Endocrinology. Vitamin D and bone health National Osteoporosis Society Guideline What is the GP s role? Vitamin D physiology

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1 Endocrinology Vitamin D and bone health What is the GP s role? Vitamin D physiology Why do people become vitamin D deficient? Which foods contain vitamin D? What are the symptoms of vitamin D deficiency? FAQs not covered by this guideline Which preparations are available to prevent deficiency? Which adults need referral? Interpreting results and treatment for children What is the evidence for universal supplementation in children? Vitamin D and non-skeletal health outcomes Vitamin D and obstetric outcomes Investigating an isolated raised alkaline phosphatase What causes raised ALP levels? An approach to an abnormal result Cushing s syndrome What causes Cushing s syndrome? Why is it missed? Why does it matter? How do we diagnose it? Investigations Management Thyrotoxicosis Aetiology Symptoms and signs Making the diagnosis Treatment Which treatment is best? Starting and monitoring antithyroid drugs Drug side-effects Thyroid function monitoring after treatment Thyroid disease and atrial fibrillation Should we treat subclinical hyperthyroidism? Only available online ( Hypothyroidism Hypercalcaemia and primary hyperparathyroidism Late-onset hypogonadism in men Opioid-induced hypogonadism Hirsutism Prolactinomas Vitamin D and bone health National Osteoporosis Society Guideline 2013 At last some national guidance on whom we should be testing and treating for vitamin D deficiency. Fortunately this new guideline is in line with our previous teaching on GP Update and may appear familiar to many of you following local guidance. What is the GP s role? After several years of confusion and controversy, the situation is becoming clearer. I think GPs have four roles with respect to vitamin D: To encourage high risk groups to take adequate vitamin D supplements. To test and treat symptomatic high risk individuals. To assess vitamin D status in those with bone disease likely to benefit from treatment. To reassure and give lifestyle advice to the worried well! The new guidance covers all of these groups. Before looking specifically at the guidance on who should be tested and treated, first a quick reminder about vitamin D physiology and why individuals become deficient. Vitamin D physiology If like me, your recollection of vitamin metabolism is a little hazy, here comes the science bit! Vitamin D comprises a group of fat-soluble pro-hormones. It is important in maintaining calcium and phosphate homeostasis and bone and muscle integrity. Humans acquire vitamin D from two sources: 90% of our requirement is synthesised in the skin this is vitamin D 3 (cholecalciferol): 7-dehydrocholesterol Vitamin D 3 UVB light % comes from ingestion of vitamin D 2 (ergocalciferol) in foods.

2 Together, these are pro-hormones and need to be activated by two hydroxylation steps in the liver and kidneys respectively: Vitamin D 2 from diet Vitamin D 3 from UVB on skin (both INACTIVE) Liver 25(OH) vitamin D Kidney 1,25(OH) 2 Vitamin D (Calcitriol) ACTIVE Once activated, calcitriol acts on intranuclear receptors which are present on most body cells. Why do people become vitamin D deficient? In short, because we don t get enough sunlight exposure and would need to eat large quantities of relatively expensive and relatively unpopular foods to make up for this! UVB sunlight provides 90% of human vitamin D requirements but for 6 months of the year the UK lies too far north for adequate UVB to synthesise vitamin D. SPF 15+ blocks 99% of vitamin D synthesis. A fair skinned young person needs 20 30min of sunlight exposure at midday to face and forearms, 3x per week for adequate vitamin D synthesis (2000IU per exposure). Elderly people and those with pigmented skin need substantially more. ENDOCRINOLOGY Which foods contain vitamin D? Recommended daily intake is 400IU (2800IU per week). Food source Oily fish (mackerel/sardine/trout/salmon/fresh tuna/ pilchards/herring) etc. Cod liver oil Egg yolk Vitamin D content IU per portion (raw > cooked) 1360IU per 15ml 20IU per yolk Small amounts can also be found in wild mushrooms, full fat margarine, fortified breakfast cereals and infant formula. So, we have identified why there is a problem but what should we do? What are the symptoms of vitamin D deficiency? Unfortunately, particularly in adults, the symptoms can be rather vague: Symptoms in children (rickets) Tetany Irritability Leg bowing or knock knees Impaired growth Skeletal deformity Muscle pain/weakness Bone pain Proximal myopathy Symptoms in adults (osteomalacia) Bone pain or tenderness or myalgia Proximal muscle weakness Tenderness over bones Insufficiency fractures AND no other plausible explanation Vitamin D and Bone Health: a practical guideline National Osteoporosis Society 2013 This guideline covers the assessment and treatment of vitamin D deficiency in adults. It does not include pregnant women or children. Who needs a vitamin D level testing? The guidance recommends considering vitamin D testing in the following groups: Patients with bone disease that may be improved with vitamin D treatment, e.g. osteomalacia or osteoporosis. Patients with bone disease who are starting treatment that requires correction of vitamin D levels (e.g. zolendronate or denosumab but not oral bisphosphonates. Patients with musculoskeletal symptoms that could be attributed to vitamin D deficiency. 183

