Guidance for the Prevention, Investigation and Treatment of Vitamin D Deficiency and Insufficiency

Guidance for the Prevention, Investigation and Treatment of Vitamin D Deficiency and Insufficiency This document includes the following: Key points and Pathway for treating Vitamin D deficiency and insufficiency in adults Section 1: Background Section 2: Prevention of vitamin D deficiency in at-risk groups Section 3: Investigation and treatment of vitamin D deficiency and insufficiency in adults Section 4 : Treatment of proven vitamin D deficiency and insufficiency for CHILDREN This guidance does not apply to patients with osteoporosis. Where patients are under the care of a specialist, clinicians may like to seek advice. Document history: This work is supported by a scoping report on vitamin D completed by the Kent, Surrey and Sussex (KSS) Health Policy Support Unit and builds on guidance documents developed by KSS and other Primary Care Trusts and Clinical Commissioning Groups. Version control: Version Date Main changes/comments V1 22 October 2012 First draft V2 29 October 2012 Incorporated comments from medicines management V3 6 February 2013 Incorporated comments from local clinicians V4 15 February 2013 Incorporated additional comments from medicines management V5 23 June 2013 Discussed and agreed by Swale Medicines Optimisation Committee V6 11 September 2013 Discussed and agreed by Medway & Swale Drugs and Therapeutics Committee. V6 2 October 2013 Ratified by Medway CCG Clinical Advisory Group. V7 13 November 2013 Approved by Medway CCG Commissioning Committee. Review date: November 2015

Key points 1 In agreement with the Institute of Medicine (IOM), the following are the recommended vitamin D thresholds in respect to bone health: serum 25OHD < 30 nmol/l is deficient serum 25OHD of 30 50 nmol/l may be inadequate in some people serum 25OHD > 50 nmol/l is sufficient for almost the whole population. Oral vitamin D3 is the treatment of choice in vitamin D deficiency. Current, licenced first line products recommended for prescribing include: Desunin 800 IU up to 5 tablets daily for 12 weeks Fultium 800 IU 4 capsules daily for 12 weeks (note: contains peanut oil). Conversion factors 10ug (micrograms) vitamin D = 400IU vitamin D 2.5 nmol/l serum 25OHD = 1 ng/ml serum 25OHD Page 2 of 16

Pathway for treating vitamin D deficiency and insufficiency in adults. No Does the patient have a risk factor for vitamin D deficiency? No further action required Yes Does the patient have at least one symptom suggesting vitamin D deficiency? No Lifestyle advice Recommend OTC supplements* Yes Have other causes for symptoms been excluded? No Manage primary diagnosis Yes Test 25-hydroxyvitamin D (25[OH]D)status Vitamin D deficiency (<30 nmol/l) Vitamin D insufficiency (30-50 nmol/l) Prescribe high dose vitamin D preparation # for 12 weeks. Lifestyle advice. Prescribe high dose vitamin D preparation # for 8 weeks THEN recommend OTC supplements.* Still symptomatic following 12 weeks treatment? Notes: # High dose vitamin D preparation: Desunin 800 IU up to 5 tablets daily for 12 weeks OR Fultium 800 IU 4 capsules daily for 12 weeks (contains peanut oil). Manufacturers licensed doses. Yes Discuss concordance Repeat 25(OH)D test Refer non-responsive patients to secondary care. No Lifestyle advice Recommend OTC supplements*. *Over the counter (OTC) supplements: Colecalciferol 800IU to 2,000IU daily. Printable vitamin D leaflet for patients with suggested OTC treatments is available via http://www.medwayccg.nhs.uk/intranet/medicinesmanagement/?assetdet8241980=369808&categoryesctl828014 6=11253 *Ensure patients who are eligible for the Healthy Start Scheme are aware they can obtain vitamin supplements free of charge. More information is available via http://www.healthystart.nhs.uk/healthy-startvouchers/healthy-start-vitamins/ Conversion factors 10ug (micrograms) vitamin D = 400IU vitamin D 2.5 nmol/l serum 25OHD = 1 ng/ml serum 25OHD Page 3 of 16

