Guidelines for Diagnosis, Measurement and Treatment of Vitamin D Deficiency

In March 2005 the Working Group of the Australian and New Zealand Bone and Mineral Society, The Endocrine Society of Australia and Osteoporosis Australia, published a position statement in regards to Vitamin D and adult bone health in the Medical Journal of Australia.1 This is a very useful resource, which has addressed many issues regarding vitamin D therapy in Australia and general practitioners are directed to utilise this document.³¹ However, there are still issues which remain unresolved including which form of vitamin D to use, monitoring the success of vitamin D therapy and accuracy of vitamin D levels with the currently available assays. These issues along with the recently published recommendations from the Position Statement will be outlined in this section.

Sources of Vitamin D

The major source of vitamin D is synthesis within skin. Provitamin D3 in skin is photolysed by ultraviolet-B radiation in sunlight to previtamin D3. This is then isomerised to vitamin D3 and transported to the liver where it is converted to 25-hydroxyvitamin D3. It then undergoes further hydroxylation in the kidney to its activated form 1, 25-dihydroxyvitamin D3.

Dietary sources of vitamin D are generally poor. Only table margarines and some low fat milks, cheeses and yoghurts have been fortified with low levels of vitamin D. Vitamin D is also found naturally in liver, fatty fish (eg tuna, salmon, sardines, mackerel and herring) and egg yolk.³² Dietary oral supplements of vitamin D are also available within Australia.

Vitamin D Deficiency in Australia – The Facts

There has been a longstanding assumption that Australians as a whole receive adequate sunlight exposure and thereby synthesise vitamin D. However, several studies identified specific groups who are at risk of vitamin D deficiency within the community. These include dark-skinned and/or veiled pregnant women,³³ mothers of infants with rickets³⁴ and institutionalised individuals, in particular the elderly.³⁵ Also individuals with malabsorptive illnesses of the gut such as Coeliac disease may not absorb adequate amounts of vitamin D from the diet.³⁶

Furthermore, in populations historically thought not to be at an increased risk of vitamin D deficiency, vitamin D deficiency rates are surprisingly high. In a community based study of women aged 20 – 92 years living in Geelong, moderate to severe vitamin D deficiency was found in 7.2% of all women and mild vitamin D deficiency was found in 30% of all women. The frequency of vitamin D deficiency was increased in the winter months compared to the summer months, with rates of moderate to severe deficiency increasing to 11.3% and mild deficiency to 43.2% of the population.³⁷ Dietary intake of vitamin D was also assessed in this study and it was found that dietary intake did not influence vitamin D levels in the summer months as the primary source of vitamin D was through exposure to sunlight. However, in the winter months dietary intakes of vitamin D were insufficient in compensating for the loss of sunlight exposure.³⁷

Classification of Vitamin D Deficiency

The following table provides a classification for vitamin D deficiency according to measured serum levels of vitamin D.

	Classification of Vitamin D Deficiency
	Classification 25-OH vitamin D levels  Mild 25 – 50 nmol/L Moderate 12.5 and 25 nmol/L Severe < 12.5 nmol/L

There also remains controversy with regards to what optimal level of measured 25-OH vitamin D3 is needed, in order to maintain adequate bone health. Measured levels above 60 nmol/L are probably needed based on a study by Trivedi et al.³⁸

Recommendations for Oral Vitamin D Intake to Avoid Deficiency

The recent position statement has recommended appropriate levels of vitamin D intake which are necessary at various life stages, in order to avoid deficiency. The recommendations for those under 70 years of age, are derived from USA dietary recommendations (US Food and Nutrition Board).³⁹

	Recommended Dietary Intake of Vitamin D
	Age Vitamin D < 50 years 200 IU (5 ug)  50 – 70 years 400 IU (10 ug)  > 70 years 600 IU (15 ug)  Elderly (NH, SAH) 1000 IU (25 ug)  Sun avoidance 1000 IU (25 ug)

Estimated dietary intake of vitamin D in adult Australians is between 80-120 IU.³² This clearly falls short of the recommendations for most Australians. Currently, there is debate among health care professionals with an interest in bone health on the merit of increased fortification of food with vitamin D. However, additional fortification with vitamin D is only likely to increase intake to approximately 200 IU daily providing sufficient Vitamin D replacement for those at low risk (less than 50 years) and for the more vulnerable groups within the community (those greater than 50 years).³²

Recommendations for Sunlight Exposure

The recommended time of exposure to sunlight in Australia is approximately 10-15 minutes on at least 4-6 occasions each week, with the face, arms and hands exposed.

