Calcium is an integral component of bone structure and strength. Approximately 99% of the body’s calcium stores are found in bone; the remaining 1% circulates in the blood, where it is bound either to plasma proteins or occurs in its freely ionized form. Skeletal bone serves as a reservoir for calcium when it is needed for other bodily functions such as muscle contraction and nerve transmission.

When the circulating concentration of calcium falls below the normal reference range of 8.5 to 10.5 mg/dL, parathyroid hormone (PTH) is released from parathyroid glands to correct this fluctuation. PTH acts via several mechanisms:

  • increased reabsorption of calcium in the kidney tubules
  • increased renal production of the active form of vitamin

D: 1,25(OH)2D (calcitriol) stimulation of osteoclasts. Osteoclasts are large, macrophagic cells responsible for bone resorption. These cells bind to bone, releasing hydrogen ions and proteolytic enzymes that dissolve its organic components, thereby liberating calcium for use in body processes while also decreasing bone mineral density (BMD). The effects of vitamin D on calcium.

Calcium Absorption

Calcium enters the body by crossing the epithelial surface of the gastrointestinal (GI) tract in a combination of passive and active processes. Calcium traverses the tight junctions between enterocytes and passively diffuses down its electrical and concentration gradient in paracellular transport, a process that occurs throughout the length of the intestinal tract. The complementary active calcium absorption mechanism is trans-cellular transport, which takes place predominantly in the duodenum and upper jejunum. Transcellular transport is a protein-mediated process that is driven by vitamin D and assumes a larger role in calcium absorption when dietary calcium intake is low.

Thus, the absorption of calcium is predominantly via an active transport mechanism in the GI tract. It has always been assumed that only the free calcium ion was absorbed via this process. The amount of calcium absorbed by the body depends on factors such as ethnicity, sex, age, vitamin D stores, and the amount of calcium ingested. As the calcium load increases and vitamin D stores decrease, less ionic calcium is able to be absorbed by the active transport process.

Because of this “saturation phenomenon,” in terms of how much calcium can be absorbed by the intestine at one time, it has generally been recommended that no single calcium dose should exceed 500 to 600 mg of elemental calcium (e.g., the amount of calcium in a supplement that is available for the body to absorb). Until recently, this idea was thought to apply to every form of calcium. However, more recent evidence shows that unlike calcium carbonate, calcium citrate forms a soluble complex that can be passively absorbed and can thus circumvent this saturable transcellular active transport process. Consequently, the absorption of calcium carbonate is more likely than the citrate salt to be affected by vitamin D stores, and it is more likely to display dose-dependent absorption. canada viagra online

In clinical terms, the absorption characteristics of calcium citrate make it a more likely candidate for dose-consolidation regimens in which only one or two doses need to be given in order to meet the usual goal of 1,000 to 1,500 mg of elemental calcium per day, the recommended intake established by the National Academy of Sciences and the National Institutes of Health (NIH). Under this guideline, it seems appropriate that one could consolidate calcium citrate products that contain 315 mg of elemental calcium (e.g., calcium citrate with vitamin D) by giving two tablets at a time; however, more data are needed to determine whether single doses of calcium carbonate beyond this level can be given without significantly compromising bioavailability.

Oral Calcium Preparations and Their Bioavailability: Passing the Acid Test?

Numerous oral calcium formulations are on the market (Table 1). These formulations differ primarily in their companion anion, which consequently imparts their physio-chemical properties. These preparations vary in their fractional content of calcium by weight (elemental calcium), ranging from calcium carbonate at 40% to calcium gluconate at only 9.3%. However, neither this factor nor the solubility of these varying salt forms is the sole determinant of bioavailability.