Section 1: Background The role of vitamin D Vitamin D is essential for the absorption and utilisation of calcium and phosphorus in the body, both of which are necessary to maintain normal calcification of the skeleton and bone mineralization 2. Vitamin D maintains neuromuscular function and various other cellular processes, including the immune system and insulin production 2. The main manifestation of vitamin D deficiency is rickets in children and osteomalacia in adults 1. Sun exposure is the main source of vitamin D, however it is also found in some foods and supplements (see appendix 1). Implications and prevalence of vitamin D deficiency Implications of vitamin D deficiency Vitamin D is essential for good bone health. Deficiency of vitamin D results in rickets in children and osteomalacia in adults; conditions characterised by pathological defects in growth plate and bone matrix mineralization 3. Patients with osteomalacia often complain of multiple symptoms including bone, joint and muscle pain, hyperalgesia, muscle weakness and a waddling gait 1. In children, failure of bone mineralization gives rise to bone deformities; bones are painful and linear growth is reduced 3. Low vitamin D levels are associated with secondary hyperparathyroidism and low bone mineral density and, thus, a higher risk of fractures 4. Some studies have suggested that low vitamin D levels are associated with an increased risk of certain cancers and other chronic diseases, however evidence of causal associations are yet to be demonstrated 4. Prevalence The National Diet and Nutrition Survey of British adults 8 indicates that up to a quarter of people in the UK have low levels of vitamin D in their blood, which means they are at-risk of the clinical consequences of vitamin D deficiency 9. Seasonal variations in vitamin D status are observed in the UK; levels are highest between July and September and lowest between January and March 3. Page 4 of 16

Factors affecting vitamin D status Factors that potentially affect vitamin D status include 3, 6 : Genetic factors Adiposity Factors affecting cutaneous synthesis of vitamin D such as: skin pigmentation and ethnicity age season and latitude melanin concentration clothing and use of sunscreens atmospheric pollution ability to spend time outdoors Medical conditions: malabsorbtion or short bowel syndrome cholestatic liver disease chronic kidney disease Medications: some anticonvulsants e.g. carbamazepine rifampicin cholestyramine glucocorticoids HAART therapy Page 5 of 16

Section 2: Prevention of vitamin D deficiency in at-risk groups The Department of Health (DH) 9 recommends at-risk groups should take vitamin D supplements as per Table 1. Table 1 DH recommendations for preventing vitamin D deficiency in at-risk groups Group Pregnant women Breastfeeding women Infants and young children People aged 65 years and over People who have low or no exposure to the sun Recommended supplementation Daily supplement containing 10 micrograms of vitamin D to build adequate fetal stores for early infancy Daily supplement containing 10 micrograms of vitamin D Infants and young children aged between 6 months and 5 years of age should take a daily supplement containing vitamin D in the form of vitamin drops to help them meet the requirement set for this age group of 7-8.5 micrograms vitamin D per day. However infants who are fed infant formula will not need vitamin drops until they are receiving less than 500ml of infant formula a day, as these products are fortified with vitamin D. Breastfed infants may need to receive drops containing vitamin D from one month of age if their mother has not taken vitamin D supplements throughout pregnancy. Daily supplement containing 10 micrograms of vitamin D Daily supplement containing 10 micrograms of vitamin D Medway CCG recommended products to purchase OTC. Healthy Start Women s Vitamin Tablets, or recommend purchase of Pregnacare Healthy Start Women s Vitamin Tablets, or recommend purchase of Pregnacare Healthy Start Children s Vitamin Drops, or recommend purchase of Abidec Multivitamin Drops. Recommend self-treatment with an OTC vitamin D supplement. Women and children from families who are eligible for the Government s Healthy Start scheme can get free vitamin supplements including vitamin D in the form of tablets for women and drops for children 9. For further information on who qualifies for the scheme and where they can obtain vitamin supplements see www.healthystart.nhs.uk. Individuals who do not qualify for the Healthy Start scheme should be advised to purchase vitamin D supplements at the appropriate strength. Page 6 of 16

Section 3: Investigation and treatment of vitamin D deficiency and insufficiency in adults It is worthwhile providing all patients with risk factors even those not exhibiting symptoms with lifestyle advice in order for them to make changes where appropriate. Indications for testing vitamin D status Routine testing of vitamin D levels in at-risk groups should not be undertaken 1. Vitamin D deficiency should be considered and checked where patients have: one or more risk factor for vitamin D deficiency AND clinical features of vitamin D deficiency See Table 2 for examples of risk factors and clinical features of vitamin D deficiency (appendix 3 lists other causes for symptoms, which may need to be excluded) these are not exhaustive lists and should not be treated as such. Appendix 2 sets out tests that may be carried out when vitamin D deficiency is suspected. Table 2 Risk factors and clinical features of vitamin D deficiency in adults i Risk factors of vitamin D deficiency in adults 5, 9 Pregnant and breastfeeding women, especially teenagers and younger women People aged 65 years and over People who have low or no exposure to the sun, for example those who cover their skin for cultural reasons, who are housebound or confined indoors for long periods People who have darker skin, for example people of African, African-Caribbean and South Asian origin Obese people (BMI>30) Diet that restricts the major food sources of vitamin D Family history of vitamin D deficiency / osteomalacia Liver or renal disease Intestinal malabsorbtion or short bowel Multiple, short interval pregnancies Taking anticonvulsants, cholestyramine, rifampicin, glucocorticoids, or antiretrovirals 5, 6,10 Clinical features of vitamin D deficiency in adults Insidious onset, widespread or localised bone pain or tenderness without preceding mechanical injury Proximal muscle weakness or muscle aches Swelling, tenderness and redness at pseudo-fracture sites Insufficiency fractures / fragility fracture i These are not exhaustive lists and should not be treated as such Page 7 of 16

