Calcium supplementation in clinical practice A review of forms, doses, and indications

Introduction

Calcium, an essential mineral, is found in great quantity in the body, and about 99% of it is present in the bones and teeth;¹Cashman KD. Calcium intake, calcium bioavailability and bone health. Br J Nutr. 2002;87 Suppl 2:S169-77. the remaining 1% is found in the blood. Besides its direct role in maintaining bone health, calcium play important roles in various body functions such as nerve conduction, muscle contraction, and blood clotting. When levels in the blood falls below normal, it will be resorbed from bone in order to maintain blood calcium levels, forming the basis of rationale to consume enough calcium to maintain adequate calcium levels in the body.²Available at: http://ag.arizona.edu/pubs/health/az1042.pdf.

Further, bone itself undergoes continuous remodelling, with constant calcium resorption and deposition; the balance between bone resorption and deposition changes with age. While bone formation exceeds resorption in periods of accelerated growth in children and adolescents, the processes are relatively equal in early to middle adulthood. With advancing age, bone breakdown exceeds formation, resulting in bone loss. Consequently, there is increased risk of bone related disorders such as osteoporosis over time, particularly among postmenopausal women.³Available at: http://ods.od.nih.gov/factsheets/calcium/#en1.

Recommended calcium intake

Calcium recommendations vary for individuals by age and gender. In general, intake recommendations for calcium and other nutrients are provided in the Dietary Reference Intakes (DRIs), the general term for a set of reference values used for assessing the nutrient intakes of healthy people (Table 1).⁴Available at: 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.  ⁵Lee WT, Jiang J. Calcium requirements for Asian children and adolescents. Asia Pac J Clin Nutr. 2008;17 Suppl 1:33-6.

Other terms related with calcium recommendations include:

• Recommended Dietary Allowance (RDA) – Average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%-98%) healthy individuals.
• Adequate Intake – Established when evidence is insufficient to develop an RDA, and is set at a level assumed to ensure nutritional adequacy.
• Tolerable Upper Intake Level – Maximum daily intake unlikely to cause adverse health effects.

Reference calcium intakes for Asians are likely to be unique and different from those of Caucasians. Furthermore, given that genetic factors, hormonal status, body size, bone structure, diets, physical activity, vitamin D status and adaptation could modify calcium retention and bone integrity; these factors need to be considered collectively to promote bone health in Asian populations.⁵Lee WT, Jiang J. Calcium requirements for Asian children and adolescents. Asia Pac J Clin Nutr. 2008;17 Suppl 1:33-6.

Calcium deficiency

Circulating blood levels of calcium are tightly regulated. Though inadequate calcium intakes from food and supplements produce no obvious symptoms in the short term, symptoms may manifest with prolonged deficiency. Over the long term, inadequate calcium intake causes osteopenia which if left untreated can lead to osteoporosis. Subsequently, there is an increased risk of bone fractures, especially in older individuals.

Diet as a source of calcium

Since the body cannot produce calcium, it has to be supplied externally, and dietary products usually help in achieving this calcium homeostasis. Humans absorb about 30% of the calcium in foods, and this varies depending upon the type of food consumed. Accordingly, identification of indigenous foods rich in calcium and high in bioavailability is needed to widen sources of dietary calcium. Table 2 enlists some good dietary source of calcium.

In addition to the amount of calcium in the diet, the absorption of dietary calcium in foods is also a critical factor in determining the availability of calcium for bone development and maintenance.1 Absorption also depends on other factors such as: amount of food consumed; age and life stage; vitamin D intake; and other components in food (Table 3).

Calcium supplements

Besides the natural dietary sources, calcium may also be supplied in form of pharmaceutical preparations i.e. supplements. While the two main forms of calcium in supplements are carbonate and citrate, other calcium forms in supplements or fortified foods include gluconate, lactate, phosphate, acetate, pidolate and orotate. With regards to delivery systems, calcium supplements are available in different forms as capsules, tablets, chews, wafers, powders, and liquids.

