role in maintaining healthy bone, as low levels of calcium, possibly driven by lack of vitamin D, leads to weakness. This is best known as the bowing-out of the leg bones that are unable to bear the weight of the body. In adults, this is osteomalacia, while in children it is called rickets.

Sources of vitamin D

Vitamin D can arise from the diet and from our own metabolism, via cholesterol, in the liver. The precursor, 7-dehydrocholesterol, is converted to vitamin D3, also known as cholecalciferol, by exposure to UV light in the skin. This intermediate is converted to 25-hydroxycholecalciferol, also known as calcidiol, or 25(OH)D, and then (by enzymes controlled by parathyroid hormone, PTH) into the active form of the vitamin, 1,25-dihydroxycholecalciferol (1,25(OH)2D), also known as calcitriol, in the kidney.

Cholecalciferol and the closely related ergocalciferol (vitamin D2) are present in several foods. Those rich in vitamin D2 include mushrooms and alfalfa shoots, while vitamin D3 is widely present in oily fish (salmon, trout, herring, mackerel, sardines, tuna etc.), cod liver oil, eggs and beef liver. Cod liver oil and oily fish are by far the richest source, but many common foodstuffs (milk, breakfast cereals, orange juice etc.) are now fortified with vitamin D, and in some countries this is demanded by legislation.

Vit Figure 1Functions of vitamin D

The primary function of vitamin D is to promote the uptake of calcium (from 10-15% to 30-40%), and phosphates (from 50-60% to approximately 80%) in the stomach and intestines, while within bone, vitamin D promotes increased bone mineral density.1

However, many organs express a receptor for vitamin D, including the brain, heart, skin, gonads, prostate and breast, implying many other roles. In the kidney, vitamin D and PTH together regulate the excretion or retention of calcium. It follows that low levels of vitamin D may lead to disease in several critical organ systems. This therefore requires
agreement of what constitutes physiological levels of the vitamin, which will in turn lead to initiatives to improve levels and so (it is hoped) reduce the risk of disease. An example of this is the hypothesis that low levels of vitamin D predispose to a risk of fracture, and that supplements will address this issue.

Reference serum levels and recommended daily intake

Calcidiol is the index of choice for defining vitamin D in the blood. Unfortunately, there is a marked lack of consensus regarding both the choice of cut-off wording and the serum levels themselves. Consequently, practitioners must refer to values provided by their own laboratory. However, in the UK, NICE defines deficiency as levels below 25nmol/L regardless of sex.2

NICE recommendations regarding the daily intake of vitamin D are shown in Table 1, but does not make any recommendations for those aged 4-65 as it assumes that the action of sunlight on the skin and a well-balanced diet will provide adequate vitamin D.2

Causes of deficiency of vitamin D

Low serum levels of vitamin D may be caused by a number of factors.

  • Lack of sunlight: this must be direct sunlight as glass cuts out the crucial UV wavelengths. There is also evidence that excessive use of sunscreen (which absorbs UV light), an ‘indoor’ lifestyle, and excessive clothing covering the body leads to deficiency. Although levels are lower in more northern latitudes, regardless of season, in countries much closer to the Equator a significant proportion of the population still have low levels of vitamin D.
  • Diet: This is likely to be less of an issue as approximately only 10% of vitamin D is taken in food. As inflammatory bowel disease can be associated with reduced absorption of iron and vitamin B12, this may also be the case for vitamin D.
  • Liver and renal disease: A healthy liver and kidney are required for the production of vitamin D. Furthermore, in poor renal function there is likely to be excessive loss of calcium, contributing to renal osteodystrophy.
  • Genetics. Loss of function or reduced function polymorphisms in genes coding for metabolic enzymes may all lead to low serum levels, and errors in genes coding for the vitamin D receptor may result in insuf!cient vitamin D entering the cell.

NICE recommends testing vitamin D status only in those who have symptoms of deficiency, are at high risk, or have a clinical reason (e.g. osteomalacia or a fall).2

Consequences of deficiency

Vit D table 1 and 2The importance of vitamin D in healthy bone development, and the proof of concept in rickets and osteomalacia, is indisputable. The fact that many different cells have receptors for vitamin D implies that it has multiple roles and so the potential to be linked to multiple diseases, as well as mortality (Table 2). Unsurprisingly, this has fuelled a great debate as to the potential value of supplementation. However, there are contradictions that underline the dangers of observational studies, and which reinforce the view that prospective interventional controlled trials of supplements alone can provide the best data. For example, the apparently powerful meta-analysis of 18 observational studies of the calcidiol (25OHD) form of vitamin D, that included 77,155 people, found a strong effect of low vitamin D with all-cause mortality. However, in the same publication, the meta-analysis of eight randomised controlled trials found no effect on mortality.3

Supplementation with oral vitamin D

Table 3 summarises a meta-analysis of randomised controlled trials of different forms of vitamin D supplements. Perhaps the strongest outcome is of an effect of vitamin D in reducing the risk of low birth weight. However, there is again an apparent
contradiction in that vitamin D2, D3, or active D (or + calcium) reduces the risk of non-vertebral fractures, while vitamin D2, D3, or D seemingly has no effect on fractures, hip fractures, or vertebral fractures.3

The same study found no effect of vitamin D2 or vitamin D3 on mortality, a finding possibly at odds with another meta-analysis, which concluded that supplementation with vitamin D3 significantly reduces overall mortality among older adults.4mA further question is of the optimum levels of serum vitamin D that bring the greater benefit. This is important as high levels of vitamin D may be due to an oral intake greater than 4,000 IU daily, leading to blood levels over 500ng/mL, which can be toxic. There are many non-specific early symptoms of vitamin D toxicity, such as anorexia, diarrhoea, constipation, nausea, vomiting, bone, muscle and joint pain, drowsiness, irregular heartbeat, polydipsia, dehydration, weakness and renal stones.5

In the UK, NICE recognises five at-risk groups: all pregnant and breastfeeding women, particularly teenagers and young women; infants and children under 5 years; people over 65; people who have low or no exposure to the sun; and people who have darker skin, for example, people of African, African-Caribbean and South Asian origin.2 These groups are advised to take a supplement that meets 100% of the reference nutrient intake for their age group. This intake should be 8.5μg/day (340 IU) for infants aged 0-6 months, 7μg/day (280 IU) for older infants and children up to five, and 10μg/day (400 IU) for adults.

