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DariCal Pharmacokinetics and Bioavailability

Gloria E. Sarto, M.D.,
INTRODUCTION:

Osteoporosis is a major health problem in the United States. In the United States, 10 million people have osteoporosis and 34 million have low bone mass placing them at increased risk for osteoporosis. Osteoporosis is a condition in which bone mass and, therefore, bone strength is decreased. In adulthood, the normal active formation- resorption cycle, which takes place within bone changes, and the rate of bone formation slows down while bone resorption may accelerate. Calcium is an essential mineral in the bone formation, yet in osteoporosis the turnover rate for calcium falls from 100% to 18% in adults in a year. Thus, the bone is in a weakened state due to decreased calcification resulting in an increased risk for fractures. The most common locations for such fractures are those bones that normally have the highest turnover rate of resorption-formation, such as the femur and the wrist. The number of osteoporosis fractures in the United States exceeds 1.3 million annually including 250,000 hip fractures. One out of every two women and one out of every four men over 50 years will have an osteoporosis related fracture in their lifetimes. (NHLBI) Maintaining adequate calcium intake throughout life is essential in preventing osteoporosis. To achieve the recommended intake of calcium (1200mgm/day) most individuals take a calcium supplement, most often in the form of calcium carbonate (OsCal®) or calcium citrate (CitraCal®). Calcium carbonate in the form of OsCal is a commonly used calcium supplement as is CitraCal.

The purpose of this study was to compare the absorbability of a new product, Product A with OsCal. Product A compound, derived from organic sources, contains a protein-mineral-calcium complex containing calcium, phosphorus, magnesium, potassium, zinc, iron, manganese and copper in addition to proteins. It is FDA approved as a calcium supplement. Product A is available as a powder which can be sprinkled over cereal or dissolved in water, coffee, etc. Additionally, it is available as a chocolate, caramel, or mint-chocolate chew.

MATERIALS AND METHODS:

Subjects:

Twenty women between the ages of 45 and 60 years in good general health were recruited for study. Individuals taking a calcium and/or vitamin supplement were asked to abstain throughout the study, starting at least one week in advance of the first test. Additionally, they were asked to avoid foods with high sodium for at least two days before the first test. The protocol and consent forms were submitted to and approved by the University of Wisconsin Human Subject’s Committee. Each subject gave written consent.

Design:

The study consisted of a two way randomized cross-over within subject design, with each individual receiving OsCal® (Glaxo- SmithKline), composed of 500mg of calcium carbonate and 200 IU of vitamin D, and Product A powder, containing 500mg of calcium and 200 IU vitamin D. The subjects were asked to present after an overnight fast. The calcium test dose was given midway through a standard light calcium restricted breakfast. Blood samples were taken prior to the breakfast and calcium test dose, and at 1, 3, 5, 7 and 9 hours after. A low calcium, low sodium lunch was provided after the 5 hour blood draw. Identical breakfasts and lunches were provided to each volunteer and for each test day. While a quality of life questionnaire was not part of the protocol, each subject was asked about taste and side effects such as intestinal distention.

Test Sources:

Os-Cal was purchased from a retail pharmacy. Product A powder was provided by U.S. Foods and Pharmaceuticals, Inc. in individual packets. Each contained 500mg of calcium and 200 IU vitamin D.

ANALYTIC METHODS:

Serum calcium was analyzed by absorptive spectrophotometry (Sigma Diagnostic Kit Instructions). Phosphate, magnesium, potassium and iron were analyzed on the 0 and 3 hour blood draws. Calcium was analyzed on all specimens. All laboratory analyses were done at the University of Wisconsin Hospitals and Clinics, Madison, WI, clinical laboratory.

Gloria E. Sarto MD, PhD, Professor, Department of Obstetrics & Gynecology, Co-Director, Center forWomen’s Health Research, University of Wisconsin-Madison


Statistical Analysis:

The primary outcome measures were the usual pharmacokinetic variables, area under the curve (AUC) as well as time of maximum serum concentration (Tmax) and the magnitude of the elevation (Cmax). Calcium concentrations in serum were obtained before, and at 1, 3, 5, 7, and 9 hours after the test dosing. The area under the curve (AUC) for serum calcium concentration vs. time was determined using the trapezoidal method. No extrapolation past the final serum sample was performed. The baseline AUC (0-9h) was calculated as 9h x [baseline calcium] and was subtracted from the actual AUC to provide the change in AUC (deltaAUC) resulting from each of the calcium / vitamin D supplements. The time of maximum serum calcium concentration (Tmax) and the magnitude of the elevation (Cmax) with respect to the baseline calcium were determined by inspection. The two deltaAUC resulting from the administration of the supplements was compared using a paired t-test. Changes in serum magnesium, phosphate, potassium, and iron between baseline and three hours after doing were also compared using a paired t-test (SigmaStat, Systat, Inc). If the data were non-normal, the Wilcoxon Signed Rank test was used instead.

