Screening and treatment of vitamin D deficiency should be based on recommended thresholds and stratification, says Dr Jill Murie
- The prevalence of vitamin D deficiency and insufficiency in the UK general population is estimated to be 16% and 50%, respectively
- The assessment thresholds for vitamin D status are as follows:
- 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
- The clinical consequences of vitamin D deficiency include decreased bone mineral density, muscle weakness, falls, and fragility fractures
- Universal screening of vitamin D deficiency in asymptomatic populations is not recommended
- Asymptomatic individuals at high risk of vitamin D deficiency should be offered a daily supplement of 400 IU
- People with musculoskeletal symptoms should be tested for vitamin D deficiency as part of their routine clinical biochemistry work up
- Patients with confirmed metabolic bone disease (e.g. osteoporosis, osteomalacia, Paget’s disease) require vitamin D testing and correction if indicated
- Where rapid correction is required, the recommended treatment is a titrated approach initiated with loading doses followed by maintenance therapy. If less urgent, maintenance therapy may be started without loading doses
- Monitoring of serum vitamin D and calcium is indicated in appropriate patients
- Vitamin D deficiency should be considered in the context of other risk factors for fragility fractures.
Vitamin D is responsible for maintaining healthy bone and muscle function.1,2 It acts by improving the absorption of calcium from the intestine and promoting the release of calcium and phosphorus from osteoclasts to form osteoid tissue. Around 80%–90% of the daily requirement of vitamin D is obtained from skin following exposure to the sun. The remaining 10%–20% is absorbed via the bowel from dietary sources, such as oily fish and eggs. Two successive hydroxylations in the liver and kidney, respectively, are necessary for the combined sources of vitamin D to be converted to 25-hydroxyvitamin D (25OHD) and the biologically more potent 1,25-dihydroxyvitamin D (1,25(OH)2D).3
A UK nationwide survey carried out between 2002 and 2004 reported that severe vitamin D deficiency affects 16% of the adult population during winter and spring, and insufficiency occurs in a further 50%.4 Risk factors for vitamin D deficiency include prolonged lack of sun exposure, nutritional insufficiency, pigmented skin, obesity, chronic liver and kidney disease, and malabsorption.5 The elderly are at particular risk, as are psychiatric populations, of whom 58% are estimated to be deficient and 36% insufficient in vitamin D, with resulting clinical consequences.6
Clinical impact of vitamin D deficiency
Vitamin D deficiency causes rickets in children and osteomalacia in adults as a result of defective bone mineralisation. Impaired muscle function arising from vitamin D deficiency results in weakness of the glutei and quadriceps. Patients report difficulty rising from a chair and they may have a waddling gait; falls and fragility fractures are more common in the elderly with a vitamin D deficiency.7
Putative non-skeletal outcomes of vitamin D deficiency include metabolic syndrome (hypertension, obesity, type 2 diabetes) and cardiovascular disease (CVD). Vitamin D deficiency is also associated with autoimmune diseases including multiple sclerosis (MS), inflammatory bowel disease, and certain cancers.8 The research associating vitamin D with non-bone- related outcomes is largely derived from observational studies; however ‘association’ does not equate to ‘causation’. Most people with vitamin D deficiency or insufficiency are asymptomatic. They may, however, have undiagnosed hypocalcaemia with secondary hyperparathyroidism and low bone mineral density (BMD).
Development of the guideline
Vitamin D and bone health: a practical clinical guideline for patient management was published in April 2013 by the National Osteoporosis Society (NOS), in collaboration with 11 other organisations including the British Orthopaedic Society and Royal Pharmaceutical Society.3 The authors of the guideline used evidence from an Institute of Medicine (IOM) report,9 supplemented by a literature review.
The IOM report derived its data from two systematic reviews from the Agency for Healthcare Research and Quality (AHRQ).10,11 Where there was no definitive evidence, the guideline authors resorted to consensus and personal experience. The NOS guideline thus adopts a ‘pragmatic approach’, combining the science of vitamin D metabolism with practical aspects relevant to primary care—stratifying risk and providing a management structure for physicians.
