Considerations With Calcium And Vitamin D Supplementation

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1 Considerations With Calcium And Vitamin D Supplementation Activity Preview Calcium is an electrolyte involved in many systems in the body including bone health, nerve signaling pathways, muscle contractions, and other intracellular processes. Approximately 99% of the body s calcium is stored and regulated via the skeletal system. During the early years of life, calcium is predominantly stored through increased bone formation. Optimization of bone health early in life is important because bone hemostasis is shifted toward bone breakdown (resorption) during the later years of life. A combination of older age and decreased calcium intake can lead to an increased risk of bone fractures. Calcium supplementation is recommended in specific patient populations to reduce the risk of fractures and subsequent complications. Although the role of vitamin D in fractures is not as well defined as calcium, appropriate vitamin D intake is involved in the absorption and hemostasis of calcium. The National Health and Nutrition Examination Survey (NHANES) found that more than 43% of the U.S. population older than 1 year of age use supplemental calcium and more than 37% use a supplement containing vitamin D. 1,2 Appropriate calcium and vitamin D intake through dietary sources along with supplementation in specific patients are required to reduce long-term complications associated with bone health. Calcium is found in a variety of dietary sources including dairy products, certain vegetables, fortified grains, and other foods. Although a variety of foods contain calcium, the amount of calcium absorbed from the diet averages approximately 30% and may not be sufficient to achieve the recommended daily intake. Calcium supplements may be appropriate in patients unable to achieve the recommended daily intake through their diet. The NHANES study observed inadequate intake of calcium in all females greater than 4 years of age, specifically adolescents and women greater than 70 years of age. In addition, insufficient calcium intake was observed in males 9 to 18 years of age and men greater than 51 years of age. 1,2 The recommended daily intake of calcium depends on the age of the patient as calcium hemostasis changes during the lifetime (Table 1). 1-3 Bone regulation is shifted toward

2 bone formation in children and adolescents leading to peak bone mass at approximately 30 years of age followed by breakdown in the later adult years. Calcium deficiency manifests over an extended period of time as the skeletal system is utilized to maintain blood calcium homeostasis. The long-term consequences of calcium deficiency manifest as osteopenia, which can lead to osteoporosis and increased risk of bone fractures. 2 Table 1. Recommended Daily Allowance of Calcium 3 Age Male Female a 0 6 months 6 12 months 1 3 years 700 mg 700 mg 4 8 years 1,000 mg 1,000 mg 9 13 years 1,300 mg 1,300 mg years 1,300 mg 1,300 mg years 1,000 mg 1,000 mg years 1,000 mg 1,000 mg years 1,000 mg 1,200 mg >70 years 1,200 mg 1,200 mg a Includes pregnant and lactating women years old. Although appropriate calcium intake is necessary in all patients to avoid long-term consequences, specific patient populations have been identified to be at a greater risk. Decrease in estrogen production in postmenopausal women increases bone breakdown and decreases absorption of calcium. Vegetarians and patients with lactose intolerance also are at risk for calcium deficiency owing to limited intake of calcium-rich foods. In addition, intake of vegetables rich in oxalic and phytic acids can decrease calcium absorption through binding in the gastrointestinal tract. Other risk factors for osteoporosis include being female, white, having a thin build, inactivity, advanced age, smoking, excessive alcohol intake, and a family history of osteoporosis. 2,3 Patients at increased risk for the consequences of calcium deficiency should be encouraged to supplement calcium intake and participate in regular weight-bearing or resistance exercise to maintain a healthy skeletal system. Calcium supplementation is an important component for bone health and body signaling, but excessive calcium intake may be detrimental. Hypercalcemia is rarely caused by overuse of supplements and is usually associated with renal insufficiency, hyperparathyroidism, and malignancy. However, excessive calcium supplementation has been associated with an increased risk of nephrolithiasis due to formation of calcium oxalate crystals. Interestingly, increased dietary intake of calcium was not associated with the increased risk of kidney stones. 2 Increased risk of cardiovascular disease and stroke has been observed with calcium supplementation. A recently published study analyzed cardiovascular death utilizing