3 GP UPDATE HANDBOOK AUTUMN 2013 It is not ALWAYS necessary to check levels in individuals starting treatment for osteoporosis with oral bisphosphonates who are going to be prescribed vitamin D as part of their treatment anyway. BUT do consider if vitamin D deficiency could be the cause of their fractures. DO NOT test: Asymptomatic high risk individuals. They should be offered supplements as per DH guidance as discussed below. Asymptomatic population risk individuals requesting tests should be offered lifestyle advice about sun exposure, diet and over the counter supplements. The test of choice is a 25OH vitamin D level. This guideline argues that whilst a raised alkaline phosphatase (ALP) is a surrogate marker for significant vitamin D deficiency, it tends to occur late and therefore is not a substitute. How do we interpret and act on results? This guideline proposes the following cut-off values for action: Vit D deficiency (<30nmol/L) Vitamin D tested (25-OHD) Vit D insufficiency (30 50nmol/L) Assess for risk factors that warrant high strength replacement: Fragility fractures, documented osteoporosis or high fracture risk Treatment with anti-resorptive medication for bone disease Symptoms of vitamin D deficiency Lifestyle factors which increase risk of full deficiency in the future, e.g. poor sunlight exposure Raised PTH Anti-epileptics or oral glucocorticoids Conditions associated with malabsorption, e.g. coeliac, chronic pancreatitis, inflammatory bowel Level optimal (>75nmol/L) No further action Vit D adequate (50 74nmol/L) 1 or more risk factors above No risk factors High strength replacement for 8 12w (see below for doses) Maintenance therapy (see below for doses) Lifestyle advice Maintenance if indicated (self-purchased) What are the high strength replacement (loading) options? Oral vitamin D 3 is the replacement and maintenance treatment of choice. If urgent replacement is required, e.g. in very symptomatic patients or those starting strong anti-resorptive medications such as zolendronate or denosumab: give IU total dose over 6 12w. Regimen can vary depending on local availabilities and most cost-effective preparation, e.g.: IU capsule once weekly for 6w IU capsule two per week for 7w 800IU capsules five per day for 10w. 184