The NOS guideline defines vitamin D deficiency as a serum 25OHD concentration, below which parathyroid hormone (PTH) increases above the normal range.3 There is debate about whether there is a continuous inverse linear relationship between vitamin D and PTH; it is thought that this correlation may be influenced by age, calcium intake, physical activity, renal function, ethnicity, magnesium status, and vitamin D binding protein. Hence, there are no agreed biochemical criteria, on which to base a diagnosis of vitamin D deficiency.3
Furthermore, having considered the AHRQ and IOM systematic reviews, the guideline acknowledges the inconsistency and heterogeneity of individual studies, their limited quality and relevance to routine clinical practice, and the indirect impact of the evidence on health outcomes (falls and fractures). Using the relationship between serum 25OHD and integrated bone outcomes (risk of rickets/ osteomalacia and decreased BMD), as adapted from an IOM schematic representation, NOS proposes that the following thresholds, based on two systematic reviews commissioned by the IOM, are adopted by UK practitioners:3
- 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.
Vitamin D measurement
The majority of vitamin D metabolites (of which there are over 40) have a short half-life in the circulatory system, compared with 25OHD, which has a half-life of 21–30 days.3 In comparison, the more potent metabolite 1,25(OH)2D, has a half-life of only 4–15 hours and is measured in pmol/l rather than nmol/l. The NOS guideline therefore recommends that vitamin D assay is based on serum 25OHD. Hydroxylation to 25OHD in the liver is dependent on solar exposure, and hence seasonality. Where there are clinical grounds for suspecting vitamin D deficiency, the guideline states that 25OHD should be measured without the need for determining serum calcium, PTH, or alkaline phosphatase.3
The NOS guideline rationalises screening for vitamin D deficiency by stratifying risk into four levels:3
- asymptomatic healthy individuals
- asymptomatic individuals at high risk of vitamin D deficiency
- patients with musculoskeletal symptoms and suspected vitamin D deficiency
- patients with diseases with outcomes that may be improved with vitamin D treatment.
Asymptomatic healthy individuals
Although vitamin D deficiency is widespread in the UK population, universal screening of asymptomatic people is not recommended. There is no evidence that supplementation with vitamin D will result in non-bone health outcomes, such as a reduction in CVD or MS.
Asymptomatic individuals at high risk of vitamin D deficiency
The NOS guideline endorses the UK Chief Medical Officer’s recommendations that adult groups at risk of vitamin D deficiency should take a daily vitamin D supplement but not be tested. All pregnant and breastfeeding women, people aged 65 years and over, and people who have low or no exposure to the sun should take a daily supplement of 10 ?g (400 IU) of vitamin D. Monitoring is unnecessary because of the low risk of toxicity.
Patients with musculoskeletal symptoms and suspected vitamin D deficiency
Vitamin D screening is justified in this patient group as part of routine clinical and biochemical investigation.
Patients with diseases with outcomes that may be improved with vitamin D treatment
There is evidence that, where bone disease (osteomalacia, osteoporosis) is confirmed or where patients have multiple musculoskeletal symptoms, vitamin D measurement and correction is beneficial; patients with Paget’s disease require correction of vitamin D deficiency prior to bisphosphonate therapy.
The guideline makes it explicit that patients with serum 25OHD >50 nmol/l are ‘reassured’ and advised to maintain their vitamin D levels through safe sunlight exposure and diet. Patients with serum 25OHD <30 nmol/l require treatment. If levels are in the range 30–50 nmol/l, treatment is advised if the patients have the following:3
- fragility fracture, documented osteoporosis, or high-fracture risk
- treatment with antiresorptive medication for bone disease
- symptoms suggestive of vitamin D deficiency
- increased risk of developing vitamin D deficiency in the future because of reduced exposure to sunlight, religious/cultural dress code, dark skin
- raised PTH
- medication with antiepileptic drugs or oral glucocorticoids
- conditions associated with malabsorption (e.g. coelic disease).
