Document Title: Document Purpose: Document Statement: Document Application: Responsible for Implementation: Vitamin D deficiency and insufficiency guidelines To improve the management of patients with Vitamin D deficiency and insufficiency in Primary and Secondary Care settings To provide guidance on dosage regimen and appropriate products Clinical Doctors and pharmacists Main imperatives of this document are: Document Classification: Clinical Practice Document Reference: Version Number: 1 Secondary Reference: Issued by: Pharmacy Effective Date: September 2012 Author: Medicines Information Pharmacist Sponsor: Associated Documents 1. APPROVAL RECORD Validated by Facilitator: Document control group Date: September 2012 Agreed by Specialist Group: MMC Date: September 2012 Agreed by Board Sub- Committee: Approved by Board Committee: Date: Date: Approved: MMC Date: September 2012 Date of Issue: September 2012 Page 1 of 10
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Vitamin D Guidelines Aim of guidelines The aim of these guidelines is to improve the management of patients with Vitamin D deficiency and insufficiency in Primary and Secondary Care settings. Introduction (1) Vitamin D compounds are fat soluble sterols which are essential for the absorption and utilisation of calcium and phosphorus (in the form of inorganic phosphate) in the body to maintain normal calcification of the skeleton and bone mineralisation. Along with parathyroid hormone (PTH) the active form of vitamin D (25-OHD) regulates serum calcium concentration by altering serum calcium and inorganic phosphate blood levels as needed. It maintains neuromuscular function and various other cellular processes, including the immune system and renin and insulin excretion affecting CVD risk. The major natural source of vitamin D is from skin photosynthesis following ultraviolet B sunlight exposure. Over 90% of the body s vitamin D is produced from the action of sunlight on the skin. Small amounts of vitamin D are also obtained from oily fish, egg yolks, mushrooms, fortified breakfast cereals, milk and margarine. The only means of confirming deficiency is by the measurement of serum 25-OHD concentrations. There is no agreed definition for vitamin D deficiency. A plasma concentration of <25nmol/L for 25-OHD levels has been used as the lower limit of adequacy of vitamin D status. There is no consensus on optimal levels of serum 25-OHD, some experts suggest that a desirable 25-OHD concentration is 75nmol/L, while others have suggested 60ng/ml to be an appropriate level. Achieving this blood level typically requires a daily vitamin D intake of 20 25mcg (800-1000IU). Reviews of the diagnosis and management of vitamin D deficiency have given some guidance on vitamin D levels, and effects on health and management of deficiency, see table 1. Table 1 Vitamin D levels, effects on health and management of deficiency Vitamin D Vitamin D status Health effect Management level <25nmol/l Deficient Rickets, Osteomalacia High dose calciferol 25-50 nmol/l Insufficient Associated with disease Vitamin D supplements 50 75 nmol/l Adequate Healthy Lifestyle advice >75nmol/l Optimal Healthy None The average adult daily diet in the UK provides only 3.7mcg of vitamin D for men and 2.8mcg for women (10mcg = 400 units). Excellent food sources (greater than 5mcg per portion) of vitamin D include 2 teaspoons cod liver oil, 70g sardines, 100g tinned salmon, pilchards or tuna, 110g of cooked mackerel or herring and 130g cooked kipper. These intakes alone, in the absence of skin synthesis, will not provide optimal vitamin D status. Vitamin D can be replenished by sun exposure without burning and no sunscreen use or via dietary sources or administration of vitamin D, either orally or intramuscularly. A US study Date of Issue: September 2012 Page 3 of 10
suggested 5-15 minutes daily sun exposure between 10am and 3pm from April to October would be sufficient to improve vitamin D status. In a fair skinned person, 20-30 minutes of sunlight exposure to the face and forearms at midday generates about 2000 units of vitamin D. UK guidance on skin cancer prevention emphasises the importance of appropriate sun protection, including use of sunscreen and spending time in the shade between 11am and 3pm. Two or 3 sunlight exposures per week are sufficient to achieve vitamin D levels in the summer if individuals have adequate levels to begin with. However, those with a deficiency, pigmented skin and the elderly need increased exposure time or frequency to get the same level of vitamin D synthesis. Sun exposure should be avoided if someone has a history of skin cancer, or conditions such as xeroderma pigmentosum or actinic keratosis. Treatment of deficiency is not the same as supplementation for insufficiency. The primary aim for deficiency is to replenish vitamin D stores then continue with a lower