Assessing vitamin D status Assay of 25-hydroxyvitamin D (25[OH]D) should be undertaken to assess vitamin D status. There is no universal consensus on the criteria for vitamin D deficiency. In agreement with the Institute of Medicine (IOM), the following are the recommended vitamin D thresholds in respect to bone health 1 : serum 25OHD < 30 nmol/l is deficient serum 25OHD of 30 50 nmol/l may be inadequate in some people serum 25OHD > 50 nmol/l is sufficient for almost the whole population. There is no agreement on optimal 25(OH)D levels 12. Treating vitamin D deficiency (25(OH)D <30 nmol/l) Patients with vitamin D deficiency should be treated with high-dose vitamin D. Colecalciferol (vitamin D3) is considered preferable to ergocalciferol (vitamin D2) because the former raises vitamin D levels more effectively and has a longer duration of action 1. Unlicensed preparations have variable availability and are potentially costly therefore licensed oral products are preferred: Desunin 800 IU up to 5 tablets daily for 12 weeks Fultium 800 IU 4 capsules daily for 12 weeks (note: contains peanut oil). Oral administration of vitamin D is recommended in most cases 1 Treatment for deficiency will be for 12 weeks before review; it is recommended therefore to avoid putting vitamin D onto repeat prescriptions. Alfacalcidol and Calcitriol are hydroxylated derivatives and should NOT be prescribed for management of Vitamin D deficiency or insufficiency or supplementation as there is no evidence to support efficacy. They should be reserved for use within their licensed indication in patients with severe renal impairment (alfacalcidol) or post-menopausal osteoporosis (calcitriol). Monitoring following treatment for vitamin D deficiency Serum calcium should be checked one month after starting treatment for vitamin D deficiency to allow detection of subclinical primary hyperparathyroidism 1. Page 8 of 16

Routine monitoring of serum 25(OH)D is unnecessary but may be appropriate 12 weeks following commencement of treatment where patients are still symptomatic, have malabsorption, or where poor concordance is suspected 1. Patients who do not respond after 12 weeks of treatment may be considered for referral to secondary care 14. Maintenance following treatment for vitamin D deficiency Colecalciferol at a dose of 800 to 2,000 IU daily 1 may be required once deficiency has been corrected for those patients who are still considered at-risk. In some cases this may be lifelong therapy. Patients who were previously prescribed AdcalD3 or equivalent can continue treatment with this preparation where appropriate. Calcium replete patients should be advised to purchase appropriate vitamin D supplements over the counter (OTC). Lifestyle advice should also be provided. Treating insufficiency (25(OH)D 30-50 nmol/l) As for deficiency, except treatment is for 8 weeks only. For Cautions - see appendix 4 Specialist advice Where patients are under the care of a specialist, clinicians may like to seek advice. Page 9 of 16

Section 4: Treatment of proven vitamin D deficiency and insufficiency for CHILDREN If a child has vitamin D insufficiency or deficiency it is probable the mother and other siblings are similarly affected. They will need testing and may need therapy as well. Serum Vitamin D (25- hydroxy vitamin D, 25OHD) level and Diagnosis 25-50 nmol/l Insufficiency and maintenance after initial treatment for deficiency Table 3: Deficiency and insufficiency treatment in children Child s Age Management strategy Product dose and frequency Under 6 months 200-400units daily Alternatively Abidec drops 0.3mL daily (= ergocalciferol 200 international units/day). Over 6 months 400-800units daily Abidec drops 0.6mL daily (= ergocalciferol 400 international units/day). <25 nmol/l Deficiency: Under 6 months Colecalciferol 3,000units given daily by oral administration for 8 12 weeks Over 6 months Over 1 year old Colecalciferol 6000units given daily by oral administration for 8 12 weeks 20,000units daily by oral administration for 15 days and stop Or 300,000 units by intramuscular injection as a single dose Colecalciferol suspension 3,000units/ml (1mL daily) Colecalciferol suspension 3000units/mL (2mL daily) Colecalciferol suspension 3,000units/ml Colecalciferol capsules 20,000units daily for 15 days then stop (if child can swallow capsules) Ergocalciferol 300,000 injection (IM) 200 international units may be inadequate for breastfed babies with low vitamin D stores at birth. Assessment of response: See monitoring requirements. In some children depending on response, a repeat dose may be required after 2-3 months. Responders should be offered long term maintenance treatment with vitamin D, see below. Calcium supplementation for children with vitamin D deficiency Calcium supplementation (50mg/kg a day see BNF) is advisable during the first 2 weeks of vitamin D therapy in the growing child. In those who are hypocalcaemic, calcium supplementation may be needed for longer, but close monitoring is required to prevent hypercalcaemia and it is advisable to refer to the paediatricians. Page 10 of 16

