ࡱ> A?:;B#` bjbjmm 4p1MDDDxd d d x \'\'\'8'H(x r(ZB*X*n*n*3367tqqqqqqq$thwqd >33>>qhhn*n*q6KKK>h&n*d n*qK>qKKRj+ d kmn*( pdM5\'FkpqrkwIw<kmkm0wd m(7_9NK: ;d777qqKd777r>>>>x x x \'x x x \'x x x hhhhhh Adult Vitamin D guidelines Particular attention has been paid to symptomatic adults during the development of this guideline. It would be usual this group would be investigated to attribute probable cause of symptoms and clarify diagnosis, ensure that alternative diagnoses are not missed, and that adequate replacement doses of vitamin D are given. Care has also been taken to ensure those patients with more complex disorders, and those who may be at particular risk from treatment with vitamin D are highlighted. The Chief Medical Officers of the UK gave advice in February 2012 to GPs, practice nurses, health visitors and community pharmacists about supplementation with vitamin D to those at high risk. Principal recommendations of this communication included supplementation with 400 units of vitamin D daily to those over the age of 65 years, and to people who are not exposed to much sun. No mention of prior investigation or subsequent monitoring was made. This current guideline should be used where the General Practitioner (or other medical staff determining management) feels a patients clinical features warrant prior assessment relating to their Vitamin D status or are otherwise not satisfied that it is straightforward in a patients case to apply the above advice (for potentially long term VitD treatment) without investigation or monitoring lest it be unsafe or inadequate. Some reasons for this may include: The patient complains of symptoms requiring diagnosis and potentially high dose treatment with vitamin D where deficiency exists The patient may be at risk of complications from treatment with vitamin D due to a hypercalcaemic disorder, previous renal stones, renal impairment, granulomatous disorder etc The patient may be unwilling to take long term supplements without definite evidence of poor vitamin D status. Treatment Protocol for Vitamin D Please see full referral guidelines in main body of text and/or discuss with endocrine registrar on-call if uncertain  Table A -Recommended Treatment TreatmentIndicationDoseFollow upLevel 1Vitamin D sufficient, but may be at risk of deficiency in futureLifestyle advice (See section 1.1)Review as clinically indicatedLevel 2Biochemical insufficiency benefit of treatment uncertain. See section 5.3 prior to commencing.800units per day** OR 20,000units*** per month Repeat Ca, AlkP, PTH in 6 months and review clinical condition. Consider whether step down to level 1 treatment appropriate, or if long term treatment required.Level 3Osteomalacia treatment of clear benefit20,000units*** three times weekly for 4 weeks, THEN 20,000units*** per week for 8 weeksRepeat Ca weeks 2 and 4. Check Ca, AlkP, PTH every 12 weeks. Step down to level 2 treatment when PTH and AlkP normal.*Level 2 treatment appears adequate. In exceptional circumstances (eg 25(OH)D <14 nmol/L AND clearly symptomatic) level 3 treatment might be warranted to rapidly increase vit D level - would then require more active monitoring) ** Fultium D3 (colecalciferol 800 units) is a newly licensed product recently approved by SMC and the Lothian Formulary Committee. ***There is no UK licensed high dose vitamin D3 preparation. Dekristol (colecalciferol 20000 units) is a German product that can be imported and formulary approval has recently been given to support its use in this guideline. Both these products contain arachis oil and are therefore unsuitable for patients with a peanut or soya allergy. **** Desunin (colecalciferol 800 units) does not contain arachis oil & is the formulary choice in NHS Borders Please note that second requests for the analysis of vitamin D within 1yr of the first result are not currently being accepted unless special circumstances can be demonstrated. 1. Background Recently there has been considerable interest in vitamin D, reflected in a large increase in the number of requests received by Glasgow Royal Infirmary clinical chemistry department over the past three years. Vitamin D has been postulated to play a role in a diverse number of conditions including coronary heart disease, immunological disorders and malignancy. This guideline is designed to give practical advice on appropriate testing of vitamin D levels, investigation of vitamin D deficiency, and when and how to treat patients with low vitamin D. 1.1. Sources of Vitamin D A major source of vitamin D comes from exposure of the skin to sunlight. Skin pigmentation, ageing and use of topical sun screen are factors which reduce the skins production of vitamin D. Unfortunately from October to April, Scotland lies above the latitude that allows exposure to the UV-B wavelengths necessary for vitamin D synthesis. For a