maintenance dose of vitamin D which may be lifelong. It is suggested that daily doses of 10,000IU or weekly doses of 60,000IU will restore body stores of vitamin D in 8-12 weeks. Large bolus doses are equally effective as daily doses and may be preferred when compliance with long term therapy is poor. Most articles do not specify whether to use ergocalciferol or colecalciferol, and state doses in international units (IU) for calciferol which can be applied to either preparation. To convert doses in international units to micrograms, divide by 40. Vitamin D is administered as either D2 or D3 salts. Both D2, ergocalciferol and D3, colecalciferol are physiologically inactive and have to be hydroxylated in the liver and kidneys to form active compounds. Colecalciferol and ergocalciferol are considered to have equal potency although colecalciferol has been reported to raise serum vitamin D concentrations more effectively than ergocalciferol due to higher affinities of colecalciferol and its metabolites for liver enzymes, plasma vitamin D binding protein and vitamin D receptors. It has been suggested that this difference in potency makes colecalciferol the drug of choice. Alphacalcidol and calcitriol should NOT be prescribed for vitamin D deficiency, but used in renal disease and in some children with metabolic bone disease of prematurity. Safety of vitamin D Vitamin D is the most likely of all vitamins to cause overt toxicity. Doses of 60,000 units daily can cause hypercalcaemia, with muscle weakness, apathy, headache, anorexia, nausea and vomiting, bone pain, ectopic calcification, proteinuria, hypertension and cardiac arrhythmias. There is wide variation in tolerance to vitamin D. At recommended supplemental or therapeutic doses toxicity is unlikely. The Food Standards Agency has suggested that using less than 20mcg (800 units) of vitamin D daily is unlikely to cause any harm in the general population. Research suggests up to 250mcg (10,000 units) can be taken daily by healthy people for up to 16 weeks without toxicity, use beyond 6 months may result in toxicity. Infants and children are generally more susceptible than adults to adverse effects. Excessive intake can lead to hypercalcaemia and its associated effects. Symptoms of toxicity include apathy, anorexia, constipation, diarrhoea, dry mouth, fatigue, headache, nausea, vomiting, thirst and weakness. Toxicity can lead to calcification of soft tissues and include bone pain, cardiac arrhythmias, hypertension, kidney damage (increased urinary frequency, decreased urinary concentration; nocturia, proteinuria), psychosis (rarely) and weight loss. If toxicity is Date of Issue: September 2012 Page 4 of 10
suspected, vitamin D must be withdrawn and serum calcium and renal function checked urgently, since emergency inpatient care with rehydration is usually indicated. Patients who are symptomatic and hypercalcaemic should have their management discussed with specialist clinicians without delay. Vitmain D requirements are possibly increased with concomitant use of barbituates, carbamazepine, phenytoin and primidone. Supplements of vitamin D also containing vitamin A should not be prescribed in pregnancy as excessive vitamin A doses are associated with foetal CNS malformations. Causes of vitamin D deficiency (2) The main causes are summarised in the table below. Reduced /skin synthesis Sunscreen use Skin pigmentation Ageing Season, latitude, time of day Patients with skin grafts Low UVB exposure among the housebound Decreased bioavailability Malabsorption (cystic fibrosis, Coeliac disease, Crohns, bypass surgery, medications that reduce cholesterol absorption) Obesity (possible reduced availability of vitamin D) Increased catabolism Drugs such as anticonvulsants and glucocorticoids activate the catabolism of both 25- OHD and calcitriol Exclusive breast feeding > 6/12, multifoetal, close pregnancies Increased urinary loss Nephrotic syndrome Impaired vitamin D hydroxylation Liver failure Impaired vitamin D activation Chronic kidney disease Inherited enzyme deficiency Acquired disorders Primary hyperparathyroidism Granulomatous disorders (TB, sarcoidosis) are associated with increased activation of calcitriol. Vitamin D disorders in adults (2) Patients with vitamin D deficiency in whom there is suspicion of malabsorption, renal or hepatic disease, or where there is a co-existing condition leading to increased risk of toxicity with treatment, should be discussed with secondary care before initiating treatment. Symptomatic deficiency: Osteomalacia (2) In adults vitamin D deficiency can lead to osteomalacia. This often presents insidiously with bone pain, proximal muscle weakness and diffuse muscular aches. It is also associated with increased fracture risk. Biochemical abnormalities include hypocalcaemia, hypophosphataemia Date of Issue: September 2012 Page 5 of 10