Appendix 1 Sources of vitamin D Sun exposure The main source of vitamin D is usually considered to be skin photosynthesis following ultraviolet B sunlight exposure 3. Environmental and personal factors greatly affect vitamin D production in the skin, making it difficult to recommend a one-size-fits-all level of exposure for the general population 4. However, the best estimates suggest that for most people, everyday casual exposure to sunlight is enough to produce vitamin D in the summer months 4. It has been suggested that during the summer, two or three exposures (of at least the face and arms without sunscreen and not behind glass) of 20 to 30 minutes between 10am and 3pm each week should provide adequate amounts of vitamin D for most individuals 5. However this may not be sufficient for some groups who require increased exposure time or frequency to get the same level of vitamin D synthesis, for example those with heavily pigmented skin and the elderly. Studies have consistently shown that vitamin D can be efficiently and sufficiently produced at doses of UV below those which cause sunburn 4. Dietary sources Vitamin D is found in a small number of foods including 3, 6 : oily fish, such as herring, mackerel, salmon, tuna, and sardines red meat, such as liver ii egg yolk mushrooms fortified foods including fat spreads, breakfast cereals and infant formula The potential contribution of diet to vitamin D supply is a topic of debate, however the general view is that it is difficult to get adequate levels of vitamin D from diet alone and the main source is skin synthesis on exposure to sunlight 4. ii Liver is also a rich source of vitamin A; consumption should therefore be limited to once a week to avoid toxicity and avoided entirely during pregnancy. Page 11 of 16

Supplements Vitamin D is present in a range of unlicensed dietary supplements and licensed medicines, which can help to boost vitamin D levels. Oral supplements are available as either ergocalciferol (calciferol, vitamin D2) or colecalciferol (vitamin D3). There is also an intramuscular ergocalciferol preparation. High doses of oral vitamin D supplements have been shown to have toxic effects. However, the threshold dose at which regular use becomes harmful is unclear 3. A printable vitamin D leaflet for patients with suggested over the counter treatments is available via http://www.imperialendo.co.uk/vitamin%20d%20patient%20information.pdf Recommended daily intake In the UK, a recommended daily intake of vitamin D has not been set for individuals leading a normal lifestyle where they are exposed to solar radiation. For adults aged over 65, and pregnant and lactating women the reference nutrient intake (RNI) is 10µg per day 7. The RNI for infants aged 0 to 6 months is 8.5µg per day, and for children aged 7 months to 3 years it is 7µg per day 7. Page 12 of 16

Appendix 2 Tests that may be carried out when vitamin D deficiency is suspected 1, 5, 10 Test Alkaline phosphatase (ALP) and phosphate C-reactive protein (CRP) Calcium Creatine kinase (CK) Full blood count (FBC) Liver function tests Parathyroid hormone (PTH) iii Renal function Urea & electrolytes (U&E) Notes Hypophosphatemia may indicate long standing vitamin D deficiency To exclude hypercalcaemia and provide a baseline for monitoring Raised CK with non-specific myalgia indicates vitamin D deficiency Anaemia may be present if there is malabsorption To exclude hepatic failure Vitamin D deficiency can lead to secondary hyperparathyroidism To exclude renal failure iii Phlebotomy needs to take place at the site where the assay is processed because the blood test for PTH is unstable. Page 13 of 16

Appendix 3* Possible causes for symptoms Hypercalcaemia Metastatic calcification Renal stones (calculi) Severe hypercalciuria Stage 4 chronic kidney disease or egfr <30ml/minute Primary hyperparathyroidism Low bone mineral density PMR / myositis (morning stiffness) Myeloma Rheumatoid arthritis Polymyalgia rheumatica * These are not exhaustive lists and should not be treated as such. Page 14 of 16