4 Do not use combined vit D/calcium tablets for the above regimens as this will overdose on calcium. If there is no need for urgent replacement, a maintenance regimen of IU per day can be started and continued long term. Annual high dose IM vitamin D injections are not recommended because of their variable bioavailability and concerns about toxicity. Whilst not mentioned in the guideline, the best option now is to prescribe generic colecalciferol at the dose you require and let the pharmacist source the most cost-effective preparation. However, local policy may vary. What are the maintenance options? Maintenance treatment should start 1m after loading treatment. Doses equivalent to IU per day are recommended. You can buy 1000IU tablets over the counter for <3p/day. This can be given as a daily or monthly dose based on patient preference. For patients with osteoporosis if calcium supplementation is also required, a combined preparation can be used for maintenance treatment. ENDOCRINOLOGY What monitoring is required? Check corrected calcium levels 1m after high dose replacement to check for unmasked primary hyperparathyroidism. If calcium level is raised stop any further vitamin D supplementation until this has been investigated (see Online handbook for more details on evaluating hypercalcemia). Routine monitoring of 25OH vitamin D levels is not required or recommended. What about high risk asymptomatic groups? Follow the Department of Health guidance and promote vitamin D supplements in the following groups: Population groups 0 6m: Formula-fed Breast-fed from well stocked mum Breast-fed from deficient mum 7m 5y 7 (280) 5y 65y (normal sun exposure) None >65y 10 (400) Pregnancy 10 (400) Lactation 10 (400) Adults with poor sun exposure 10 (400) Recommended vitamin D supplementation in µg/day (IU) None None 7 (280) from 1m old FAQs not covered by this guideline Here are the things we are frequently asked on courses which are not yet covered by the national guidelines. Which preparations are available to prevent deficiency? For children: Healthy start vitamins if eligible (300IU per 5 drops). Abidec (400IU per 0.6ml) on FP10 or OTC 3.96 for 25ml (N.B. contains peanut oil). Dalivit (400IU per 0.6ml) on FP10 or OTC approx. 7 for 50ml. For pregnant/breast-feeding women: Should not take a standard multivitamin because they contain vitamin A (harmful to fetus). Healthy start if eligible (400IU). Pregnacare or similar pregnancy multivitamins from chemist (not FP10) check 400IU. OTC colecalciferol 400IU ( 2 to 3.30 for a 3m supply). Generic colecalciferol on FP10 (currently Pro-D3 400IU caps are best buy for NHS). 185

5 For vulnerable adults and the elderly: OTC vitamin D (as above 400IU). FP10 generic colecalciferol (currently Pro-D3 400IU caps are best buy for NHS). The majority of patients should be encouraged to take responsibility for this part of their nutrition but clearly as GPs we will make judgements that for concordance or social-economic reasons FP10 is preferable follow local guidelines for now if you have them. GP UPDATE HANDBOOK AUTUMN 2013 Which adults need referral? NHS North Central London 2012 When you decide to refer will depend on your own expertise, local guidelines and availability of treatment in your local area. These guidelines recommend referral of adults with: Focal bony pain. Skeletal deformity. Atypical clinical presentation. Unexplained weight loss. Renal stones. Secondary causes e.g. renal/liver disease, sarcoid, parathyroid disorders, TB, lymphoma or metastatic cancer. They suggest discussing the following cases before starting treatment: Pregnant and breast feeding women. Failure to respond to course of treatment. History of renal stones. Atypical biochemistry. Interpreting results and treatment for children NHS North Central London Remember, if a pregnant woman or child is found to be deficient, think about levels in the rest of the family. Refer to specialists any child: aged < 1y with bone deformity with short stature with 25-OHD <25nmol/L. For those with 25-OHD <25nmol/L start treatment whilst waiting for specialist appointment: Age 1 6m colecalciferol 3000IU daily for 8 12w Age 6m 12y colecalciferol 6000 IU daily for 8 12w Age 12 18y colecalciferol IU daily for 8 12w Calcium supplements 50mg/kg/day advisable in growing children. Possible preparations for children include ProD3 Forte Liquid 3000IU/ml. What is the evidence for universal supplementation in children? The DH recommends that all children from 7m to 5y should receive daily vitamin D supplements. A meta-analysis looked at the impact of vitamin D supplementation in healthy children and found that there was no benefit in terms of bone density unless the children were vitamin D deficient (BMJ 20;342:c7254). However, the authors acknowledge that at a population level, determining which children are deficient would be costly and invasive, so public health measures as recommended by the DH seem sensible. Vitamin D and non-skeletal health outcomes JAMA 20;305:2565 NEJM 20;364: We are often asked about the evidence that vitamin D deficiency may be implicated in other major health issues. The evidence relating to this has been sketchy and difficult to pull together. These editorials written by members of the Institute of Medicine explain why they felt unable to make specific evidence-based recommendations on vitamin D intake in relation to the