3 information from the NHANES III database. The authors found no clear association between dietary or supplemental calcium and cardiovascular death. There was increased mortality associated with cardiovascular disease with serum calcium levels <1.16 mmol/l and with ischemic heart disease in women with serum calcium levels >1.31 mmol/l. 4 A majority of the other studies that show a positive correlation are observational and robust prospective studies have yet to be conducted to elucidate this association. Overall, the data raise questions regarding appropriate supplementation of calcium and association with cardiovascular disease. Patients should be thoroughly evaluated to determine the risk-to-benefit ratio of adding calcium supplementation. A variety of oral calcium supplements are currently available over the counter (OTC). The calcium salt in the product determines the amount of elemental calcium and adverse effect profile. Calcium carbonate products are available as capsules, tablets, suspensions, and most notably as a chewable tablet for acid suppression. It contains 40% elemental calcium and must be taken with meals because it requires an acidic environment for optimal absorption. 5 Calcium citrate is another common OTC calcium supplement that contains 21% elemental calcium and may be taken with or without a meal. 6 Other calcium salts are available, such as calcium acetate. Although ingestion of calcium acetate will have inherent absorption of calcium, these products are utilized as a binding agent to treat patients with hyperphosphatemia. Following ingestion with a meal, these phosphate binders will preferentially bind to phosphorus in food thereby preventing absorption. These products are useful for patients with chronic kidney disease unable to properly eliminate phosphorus. It is important for health care providers to evaluate the calcium salt to ensure the patient is taking the supplement appropriately and in sufficient quantity. Common adverse effects associated with calcium supplementation include the abdominal discomforts of gas and constipation. Gastrointestinal adverse effects are more commonly seen with use of calcium carbonate salts compared with calcium citrate. Decreasing the dose and increasing the frequency of supplementation may help reduce these symptoms. Changing to a different calcium salt should be considered in patients who are unable to tolerate the abdominal adverse effects. Absorption of calcium supplements depends on a variety of factors. In general, with an increased dose of calcium, the percent absorbed conversely decreases. Patient counseling should include instructions to take no more than 500 mg of calcium at a time and separate calcium supplements throughout the day to achieve the appropriate daily intake. Calcium will bind with specific medications if taken concomitantly, thereby decreasing absorption and efficacy of the medication. Quinolones, tetracyclines, and levothyroxine will bind to calcium salts in the gastrointestinal tract. Although thiazide diuretics do not have a direct interaction with calcium absorption, these diuretics are calcium sparing and concomitant use may increase the risk of hypercalcemia. An overall review of the patient s medication list should include assessment of supplements to avoid interactions.