Calcium supplements: A critical factor in practice

Adequate calcium consumption leads to considerable health benefits, and administration of calcium in form of supplements may be particularly important in clinical practice. A study assessing factors influencing calcium intake among women (n=104) with low bone mass found that combining dietary and supplemental calcium, about 77% of women were adherent to calcium recommendations at follow-up. Adherence was defined as meeting ≥ 85% of recommended calcium intake. About 91.3% women were using calcium supplements at baseline.⁶French MR, Vernace-Inserra F, Hawker GA. A Prospective Study to Identify Factors Affecting Adherence to Recommended Daily Calcium Intake in Women with Low Bone Mineral Density. Journal of the American College of Nutrition 2008;27(1):88-95. The most frequently reported barriers to obtaining adequate calcium intake as identified by these women were: uncertainty regarding calcium food sources and supplements, concerns related to weight gain, and the fat content of some calcium-rich foods. Interestingly, use of a calcium supplement was the only significant independent predictor of calcium adherence at follow-up. Thus, in addition to strategies to increase consumption of dietary sources of calcium, supplementation should be considered as an acceptable method of increasing calcium intake.

Carbonate vs. citrate

Different calcium formulations differ in the amount of elemental calcium present, which is usually listed in the supplement facts panel, thus, making it easier for the consumers, and they do not need to calculate the amount of calcium supplied by various forms of calcium supplements. While calcium carbonate is 40% calcium by weight, calcium citrate is 21% calcium (Figure 1).³Available at: http://ods.od.nih.gov/factsheets/calcium/#en1.

Therefore, a drawback associated with the use of calcium citrate supplements is the need to take more tablets/capsules to match the dose equivalent to that of calcium carbonate; this requirement for additional tablets may affect compliance. Accordingly, supplements containing calcium carbonate may, thus, have an advantage with regards to compliance since it provide greater amounts of elemental calcium, and consequently require fewer tablets than other forms of calcium.

Further, while calcium citrate is beneficial in individuals with hypo/achlorhydria and is mostly used after bariatric surgery, calcium carbonate can be used across all specialties.⁷Tondapu P, Provost D, Adams-Huet B, et al. Comparison of the absorption of calcium carbonate and calcium citrate after Rouxen- Y gastric bypass. Obes Surg. 2009 Sep;19(9):1256-61.

Cost-benefit ratio favours calcium carbonate

Calcium carbonate, the more commonly available form, is convenient, and is absorbed most efficiently when taken with food. Varying results were yielded in studies assessing calcium carbonate and calcium citrate, which may reflect differences in methodology. In a study, measuring ionized serum calcium, total serum calcium, and PTH levels over a 24-hour period, along with urine calcium excretion in vitamin D-sufficient postmenopausal women, the cost-benefit analysis favored the use of calcium carbonate.⁸Heaney RP, Dowell MS, Bierman J, et al. Absorbability and cost effectiveness in calcium supplementation. J Am Coll Nutr. 2001;20:239-246.

Calcium lactate and calcium gluconate

Calcium lactate and calcium gluconate are less concentrated forms of calcium,⁹Straub DS. Calcium Supplementation in Clinical Practice: A Review of Forms, Doses, and Indications. Nutr Clin Pract June 2007;22(3):286-296.  and are usually not considered practical for clinical practice – while calcium lactate contains 13% elemental calcium, calcium gluconate contains only 9% elemental calcium (Figure 1).

Therefore, since supplements having these calcium forms contain a small concentration of elemental calcium, they share the same limitation as that of calcium citrate, and it will require many tablets to be consumed to reach desirable doses.

