About vitamin D

The functions, sources and metabolism of vitamin D were described in our recent article on vitamin D deficiency in children.1 In summary, vitamin D regulates calcium and phosphate absorption and metabolism, which is essential for healthy bones. It may also help to maintain a healthy immune system and regulate cell growth and differentiation. The main source of vitamin D is from the action of UVB sunlight on the skin, which results in the formation of vitamin D₃ (colecalciferol). The rest comes from the diet, as either vitamin D₂ (ergocalciferol) from plant sources, or vitamin D₃ from animal sources. Vitamins D₂ and D₃ undergo a first hydroxylation in the liver to form 25-hydroxycholecalciferol (25OHD; calcidiol); then, to become fully active, 25OHD is further hydroxylated in the kidney to form 1α,25-dihydroxycholecalciferol (1α,25(OH)₂D; calcitriol).

Vitamin D deficiency

Extensive covering with clothing, failure to spend time outdoors or the use of anti-UVB sunscreens results in decreased skin synthesis of vitamin D and increases the likelihood of primary vitamin D deficiency, as does an inadequate diet.1 In people aged over 65 years, an inadequate diet, reduced gut absorption and reduced mobility increase that risk, especially in those in residential care.3^,4^,9

In adults, vitamin D insufficiency can be asymptomatic or may present with the insidious onset of non-specific musculoskeletal aches.10 Most patients with vitamin D deficiency who present clinically do so because of muscle weakness, or muscle aches and pains. Muscle weakness may be marked and is usually most noticeable in the quadriceps and glutei, when it can result in difficulty in rising from a chair and in a waddling gait. There may also be localised or generalised bone pain, local bone tenderness and, rarely, swelling and redness at pseudofracture sites (Looser's zones on X-ray). There may also be fractures. However, there may be no clinical features, even in those with proven defective mineralisation of bone, or osteomalacia, on bone biopsy. In the presence of osteoporosis, vitamin D insufficiency further amplifies bone loss and this may increase fracture risk.11 In a study involving Swedish women aged 75 years, a 25OHD concentration below 50nmol/L (20µg/L) doubled the fracture risk (hazard ratio [HR] 2.04, 95% CI 1.04-4.04).12 Vitamin D deficiency may also lead to secondary hyperparathyroidism, and when this occurs, there is a significant increase in fracture risk.

Epidemiological studies have shown an association between vitamin D insufficiency and an increased likelihood of cancer, type 2 diabetes mellitus, metabolic syndrome, hypertension, multiple sclerosis and inflammatory bowel disease.13–15 However, it is not known whether correction of vitamin D insufficiency weakens these associations. A recent double-blind randomised placebo-controlled trial found that vitamin D plus calcium did not reduce the likelihood of colorectal cancer.16

Secondary vitamin D insufficiency, requiring prophylactic supplementation, can occur with fat malabsorption (e.g. due to coeliac disease, pancreatic insufficiency); gastrointestinal bypass surgery; gastrectomy; parenteral nutrition; or medication (e.g. carbamazepine, phenytoin). Hepatic disorders impair vitamin D hydroxylation and renal failure impairs vitamin D activation.

Diagnosing vitamin D deficiency

Vitamin D concentration

The mainstay in the diagnosis of vitamin D deficiency, apart from being alert to it as a potential cause of non-specific musculoskeletal symptoms, is measurement of serum concentrations of 25OHD.1 However, there is no consensus about the definition of a replete or deficient vitamin state with respect to 25OHD concentrations.1 A 25OHD concentration below around 25nmol/L (10µg/L) is probably consistent with vitamin D deficiency, which may be associated with osteomalacia. Concentrations of 30-50nmol/L (12-20µg/L) are generally considered a sign of vitamin D insufficiency, in which there may be biochemical disturbances with or without non-specific musculoskeletal symptoms.1 Consequently, some specialists argue that true vitamin D sufficiency, in which all parameters of calcium metabolism are entirely normal, only occurs when serum 25OHD concentrations are at least 50nmol/L (20µg/L).1 However, we know of no published outcome data to show that long-term health is improved by giving vitamin D supplements to keep the serum concentration at 50nmol/L or higher.

