Vitamin D and Calcium Guideline Vitamin D Functions of Vitamin D 2 Serum Levels 2 Deficiency 2 Toxicity 2 Dietary Reference Intakes 3 Sources of Vitamin D 3 Therapeutic Options 4 Adults 4 Children (0 18 years) 5 Special populations 5 References 6 Calcium Functions of Calcium 7 Serum Levels 7 Deficiency 7 Toxicity 7 Special considerations: cardiovascular disease 7 Dietary Reference Intakes 8 Food Sources of Calcium 9 References Clinician Lead and Guideline Development 10 Most recent guideline approval: November 2011 Guidelines are systematically developed statements to assist patients and providers in choosing appropriate health care for specific clinical conditions. While guidelines are useful aids to assist providers in determining appropriate practices for many patients with specific clinical problems or prevention issues, guidelines are not meant to replace the clinical judgment of the individual provider or establish a standard of care. The recommendations contained in the guidelines may not be appropriate for use in all circumstances. The inclusion of a recommendation in a guideline does not imply coverage. A decision to adopt any particular recommendation must be made by the provider in light of the circumstances presented by the individual patient. Vitamin D and Calcium Guideline Copyright 2012 Group Health Cooperative. All rights reserved.
Vitamin D Functions Vitamin D is a fat-soluble vitamin that helps the body to absorb calcium. Serum levels Routine screening for vitamin D deficiency is not recommended. Consider vitamin D testing for: Patients with osteoporosis or a low-trauma impact fracture Patients who are homebound or in long-term care facilities Patients with a medical condition that increases the risk of vitamin D deficiency or insufficiency (e.g., kidney disease or liver disease) Patients on certain medications (e.g., antiseizures, glucocorticoids, AIDS medications, antifungals, cholestyramine) Patients with malabsorption syndromes (e.g., cystic fibrosis, inflammatory bowel disease, bariatric surgery, radiation enteritis) Patients with hypocalcemia, hypophosphatemia, or hyperparathyroidism Patients with suspected rickets Dark-skinned infants Deficiency Too little vitamin D can lead to: Osteoporosis or osteomalacia in adults Rickets in children Toxicity Too much vitamin D can lead to: Hypercalcemia, which can present as nausea, vomiting, constipation, poor appetite, weight loss, polyuria, confusion, and disorientation Nephrolithiasis Nausea, vomiting, constipation, poor appetite, and weight loss Vitamin D and Calcium Guideline 2
Dietary reference intakes for vitamin D For information on side effects, contraindications, formulary status (e.g., prior authorization), and other pharmacy-related issues, see the Group Health Formulary. As human milk is a poor source of vitamin D, breastfed infants should be prescribed a daily vitamin D supplement. Table 1. Recommended Dietary Allowance (RDA) for vitamin D 1 Age RDA (IU/day) Upper Limit (IU/day) Infants 0 6 months 1 400 1,000 Infants 6 12 months 1 400 1,500 1 3 years 600 2,500 4 8 years 600 3,000 9 13 years 600 4,000 14 18 years 600 4,000 19 30 years 600 4,000 31 50 years 600 4,000 51 70 years 600 4,000 Over 70 years 800 4,000 Females 14 18 years, pregnant/lactating Females 19 50 years, pregnant/lactating 600 4,000 600 4,000 1 These RDAs are based on the IOM recommendations. Sources of vitamin D The body makes vitamin D when the skin is directly exposed to sun. Despite the importance of sun exposure for the vitamin D synthesis, sunscreen or protective clothing should be worn when out in the sun for more than a few minutes to lower the risk for skin cancer. Table 2. Food sources of vitamin D 1 Food Portion size IUs per serving Vitamin D fortified milk (nonfat, reduced-fat, whole) 8 oz 115 124 Vitamin D fortified yogurt 6 oz 88 Salmon (sockeye), cooked 3 oz 447 Mackerel 3 oz 388 Tuna 3 oz 154 Vitamin D fortified orange juice 8 oz 137 1 These food sources are a subset of those identified by the NIH Office of Dietary Supplements. Vitamin D and Calcium Guideline 3
Therapeutic options Vitamin D is available in two forms, D2 (ergocalciferol) and D3 (cholecalciferol). Both forms and multiple dosing regimens effectively raise serum vitamin D levels. There is insufficient evidence to determine a preferred regimen. The cumulative amount of vitamin D appears to be most important. The following recommendations were adapted from UpToDate and from the Endocrine Society clinical practice guideline (Holick 2011). Adults Table 3. Recommended pharmacologic options for treating vitamin D deficiency in ADULTS 1 Eligible population Medication Dose Duration Adults with Vitamin D2 vitamin D (ergocalciferol) deficiency Vitamin D3 (less than 20 ng/ml) 2 (cholecalciferol) 50,000 IU/week 3,000 5,000 IU/day 6 Repeat vitamin D level at 12 weeks, or 4 weeks after completion of therapy: Less than 20 ng/ml Greater than 20 ng/ml 4 8 weeks Continue treatment for another 8 weeks then retest. 