Calcium acetate, calcium pidolate and calcium orotate

Calcium acetate, calcium pidolate and calcium orotate are less concentrated forms of calcium; calcium acetate contains 25% elemental calcium, calcium pidolate contains 13.50%, while calcium orotate contains only 10- 11% of elemental calcium (Figure 1). The FDA approved indication of calcium acetate is hyperphosphatemia, as it is a potent phosphate binder, so is mostly used in nephrology, and is also associated with lower risk of hypercalcemia and lower incidence of muscle cramps.¹⁰Data on file. Walter-Bushnell.    ¹¹Nieper HA. The anti-inflammatory and immune-inhibiting effects of calcium orotate on bradytrophic tissues. Agressologie. 1969;10(4):349-57.   ¹²Nieper HA. The clinical effect of calcium-diorotate on cartilage tissue, the specific function dependent upon the pentose metabolism of bradytrophic tissue [in German]. Z präkt Geriatrie. 1973;3(4):82-9.

Further, as these forms contain lesser amount of elemental calcium, these will require many tablets to be consumed to reach desirable doses, and are also not cost effective.

Calcium-fortified beverages

Ingesting milk is probably the best way to obtain calcium by dietary sources. However, many patients need alternative beverage options owing to lactose intolerance, a dislike of dairy products, or hyperlipidemia.¹³Available at: http://www.medscape.com/viewarticle/570851_2.  Calcium-fortified beverages, another convenient and popular way to increase calcium intake, may prove especially helpful for individuals having difficulty swallowing large tablets, for children, and individuals with dairy allergies or intolerances. In fact, replacing sweet beverages at dinner with low-fat milk or calciumfortified beverages might be suggested to improve the nutrient density of meals.¹⁴Hoerr SL, Nicklas TA, Franklin F, Liu Y. Predictors of calcium intake at dinner meals of ethnically diverse mother-child dyads from families with limited incomes. J Am Diet Assoc. 2009;109(10):1744-50.

Examples of calcium-fortified foods include orange juice, soy and rice milk; calcium-rich mineral water may also provide a calorie-free, calcium-rich source. van der Hee et al also identified calcium-fortified ice cream formulations as a good vehicle for delivery of calcium.¹⁵van der Hee RM, Miret S, Slettenaar M, et al. Calcium absorption from fortified ice cream formulations compared with calcium absorption from milk. J Am Diet Assoc. 2009 May;109(5):830-5.

Yet, bioavailability of calcium from these fortified foods may be a limitation for their use in clinical practice, and it varies considerably. Therefore, this factor should be considered when advising patients on the use of these fortified foods. Generally, information regarding the bioavailability of calcium-fortified products is not included on the nutrition label, thus, making it difficult for the consumers to calculate the amount of calcium they get from a particular calcium-fortified beverage. While most consumers assume that calcium absorption from fortified foods is equal to that of milk, often this is not the case.

Interestingly, higher consumption of milk or other food sources of calcium could provide limited protection against hip or forearm fractures. In a 12-year prospective study among 77761 adult women, aged 34 through 59 years, who had never used calcium supplements, Feskanich et al found no evidence that higher intakes of milk or calcium from food sources reduce fracture incidence; a finding that further underscores the importance of calcium supplementation.¹⁶D Feskanich, W C Willett, M J Stampfer, and G A Colditz (Milk, dietary calcium, and bone fractures in women: a 12-year prospective study.). American Journal of Public Health. 1997;87(6):pp. 992-997.

Indications for calcium supplementation

Besides calcium deficiency (individuals who fail to meet the adequate intake for calcium) being the most direct indication for calcium supplementation, other possible indications include:

• Individuals with osteopenia or osteoporosis – One in two women and one in five men suffer from osteoporotic fractures after the age of 50¹⁷More J. Children’s bone health and meeting calcium needs. J Fam Health Care. 2008;18(1):22-4.
• Perimenopausal and postmenopausal women¹⁸North American Menopause Society. The role of calcium in peri- and postmenopausal women: 2006 position statement of the North American Menopause Society. Menopause. 2006 Nov-Dec;13(6):862-77; quiz 878-80.
• Mothers who breastfeed/lactating women
• Amenorrheic women
• Vegetarians
• Residents of long-term care facilities
• Individuals who are lactose intolerant or receiving chronic corticosteroid therapy
• Patients with inflammatory bowel or celiac disease.