4 Vitamin D (calciferol) is a prohormone essential for absorption of calcium and regulation of calcium hemostasis. It is a lipophilic vitamin that has two major forms in the body: ergocalciferol (vitamin D 2 ) and cholecalciferol (vitamin D 3 ). Ergocalciferol is found in fortified foods and OTC supplements. Cholecalciferol is unique in that it can be synthesized in human skin through exposure to sunlight and it is also found in food from animal sources. 2 These forms of vitamin D act similarly in the body and require activation by enzymes. The first step of metabolism occurs in the liver, converting the inactive forms to 25-hydroxyvitamin D (25OHD or calcidiol). 25OHD is the predominant form of vitamin D found circulating in the body bound to vitamin D proteins. The final step of metabolism converts 25OHD to 1,25-dihydroxyvitamin D (calcitriol) in the kidney. Calcitriol is the active form of vitamin D that regulates calcium and phosphorus in the body. Unfortunately, this form of vitamin D is generally poor for evaluating vitamin D status because of its very short half-life and its production is not directly related to the amount of vitamin D intake. Since vitamin D cannot be directly measured due to sequestration in fatty tissues, 25OHD is utilized as a surrogate biomarker for supply of vitamin D to the body. Measurement of this precursor takes into account both forms of vitamin D from oral intake and skin biosynthesis. The target goal of vitamin D that correlates with optimal bone health has not been established. The Institute of Medicine has suggested that 25OHD levels should be >20 ng/ml. 3 Although the therapeutic range remains undefined, higher levels may be associated with increased risk of cancer and bone fractures. 2,3 The benefit of vitamin D intake for decreasing the risk of bone fractures is unclear. The available data are confounded by the utilization of calcium supplementation with vitamin D. Although there is currently not a measurable benefit to the addition of vitamin D supplementation, appropriate intake may improve calcium absorption and reduce the risk of hip fractures when used in combination with calcium supplementation. According to the NHANES report, 41.6% of adults had 25OHD levels below the recommend goal. 1,2 Vitamin D supplementation should be provided daily; it is absorbed readily regardless of food. Recommendations for intake depend on age and whether the patient is considered deficient based on measured 25OHD levels (Table 2). 3 Other supplemental sources of vitamin D including multivitamins or combination calcium and vitamin D products should be noted to ensure the patient is receiving the appropriate amount of vitamin D. Vitamin D supplementation is well tolerated with minimal adverse effects, although excessive vitamin D intake may precipitate hypercalcemia.

5 Table 2. Recommended Daily Allowance of Vitamin D 3 Age Male Female a 0 6 months 6 12 months 1 3 years 600 IU 600 IU 4 8 years 600 IU 600 IU 9 13 years 600 IU 600 IU years 600 IU 600 IU years 600 IU 600 IU years 600 IU 600 IU years 600 IU 600 IU >70 years 800 IU 800 IU a Includes pregnant and lactating women years old. Ergocalciferol and cholecalciferol products are available to supplement vitamin D intake. The evidence comparing the efficacy of these products is controversial. Some studies have shown a better and more sustained response in measured 25OHD levels with cholecalciferol compared with ergocalciferol. Although the difference in efficacy remains unclear, it may be beneficial to recommend cholecalciferol as first-line therapy especially in patients with low 25OHD levels. Case Study Gloria Brown, a 57-year-old white woman, is a new patient visiting your pharmacy today. Gloria has not seen a physician in over 10 years. She is perimenopausal and currently has no known chronic conditions requiring medications. She informs you that her father died of a stroke at the age of 72 years and her mother was healthy but seemed to lose height as she aged. Gloria takes a multivitamin and calcium supplement (500 mg) daily in the morning, chewable acid suppressants, and acetaminophen occasionally for joint pain. She currently works as a teacher and spends most of her time indoors at work and rarely spends time outside due to severe allergies. On appearance, you notice that she is a thin, petite woman approximately 5 feet tall. Gloria recently saw a story on the news regarding increased risk of cardiovascular disease with calcium supplements. She had occasionally taken calcium supplements but temporarily stopped after seeing the news story. She wishes to know more information about this topic and whether she should continue to take calcium supplements. You ask Gloria open-ended questions regarding her diet, supplements, and use of chewable acid suppressants. She states that her diet consists of cereal for breakfast, salads for lunch, yogurt as a snack, and either beef or chicken with vegetables for dinner. The multivitamin she takes as a supplement contains 200 mg calcium and 600 IU of vitamin D. She uses the acid suppressant tablets rarely and only with spicy food or holiday meals. She notes that although they are effective at reducing her acid reflux, she feels bloated after taking the chewable tablets.