Other biochemical markers

Routine biochemical profiles of serum calcium, phosphate and alkaline phosphatase may sometimes be helpful in the diagnosis of vitamin D deficiency. However, serum calcium and phosphate concentrations only fall in longstanding, symptomatic, vitamin D deficiency. Levels of alkaline phosphatase (total and bone-specific) increase early in vitamin D deficiency. This is a non-specific finding, but may be helpful in diagnosing individuals with otherwise unexplained elevations in alkaline phosphatase.

Radiological assessment

Radiological assessment is not routinely indicated in asymptomatic individuals. X-rays of locally painful or tender areas, and of the ribs, lumbar spine and pelvis may suggest longstanding, symptomatic deficiency by identifying Looser's zones, cortical thinning and reduced mineralisation; they also help in excluding other conditions. Commonly, the clinical picture involves general skeletal deformity that may include vertebral crush fractures, trefoil pelvis, and spontaneous fractures of the ribs, pubic rami or femoral neck.

Bone biopsy

Bone biopsy, a long-established way of confirming osteomalacia, shows widened osteoid seams, even in patients without symptoms of the condition. However, it is rarely used now that immunoassays of serum 25OHD are available.

When to refer

It is advisable to refer a patient with vitamin D deficiency to a relevant specialist if there is no obvious cause; if there is unexplained weight loss or anaemia or any other suggestion of coeliac disease or fat malabsorption; if medication (e.g. antiepileptic drugs, rifampicin) might be the cause; if the patient has hepatic or renal disease; or if there is any illness associated with undue sensitivity to vitamin D and so an increased risk of toxicity with treatment (e.g. sarcoidosis, tuberculosis, lymphoma, primary hyperparathyroidism).17 Also, symptomatic patients who have taken supplements as directed for about 2 months with no improvement clinically or in vitamin D status should be referred to a specialist.

Preventing vitamin D deficiency

In people with fair skin, exposure of the hands, arms, face, or back to suberythemal doses of sunlight in the UK, from April to September, for 15 minutes two or three times a week, should result in sufficient skin synthesis of vitamin D; those with darker skin may need longer exposure.1^,18 In the UK, guidance from the Committee on Medical Aspects of Food and Nutrition Policy (COMA) states that, for adults aged 65 years or older or those at risk (e.g. women who wear clothes to cover themselves extensively), the RNI for vitamin D is 10µg (400 IU) daily.19 It does not include a reference nutrient intake (RNI) for adults aged 18-64 years. By comparison, in the USA, the Institute of Medicine of the National Academy of Sciences has set an 'Adequate Intake' for vitamin D of 5µg (200 IU) daily for people aged 19-50 years; 10µg (400 IU) daily for those aged 51-70 years; and 15µg (600 IU) daily for those aged over 70 years.20

Foods with a high vitamin D content (10-20µg per 100g) include herring, sprat, pilchards, sardines and rainbow trout.21^,22 Those with a moderate content (5-10µg per 100g) include salmon, tuna, mackerel, margarine and some supplemented breakfast cereals.21^,22 Those with a low content (1-5µg per 100g) include eggs, ghee, tinned evaporated milk, some supplemented breakfast cereals, and oysters.21^,22 Those with trace amounts (below 1µg per 100g) include other shellfish, butter, milk and cheeses.21^,22 In a survey in Great Britain of the diet and nutrition of adults aged 19-64 years living in private households, carried out between July 2000 and June 2001, the mean daily intake of vitamin D from food sources was 3.7µg for men and 2.8µg for women.23

Either colecalciferol or ergocalciferol can be used to prevent primary vitamin D deficiency. A daily dose of 10µg (400 IU) is adequate to prevent simple vitamin D deficiency in otherwise healthy adults at risk of deficiency.24 Those adults at high risk of vitamin D deficiency (e.g. south Asians, people aged over 65 years and living alone) may require higher doses (e.g. 20µg [800 IU] daily).24–26

Treating primary deficiency

Adults with confirmed primary vitamin D deficiency need a minimum daily dose of oral vitamin D of 20µg (800 IU).24 With this dose, it takes at least a year for bone to normalise.27 Higher doses of vitamin D, to a maximum of 55µg (2,200 IU) daily, may be needed to achieve adequate repletion with vitamin D, especially in older patients, and in 'at risk' ethnic minorities (e.g. south Asian, African Caribbean and Middle Eastern) and to achieve optimal health benefits for bone and soft tissue.28 Once vitamin D deficiency or insufficiency has been corrected, patients will generally need lifelong preventative vitamin D supplementation.