fair-skinned person, 20 to 30 minutes of sub-erythematous sunlight exposure at midday on the face and forearms two or three times weekly between April and October are sufficient to achieve healthy vitamin D levels in summer in the UK. However, for individuals with pigmented skin, and to a lesser extent the elderly, exposure time or frequency need to be increased two- to ten-fold to get the same vitamin D synthesis (depending upon skin pigmentation). The advice from the chief medical officer, Harry Burns, in the Scottish government CMO letter to health professionals August 2011 was: In conveying a general message about sun exposure, 10-15 minutes of sun exposure each day in Scotland are thought to be safe for all skin types. However, it should be borne in mind that this is close to the exposure level which presents a risk for all skin cancers for those with fairer skins and, conversely, 10-15 minutes may not be sufficient for those with darker skins. Dietary sources include oily fish such as trout, salmon, mackerel, herring, sardines, anchovies, pilchards or fresh tuna which should be consumed 2 to 3 times per week. Cod liver oil and egg yolks also contain vitamin D. Some breakfast cereals are supplemented, and in the UK margarine and infant formula milk have statutory supplementation. 1.2. Vitamin D metabolism and regulation Vitamin D is made from a precursor (7-dehydrocholesterol) in the skin on exposure to ultraviolet irradiation and is also absorbed from dietary sources. Vitamin D2 (ergocalciferol) is provided by plant sources, and vitamin D3 (cholecalciferol) is synthesized in the skin and present in oil rich fish. Both these forms have equivalent biological potencies and are activated efficiently by hydroxylase enzymes in humans. Vitamin D undergoes 25-hydroxylation in the liver to 25(OH)D, which has a half life of 2 to 3 weeks. This hydroxylation process is not tightly regulated and therefore the blood levels of 25(OH)D reflects the amount of vitamin D entering the circulation. 25(OH)D is then further hydroxylated in the kidney to the active form 1,25(OH)D, which has a half life of 6 to 8 hours. The renal hydroxylation is tightly regulated; PTH and hypophosphataemia induce the enzyme, while calcium, fibroblast growth factor 23 (FGF23) and 1,25(OH)D repress it. FGF23 is produced by bone cells, and its role in calcium and phosphate homeostasis is not yet fully understood. 1.3. Definition of insufficient vitamin D There are a number of sources of variation in 25(OH)D levels between individuals; it is therefore difficult to assess the significance of vitamin D deficiency based on 25(OH)D concentrations alone. Furthermore, a number of factors such as duration of deficiency, race, age, responsiveness of vitamin D receptor, Ca intake, and Ca requirements are likely to modify the clinical consequences of vitamin D deficiency. Genetic variation in the vitamin D metabolic pathway effecting the uptake and hydroxylation of vitamin D explains some of the inter-individual variability of 25(OH)D concentration NOTEREF _Ref318795715 \f \h 6. A vitamin D (25(OH)D) level of 25nmol/L is generally recognized as the lower limit required for bone health, based on levels below this being found in patients with osteomalacia and rickets,. However, a cross-sectional study of iliac bone biopsy specimens obtained at autopsy revealed that even patients with very low vitamin D levels did not consistently have evidence of osteomalacia; in fact the majority of patients with 25(OH)D levels below 25nmol/L had normal osteoid. A minimum 25(OH)D level that is inevitably associated with manifest mineralization defects cannot therefore be established. Several studies have tried to assess optimal levels for 25(OH)D, based on levels required for maximal intestinal absorption of calcium, and levels below which PTH begins to rise. Different studies have shown this value to be between 50 and 100nmol/L. The paper looking at iliac bone biopsy specimens found no pathologic accumulation of osteoid in any patient with circulating 25(OH)D levels above 75nmol/L NOTEREF _Ref318795909 \f \h 9. Unfortunately blood biochemistry such as PTH and alkaline phosphatase were not analysed, and information about medical history was not collected. Provocative testing is another method which has been used to quantify optimal vitamin D levels; healthy adults with 25(OH)D levels above 50nmol/L demonstrated no change in PTH levels when challenged with high dose vitamin D. There is therefore a feeling that these higher levels of vitamin D should be considered optimal and used as a target for treatment. At the present time, interventional evidence is lacking to make this recommendation. 