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Original Research |
Valio Research Centre (M.N., R.K.), Pharmacology, University of Helsinki, Helsinki, FINLAND
Institute of Biomedicine (M.N., R.K.), Nutrition, University of Helsinki, Helsinki, FINLAND
Department of Applied Chemistry and Microbiology (M.K., C.L-A.), University of Helsinki, Helsinki, FINLAND
Stat-Consulting (T.P.), Helsinki, FINLAND
Foundation for Nutrition Research (R.K.), Helsinki, FINLAND
Address reprint requests to: Dr. Riitta Korpela, PO Box 30, 00039 Valio, FINLAND. E-mail: riitta.korpela{at}valio.fi
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSREFERENCES |
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Objective: We examined the effect of additional caseinphosphopeptides in milk and fermented milk on acute calcium metabolism by measuring intact PTH (iPTH), ionized calcium (iCa), total calcium (Ca) and phosphate (P) from serum, and 24-hour calcium from urine (U-Ca).
Methods: The study consisted of two separate parts, both applying a double-blind randomized crossover study with two interventions, in nine postmenopausal women. The acute effect on calcium metabolism was analysed by measuring iPTH, iCa, Ca and P from serum during the first six hours after the administration of the study milks. U-Ca was analysed 24 hours prior to the study and 0, 2, 4, 6, 12 and 24 hours after the administration of the study milks. The study included two parts, both consisting of two study days with a one-week washout period in between. In the first part the effect of control milk and CPP-enriched milk was measured. The second part evaluated the effect of fermentation by giving subjects milk or fermented milk, both enriched with CPPs.
Results: In the first part of the study there were no statistically significant differences in iPTH, iCa, Ca, P or U-Ca between the groups receiving control milk compared to CPP-containing milk. There was no difference in the AUC(0–6) of iCa and iPTH. In the second part, fermentation did not affect calcium metabolism, when results from the CPP-enriched milk and CPP-enriched fermented milk groups were compared.
Conclusion: One gram of caseinphosphopeptides does not affect calcium metabolism acutely in postmenopausal women.
Key words: caseinphosphopeptides, calcium metabolism, fermentation, postmenopausal women
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSREFERENCES |
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An in vitro rat study has shown that the amount of soluble calcium is increased in the intestine by additional CPPs, and it may thus increase calcium absorption [4]. Despite this, animal studies investigating the effect of CPPs on calcium absorption have produced inconsistent results [5–8]. Measuring the effect of CPPs in humans, the calcium absorption has shown to be affected by calcium status [9]. Even though the addition of 87.5 mg of CPPs did not increase calcium absorption in postmenopausal women, the effect was detected in women with low calcium absorption levels [9]. Calcium absorption is also affected by different dietary components. As phytates are known to reduce calcium absorption, CPPs’ ability to increase calcium absorption from phytate-containing meals has been studied in humans. One gram of CPPs increased calcium absorption by 30% when it was ingested with a rice-based gruel compared to whole-grain gruel. Two grams of CPPs did not produce an additional increase in calcium absorption in the rice-based gruel [10]. Contradictory results were shown in another study where 1 g of CPPs did not increase calcium absorption from either low-phytate or high-phytate-containing meals [11].
Fermentation may increase the bioavailability of different nutrients, since it causes proteolysis in milk and degradation of proteins, which enlarges the area susceptible to enzymes and also slows gastrointestinal transit time [12]. It has been postulated that fermentation increases calcium absorption also through increased production of CPPs during food processing, which increases the production of more soluble calcium compounds [1]. In previous studies fermentation has been shown to affect calcium metabolism acutely by increasing serum ionized calcium (iCa) and intact PTH (iPTH) levels [13,14]. Data from studies using isotope methods have questioned the effect of fermentation [15,16].
The discrepancies between the results of CPPs studies may be due to the different methods applied. Previous human studies have used calcium isotopes for measuring calcium absorption. Acute effects on calcium metabolism can be measured by changes in iPTH, iCa, Ca and U-Ca during the hours following the ingestion of calcium [17,18]. Oral calcium load suppresses iPTH and increases Ca and U-Ca acutely [19]. Rises in iCa and U-Ca have been shown to correlate with intestinal calcium absorption [20]. To our knowledge no earlier studies exist on the effects of CPPs on the acute metabolism of calcium. The aim of this study was to examine the acute effect of CPPs on calcium metabolism when they were ingested with milk or fermented milk.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSREFERENCES |
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The study consisted of two separate parts, both applying a double-blind randomized crossover study with two interventions (Fig. 1). The aims of these parts were to compare milk enriched with CPPs (CPP milk) to control milk and fermented milk enriched with CPPs (FCPP milk) to CPP milk. This design, instead of a three-period, three-treatment cross-over design, was used to avoid complicated carry-over and period effects and problems caused by possible dropouts and to focus only on the primary comparisons. In all the interventions the study milk was given with a standardized breakfast and the follow-up was for 24 hours. The acute effect on calcium metabolism was analysed by measuring iPTH, iCa, Ca and P from serum 0, 1, 2, 4 and 6 hours after the administration of the study milks. U-Ca was analysed 24 hours prior to the study and 0, 2, 4, 6, 12 and 24 hours after the administration of study milks. Between the study days there was a one-week washout period. In the first part of the study, the interventions to be compared were CPP milk and control milk, which were given in randomized order. In the second part of the study, after a one-week washout period, the interventions were FCPP milk and CPP milk, again given in randomized order. Randomization was carried out by means of random permuted blocks. The milk used in all the interventions was calcium-fortified milk containing 3.8 g protein, 0 g fat, 5.1 g carbohydrates and 180 mg Ca/100 g. The daily dose was 2.8 dL, containing 500 mg of calcium. To the CPP-enriched milk, 1000 mg of CPPs (Phospho Peptide CE 90 CPP, DMV International, Veghel, Netherlands) was added. On the study day identical meals containing 190 mg calcium were given to all the subjects (Table 1). All the subjects were given milk products the previous day in order to control the amount of calcium (600 mg) in their diets the day before the study day, when urine samples were collected.