Oral vitamin D3 (colecalciferol), which is derived from animal sources, is recommended in preference to D2 (ergocalciferol), which comes from plant extracts, unless D3 is prohibited because of religious observance or culture. A titrated approach initiated with oral loading doses, taken with food to improve absorption is suggested. An example regimen for rapid correction of vitamin D deficiency is shown below:3
- 50,000 IU capsules, one given weekly for 6 weeks (300,000 IU)
- 20,000 IU capsules, two given weekly for 7 weeks (280,000 IU)
- 800 IU capsules, five a day given for 10 weeks (280,000 IU).
Fixed regimens need a minimum daily dose of 800 IU. There is considerable individual variation, and higher daily doses of 2000 IU (or higher in current daily practice) may be needed to achieve adequate replacement. The broad dosage ranges of licensed vitamin D preparations now available recognise this requirement. Monitoring may be necessary in some circumstances.3
The guideline emphasises the need for treatment in secondary care, if more aggressive treatment is indicated. For people with symptomatic disease, or requiring a potent antiresorptive agent (zolendronate or denosumab), the treatment regimen should be based on fixed loading doses followed by regular maintenance therapy.3
Maintenance treatment comprises 800 IU to 2000 IU (occasionally up to 4000 IU is required) daily or intermittently, depending on individual response. Higher doses (i.e. higher than 4000 IU) are required for people unable to maintain vitamin D because of malabsorption, and lower doses for patients with genetic abnormalities in vitamin D metabolism and co-morbidities including renal disease or hyperparathyroidism. The parenteral route is not recommended, although it may be indicated if concordance is a problem. Titrated supplementation with either calcium-only supplements or calcium and vitamin D combined supplements is recommended for patients with osteoporosis who do not have a regular intake of at least 700—mg calcium per day.3
The guideline acknowledges that a robust evidence base for monitoring patients is lacking. Advice is somewhat ambiguous, as routine monitoring is considered unnecessary, but deficiency after loading doses and during maintenance therapy warrants re-testing. Monitoring of vitamin D is appropriate for patients with symptomatic vitamin D deficiency, malabsorption, and concordance issues. The guideline also recommends that calcium levels are measured 1 month after the last loading dose and after commencing vitamin D supplementation in case of primary hyperparathyroidism. Dosages of vitamin D below 10,000 IU/day are not usually associated with toxicity and hypercalcaemia. Importantly, chronic hypercalcaemia can lead to renal and cardiovascular damage.3
Read codes designated for vitamin D deficiency, assessment of bone mineral density by DXA, and diagnosis of osteoporosis and fragility facture are summarised in Table 1 (see above). In some cases the Read codes are relevant to the quality and outcomes framework of the general medical services contract.
|Read description||Read code|
|Vitamin D3 level||4QB40|
|25-hydroxyvitamin D3 level||4QB42|
|Serum 1,25 dihydroxyvitamin D3||44L0.|
|Vitamin D3 level||4QB41|
|Provision of information about vitamin D supplements||67DE|
|Referral for DXA scan||8HQ8.|
|Forearm DXA scan result osteoporotic||58E4|
|Forearm DXA scan T-score||58E2|
|Initial osteoporosis assessment||66a0.|
|Follow-up osteoporosis assessment||66a1.|
|DXA=dual-energy X-ray absorptiometry|
Implications for commissioners
Testing and monitoring
To avoid excessive laboratory costs, prudent testing and adequate dosing without risk of toxicity is required.
A vitamin D assay costs £20–£50 per test,6,12 not including treatment room/nurse time; dual-energy X-ray absorptiometry scans cost around £60.13 A more cost effective option is the FRAX® online resource,14 which gives the 10-year probability of major osteoporotic fracture (clinical spine, forearm, hip, or shoulder fracture). By comparison, osteoporotic fractures cost the NHS over £1.73 billion each year.15 Screening using the FRAX tool is a cheap and effective way of identifying people at risk of osteoporotic fracture to reduce the financial burden of treating this condition in the NHS.