Calcium supplementation is contraindicated in patients with hypercalcemia, which may be caused by sarcoidosis, hyperparathyroidism, hypervitaminosis D, and certain cancers.⁹Straub DS. Calcium Supplementation in Clinical Practice: A Review of Forms, Doses, and Indications. Nutr Clin Pract June 2007;22(3):286-296.

Role of Vitamin-D co-supplementation

Vitamin-D is essential for intestinal calcium absorption and plays a central role in maintaining calcium homeostasis and skeletal integrity,¹⁹Cashman KD. Calcium and vitamin D. Novartis Found Symp. 2007;282:123-38; discussion 138-42, 212-8.   and since calcium absorption is dependent on an adequate level of the active form of vitamin-D, the latter should also be supplemented concurrently in addition to calcium. The patient compliance may be enhanced by combining both the salts in one drug as a fixed dose combination.

Dosing

Several controlled clinical trials of calcium plus vitamin D have confirmed reductions in clinical fractures. Thus, it is a standard practice to ensure adequate calcium and vitamin D intake in patients with osteoporosis, whether they are receiving additional pharmacologic therapy or not. For Men and women of age 51 and above, the estimated adequate daily calcium intake is 1200 mg per day in divided doses.

Dosing of calcium supplements can affect both the absorption of calcium and parathyroid hormone (PTH) levels. Essentially, the percentage of calcium absorbed depends on the total amount of elemental calcium consumed at one time, and absorption is highest in doses ≤ 500 mg.²⁰Harvey JA, Zobitz MM, Pak CY. Dose dependency of calcium absorption: a comparison of calcium carbonate and calcium citrate. J Bone Miner Res. 1988;3:253-258.   In a study, calcium absorption using three different doses was measured in 21 subjects (4 men; 17 women; age 22-60); doses of 500 mg, 1000 mg, and 2000 mg of elemental calcium were given to all of the subjects in the form of calcium carbonate and calcium citrate. Nine subjects underwent two additional loads with 0.2 g of elemental calcium as calcium carbonate and as calcium citrate. Results showed that urinary calcium increased rapidly at the 200- mg and 500-mg doses; there was only a slight additional increase after the 1000-mg and 2000-mg doses. It may, thus, be advisable that someone who takes 1000 mg/day of calcium from supplements might split the dose and take 500 mg at two separate times during the day.

Similar conclusive evidence was provided in a different study conducted on 30 healthy women, age 21-34 yrs, that assessed timing, dosage, and whether small repetitive doses of calcium are more effective.²¹Karkkainen MU, Lamberg-Allardt CJ, Ahonen S, Valimaki M. Does it make a difference how and when you take your calcium? The acute effects of calcium on calcium and bone metabolism. Am J Clin Nutr. 2001;74:335-342.   Markers of bone formation and resorption and PTH levels were measured. The timing of supplementation did not exhibit significant difference in PTH levels whether calcium was taken during the day or at night (9 AM vs. 9 PM). The size of the dose clearly had an effect on PTH levels: the higher the dose of calcium, the lower the PTH level. Small 200-mg doses of calcium given 4 times/day also produced lower PTH levels. In addition, there was no significant effect on markers of bone formation or resorption in any of the dosing schedules. Thus, in practice, the dose of calcium should not exceed 500 mg at one time to obtain optimalclinical outcomes related to calcium supplementation; for instance, a formulation containing 400 mg of calcium may be taken thrice daily for optimal outcomes.

Summary

Calcium plays an important role in bone health throughout the lifecycle, and is also required to maintain health in general. Therefore, it is paramount to ensure adequate calcium intake. Calcium supplements may be recommended to help the patient bridge the gap when diet cannot provide sufficient calcium to meet the body’s needs. In practice, for men and women of age 51 and above, a formulation containing 400 mg of calcium may be taken thrice daily to obtain optimal clinical outcomes related to calcium supplementation.