1.3.1. Problems of widespread mildly reduced levels and seasonal variation A study of 7437 white British adults aged 45 years looked at the prevalence of vitamin D deficiency and insufficiency. They showed a clear circannual variation in vitamin D levels, which peaked in August to October, and troughed January to March. The percentage of subjects with vitamin D levels below 25nmol/L was 15.5% in winter/spring and 3.2% summer and autumn. This rose to 21.4% and 4.5% respectively in obese individuals, and 23.5% and 8.3% for those living in Scotland. It is unknown whether seasonal low levels of vitamin D are harmful or not. In the above study, further cut offs of <40nmol/L and <75nmol/L were also measured; 46% of the total had vitamin D values below 40nmol/L, and 87% below 75nmol/L during winter and spring. These percentages increased in obesity, female sex, and Scottish region of residence so that 92% of Scottish residents had values below 75nmol/L in winter and spring. These figures have huge implications in terms of patient numbers if a decision was taken to adopt higher cut off values for defining vitamin D deficiency. 1.3.2. Conclusions While definitions remain controversial, it seems reasonable in general to suggest that: 25(OH)D <25nmol/l is presumed to indicate inadequate stores, unless mitigating factors suggest not reflecting the true long term position, and <14nmol/l would always indicate deficiency. 25(OH)D >50nmol/l is presumed to indicate no significant deficiency requiring vitamin D treatment unless mitigating factors suggest not reflecting true longterm position, and >75nmol/l would always indicate adequate stores. Factors increasing the significance of 25(OH)D <50nmol/l include clinical and biochemical features fitting with vitamin D deficiency (see sections 3 and 4), and reasons to feel that the vitamin D is usually lower than when measured (eg level was measured during seasonal or personal high point). 2. Actions of Vitamin D The vitamin D receptor is expressed in most tissues and has been shown to regulate cellular differentiation and function in many cell types. A recent feature in the New England Journal of Medicine noted a number of significant associations with low levels of 25(OH)D in observational studies. These included increased risk of metabolic, neoplastic, and immune disorders including type 1 diabetes mellitus and multiple sclerosis. A recent retrospective, observational study showed a J-shaped association between 25(OH)D levels and mortality. The major physiologic effects of vitamin D involve regulation of intestinal calcium transport. Calcium absorption via the transcellular route and vesicular transport are dependent on 1,25(OH)D. Paracellular calcium absorption may also be enhanced by 1,25(OH)D. Under normal dietary conditions approximately 30% to 35% of the 700 to 900mg daily calcium intake is absorbed, this drops to 10% to 15% without vitamin D. 1,25(OH)D regulates cell proliferation in the parathyroid glands and decreases transcription of the PTH gene. In the kidney, 1,25(OH)D stimulates calcium reabsorption from the glomerular filtrate. In the bone 1,25(OH)D has numerous effects: it represses synthesis of type 1 collagen, induces synthesis of osteocalcin, and increases osteoclastic bone resorption. However, in studies of 1,25(OH)D-deficient rats, the major osseous consequences of hormone deficiency can be reversed when mineral ion homeostasis is normalized. Also, parenteral calcium infusions have been shown to heal osteomalacic lesions in children with mutant vitamin D receptors. These findings would suggest that the major role of 1,25(OH)D in bone is to provide the appropriate micro-environment for bone mineralization through stimulation of calcium absorption in the intestine. 3. Presentation of Vitamin D Deficiency Vitamin D deficiency in childhood, before epiphyseal closure, results in rickets with skeletal abnormality and muscle weakness. In adulthood the epiphyses are closed, and there is enough mineral in the skeleton to prevent skeletal deformity. The abnormal mineralization causes decreased bone mineral density, bone and muscle pains, and weakness; this is known as osteomalacia. In a report of 17 patients with osteomalacia on biopsy, bone pain, bone tenderness and muscle weakness were the commonest symptoms present in 84% of the patients. Bone pain was most pronounced in the lower spine, pelvis and lower extremities. The pain was characterised as dull and aching, and aggravated by activity and weight bearing. In the same series, fractures occurred in 76%, with little or no trauma and typically involving the ribs, vertebrae and long bones. Muscle weakness was proximal and may be associated with muscle wasting, hypotonia and discomfort with movement. Other symptoms were less common (<25% of patients) and included difficulty walking and waddling gait, muscle spasms, cramps, positive Chvosteks sign, tingling/numbness, inability to ambulate NOTEREF _Ref318796594 \h  \* MERGEFORMAT 16,. Adults may also be asymptomatic, and may be diagnosed on biochemistry findings of raised alkaline phosphatase, raised PTH, hypocalcaemia, and hypophosphataemia. 