Vit D table 3

 

Women and vitamin D

Notwithstanding the above, what are the salient points for women and vitamin D? Apart from pregnancy and lactation, NICE gives no sex-specific recommendations, although much literature and many misconceptions abound. For example, NICE states that low vitamin D status has been associated with some diseases and other long-term conditions such as osteoporosis, diabetes and some cancers, although the evidence is inconclusive.

Race and ethnicity

As vitamin D production requires sunlight, reduced exposure may lead to deficiency. In a study from Manchester in the UK, South Asian women had lower levels of serum vitamin D (possibly due to increased skin pigmentation and/or reduced dietary intake)
and reduced bone mineral density, but the two were unrelated.6 In the USA, African Americans have lower vitamin D levels than white populations. However, in a prospective study of almost 200,000 post-menopausal women, black participants had half the prevalence of osteoporosis and half the fracture risk of white women.7 This suggests that blood vitamin D level bears little direct relevance to bone health in this group, and contradicts the view that, in these groups, vitamin D is crucial to bone mineral density.

Pregnancy

Low blood vitamin D during pregnancy led to the hypothesis that it could result in low bone mineral density in the babies once delivered. If so, this would be evidence in favour of vitamin D supplements. This hypothesis was robustly tested in 3,960 mother and offspring pairs, with the result that there were no relevant associations between maternal
vitamin D and the bone mineral density of the child measured up to nine years later.8

Observational studies found low maternal vitamin D to be linked to gestational diabetes, pre-eclampsia, small for gestational age infants, bacterial vaginosis and lower birth weight infants, but had no effect on the rate of caesarean section.3,9 One of the two firm results of meta-analysis is that vitamin D Breastfeeding Breast milk is relatively deficient in vitamin D, regardless of the maternal status, leading to the concept that exclusively breastfed infants should be given supplements, especially if dark-skinned.2,10
NICE has also recommended that lactating women take supplements. This approach is certainly successful in increasing serum vitamin D in both mother and infant.11 The importance of this issue is demonstrated by the development of rickets in infants exclusively breastfed.12 Low vitamin D in some infants may be related to advice to keep babies out of the sun. For those unable to breastfeed, formula must be forti!ed with the vitamin.

Breast cancer

Many observational studies link vitamin D with breast cancer. In one, looking at 512 women with the disease over 12 years, at which point the risk of metastatic disease was increased by 94%, and the risk of death by 73% in vitamin de!ciency women compared to those with normal levels.13 Unfortunately, this may not be causal as many other factors are likely to be important. Although a meta-analysis of 21 studies in breast cancer found a strong effect of low serum vitamin D (as calcidiol [25OHD]), nine studies of postmenopausal breast cancer and six studies of premenopausal breast cancer found no such effect. A pooled analysis of three studies of calcitriol (1,25(OH)2D) failed to find a link with breast cancer.14

Osteoporosis, falls and fractures

Although vitamin D is low in osteoporosis, this does not prove that lack of the vitamin causes the disease. Instead, the culprit lesion may be defects in the vitamin D receptor on cells responsible for bone turnover.15 Furthermore, there is no evidence that high levels, whether natural or supplemented, reduce the risk of osteoporosis. Nevertheless, many recommend that those with osteoporosis and others with reduced exposure to sunlight take supplements of both vitamin D and calcium to ensure that the cells within bone have adequate materials to build a !rm bone structure.

Many observational studies have reported low serum vitamin D in those with falls or fractures.3 Although one study has reported a reduction in the risk of falls and fractures by 12% in those taking supplements of vitamin D of a dose of 700 IU/day, or if serum levels were greater than 62.5 nmol/L, another found that supplements in older women increased serum vitamin D, but resulted in an increased risk of falls and fractures.16 Sunlight increases both vitamin D and bone mineral density, and reduces the risk of hip fracture. Notably, NICE does not make speci!c recommendations regarding falls and fractures, possibly because it considers it has covered this area with its guidance regarding supplements of vitamin D in the over-65’s.

Summary

  • Vitamin D is required for healthy bones
  • We need sunlight and good renal and liver function for the synthesis of vitamin D, although it can also be taken in diet
  • Severe de!ciency causes the bone diseases rickets and osteomalacia
  • Supplementation with vitamin D can help prevent low birth weight and non-vertebral fractures
  • Roles for vitamin D in other aspects of health are controversial.

References
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2. National Institute for Health and Care Excellence. Public Health Guidance 56. Vitamin D: increasing supplement use among at-risk groups. www.NICE.org.uk
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15. Mohammadi Z, Fayyazbakhsh F, et al. J Diabetes Metab Disord. 2014 Oct 17;13(1):98. doi: 10.1186/s40200-014-0098
16. Thatcher TD, Clarke BL. Mayo Clin Ptoc 2011:86;50-60.
17. Bischoff-Ferrari HA, Willett WC, et al. Arch Intern Med. 2009;169:551-61