(both of which tend to be associated with longstanding symptomatic vitamin D deficiency) and raised alkaline phosphate, which rises early in vitamin D deficiency. Investigations (2) Renal functions test (U&E, egfr) Bone profile (Ca, PO4) Liver function tests Ferritin (to indentify multiple vitamin deficiencies) TFTs to exclude hypothyroidism ESR where polymyalgia, inflammatory arthritis, or myeloma might be considered PTH will be elevated in vitamin D deficient states, but routine measurement is not indicated except for patients with CKD. Persistently painful areas of bone may require further imaging to exclude other causes. Management of Vitamin D deficiency and insufficiency in adults (1) Table 2 Dose of calciferol for treatment and maintenance therapy of vitamin D deficiency in adults Deficiency (25-OHD <25nmol/l) / treatment/ loading dose Adults 10,000 IU calciferol daily for 8-12 weeks or 60,000IU calciferol weekly for 8-12 weeks or Calciferol 300,000 or 600,000 IU orally once or twice only or Calciferol 300,000 or 600,000 IU by IM injection once or twice only The above doses which are used for deficiency treatment are contraindicated in patients with hypercalcaemia or metastatic calcification, or where there may be significant interactions with other medications. Insufficiency (25-OHD 25-50nmol/l) or maintenance therapy following deficiency Adult 1,000-2,000IU calciferol daily or 10,000IU weekly Monitoring in adults (2) No routine monitoring is necessary for patients on long term maintenance doses of vitamin D up to 2,000IU a day. There is no indication to monitor ALP routinely Vitamin D status and serum calcium should be checked at 8-12 weeks following treatment for deficiency. Calcium levels should also be monitored at 4 and 8 weeks if: Risks of hypercalcaemia are higher than average such as in CKD, active TB, and patients on thiazide diuretics in combination with calcium supplements. Patients on digoxin and other cardiac glycosides where drug effects may be accentuated by vitamin D Any symptoms or signs of hypercalcaemia (anorexia, nausea, thirst, polyuria, vomiting, diarrhoea, confusion) Date of Issue: September 2012 Page 6 of 10
.Vitamin D disorder in children (2) Any child whom you suspect to be hypocalcaemic secondary to vitamin D deficiency should be urgently referred to secondary care. Paediatric reference ranges and definitions of deficiency are the same as for adults (see table 1). Children at risk of vitamin D deficiency /insufficiency: Maternal vitamin D deficiency Pigmented skin Lack of sunlight exposure Exclusively breast feed / delayed weaning/ multifoetal/ close pregnancies Malabsorption e.g.cystic fibrosis Medications e.g. anticonvulsants Rickets (2) The commonest cause of rickets is simple nutrient deficiency from low sun exposure combined with inadequate dietary intake. Malabsorption syndromes such as coeliac disease and cystic fibrosis should be considered, especially where there is a poor response to vitamin D treatment. Certain metabolic, renal and liver diseases can also lead to rickets. Peak incidence of rickets is between 3 and 18 months of age. A deficient state exists for months before there are any signs on physical examination. Children with rickets are often miserable and in pain. Symptoms and signs of rickets Bowing of legs (genu varum) or knock knees (genu valgum) Anterior bowing of femur Painful wrist swelling (distal radius) Prominent costochondral joints rickety rosary Softening of the skull with frontal bossing, and delayed fontanelle closure Spinal curvature Bone pain Dental deformities (delayed tooth formation, enamel hypoplasia) Investigations (2) Definitive diagnosis is based on specific radiological changes supported by; Renal function tests (U&E, egfr) Bone profile (Ca, PO4) Liver function tests (raised ALP) Hb and Ferritin (to identify multiple vitamin deficiencies) Date of Issue: September 2012 Page 7 of 10
Management of Vitamin D deficiency and insufficiency in children (1) Table 3 Dose of calciferol for treatment and maintenance therapy of vitamin D deficiency in children (1) Deficiency (25-OHD <25nmol/l) Child 1-6 months: 3,000IU calciferol daily, adjusted as necessary for 8-12 weeks 6 months-12 years: 6,000IU calciferol daily, adjusted as necessary for 8-12 weeks or 12-18 years: 10,000IU-40,000IU daily, adjusted as necessary Over 1 year: 300,000IU calciferol in 2 divided doses in poor compliance (Stoss regimen, discuss with local paediatrician) The above doses which are used for deficiency treatment are contraindicated in patients with hypercalcaemia or metastatic calcification, or where there may be significant interactions with other medications. Insufficiency (25-OHD 25-50nmol/l) or maintenance therapy following deficiency Child Under 6 months 200-400IU calciferol daily Over 6 months 400-800IU calciferol daily Monitoring in children following treatment