Results

The results of the comparison of the two supplements are given in Table: I.

Table: I


§: Data failed test for normality – paired t-test replaced with Wilcoxon Signed Rank. Values in parentheses are the 25 and 75% confidence intervals.

No significant difference was noted in the change in serum calcium AUC over the period 0-9 hours after a 500mg dose of OsCal or Product A in combination with 200 IU Vitamin D. The power to detect a difference with an alpha error of 0.1 was 0.1.

There were no significant differences in the Cmax or Tmax values for calcium for either formulation. Similarly, there were no statistically significant differences in the changes from baseline to the 3 hour-post dose sample for potassium, magnesium, or iron. In contrast, the Product A yielded a higher change in serum phosphate concentration than did the OsCal product. The serum phosphate rose to 4.7 mg/dl in one OsCal treatment (ULN 4.5 mg/dl) and in two treatments with Product A, but not within a given subject. All participants found Product A to be palatable and there were no gastro-intestinal complaints.Discussion:

The most commonly used commercial supplements are calcium carbonate (OsCal) or calcium citrate (CitraCal). Heaney et ali compared marketed calcium carbonate, OsCal, marketed calcium citrate, CitraCal, and a gelatin capsule containing precipitated calcium carbonate, and found them to have equivalent bioavailability. Calcium (500 mg) sources were given only on the test day and only at breakfast. All these calcium sources produced identical 24h time courses. Serum total calcium (mg/ dl) peaked at 5 hours for OsCal and CitraCal.

Standard bioequivalence analysis indicated that the carbonate and citrate test sources were bioequivalent with respect to serum total and ionized calcium. Although in the study, the AUC was calculated out to 24 hours, a subsequent study by Heaneyii has shown that 9 hours is sufficient. Heaney suggested that the curve of absorptive calcium can be captured by approximately six blood samples at 0,1,3,5, 7 and 9 hours after ingesting a test dose of 500mg calcium.

This study showed Product A equivalent to OsCal in calcium, potassium, magnesium and iron. DariCal however, surpassed OsCal in regards to phosphate content or absorption. This may be of significance in that phosphorus is as important as calcium in supporting bone augmentation and maintenance.iii Hypophosphatemia is associated with limited mineralization of new bone at all ages, impaired osteoblast function and enhanced osteoclastic resorption.iv While most adults get sufficient phosphorus through their diets, there is a percent of older adults who do not have intakes of the recommended daily allowance. Additionally, when individuals take high dose supplements of calcium in the form of carbonate or citrate, much of their dietary phosphorus may be bound and thus not absorbed. Thus, the phosphate content in Product A is an added benefit. Recent studies show that organic source proteins are instrumental in suppressing osteoclast activity and stimulating osteoblasts, resulting in increased bone formation.v,vi,vii The protein fraction in the compound of Product A, likewise may prove to suppress osteoclast activity and thus inhibit bone resorption as well.

Sponsored by USFP

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1 Heaney RP, Dowell MS, Bierman J, Hale CA, Bendich A. Absorbability and Cost

Effectiveness in Calcium Supplementation. J Am Col Nutr. 2001;20(3):239-246.

2 Heaney RP. Quantifying Human Calcium Absorption Using Pharmacokinetic Methods.

J Nutr. 2003;133:1224-1226.

3 Heaney RP. Phosphorus Nutrition and the Treatment of Osteoporosis. Mayo Clin Proc. 2004;79:91-97.

4 Shapiro R, Heaney RP. Co-dependence of calcium and phosphorus on growth and bone development

under conditions of varying deficiency. Bone. 2003;32:532-540.

5 Toba Y, Takada Y, Matsuoka Y, Morita Y, Motouri M, Hirai T, Suguri T, Aoe S, Kawakami H,

Kumegawa M, Takeuchi A, Itabashi A. Milk Basic Protein Promotes Bone Formation and Suppresses

Bone Resorption in Healthy Adult Men. Biosci Biotechnol Biochem. 2001 Jun;65(6):1353-7.

6 Yamamura J, Aoe S, Toba Y, Motouri M, Kawakami H, Kumegawa M, Itabashi A, Takada Y. Milk Basic

Protein (MBP) Increases Radial Bone Mineral Density in Healthy Adult Women. Biosci Biotechnol

Biochem. 2002 Mar;66(3):702-4.

7 Aoe S, Koyama T, Toba Y, Itabashi A, Takada Y. A Controlled Trial of the Effect of Milk Basic Protein

(MBP) Supplementation on Bone Metabolism in Healthy Menopausal Women. Osteoporos Int. 2005

Dec;16(12):2123-8.



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