This recommendation is based on the assumption that whole body exposure of 10-15 minutes to midday sun in summer will provide approximately 1 minimal erythemal dose [MED]. This is the amount of sun exposure which produces faint redness of the skin and is equivalent to an intake of 15,000 IU (375ug) of vitamin D3 (cholecalciferol) orally. Therefore, by exposing just the hands, face and arms, which is equivalent to 15% body surface area (i.e. 1/3 of MED) for 10-15 minutes, will result in production of around 1000 IU of vitamin D₃ (cholecalciferol) within the body. However, it is important to realise that the 1/3 of MED varies with latitude, season, time of day and skin type, as illustrated below.

	Recommended sun exposure times (minutes)
	which result in 1/3 MED for people with moderately fair skin at different times of day Region December – January July – August   At 10:00 or 14:00 At 10:00 or 14:00  At 12:00 Northern Australia       Cairns 6–7 9–12 7 Townsville 5–7 9–13 7 Central Australia        Brisbane 6–7 15–19 11 Perth 5–6 20–28 15 Southern Australia       Sydney 6–8 26–28  16  Adelaide 5–7 25–38 19 Melbourne 6–8 32–52 25 Hobart 7–9 40–47 29 New Zealand       Auckland 6–8 30–47 24 Christchurch 6–9 49–97 40 "Working Group of the Australian and New Zealand Bone and Mineral Society, Endocrine Society of Australia and Osteoporosis Australia. Vitamin D and adult bone health in Australia and New Zealand: a position statement. MJA 2005; 182: 281-285. ©Copyright 2005. The Medical Journal of Australia - reproduced with permission".

In general around 10 minutes per day all year around in warmer climates and in cooler climates 10 minutes in summer and 30-45 minutes in winter is adequate.

The use of sunscreen does affect the production of pre-vitamin D within the skin. Sunscreen protects against UVA and UVB ultraviolet light. It is the UVB which is responsible for Vitamin D formation in skin, as well as skin cancer development. There obviously needs too be a balance between being ‘sun-smart’ and receiving the necessary amount of sunlight exposure to maintain adequate vitamin D levels. It is probably reasonable to avoid the use of sunscreen for short periods in the sun, such as when exposure is 5–15 minutes (<1/2 MED). Short term sun exposure is also more beneficial than prolonged periods within the sun for enhancing vitamin D levels.⁴⁰ Prolonged sun exposure leads to irradiation and degradation of pre-vitamin D3 in the skin to inert by-products.⁴⁰ Caution still needs to be exercised for exposure to sunlight between 10:00 am and 14:00pm (or 11:00 and 15:00 during daylight saving) in the warmer months, due to skin cancer risk. Any prolonged exposure to sunlight beyond 15 minutes, necessitates the use of sunscreen.

Preparations of Oral Vitamin D Supplements Available in Australia

There are two forms of oral vitamin D supplements available within Australia.

• Cholecalciferol (vitamin D₃)
  - This form of vitamin D is produced in skin through UV light exposure of 7-dehydrocholesterol which ultimately leads to cholecalciferol production.
• Ergocalciferol (vitamin D₂)
  - Produced by UV irradiation of the plant steroid ergosterol. This is the major form of supplementation of vitamin D available in Australia. (However, newer vitamin D₃ containing preparations have recently been released.

	Ostelin (Ergocalciferol 1000 IU/capsule) Osteovit (Cholecalciferol 1000 IU/capsule) Cod liver oil tablets (Cholecalciferol containing approximately 400 IU of vitamin D; these also contain vitamin A) Combined calcium & vitamin D supplement (quantity of cholecalciferol varies from 32-200 IU/tablet, depending on brand of supplement) Calcitriol (for use in those with significant renal or liver disease) (1-25-OH Vitamin D)

Correction of vitamin D deficiency

The recent position statement has recommended that correction of moderate to severe vitamin D deficiency (25-OH vitamin D ≤ 25 nmol/L) requires the administration of 3000-5000 IU (75 –125 µg) of oral vitamin D (Ostelin or Osteovit) per day for at least 6 – 12 weeks, followed by 1000 IU per day.1 Large doses of vitamin D are required to replenish vitamin D stores in deficient individuals.