A number of preparations are available for vitamin D deficiency:
- the first colecalciferol-only licensed preparation available in the UK, was approved in 2012 and has a daily dosing range of 800–3200 IU. Each capsule contains colecalciferol 800 IU vitamin D3; it costs £3.60 for 30 capsules. While the capsule is not made of animal gelatin, it does contain peanut oil16,17
- the first licensed vitamin D3 tablet has a broader dosing range (800 IU–4000 IU) and is suitable for vegetarians and those at risk of peanut and soya allergy at £3.60 for a 30-tablet pack16,18
- a range of other vitamin D tablet and capsule formulations are also available.
Although ultraviolet B sun lamps will stimulate the body to synthesise vitamin D, the optimal lamp type has not been medically established and these devices also carry a risk of skin cancer.
Role of primary care
In primary care, we are confronted with inactivity, increasing obesity, unhealthy diets, and office-based lifestyles, and recreation is dominated by computer-based technology resulting in suboptimal BMD and muscle strength. Ageing practice populations compound the problem with falls and fractures.
General practitioners and pharmacists can make an important contribution to reducing polypharmacy, improving patient safety, and reducing iatrogenic bone disease. Examples of drugs and their negative association with bone health include:
- proton pump inhibitors—associated with an increased risk of hip and other fractures19,20
- long-term treatment with anti-epileptic drugs—associated with decreased BMD, osteopenia, osteoporosis, and fractures21
- antipsychotic-induced hyperprolactinaemia—results in bone demineralisation and fractures22
- metformin, insulin, and thiazolidinediones—these have a direct effect on bone in patients with diabetes23
- androgen-deprivation therapy for prostate cancer—associated with an increased risk of osteoporotic vertebral fractures.24
The NOS guideline on vitamin D and bone health is a self-effacing document that acknowledges inconsistency in research evidence and surrogate health outcome measures, and non-specificity in clinical symptoms, resulting in intuitive clinical decision making in daily practice. Vitamin D supplementation is associated with a paucity of large interventional (observational or randomised) studies. Patient safety may be compromised because of toxicity, but laboratory monitoring is costly.
There is currently a national policy of routinely treating people aged over 75 years and those receiving bisphosphonates with calcium and vitamin D supplements to reduce the incidence of osteoporotic fractures. However, calcium with or without vitamin D is associated with a moderately increased risk of myocardial infarction.25
The Vitamin D Individual Patient Analysis of Randomized Trials (DIPART) group has demonstrated that use of vitamin D alone, regardless of dose, does not reduce the risk of fractures. By comparison, combined calcium and vitamin D reduces the overall risk and the risk of hip fracture.26
The morbidity, mortality, and disability arising from falls and fractures is a priority for commissioners. It is incumbent on primary care services to identify and treat patients with confirmed, suspected, or asymptomatic vitamin D deficiency. Judicious screening, targeted testing, and routine supplementation of high-risk groups is a priority. The risks, and overall health benefits of combining vitamin D with calcium warrant further research and guidance.
- Although vitamin D deficiency is undoubtedly common and correction is relatively simple through diet, sun exposure, and supplementation, the evidence for clinical benefit of treating vitamin D deficiency is not clear cut
- CCGs, through their Health and Wellbeing boards, should look at vitamin D deficiency and fracture prevention as a community health issue and with their colleagues in public health departments assess the priorities for a strategy to address this
- The article recommends targeting interventions to high-risk groups and CCGs should identify these in their Health and Wellbeing Strategy and work with partner agencies to devise plans to implement these interventions (e.g. with certain faith groups and institutionalised patients or via education programmes in schools).
CCG=clinical commissioning group
- Holick M. Vitamin D deficiency. N Engl J Med 2007; 357 (3): 266–281.
- Francis R, Anderson F, Patel S et al. Calcium and vitamin D in the prevention of osteoporotic fractures. QJM 2006; 99 (6): 355–363.
- National Osteoporosis Society. Vitamin D and bone health: a practical clinical guideline for patient management. Bath: NOS, 2013. Available at: www.nos.org.uk/page.aspx?pid=1074&srcid=299
- Hypponen E, Power C. Hypovitaminosis D in British adults aged 45y: nationwide cohort study of dietary and lifestyle predictors. Am J Clin Nutr 2007; 85 (3): 860–868.