6 prevention of cardiovascular disease, diabetes and cancer. They reviewed all available evidence and concluded: 1 The evidence that vitamin D prevents cardiovascular disease, diabetes, cancer and other non-skeletal outcomes is inconclusive and does not meet criteria to establish a cause and effect relationship. 1 The available studies use 25-OHD as their main marker of vitamin D exposure. Whilst this is useful, it does not demonstrate causation there is significant overlap with confounding factors, eg. obesity, low levels of physical activity outdoors and poor nutrition which can contribute both to vitamin D deficiency and cardiovascular disease and diabetes. 1 In the small number of RCTs that have been performed, there has been no consistent demonstration of a reduction in cardiovascular disease associated with vitamin D compared with placebo. A further systematic review looked at all the available evidence relating to vitamin D status and cardiovascular disease (Ann Int Med 20;155:820). They concluded that whilst there are biologically plausible pathways by which vitamin D deficiency may affect endothelial dysfunction and atherosclerosis, low levels of vitamin D may well be a surrogate marker for poor general health. They felt that until further robust studies were completed, vitamin D should not be recommended as a treatment for cardiovascular disease. ENDOCRINOLOGY Three large RCTs looking at vitamin D and the prevention of cardiovascular disease, cancer and type 2 diabetes are currently in progress and should report in the next 5 6 years. A case-control study looked at rates of vitamin D deficiency amongst patients with bronchiectasis (Thorax 2013;68:39). It found that: 1 50% of bronchiectasis sufferers were vitamin D deficient compared with 12% of matched controls. 1 Those sufferers who were vitamin D deficient were also more likely to be chronically colonised with bacteria e.g. pseudomonas, had more exacerbations and worse quality of life. The authors propose that vitamin D deficiency may inhibit neutrophil phagocytosis and are proposing further work to evaluate vitamin D as a therapy for bronchiectasis. NB They are not suggesting vitamin D deficiency causes bronchiectasis, rather that it may be a consequence or marker of more severe disease. Vitamin D and obstetric outcomes BMJ 2013;346:f69 In the UK, the government recommend that all pregnant and breast-feeding women should take vitamin D supplements at 400IU per day. It is well evidenced that adequate maternal vitamin D levels reduce the risk of osteomalacia in the mother and rickets in the infant. However, it has also been proposed that low vitamin D levels may have other adverse obstetric outcomes. This imperfect meta-analysis combined available observational studies looking at this issue and identified an association between low vitamin D levels and small for gestational age, gestational diabetes, bacterial vaginosis, low birth weight and pre-eclampsia. Clearly this is an association rather than causative link and could be a surrogate marker for other factors adjustment for confounding was poor in the included studies. They were not able to establish the optimal dose for supplementation, though they acknowledge that other countries recommend significantly higher doses than the UK ( IU per day). Nor were they able to demonstrate a dose response relationship between vitamin D levels and adverse outcomes. Vitamin D deficiency 1 As a primary care team, remember to recommend supplements to high risk groups to prevent defi ciency. 1 Test vitamin D levels only in individuals who are in high risk groups AND have symptoms or who are starting denosumab or zolendronate for osteoporosis. 1 For everyone else, offer lifestyle advice (sunshine, cod liver oil) and OTC supplements. 1 Patients with defi ciency (< 30nmol/L) need high dose replacement of IU divided over 8 12w and then maintenance treatment. 187

7 1 Check calcium levels 1m after completing high dose replacement if high investigate. 1 Refer all children with vitamin D defi ciency (<30nmol/L), who are aged <1y, have bony deformity or short stature. 1 There is currently no good quality evidence that vitamin D levels affect other health outcomes such as cardiovascular disease, cancer, multiple sclerosis or cot death. GP UPDATE HANDBOOK AUTUMN 2013 Do you work in an area with large high risk populations for vitamin D defi ciency? Find out what your local PCT guidance is with respect to testing and prescribing vitamin D supplementation. Do you recommend vitamin D supplements and lifestyle measures to your higher risk groups to avoid vitamin D insuffi ciency? Personal learning points/actions: 188

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