3.1. People at risk Vitamin D deficiency should be considered in those at risk, and appropriate investigation performed. Those with reduced intake or synthesis of vitamin D: Dark skinned people People who cover up (eg muslim women, people with skin photosensitivity) Housebound, institutionalized and elderly people Non-fish eaters (eg vegetarian diets) People with fat malabsorption, coeliac disease, small bowel disease and short bowel syndrome (due to reduced absorption of fat soluble vitamins) Those with altered metabolism of 25(OH)D: People on a range of medications including anticonvulsants, rifampicin and medications to treat AIDS/ HIV because these drugs enhance the catabolism of 25(OH)D and 1,25(OH)2D. These people are at risk of hypocalcaemia, and specialist advice should be considered. Chronic granulomatous disorders, some lymphomas and hyperparathyroidism. These people are at risk of hypercalcaemia and specialist advice should be considered. Conditions with inadequate vitamin D action requiring specialist management: Hypoparathyroidism most commonly following neck surgery Hypomagnesaemia which inhibits PTH release leading to hypoparathyroidism People with chronic renal impairment who have a reduced capacity to hydroxylate 25(OH)D into its active form. These people should be discussed with the renal team (see section 5.1) Tumour induced osteomalacia tumour production of fibroblast growth factor 23 (FGF23) inhibits phosphate transport in the renal tubule, and 1-hydroxylation of vitamin D by the kidney NOTEREF _Ref326310486 \h  \* MERGEFORMAT 5. Other causes: Obese people (probably due to reduced bioavailability) People with nephrotic syndrome who lose 25(OH)D bound to vitamin D binding protein in the urine 4. Investigation Vitamin D deficiency should be considered in people complaining of bone pain, muscle pain or weakness, particularly those who are at risk (see above). It should also be considered in people who have indicative biochemistry performed for other reasons. The characteristic biochemical picture is of raised alkaline phosphatase (AlkP), raised PTH, hypocalcaemia and hypophosphataemia. The key diagnostic test is decreased serum 25(OH)D, but it takes several weeks for a result to become available. The 1,25(OH)D may be normal in vitamin D deficiency, probably as a result of maximal stimulation of 1 alpha-hydroxylase due to low phosphate and raised PTH levels; this is therefore not routinely measured. In retrospective reviews of biopsy proven nutritional osteomalacia, the AlkP was elevated in 95 100%, 25(OH)D less than 37.5nmol/l in 100% and the PTH elevated in 100% of patients. Serum Ca and Phosphorus were reduced in far fewer patients (27 38%) NOTEREF _Ref326309596 \h  \* MERGEFORMAT 17. The latest Glasgow vit D assay is an immunoassay which shows only 50% cross-reactivity with vitamin D2 (ergocalciferol). This means that patients on ergocalciferol could have their 25-vit D underestimated (indeed, these patients should have vit D status measured by tandem mass spec). Accordingly, the guideline for Lothian encourages using cholecalciferol preparations. Patients on vitamin D treatment do not generally require monitoring of vitamin D levels however, so this would only become an issue in special circumstances such as suspected poor compliance or malabsorption. Reduced 1 alpha-hydroxylase activity due to renal insufficiency, tumour-induced osteomalacia or genetic abnormality (which usually present in childhood) will result in low 1,25(OH)D and raised levels of 25(OH)D. These forms of osteomalacia should be considered if the biochemistry is not typical. The possibility of tumour induced osteomalacia should be considered in those with typical features of vitamin D deficiency and hypophosphataemia who do not respond to vitamin D. Hypoparathyroidism, commonly due to previous surgery but also secondary to low magnesium and other rare causes, can result in hypocalcaemia, hyperphosphataemia with low (or normal) PTH and should be referred to the endocrine team for management. Consideration should be given to the reason for vitamin D deficiency, and coeliac serology should be considered in cases where a clear underlying cause is not apparent. Vitamin D should not be measured in those with conditions not linked to bone disease, such as cardiovascular disease or malignancy. There is insufficient evidence to recommend supplementation with vitamin D in this group, and testing is therefore not justified and may lead to harm NOTEREF _Ref323550711 \h 2. 