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The volume of urine was measured and a urine sample was stored at -20°C until the calcium and creatinine concentration analyses, which were carried out by routine laboratory methods. The amount of creatinine in the urine confirmed the normal renal function.
Statistical Analysis
The mean value, the area under the curve (AUC) and the maximal change from baseline during the six-hour follow-up were calculated for response variables, Ca, P, iCa and iPTH. The AUC values were determined using the changes from the baseline (0 hour), and the maximal changes were assessed instead of peak values in order to control for the differences in the baseline values. A paired t test was used to compare the interventions. A value of p < 0.05 was considered significant. SPSS (Version 10.0) was used for statistical analysis.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSREFERENCES |
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DISCUSSION |
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In this study design, CPPs in milk products did not affect calcium metabolism acutely (Tables 2 and 3, Figs. 2 and 3). CPPs stimulate calcium absorption through a passive absorption mechanism, independent of vitamin D [6]. Vitamin D increases the absorption of calcium; thus, the effect of CPPs on calcium absorption may be seen more clearly in vitamin D-deficient subjects, as it has been shown on vitamin D-depleted infants [3]. However, vitamin D status was not measured in this study. The study was conducted during summer, when vitamin D status in Finland, the location of the study, is known to be higher than in winter; this might have diluted the effect of CPPs. In other human studies vitamin D (25-dihydroxy-cholecalciferol) status has not been controlled for and serum values have varied from 10 to 110 mol/L [10,11].
The effect of other nutrients on calcium metabolism during the study day was excluded by controlling calcium intake 12 hours prior to the study and by serving identical meals during the study days. In this study, no differences existed between the study milks in the amounts of calcium, phosphate, sodium or protein. Phosphorus has been shown to increase iPTH [21]. In our study the intake of phosphorus was constant during each study day. It has been reported that even small amounts (250 mg) of calcium affect calcium metabolism, the effect of calcium absorption occurring 0.5–2 hours after ingestion [19]. The possible effect of the small dose of calcium ingested with breakfast and lunch (35 mg and 65 mg calcium, respectively) should not have had an effect on iCa and iPTH, when the blood samples were taken.
The effect of CPPs on calcium absorption has been shown to be affected by calcium intake, calcium status and dietary casein level [9,23]. CPPs have been reported to have their greatest effects on women with low calcium absorption levels [9]. In our study the subjects were postmenopausal without hormone replacement therapy, when calcium absorption is decreased [22]. The subjects were also asked to maintain their normal diet throughout the study, and the use of mineral and vitamin supplements or herbal products was prohibited, as was sunbathing. The study was conducted with the same subjects in a short period of time during the same season; thus, there should not have been any changes in the calcium absorption levels of the subjects.
It has been suggested that different CPP:calcium ratios have different effects on calcium absorption depending on the meal it is ingested with [10]. Ratios varying from 0.35 to 4 have been studied in different settings with controversial results [9–11]. In our study the CPP:calcium ratio was 2.
After 2.5 hours of small calcium loads, 95% of calcium ingested is absorbed [17]. Passive absorption peaks at six hours after the ingestion of calcium. In our study the levels of iPTH seemed to be lower at the two-hour blood sample compared to the first blood sample. At four and at six hours the levels stayed stable in both groups, indicating a later absorption of calcium. In six hours there was not a significant difference in iPTH after control milk compared to CPP milk (Fig. 2). Measurements were not taken after more than six hours, but a possibility exists that the quantitative effect of CPPs may have occurred and been clear beyond six hours.
CPP milk was used as study milk in both interventions. Although these interventions are studied separately, there is a difference between the AUC change values between the first and second intervention after CPP milk. The differences in AUC may be due to one differing value in the curve. If the maximal results and Figs. 2 and 3 are compared, the difference between the values is not as marked. The possible carry-over effect was controlled by one week’s being used as washout period; thus, it should have not affected the results.
Calcium absorption has been reported to increase with fermented dairy products [13,14]. It has also been stated, however, that slow release of newly formed CPPs throughout the digestive tract may have a greater effect than preformed CPPs resulting from fermentation [11]. In this study we did not find any acute effect of fermentation on calcium metabolism (Table 3); this may be due to the large amounts of CPPs in both study milks.
According to this study, neither control milk nor fermented milk enriched with 1 g of CPPs influenced calcium metabolism in healthy postmenopausal women within the first six hours following ingestion. This result does not, however, exclude the possible positive effect of CPPs in vitamin D deficient people, who have an increased need of calcium, or in those with poor calcium absorption levels. There are many variables that may have affected the result of the study, such as the study design, habitual calcium intake of the subjects and the amount and form of CPPs. Further in vivo studies with different designs are needed before the conclusions can be drawn as to the effect of CPPs on calcium absorption and bioavailability.
Received December 24, 2001. Accepted August 15, 2002.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSREFERENCES |
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This article has been cited by other articles:
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  E. Lopez-Huertas, B. Teucher, J. J Boza, A. Martinez-Ferez, G. Majsak-Newman, L. Baro, J. J Carrero, M. Gonzalez-Santiago, J. Fonolla, and S. Fairweather-Tait Absorption of calcium from milks enriched with fructo-oligosaccharides, caseinophosphopeptides, tricalcium phosphate, and milk solids Am. J. Clinical Nutrition, February 1, 2006; 83(2): 310 - 316. [Abstract] [Full Text] [PDF]
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-) and after control milk (-
-).