for deficiency (2) All patients receiving pharmacological doses of vitamin D or its analogues should have their plasma-calcium concentration checked at intervals (initially once or twice weekly) and whenever nausea or vomiting occurs. After 3 months vitamin D, serum calcium and ALP should be rechecked. The aim of treatment should be to reach a total Vitamin D level of >80nmol/l, normal ALP for age and resolution of radiological changes if patient had clinical ricketts. If the vitamin D level is not >80n/mol/l continue treatment for further 2-3 months and recheck. Once the total vitamin D level is within the normal range treatment should be changed to maintenance supplements as this group of children are likely to have ongoing risk factors for vitamin D deficiency. The family and siblings of children with rickets are highly likely to be vitamin deficient. It is good practice to review family members and provide supplementation for those at high risk. No routine monitoring is normally needed on maintenance doses. Vitamin D supplements are advised by the DOH for specific groups: (3) All pregnant / breastfeeding women All infants / toddlers from 6mths 5yrs (unless drinking 500ml or more of infant formula) 400IU/day 280IU/day Breastfed babies 1mth 6mths If mother is Vitamin D insufficient / deficient 340 IU/ day People with low sun exposure e.g. confined Indoors or with covered skin 400 IU/ day > 65 yrs old 400IU/ day Date of Issue: September 2012 Page 8 of 10
Vitamin D and renal disease (2) In CKD there is decreased activation of vitamin D in the kidney, along with decreased gut calcium absorption and increased phosphate retention. As the egfr declines these processes may trigger secondary hyperparathyroidism with bone reabsorption, Pathological fractures and metastatic calcification leading to an increased risk of CVD. Up to 30% of CKD stage 3 patients will have disturbance of calcium metabolism. Check the PTH (1-6pmol/l) when the egfr falls to about 45. If the PTH is raised (>7 pmol/l) check vitamin D levels (25 OHD). If this is low, indicating vitamin D deficiency treat with dose aimed at achieving optimal levels (1,000IU a day). Repeat PTH and 25 OHD at around three months. If the PTH remains high (>10 pmol/l) and vitamin D levels are replete suggesting secondary hyperparathyroidism, refer or discuss with Nephrologists. As the egfr declines further there will be inadequate production of active vitamin D (calcitriol). For these patients replacement with alphacalcidol will be needed under the supervision of the renal department. Available vitamin D products (5,6) There a number of vitamin D products available on the market. Below is a small selection of the most suitable for the locality. Products Brand Vitamin D strength Colecalciferol tablets Fultium- 800IU D3 Colecalciferol ProD3 1000 IU capsules 2500 IU 10,000 IU 20,000 IU Liquid Available as 2000 IU/mL or Comments Has a UK licence Does not have a UK licence Is the product of choice for treatment option in adults Obtained from AAH 3000 IU/mL Colecalciferol liquid 3000 IU/ ml Does not have a UK license Is the product of choice for treatment option in children, vegans and those with swallowing difficulties Routine use of liquid preparations is not recommended as there are other cost effective preparation are available. Available from Martindale pharmaceuticals Ergocalciferol Injection 300,000 IU/1mL or 600,000 IU/1.5mL Please check with pharmacy stock availability. Has a UK licence e Date of Issue: September 2012 Page 9 of 10
Vitamin D products suitable for maintenance doses (5) Products (Branded) Vitamin D strength Comments per tablet Adcal D3 400IU Adcal D3 is the only calcium and vitamin Calceos Calcichew D3 Forte Natecal D3 Kalcipos-D 800IU D product stocked at BTUH All contain calcium All are licensed Products (Branded) Cacit D3 Calfovit D3 Vitamin D strength per sachet 440 IU 800 IU Example of children s products or maintenance doses (5) Products (Branded) Vitamin D strength Comments Ketovite liquid 400IU in 5ml All contain multivitamins Dalivit Drops 400IU in 0.6ml All are licensed Abidec Drops References: 1. Medicines Q&A; What dose of vitamin D should be prescribed for treatment of vitamin D deficiency, Date prepared: 29 th October 2012, www.nelm.nhs.uk. 2. Vitamin D guidance; Barts and The London Clinical Effectiveness Group, January 2011 3. VitaminD-advice on supplements for risk groups; DoH, CEM/CMO/2012/04, published 2 nd February 2012. UK CMO CAS Letter Vitamin D 02022012.pdf 4. East and South East England Specialist Pharmacy Services, Vitamin D deficiency and insufficiency, using appropriate products, April 2012, www.nelm.nhs.uk 5. BNF 63, March 2012 6. East & South East England Specialist Pharmacy Services, Vitamin D deficiency and insufficiency, Using appropriate available products, www.nelm.nhs.uk Date of Issue: September 2012 Page 10 of 10