- Pearce S, Cheetham T. Diagnosis and management of vitamin D deficiency. BMJ 2010; 340: b5664.
- Murie J, Messow C, Fitzpatrick B. Feasibility of screening for and treating vitamin D deficiency in forensic psychiatric inpatients. J Forensic Leg Med 2012; 19 (8): 457–464.
- Reginato A, Falasca G, Pappu R et al. Musculoskeletal manifestations of osteomalacia: report of 26 cases and literature review. Semin Arthritis Rheum 1999; 28 (5): 287–304.
- Peterlik M, Cross H. Vitamin D and calcium deficits predispose for multiple chronic diseases. Eur J Clin Invest 2005; 35 (5): 290–304.
- Institute of Medicine. Dietary reference intakes for calcium and vitamin D. Washington: The National Academy Press, 2011.
- Chung M, Balk E, Brendel M et al. Vitamin D and calcium: a systematic review of health outcomes. Evid Rep Technol Assess (Full Rep) 2009; 183: 1–420.
- Cranney A, Horsley T, O’Donnell S et al. Effectiveness and safety of vitamin D in relation to bone health. Evid Rep Technol Assess (Full Rep) 2007; 158: 1–235.
- Royal National Orthopaedic Hospital NHS Trust website. Vitamin D in children.
www.rnoh.nhs.uk/clinical-services/paediatric-adolescents/vitamin-d-children (accessed 8 August 2013).
- North Bristol NHS Trust website. Osteoporosis service. www.nbt.nhs.uk/our-services/a-z-services/osteoporosis/osteoporosis-service (accessed 8 August 2013).
- FRAX website. WHO fracture risk assessment tool. Available at: www.shef.ac.uk/FRAX (accessed 18 July 2013).
- National Osteoporosis Guideline Group (NOGG). Osteoporosis—clinical guideline for prevention and treatment: executive summary. NOGG, 2013. Available at: www.shef.ac.uk/NOGG/NOGG_Executive_Summary.pdf
- MIMS online. www.mims.co.uk (accessed 5 August 2013).
- Internis Pharmaceuticals Ltd. Fultium-D3 800IU capsules—summary of product
characteristics. January 2012. www.medicines.org.uk/emc/medicine/25664/SPC
- Meda Pharmaceuticals. Desunin 800IU tablets—summary of product characteristics. October 2013. www.medicines.org.uk/emc/medicine/27007/SPC/Desunin+800+IU+Tablets/
- Yang Y, Lewis J, Epstein S, Metz D. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 2006; 296 (24): 2947–2953.
- Gray S, LaCroix A, Larson J et al. Proton pump inhibitor use, hip fracture, and change in bone mineral density in postmenopausal women: results from the Women’s Health Initiative. Arch Internal Med 2010; 170 (9): 765–771.
- Medicines and Healthcare Products Regulatory Agency website. Drug Safety Update April 2009; 2 (9): 2. Available at: www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON087970 (accessed 17 July 2013).
- Kishimoto T, De Hert M, Carlson H, Correll C. Osteoporosis and fracture risk in people with schizophrenia. Curr Opin Psychiatry 2012; 25 (5): 415–429.
- Montagnani A, Gonnelli S, Alessandri M, Nuti R. Osteoporosis and risk of fractures with diabetes: an update. Aging Clin Exp Res 2011; 23 (2): 84–90.
- Ross R, Small E. Osteoporosis in men treated with androgen deprivation therapy for prostate cancer. J Urol 2002; 167 (5): 1952–1956.
- Bolland M, Grey A, Avenell A et al. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis. BMJ 2011; 342: d2040.
- DIPART (Vitamin D Individual Patient Analysis of Randomized Trials) Group. Patient level pooled analysis of 68 500 patients from seven major vitamin D fracture trials in US and Europe. BMJ 2010; 340: b5463. G