5. Management and vitamin D replacement considerations (See treatment protocol) The general approach is as shown in the algorithm (page 1), and is centred on clinical features and biochemical investigation. Characteristic findings of vitamin D deficiency should be confirmed, whilst being alert to alternative causes and biochemical findings indicating different management or specialist referral is appropriate. If there is any doubt about how a patient should be managed, advice can be sought from the endocrine registrar on call (#6800) or from the rheumatology team (SpR phone 31807). 5.1. When should referral to secondary care be considered? Patients with severe pain or weakness Those with severe hypocalcaemia (Ca++ usually <1.9mmol/l with muscle twitches, convulsions, Chvosteks sign, Trousseaus sign, carpal spasm, papilloedema, prolonged QT interval on ECG) or hypomagnesaemia, who may need iv replacement Any patient who does not respond to vitamin D replacement as expected Conditions with increased metabolism of 25(OH)D to 1,25(OH)D who are at risk of hypercalcaemia (see people at risk section 3.1) Patients with renal failure who may need activated vitamin D, or lower doses of vitamin D, should be discussed with the renal team; referral guidelines can be found here:  HYPERLINK "http://www.edren.org/pages/gpinfo/when-to-refer-to-the-renal-unit.php" http://www.edren.org/pages/gpinfo/when-to-refer-to-the-renal-unit.php For advice:  HYPERLINK "mailto:rierenaladvice@luht.scot.nhs.uk" rierenaladvice@luht.scot.nhs.uk Patients with nephrotic syndrome Patients with GI disorders who may require high doses or parenteral administration of vitamin D Patients with probable primary hyperparathyroidism (raised Ca and normal or high PTH) should be referred to endocrinology Patients with hypoparathyroidism should be referred to endocrinology (Low PTH, low Ca, low/normal 25(OH)D, low 1,25(OH)D, high PO4, normal AlkP particularly in patients with history of neck surgery). Patients with osteoporosis should be managed as per osteoporosis guidelines, consider referral to the metabolic bone clinic 5.2. General considerations There is variable inter-individual response to treatment with oral vitamin D in terms of serum 25(OH)D levels,. It has been estimated that 1000IU daily of oral cholecalciferol will eventually raise serum 25(OH)D by 25nmol/l NOTEREF _Ref318798428 \f \h 22, however this was in vitamin D replete subjects. It has been suggested that in adults 10000IU daily, or 60000IU weekly, will lead to restoration of body stores in 8 to 12 weeks, although the evidence behind this was not cited NOTEREF _Ref326310351 \h  \* MERGEFORMAT 8. These guidelines use a more conservative dosing regimen. Vitamin D has a high therapeutic index, and most reports of toxicity involve serum levels of greater than 350nmol/L. Vitamin D doses of 10000IU per day NOTEREF _Ref326309124 \h  \* MERGEFORMAT 21, and even 40000IU per day, have been shown to be safe in vitamin D replete populations. Despite high serum levels of vitamin D in these subjects, hypercalcaemia did not occur. This makes vitamin D a safe treatment with relatively few contra-indications; hypercalcaemic disorders being the main one. Normally as vitamin D stores become replete PTH down regulates, and in turn down regulates 1-alfa-hydroxylase activity. Any condition which causes the activity of 1-alfa-hydroxylase to remain inappropriately high (hyperparathyroidism, granulomatous disorders etc) require caution to avoid hypercalcaemia, and specialist referral is appropriate. Calcium should be monitored to ensure that hypercalcaemia does not occur, particularly in patients with renal dysfunction. Vitamin D levels need not be routinely rechecked. Hydroxylated vitamin D such as alfa-calcidol (1(OH)D) or calcitriol (1,25(OH)D) can cause hypercalcaemia, and are not effective at replenishing vitamin D stores. These preparations may occasionally be used for vitamin D deficiency in secondary care to induce a rapid response, but should not be used long term. Their use is largely limited to patients with severe renal impairment leading to reduced renal hydroxylation of 25(OH)D and secondary hyperparathyroidism. These patients should be discussed with a renal physician (see section 5.1). 5.3 Treatment Recommendations All patients should be given lifestyle and dietary advice in the first instance, as described in section 1.1. Patients with symptoms of osteomalacia and typical biochemistry require treatment with high dose vitamin D. Treatment should be given with oral colecalciferol, in the form of Dekristol. For adults 20,000 to 60,000units per week should be given (see treatment protocol). Biochemistry should be monitored to ensure that it normalizes, and patients referred to a specialist if this is not the case. Patients without these typical features should be assessed carefully with the aid of the treatment algorithm on page 1. The evidence supporting intervention in people with vitamin D values between 25-50nmol/L (even with raised PTH) is lacking. Assessment of the importance of the vitamin