A number of forms are available for calcium supplementation; amongst these calcium carbonate is cost-effective, provides maximum elemental calcium, requires least no. of tablets and can be used in multiple indications such as during adolescence, pregnancy and lactation, for prevention of osteopenia/osteoporosis, in postmenopausal osteoporosis etc. Calcium carbonate should be taken with meals to optimize absorption. Though fortified beverages provide an easy source of calcium, the absorption of calcium from these forms is generally less than that of milk, and may not be considered a reliable source of bioavailable calcium.

References

1. Cashman KD. Calcium intake, calcium bioavailability and bone health. Br J Nutr. 2002;87 Suppl 2:S169-77.
2. Available at: http://ag.arizona.edu/pubs/health/az1042.pdf.
3. Available at: http://ods.od.nih.gov/factsheets/calcium/#en1.
4. Available at: 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.
5. Lee WT, Jiang J. Calcium requirements for Asian children and adolescents. Asia Pac J Clin Nutr. 2008;17 Suppl 1:33-6.
6. French MR, Vernace-Inserra F, Hawker GA. A Prospective Study to Identify Factors Affecting Adherence to Recommended Daily Calcium Intake in Women with Low Bone Mineral Density. Journal of the American College of Nutrition 2008;27(1):88-95.
7. Tondapu P, Provost D, Adams-Huet B, et al. Comparison of the absorption of calcium carbonate and calcium citrate after Rouxen- Y gastric bypass. Obes Surg. 2009 Sep;19(9):1256-61.
8. Heaney RP, Dowell MS, Bierman J, et al. Absorbability and cost effectiveness in calcium supplementation. J Am Coll Nutr. 2001;20:239-246.
9. Straub DS. Calcium Supplementation in Clinical Practice: A Review of Forms, Doses, and Indications. Nutr Clin Pract June 2007;22(3):286-296.
10. Data on file. Walter-Bushnell.
11. Nieper HA. The anti-inflammatory and immune-inhibiting effects of calcium orotate on bradytrophic tissues. Agressologie. 1969;10(4):349-57.
12. Nieper HA. The clinical effect of calcium-diorotate on cartilage tissue, the specific function dependent upon the pentose metabolism of bradytrophic tissue [in German]. Z präkt Geriatrie. 1973;3(4):82-9.
13. Available at: http://www.medscape.com/viewarticle/570851_2.
14. Hoerr SL, Nicklas TA, Franklin F, Liu Y. Predictors of calcium intake at dinner meals of ethnically diverse mother-child dyads from families with limited incomes. J Am Diet Assoc. 2009;109(10):1744-50.
15. van der Hee RM, Miret S, Slettenaar M, et al. Calcium absorption from fortified ice cream formulations compared with calcium absorption from milk. J Am Diet Assoc. 2009 May;109(5):830-5.
16. D Feskanich, W C Willett, M J Stampfer, and G A Colditz (Milk, dietary calcium, and bone fractures in women: a 12-year prospective study.). American Journal of Public Health. 1997;87(6):pp. 992-997.
17. More J. Children’s bone health and meeting calcium needs. J Fam Health Care. 2008;18(1):22-4.
18. North American Menopause Society. The role of calcium in peri- and postmenopausal women: 2006 position statement of the North American Menopause Society. Menopause. 2006 Nov-Dec;13(6):862-77; quiz 878-80.
19. Cashman KD. Calcium and vitamin D. Novartis Found Symp. 2007;282:123-38; discussion 138-42, 212-8.
20. Harvey JA, Zobitz MM, Pak CY. Dose dependency of calcium absorption: a comparison of calcium carbonate and calcium citrate. J Bone Miner Res. 1988;3:253-258.
21. Karkkainen MU, Lamberg-Allardt CJ, Ahonen S, Valimaki M. Does it make a difference how and when you take your calcium? The acute effects of calcium on calcium and bone metabolism. Am J Clin Nutr. 2001;74:335-342.