3 The amount of vitamin D needed to maintain optimal levels is usually 800 2,000 IU/day. 5 1 Risks of treatment include hypervitaminosis D, hypercalciuria, and hypercalcemia. Hypercalciuria may occur without hypercalcemia. In patients on long-term high-dose vitamin D therapy, it is prudent to measure serum calcium and 24-hour urine for calcium/fractional excretion of calcium once after 6 12 months of therapy. 2 Vitamin D levels greater than 20 ng/ml may be treated with the usual vitamin D supplement dosing. There is no need for follow-up testing in patients with vitamin D levels greater than 20 ng/ml. 3 If still less than 20 ng/ml, then increase dose to 50,000 IU twice a week and evaluate for malabsorption. 4 If originally deficient, recheck once more in 4 months to be sure that levels are maintained. 5 There is no consensus in the literature regarding appropriate maintenance dosing. The vitamin D source may be cholecalciferol 400 IU or 1000 IU, cal carbonate/vit D 600/400, or cal citrate/vit D 315/200. 6 The recommendations for daily dosing of vitamin D3 are based on local expert opinion. The Endocrine Society clinical practice guidelines recommend 6,000 IU/day; however, the Group Health guideline team considered this dose to be too high. Vitamin D and Calcium Guideline 4
Children (0 18 years) Table 4. Recommended pharmacologic options for treating vitamin D deficiency in CHILDREN 1 Eligible population Patients aged 0 18 years with vitamin D deficiency (less than 20 ng/ml) Medication Dose Duration Vitamin D2 (ergocalciferol) Vitamin D3 (cholecalciferol) 50,000 IU/week 2,000 IU/day Repeat vitamin D level at 10 weeks or 4 weeks after completion of therapy: Less than 20 ng/ml Greater than 20 ng/ml 3 6 weeks Continue treatment for another 6 weeks, then retest. 2 The amount of vitamin D needed to maintain optimal levels is usually 400 1,000 IU/day. 4 1 Risks of treatment include hypervitaminosis D, hypercalciuria, and hypercalcemia. Hypercalciuria may occur without hypercalcemia. In patients on long-term high-dose vitamin D therapy, it is prudent to measure serum calcium and 24-hour urine for calcium/fractional excretion of calcium once after 6 12 months of therapy. 2 If still less than 20 ng/ml, increase dose to 50,000 IU twice a week and evaluate for malabsorption. 3 If originally deficient, recheck once more in 4 months to be sure that levels are maintained. 4 There is no consensus in the literature regarding appropriate maintenance dosing. The vitamin D source may be cholecalciferol 400 IU chewable or drops. Special populations Patients requiring higher dosing Selected patients (e.g., obese patients, patients with malabsorption syndromes, and patients on medication affecting vitamin D metabolism) may require a higher dose of vitamin D to treat deficiency (at least 6,000 10,000 IU/day) followed by maintenance therapy of at least 3,000 6,000 IU/day (Holick 2011). Patients requiring lower dosing Consider lower dosing (less than 50,000 IU/week) in patients with hyperparathyroidism, sarcoidosis, tuberculosis, and lymphoma. Vitamin D and Calcium Guideline 5
References Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011 Jul;96(7):1911 1930. Institute of Medicine (IOM). Dietary Reference Intakes for Calcium and Vitamin D. http://www.iom.edu/~/media/files/report%20files/2010/dietary-reference-intakes-for-calcium-and- Vitamin-D/Vitamin%20D%20and%20Calcium%202010%20Report%20Brief.pdf. National Institutes of Health (NIH) Office of Dietary Supplements. Dietary Supplement Fact Sheet: Vitamin D. http://ods.od.nih.gov/factsheets/vitamind-healthprofessional UpToDate. Treatment of vitamin D deficiency in adults. http://www.uptodate.com/contents/treatment-of-vitamin-d-deficiency-inadults?source=search_result&search=vitamin+d+deficiency&selectedtitle=1%7e150#h20. UpToDate. Vitamin D insufficiency and deficiency in children and adolescents. http://www.uptodate.com/contents/vitamin-d-insufficiency-and-deficiency-in-children-andadolescents?source=search_result&search=vitamin+d+deficiency&selectedtitle=2%7e150#h23365861. Vitamin D and Calcium Guideline 6
Calcium Functions Building and maintaining strong bones and teeth Mediating skeletal and vascular muscle function Sending and receiving nerve signals Releasing hormones and other chemicals Serum levels Routine screening for serum calcium levels is not recommended. Deficiency Inadequate intake of calcium produces no obvious signs or symptoms in the short term; over the long term, insufficient calcium intake can lead to: Osteoporosis or osteomalacia in adults Rickets in children Toxicity Too much calcium can lead to: Constipation, fatigue, and depression Nephrolithiasis Special considerations: cardiovascular disease A recent meta-analysis that included 15 randomized controlled trials with 11,971 participants investigated whether calcium supplements increase the risk of myocardial infarction. Results from this analysis suggested that, when given alone, calcium may increase the risk of myocardial infarction (hazard ratio 1.31; 95% CI, 1.02 1.67; NNT = 69). However, this study should be interpreted with caution as it had several methodological limitations: the analysis only included studies involving calcium supplements, not calcium plus vitamin D, which is a more common regimen; none of the studies were designed primarily to examine cardiovascular disease; dietary calcium intake was not controlled for in the analysis; and seven of the trials had incomplete or no information on baseline cardiovascular risk factors. Additionally, the analysis found no significant increase in clinical outcomes such as stroke or death seemingly contradictory findings that raise questions about the conclusions of the analysis (Bolland 2010). Another systematic review and meta-analysis did not find that calcium supplements, with or without vitamin D, increased the risk of cardiovascular disease among adults. Results from this analysis should also be interpreted with caution, as it included only a small number of studies, none of which were designed to specifically assess the effects of supplementation on cardiovascular outcomes (Wang 2010). Vitamin D and Calcium Guideline 7
Dietary reference intakes for calcium Table 1. Recommended Dietary Allowance (RDA) for calcium 1,2,3,4,5 Age RDA (mg/day) Upper limit (mg/day) Infants 0 6 months 200 1,000 Infants 6 12 months 260 1,500 1 3 years 700 2,500 4 8 years 1,000 2,500 9 13 years 1,300 3,000 14 18 years 1,300 3,000 19 30 years 1,000 2,500 31 50 years 1,000 2,500 Males 51 70 years 1,000 2,000 Females 51 70 years 1,200 2,000 Over 70 years 1,200 2,000 Females 14 18 years, pregnant/lactating Females 19 50 years, pregnant/lactating 1 2 3 4 5 1,300 3,000 1,000 2,500 These RDAs are based on the IOM recommendations. Calcium may be taken as a supplement. Group Health carries the following formulations: Calcium carbonate/vit D 600/400 Calcium citrate/vit D 315/200 Calcium carbonate absorption may be impaired in patients with high gastric ph. This includes patients taking acid-suppressing drugs (e.g., proton pump inhibitors) and the elderly. Calcium citrate may be preferred in patients with high gastric ph. Generally, calcium absorption is enhanced with food. However, certain foods such as spinach, rhubarb, nuts, beans, seeds, grains, or high-fat or high-fiber meals may decrease absorption. Absorption is best if no more than 500 600 mg calcium is taken at a time. Vitamin D and Calcium Guideline 8
Food sources of calcium Table 2. Food sources of calcium 1 Food Portion size Milligrams (mg) per serving Milk (nonfat, reduced-fat, whole) 8 oz 272 296 Soy beverage, calcium-fortified 8 oz 80 500 Yogurt, plain, low-fat 8 oz 415 Yogurt, fruit, low-fat 8 oz 313 384 Mozzarella cheese, part-skim 1.5 oz 333 Cheddar cheese 1.5 oz 306 Sardines (canned in oil with bones) 3 oz 324 Salmon (pink, canned, solid with bones) 3 oz 181 Fortified breakfast cereals 1 cup 100 1,000 Calcium-fortified orange juice 8 oz 378 1 These food sources represent a subset of those identified by the NIH Office of Dietary Supplements. References Bolland MJ, Avenell A, Baron JA, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ. 2010 Jul 29;341:c3691. Institute of Medicine (IOM). Dietary Reference Intakes for Calcium and Vitamin D. http://www.iom.edu/~/media/files/report%20files/2010/dietary-reference-intakes-for-calcium-and- Vitamin-D/Vitamin%20D%20and%20Calcium%202010%20Report%20Brief.pdf. National Institutes of Health (NIH) Office of Dietary Supplements. Dietary Supplement Fact Sheet: Calcium. http://ods.od.nih.gov/factsheets/calcium-healthprofessional. Wang L, Manson JE, Song Y, Sesso HD. Systematic review: Vitamin D and calcium supplementation in prevention of cardiovascular events. Ann Intern Med. 2010 Mar 2;152(5):315 323. Vitamin D and Calcium Guideline 9
Clinician Lead and Guideline Development Content Expert James Benson, MD, Endocrinology Clinical Improvement & Prevention Clinician Lead John Dunn, MD, MPH, Associate Medical Director, Preventive Care Contact: dunn.jb@ghc.org Guideline Coordinator Avra Cohen, RN, Clinical Improvement & Prevention Contact: cohen.al@ghc.org Guideline Team Members Travis Abbott, MD, Family Medicine Vivien Chan, PharmD, Pharmacy Emily Chao, MD, Pediatrics Rebecca Doheny, MPH, Epidemiologist, Clinical Improvement & Prevention Fred Heidrich, MD, Family Medicine Paula Lozano, MD, MPH, Assistant Medical Director of Preventive Care Robyn Mayfield, Health Education Specialist, Clinical Improvement & Prevention Michelle Seelig, MD, Family Medicine Ann Stedronsky, Clinical Publications, Clinical Improvement & Prevention Most Recent Guideline Approval: December 2011 Process of Development This evidence-based guideline was developed using an explicit evidence-based process, including systematic literature search, critical appraisal, and evidence synthesis. The following specialties were represented on the development and/or update teams: endocrinology, family medicine, pediatrics, and pharmacy. Vitamin D and Calcium Guideline 10