There are no specific guidelines in the position statement on correction of mild vitamin D deficiency, doses of 1000-2000 IU (25-50ug) of oral vitamin D daily are reasonable . For individuals with measured 25-OH vitamin D levels greater than 50 nmol/L, the intake of oral vitamin D should correspond closely to the age recommendations for maintenance of Vitamin D levels. (See table: Recommended Dietary Intake of Vitamin D)

Calcitriol, which is an activated form of vitamin D (1-25- OH Vitamin D), is only recommended for individuals with severe liver or kidney disease as it can cause side effects including hypercalcaemia, is expensive, and is only justified in those who cannot convert standard Vitamin D supplement to activated Vitamin D.

Monitoring of Vitamin D Therapy

Assessing the adequacy of vitamin D replacement therapy can prove difficult. This is partly due to methodology issues for measuring 25-OH vitamin D. Most commercially available assays in Australia measure 25-OH vitamin D3 and may not accurately assess vitamin D replacement as most commercially available forms of oral vitamin D in Australia are found as vitamin D2 (ergocalciferol). This may result in measured vitamin D levels not altering despite lengthy treatment with oral vitamin D2. In this scenario, where the patient is taking oral vitamin D2, it may be more appropriate to assess parathyroid hormone (PTH) level responses to oral vitamin D2 therapy rather than measuring 25-OH vitamin D levels, particularly in cases of moderate or severe vitamin D deficiency. There are vitamin D3 oral supplements available on the Australian market. Some of these supplements also contain vitamin A and must be used with caution in some individuals, particularly pregnant women. However these therapies do offer the advantage of being measurable on the commercially available vitamin D assays. Currently, this should not negate the use of oral forms of vitamin D replacement which contain 25-OH vitamin D2, yet,, there is increasing evidence that vitamin D3 is probably more beneficial for vitamin D replacement therapy than vitamin D2.⁴¹

There is often a lag time in response of measured 25-OH levels to oral vitamin D replacement. This is due to the highly fat soluble nature of vitamin D and its distribution within the large body fat compartment, before distribution within the smaller extracellular fluid compartment. It takes several months to correct vitamin D deficiency, particularly in Australia due to availability of only low dose oral vitamin D preparations.

When commencing vitamin D therapy it is advisable to measure 25-OH vitamin D levels, as well as a baseline PTH level, calcium and albumin, phosphorus and ALP (alkaline phosphatase). For monitoring of response to vitamin D replacement, it is best to measure 25-OH vitamin D 3-4 months after commencing therapy. There are no guidelines as to how frequently vitamin D levels should be measured after this, but in the author’s opinion it is probably reasonable to check the levels 3-4 months after any change in dose and once levels are stable to measure them on an annual basis. If using vitamin D2 as replacement, it may be worthwhile measuring the PTH level, as this will reflect adequacy of replacement. In this setting, a measure of calcium and albumin levels is also important, to allow correct interpretation of PTH levels..

Toxicity from inactivated vitamin D therapy is unlikely even with doses up to 4000 IU (100 ug) daily, however is common with activated 1-25-OH Vitamin D replacement.¹⁰³ 

Beneficial Effects of Vitamin D

In women with established osteoporosis, it is important to ensure that vitamin D levels are in an optimal range, along with calcium intake. Supplementation with vitamin D in postmenopausal women in a meta-analysis has been shown to reduce the incidence of vertebral fractures, with a trend in reduction of non-vertebral fractures.¹⁰⁴ Vitamin D supplementation, if given in high doses appears to be most effective in the institutionalised elderly¹⁰⁵ in terms of reduction in fractures. One recent meta-analysis of seven randomised controlled trials found that 700-800 IU of vitamin D daily with or without concurrent calcium supplementation was required to prevent hip and other non-vertebral fractures in ambulatory or institutionalised elderly over 60 years of age.¹⁰⁶ However, this finding remains controversial as a recent randomised control trial in the UK of community dwelling women over 70 years of age, who were given 800 IU of vitamin D (cholecalciferol) and 1000mg of supplemental calcium did not show a benefit.¹⁰⁷

Vitamin D may reduce fractures in many ways other than increasing bone density. In a recent meta-analysis Vitamin D therapy was found to reduce the likelihood of falls in the elderly who were community dwelling or institutionalized.¹⁰⁸ This effect was evident particularly for women, but not for men with a limited number of males in the analysis.¹⁰⁸ Doses of 800 IU/daily of vitamin D were needed to prevent falls, with lower doses being ineffective.^108,109 The potential benefits for vitamin D on falls risk probably stems from improvements in musculoskeletal function.^110,111

Content updated February 20, 2006