Preventing falls and fractures

A meta-analysis of five double-blind randomised controlled trials, involving a total of 1,237 older people (mean age 70 years) and lasting between 3 months and 3 years, found that vitamin D supplements reduced the risk of falling by 22% (odds ratio [OR] 0.78, 95% CI 0.64-0.92); the number-needed-to-treat (NNT) to prevent one fall was 15 (95% CI 8-53).29 The studies included did not specifically look at people with vitamin D deficiency or insufficiency, and in three of the trials, the vitamin D was combined with calcium.

Another double-blind randomised placebo-controlled trial, involving 625 older people (mean age 83.4 years) living in residential care given either oral ergocalciferol (initially 250µg [10,000 IU] weekly then 25µg [1,000 IU] daily) or placebo for 2 years, assessed falls (the primary outcome measure) and fractures recorded prospectively in study diaries by care staff.30 All participants also received daily calcium (600µg as calcium carbonate). The treatment reduced the likelihood of falling by 27% (incident rate ratio 0.73, 95% CI 0.57-0.95). The difference in fracture rate between the two groups was not significant.

A meta-analysis of 12 double-blind randomised controlled trials, involving a total of 19,114 people aged 60 years or more and lasting 1-5 years, looked at the effectiveness of supplementation with colecalciferol 17.5-20µg (700-800 IU) daily in preventing hip and non-vertebral fractures in older people.31 The relative risk of hip fracture was reduced by 26% (relative risk [RR] 0.74, 95% CI 0.61-0.88) and any non-vertebral fracture by 23% (RR 0.77, 95% CI 0.68-0.87) with vitamin D compared with calcium or placebo.

A systematic review looked at 38 randomised or quasi-randomised trials, involving a total of 49,433 participants and lasting 2-5 years, which assessed the effects of vitamin D or analogues, with or without calcium, in the prevention of fractures in postmenopausal women, or men aged over 65 years.32 The main findings were that vitamin D given alone in daily doses of 20µg (800 IU) or less had no effect on hip fracture (seven trials, 18,668 participants); vertebral fracture or deformity (four trials, 5,698 participants); or any new fracture (eight trials, 18,903 participants). However, vitamin D plus calcium helped prevent hip fractures (seven trials, 10,376 participants, RR 0.81, 95% CI 0.68-0.96) and non-vertebral fractures (seven trials, 10,376 participants, RR 0.87, 95% CI 0.78-0.97), but not vertebral fractures. The reviewers concluded that frail older people confined to institutions may sustain fewer hip and other non-vertebral fractures if given vitamin D plus calcium, but that the effectiveness of vitamin D alone in fracture prevention is unclear. UK guidelines33 and those for other developed countries, such as New Zealand,34 recommend that institutionalised older people are given calcium plus vitamin D to reduce fracture risk.

Another double-blind randomised placebo-controlled trial (mean follow-up 7 years), involving 36,282 healthy post-menopausal women (mean age 62 years), assessed the efficacy of vitamin D₃ (10µg [400 IU]) plus calcium (1,000µg as calcium carbonate) daily in the prevention of hip fractures.35 The decrease in total hip bone density was less with supplementation (mean difference at year 9, 1.06%, p=0.01). Supplementation did not reduce the likelihood of hip fracture, but increased the risk of kidney stones (2.47% vs. 2.10% with placebo, HR 1.17, 95% CI 1.02-1.34).

Supplements

Many people self-supplement with over-the-counter preparations (e.g. capsules, liquids) of cod or halibut liver oils containing 2.5-20µg (100-800 IU) doses of vitamin D.

Most prescribable vitamin D supplements also contain calcium, vitamin A or multivitamins, even though calcium and other vitamins in supplements are not required for the prevention or treatment of isolated primary vitamin D deficiency. Preparations available on the NHS cover the range of supplemental doses suggested for adults of different ages and ethnic groups, provided the concomitant calcium is tolerated or taking vitamin A is acceptable. Alfacalcidol or calcitriol should not be used for the routine treatment of primary vitamin D deficiency as, unlike vitamin D, they carry a higher risk of toxicity and require long-term close monitoring. There are no suitable preparations available on the NHS for situations where stand-alone vitamin D supplementation would be preferable, as in pregnancy (when excess vitamin A must be avoided).1 In people without osteoporosis, there is no advantage in using the more expensive vitamin D plus calcium combinations in prevention, when vitamin capsules provide an adequate amount of vitamin D at a fraction of the cost. The high-dose oral preparations of vitamin D alone require specialist advice before use. An alternative to daily oral treatment is intermittent vitamin D in a parenteral formulation at doses of 2.5-7.5µg (100,000-300,000 IU) every 6 months;36 or 1.25µg (50,000 IU) orally once monthly.37 These regimens are not suitable for pregnant or breastfeeding women.