D level in the context of symptoms, biochemistry, risk factors and time of year is important when considering the most appropriate management strategy. These guidelines recommend measuring PTH in this group in order to help with risk stratification. This recommendation is based on evidence that PTH has an inverse relationship with BMD, independent of vitamin D level,. PTH also correlates with markers of bone turnover NOTEREF _Ref323551609 \h 26. A study of British Asians showed PTH to be the best underlying marker of histological ostoemalacia. However, other factors should also be considered including time of year, intercurrent illness, and fracture risk, in order to assess if vitamin D treatment is worthwhile. A trial of treatment may be undertaken, with a review at 6 months to consider whether there has been symptomatic benefit or biochemical improvement. Following a course of treatment, patients should always be reassessed in order to ensure that the treatment has had the desired effect, and to consider whether long term vitamin D replacement will be required. This should be done by reassessing their clinical condition for signs and symptoms of vitamin D deficiency. Also, any biochemical abnormality should be repeated following a course of treatment to ensure normalisation (eg raised PTH, AlkP). A repeat vitamin D level is generally not required, unless it is felt that the initial test did not reflect current vitamin D levels due to mitigating factors already discussed. In these cases, if a repeat vitamin D level is requested within 1 year, the request must be discussed with the biochemist in Glasgow or it will routinely be refused. Long term treatment should be considered in those with ongoing, irreversible risk factors. If diet and sunlight exposure cannot be improved in this group, then low dose treatment with 800units of vitamin D daily may be required to prevent repeated episodes of ostoemalacia. Evidence to support this is lacking. 5.4. Supplementation with low dose vitamin D Recent endocrine society clinical practice guidelines NOTEREF _Ref326309251 \h  \* MERGEFORMAT 7 suggest that adults aged 19 70 years require at least 600IU/day of vitamin D to maximise bone health and muscle function. It is unknown whether this is enough to provide all the potential nonskeletal health benefits associated with vitamin D. Similarly adults over 70 years require at least 800IU/day of vitamin D. To raise blood level of 25(OH)D consistently above 75mmol/L may require at least 1500 2000IU/day. There is evidence that bone mineral density is higher in people with vitamin D levels greater than 50nmol/L. There is also meta-analysis evidence that supplementing elderly patients with vitamin D reduced non-vertebral fracture risk (>400units per day) and reduced falls risk (>700units per day and 25(OH)D levels >60nmol/L) NOTEREF _Ref318795715 \h  \* MERGEFORMAT 6. However, the evidence is not consistent, and some recent trials show no benefit on fracture and falls with vitamin D supplementation in the elderly NOTEREF _Ref326310116 \h  \* MERGEFORMAT 13, Calcium and vitamin D supplementation is recommended for certain elderly patients classed as being at risk of falls as part of the falls risk strategy (see the NHS Lothian Falls Policy). The Chief medical officers of the UK have also recommended routine supplementation with 400units of vitamin D per day in those over 65years, and those not exposed to much sun. This is a rapidly emerging field, and future trials may help to guide us on who might benefit most from vitamin D supplementation in due course. 5.5. Non musculoskeletal conditions and screening There is observational evidence that low vitamin D levels are associated with increased mortality NOTEREF _Ref326312440 \h  \* MERGEFORMAT 14, cardiovascular mortality, type 2 diabetes, cancer, multiple sclerosis, and various other conditions. As these studies are observational however, they cannot prove causality. There is no interventional evidence to support treatment with vitamin D for these conditions NOTEREF _Ref323550711 \h 2. 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Safety of vitamin D3 with multiple sclerosis. Am J Clin Nutr. 2007;86:645-51  Collins D, Jasani I, Fogelman I et al. Vitamin D and bone mineral density. OsteoporosInt. 1998;8:110-4  Mezquita-Raya P, Munoz-Torres M, De Dios Luna J et al. Relation between vitamin D insufficiency, bone mineral density, and bone metabolism in healthy postmenopausal women. Journal of Bone and Mineral Research. 2001;16(8):1408-15  Nisbet JA, Eastwood JB, Colston KW et al. Detection of osteomalacia in British Asians: a comparison of clinical score with biochemical measurements. Clin Sci 1990;78:383-9  Aloia, JF. The 2011 report on dietary reference intake for vitamin D: Where do we go from here? 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