6 Question 1 What would you recommend for Gloria regarding continuing calcium supplementation? a. Discontinue calcium supplements because she is at high risk for a cardiovascular event based on her family history. b. Continue to take calcium supplements because she is at high risk for osteoporosis. c. Discontinue calcium supplements because she is receiving adequate amounts of calcium from her diet and use of acid suppressants. d. Discontinue calcium supplements because she is at risk for developing kidney stones. The correct answer is b. Although there is a significant cardiovascular event in Gloria s immediate family, it is outside the age range to be considered a contributing risk factor. She currently has multiple risk factors for developing osteoporosis including her family history and being white and petite. The risk of osteoporosis outweighs the cardiovascular risk in this patient. She should be advised to visit a physician for assessment of other possible contributing factors to cardiovascular health including vital signs and cholesterol panel. Answer a is incorrect because Gloria s risk factors for osteoporosis are significantly higher than her corresponding risk factors for cardiovascular disease. Answer c is incorrect because despite the calcium-rich diet that Gloria is taking, she is at high risk for osteoporosis and requires appropriate supplementation with calcium. Although she currently is taking calcium-containing acid suppressants, she does not take them regularly enough to provide adequate daily calcium supplementation. Answer d is incorrect because dietary calcium has not been linked with an increased risk of kidney stone production. In addition, she is currently taking less than the daily recommended amount of calcium for patients her age. This may become an issue if she exceeds the recommended daily calcium supplementation by taking excessive amounts of calcium supplements and calcium-containing acid suppressants. You discuss with Gloria the evidence supporting the cardiovascular risk associated with calcium supplementation and her risk factors for developing osteoporosis. Gloria agrees with your assessments and plans to set up an appointment with a physician for a thorough physical and evaluation. In the meantime, she wishes to continue taking calcium and would like to know if she is appropriately taking her calcium supplements and whether she needs to take vitamin D. Question 2 What would you recommend for Gloria regarding calcium and vitamin D supplementation?

7 a. Continue her current regimen of a multivitamin and calcium tablet in the morning and add a 600 IU vitamin D tablet to the regimen. b. Increase her use of the calcium-containing acid suppressants by taking one with lunch and dinner. c. Increase her calcium intake by continuing her multivitamin in the morning and moving the calcium tablets to one with lunch and one with dinner. d. Increase her calcium intake by adding an additional calcium tablet to her morning regimen. The correct answer is c. Gloria requires 1,200 mg calcium supplementation daily according to the Institute of Medicine s recommendation on daily calcium intake for women her age. Answer a is incorrect because she is currently taking 700 mg, which is less than the recommended daily calcium intake. In addition, she currently is taking the recommended daily amount of vitamin D through her multivitamin. Because Gloria currently does not have any labs to suggest vitamin D deficiency, she does not require any further vitamin D supplementation. Answer b is incorrect because these are calcium carbonate containing supplements, which have reportedly given her abdominal discomfort and intolerance. Although these are a viable option for supplementation of calcium, it would be more appropriate to recommend a calcium citrate product to decrease the risk of adverse effects that she has experienced with products containing calcium carbonate. Answer d is incorrect because calcium absorption decreases with increasing amount of calcium. The maximum amount of calcium that should be administered per dose is 500 mg.

8 References 1. Bailey RL, Dodd KW, Goldman JA, Gahche JJ, Dwyer JT, Moshfegh AJ, et al. Estimation of total usual calcium and vitamin D intakes in the United States. J Nutr. 2010;140: National Institutes of Health, Office of Dietary Supplements. Dietary Supplement Fact Sheet: Calcium. Available at: HealthProfessional/. Accessed May 17, Institute of Medicine Committee to Review Dietary Reference Intakes for Vitamin D and Calcium; Ross AC, Taylor CL, Yaktine AL, Del Valle HB, eds. Dietary Reference Intakes for Vitamin D and Calcium. Washington, DC: National Academies Press; Van Hemelrijck M, Michaelsson K, Linseisen J, Rohrmann S. Calcium intake and serum concentration in relation to risk of cardiovascular death in NHANES III. PLoS One. 2013;8:e Calcium Carbonate. In: DRUGDEX System [intranet database]. Version 5.1. Greenwood Village, CO: Thomson Healthcare. Accessed May 17, Calcium Citrate. In: DRUGDEX System [intranet database]. Version 5.1. Greenwood Village, CO: Thomson Healthcare. Accessed May 17, 2013.

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