Contraindications, precautions and interactions

Vitamin D is contraindicated in patients with hypercalcaemia or metastatic calcification. Relative contraindications include primary hyperparathyroidism, renal stones and severe hypercalciuria. Patients with mild to moderate renal failure or known to have mild hypercalciuria should be supervised carefully when taking vitamin D. Serum calcium concentrations should be checked regularly for a few weeks after starting treatment for vitamin D deficiency and then vitamin D, parathyroid hormone (PTH) and calcium concentrations should be checked after 3-4 months of treatment to assess efficacy and adherence to therapy. Thereafter, vitamin D and calcium concentrations should be checked every 6-12 months. In patients with a history of renal stones, urinary calcium excretion should be measured to exclude hypercalciuria, a problem which requires specialist referral.

Concomitant treatment with phenytoin, barbiturates or corticosteroids can decrease the effect of vitamin D because of changes in metabolic activation. The effects of digoxin and other cardiac glycosides may be accentuated by oral administration of calcium plus vitamin D, so strict medical supervision is needed in patients on this combination and, if necessary, monitoring of ECG and calcium concentrations. The risk of hypercalcaemia should also be considered in patients on thiazide diuretics, as they can reduce urinary calcium excretion. Calcium salts may reduce absorption of levothyroxine, bisphosphonates, sodium fluoride, quinolone or tetracycline antibacterials or iron. So it is advisable to allow 2-4 hours before taking a calcium-containing vitamin D supplement when on such medication.

Non-adherence to therapy

The commonest reason for PTH concentrations to fail to normalise in patients being given vitamin D for deficiency is non-adherence to therapy. For example, one study of patients whose PTH concentrations failed to normalise, found that only 17% of prescriptions for vitamin D had been collected.27 This problem may be overcome by, for example, giving intermittent high-dose parenteral or oral vitamin D.36^,37

Vitamin D toxicity

At recommended supplemental or therapeutic doses vitamin D toxicity does not occur in the absence of conditions that cause undue sensitivity to vitamin D. The Food Standards Agency has suggested 25µg (1,000 IU) of vitamin D daily is unlikely to cause any harm in the general population.38 Research suggests up to 250µg (10,000 IU) can be taken daily by healthy people for up to 16 weeks without toxicity.29 Early symptoms of toxicity include symptoms of hypercalcaemia such as thirst, polyuria and constipation. Toxicity can lead to renal failure, which can rapidly become irreversible. If toxicity is suspected, vitamin D must be withdrawn and serum calcium and renal function checked urgently, since emergency inpatient care with rehydration is usually indicated.

Click here to view a table showing the approximate cost of vitamin D therapy

Conclusion

Primary vitamin D deficiency is common in adults of all ages in the UK and other developed countries. People particularly at risk include certain ethnic minority groups (e.g. south Asian, African Caribbean, Middle Eastern); housebound people; those aged over 65 years; those in residential care; and those inadequately exposed to spring/summer sunshine. Non-specific aches and pains are early symptoms of vitamin D deficiency, but deficiency needs to be confirmed by measurement of 25-hydroxycholecacliferol serum concentrations. The clinical manifestations of primary vitamin D deficiency can be treated with an oral supplement of 20µg (800 IU) ergocalciferol daily. Vitamin D and calcium supplementation can help prevent falls and may reduce the likelihood of hip and non-vertebral fractures in institutionalised elderly people, so should be offered to such individuals. It is, however, worth bearing in mind the recent evidence that a combination of vitamin D 10µg (400 IU) plus calcium 1,000µg daily may increase the likelihood of kidney stones in healthy postmenopausal women. Current evidence does not support routine population-based preventative supplementation with vitamin D alone in all high-risk groups.