Table 1 Oral Calcium Supplements

Trade Name Salt Form Calcium Content (by Weight)
Alkalak, Alka-Mints, Amitone, Calcarb, Calci-Chew, Cal-Mint, Calci-Mix, Calgest, Caltrate, Chooz, Florical, OsCal, Oysco, Titralac, Tums Calcium carbonate 40%
Cal-Citrate, Citracal Calcium citrate 24.1%
N/A Calcium formate 30.8%
Cagluc Calcium gluconate 9.3%
Phos-Lo Calcium acetate 25%

Heaney et al. showed that the degree of dietary calcium absorption was largely independent of the solubility of the salt form and concluded that two of the most commonly used oral supplemental calcium salt forms (citrate and carbonate) were bioequivalent. This assertion, however, correlates poorly with other controlled trials of the relative bioavailability of these two salts. tadalis sx

Harvey et al. gave radiolabeled calcium supplements of both salt forms to a small group of healthy women. The researchers observed that citrate was better absorbed than carbonate (39.2 ± 8.6°% vs. 31.2 ± 9.4°%; P < 0.001). Hansen et al. showed a significantly greater absorption of citrate solution than carbonate solution in middle-aged men but found no difference in absorption between citrate suspension and carbonate solution.

When Heller et al. gave citrate and carbonate supplements with breakfast to 18 healthy patients, the increase in both the serum calcium concentration and the calcium area-under-the-curve (AUC) concentration (measured up to six hours after the dose) observed in the citrate group was significantly greater than in the carbonate group.

Hanzlik and Harvey and their colleagues also found a more pronounced increase in serum calcium levels and a greater urinary calcium excretion, respectively, in patients receiving citrate. In the latter of these two studies, a subgroup of patients was analyzed specifically for the relative bioavailabil-ity of the two agents. The citrate form was absorbed at a rate of 40.2 ± 6.7%, compared with 31.4 ± 1% for carbonate. Thus, more studies suggest a somewhat greater bioavailability of calcium citrate than calcium carbonate in a variety of patient populations.

With many patients now taking potent acid-lowering agents such as proton pump inhibitors (PPIs), more attention is being paid to the relative bioavailability of calcium salts in low-acid environments. In one case-control study, the use of PPIs for at least one year was found to be an independent risk factor for hip fractures, and the relationship was related to the dose of the PPI. In the authors’ discussion, they cited calcium mal-absorption as the most likely culprit for this adverse outcome.

Calcium carbonate is relatively insoluble at neutral pH and therefore needs to be in an acidic environment to ensure optimal absorption. Conversely, as confirmed in one study comparing the bioavailability of citrate and carbonate in achlor-hydric patients, the absorption of the citrate salt does not appear to be reduced in this setting.

One prospective randomized, placebo-controlled, crossover, double-blind study directly addressed calcium absorption and PPIs in community-dwelling elderly women over 65 years of age. After seven days of taking  (Prilosec canadian, Astra-Zeneca) 20 mg once daily, calcium carbonate absorption was reduced by 41% (95% confidence interval [CI], -86% to 3%), when compared with placebo. In the study, patients took their calcium supplement on an empty stomach after an overnight fast. Although the findings were not conclusive, some experts believe that taking carbonate with food (thus increasing stomach acid secretion) may improve absorption in these relatively achlorhydric environments. More data are needed on comparative studies between the two salts in the milieu of PPI use, but the current evidence points toward a preference to use the citrate salt in patients who need to be maintained on long-term PPI regimens. This would be especially true for patients who do not ingest full or regular meals when they take calcium supplements.

One exception to the “if on a PPI, use calcium citrate” adage might pertain to patients on hemodialysis or other patients with severe renal impairment. The citrate salt enhances aluminum absorption, thereby potentiating the aluminum-related neuro-toxicity and osteoporosis sometimes seen in this patient pop-ulation. Calcium acetate, which is more water-soluble and already marketed as a phosphate binder for end-stage renal disease (ESRD), is also thought to be well absorbed in low-acid environments, especially when it is taken with meals. Therefore, calcium acetate should be the calcium supplement of choice for patients with ESRD who are taking PPIs. The usual dose of six calcium acetate tablets daily yields almost 1 g of elem ental calcium.