Appendix 4 Cautions The information provided below does not replace the necessity to refer to the summary of product characteristics and patient information leaflet provided by the manufacturer. Contraindications Contraindications include 10, 15, 16 : Hypersensitivity to vitamin D or any of the excipients in the product Hypervitaminosis D Nephrolithiasis Diseases or conditions resulting in hypercalcaemia and/or hypercalciuria Severe renal impairment Metastatic calcification Drug interactions Drug interactions are as follows 15, 16 : Concomitant treatment with phenytoin or barbiturates can decrease the effect of vitamin D because of metabolic activation. Concomitant use of glucocorticoids can decrease the effect of vitamin D. The effects of digitalis and other cardiac glycosides may be accentuated with the oral administration of calcium combined with vitamin D. Strict medical supervision is needed and, if necessary monitoring of ECG and calcium. Thiazide diuretics reduce the urinary excretion of calcium. Due to the increased risk of hypercalcaemia, serum calcium should be regularly monitored during concomitant use of thiazide diuretics. Simultaneous treatment with ion exchange resins such as cholestyramine or laxatives such as paraffin oil may reduce the gastrointestinal absorption of vitamin D. The cytotoxic agent actinomycin and imidazole antifungal agents interfere with vitamin D activity by inhibiting the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D by the kidney enzyme, 25-hydroxyvitamin D-1-hydroxylase. Patients should avoid taking vitamin D at the same time of day as orlistat as this reduces absorption. Vitamin D toxicity Page 15 of 16

Vitamin D toxicity is rarely seen 1 however if toxicity is suspected, vitamin D should be withdrawn and serum calcium and renal function checked urgently 10. Early signs of toxicity include symptoms of hypercalcaemia such as thirst, polyuria and constipation 10. References [1] National Osteoporosis Society (2013) Vitamin D and bone health: A practical clinical guideline for patient management, online: http://www.nos.org.uk/document.doc?id=1352 [2] UKMi (2010) What dose of vitamin D should be prescribed for the treatment of vitamin D deficiency? online: http://www.nelm.nhs.uk/en/nelm-area/evidence/medicines-q--a/what-dose-of-vitamin-d-should-be-prescribed-forthe-treatment-of-vitamin-d-deficiency/ [3] SACN (2007) Update on vitamin D: Position status by the Scientific Advisory Committee on Nutrition, London: TSO. [4] British Association of Dermatologists, Cancer Research UK, Diabetes UK, the Multiple Sclerosis Society, the National Heart Forum, the National Osteoporosis Society and the Primary Care Dermatology Society (2010) Consensus vitamin D position statement, online: http://www.sunsmart.org.uk/prod_consump/groups/cr_common/@nre/@sun/documents/generalcontent/cr_052628. pdf [5] Pearce SHS, Cheetham TD (2010) Diagnosis and management of vitamin D deficiency, BMJ, 340: 142-147. [6] Holick MF (2007) Vitamin D deficiency, NEJM, 357,3, 266-281. [7] Department of Health (1991) Dietary reference values for food energy and nutrients for the United Kingdom: Report of the panel on dietary reference values of the committee on medical aspects of food policy, Report on health and social subjects 41, London: HMSO [8] Department of Health (2011) National diet and nutrition survey: Headline results from years 1 and 2 (combined) of the rolling programme 2008/9 2009/10, online: http://www.dh.gov.uk/en/publicationsandstatistics/publications/publicationsstatistics/dh_128166 [9] Department of Health (2012) Vitamin D Advice on supplements for at-risk groups, online: http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/@dh/@en/documents/digitalasset/dh_132508.pdf [10] Anon (2006) Primary vitamin D deficiency in adults, DTB, 44, 25-29. [11] Department of Health (1998) Nutrition and bone health: with particular reference to calcium and vitamin D, London: The Stationary Office. [12] RCPCH (2012) Position statement vitamin D, online: http://www.rcpch.ac.uk/positionstatements [13] Endocrine Society Task Force (2011) Evolution, treatment, and prevention of vitamin D deficiency, online: http://www.endo-society.org/guidelines/final/upload/final-standalone-vitamin-d-guideline.pdf [14] Joint Formulary Committee (2012) British National Formulary, 64 th ed. London: BMJ Group and Pharmaceutical Press. [15] SPC Desunin 800IU tablets, online: http://www.medicines.org.uk/emcmobile/medicine/27007/spc#productinfo [16] SPC Fultium-D3 800IU capsules, online: http://www.medicines.org.uk/emc/medicine/25664/spc Acknowledgements NHS Surrey (2012) Guidelines for the treatment of vitamin D deficiency and insufficiency in adults. East Kent Hospitals NHS Trust (2012) Draft assessment and management of vitamin D deficiency and insufficiency in adults. Page 16 of 16