European Journal of Nutraceuticals & Functional Foods

DDOOOOFFISSN 1722-6996 AIHTEI

Anno 16 • January/February 2005

Published by Tekno Scienze

Wei

gh

t C

on

tro

lJa

nuar

y/Fe

bru

ary

2005

■ Ag

roFO

OD

indu

stry

hi-t

ech

2

NEGATIVE STUDIESOnly a small number of animal and human studies did notsupport the idea of an anti-obesity effect of dietary Calcium.Feeding normal or high-energy-density diets differing in calciumcontent (0.2-1.8%) to normal and obese rats and mice had nosignificant effect on energy intake, body weight, body fat and didnot show the inverse relationship between 1,25-dihydroxy-vitamin D3 or PTH and body weight proposed by Zemel and co-workers21.In human studies, the administration of 1g/day “extra calcium”did not promote post-partum loss of body weight and fat inlactating and non-lactating mothers22 or increased weight andfat loss only non-significantly in 100 pre- and post-menopausalwomen following an energy-restricted diet over 25 weeks23. Andthe 4th Tromso study, a Norwegian population study in 9252 menand 9662 women, did show even a positive association betweencalcium intake and BMI in men and an unexpected negativeassociation between vitamin D intake and BMI in both sexes24.

QUANTITATIVE ASPECTSA quantitative re-analysis of the data from Davies and Heaney10

using simple bivariate and multiple regression models revealed,that calcium intake accounted for ~3% of the variation in BMI inyoung women and that each 100 mg increment in daily calciumintake would decrease average BMI by 0.3 kg/m2 (according to aregression coefficient of 0.003).The apparent weakness of this association may be partly due tothe fact, that the respective studies had not been designed toinvestigate the effect of calcium on body weight, but had skeletalendpoints. Indeed, other studies showed somewhat greatereffects in adults (Table 2).The actual importance of these effects becomes evidentregarding population means (i.e. for weight, BMI or body fat).In young women, an increase in calcium intake by 600 mg/dfrom 500 to 1100 mg/d causes a drop in mean BMI of 1.8 kg/m2

(-8%), but decreases the predicted prevalence of overweight(BMI>26 kg/m2) substantially by 78% from 16.6 to 3.6 percentand the prevalence of obesity (BMI>30 kg/m2) by 84% from0.99 to 0.16 percent of that age group (26). Midlife weight gaindecreased by 97% from 0.4 kg/y to 0.01 kg/y comparing womenat the 25th percentile of calcium intake with those atrecommended calcium intake27. And 3.5-4.5% less body fat inpre-school boys and girls (body fat ~18/21%), according to oneadditional serving calcium per day (300 mg), means a drop of–20%15.

MECHANISMSHow does calcium work? Although the physiological or cellbiological basis for the changes in body weight and body fat hasnot fully been elucidated, a hypothesis has been developed byZemel and co-workers5, which is based largely on experiments inthe obese agouti mutant mouse28-32. According to thishypothesis, increased circulating [Ca2+] due to the consumptionof relatively large amounts of dietary calcium decreases counter-regulatory serum concentrations of the calcitropic hormones PTH(parathyroid hormone) and calcitriol (1,25-dihydroxy-vitamin D3),which in turn down-regulates Ca2+ influx into adipocytes andthereby intracellular calcium29,33,34. Decreased adipocyteintracellular [Ca2+] stimulates lipolysis, fatty acid oxidation19 and

Various studies over the last years have shown that increasedcalcium uptake can significantly fight overweight and obesity.In this article, Dr. Gerhard Gerstner from JungbunzlauerLadenburg GmbH, a leading manufacturer of highly bioavailableorganic calcium salts used in food and pharmaceuticals, sums upthe facts.

INTRODUCTIONThe recommended daily intake of calcium (1000 mg/day for mostadults, 1200 mg/day for pregnant women) has been set to meetthe requirements of bone health and the prevention ofosteoporosis. Beyond it, calcium plays an essential role innumerous other vital functions such as regulation of cellmembrane fluidity and permeability, nerve conduction, musclecontraction and blood clotting. Calcium has anti-hypertensiveproperties and the consumption of calcium in sufficient amountsmay reduce the risk of colon cancer.

ANTI-OBESITY EFFECT OF CALCIUM: POSITIVE STUDIESRecently, an anti-obesity-effect of dietary calcium has beendiscovered1-3. Although first observations showing an inverserelation between calcium intake and obesity were publishedsince the end of the 1980’s4, this idea has become popular in thescientific community following the paper of Zemel5 and co-workers. This publication was based to a good deal oninvestigations in obese and insulin resistant mice (mutant“agouti mouse”) and led to an intensive re-examination andextended interpretation of data from several epidemiologicalstudies:A new evulation of the Data from US American NHANES III(National Health and Nutrition Examination Survey)5, the CSFIIstudy (Continuing Survey of Food Intake by Individuals)6, theCARDIA study7, the Quebec Family Study8 and the HERITAGEFamily Study9 showed accordingly a significant inverserelationship between calcium consumption and body weight, thebody mass index (BMI = body weight / body length [kg/m2]),body fat distribution or the prevalence of obesity, respectively.Positive results were independent from whether calcium intakeitself was estimated in the respective study or milk was taken asa measure of calcium intake. The anti-obesity effect of calciumhas been demonstrated in black and white people and in bothsexes, although in the HERITAGE Family Study the strongesteffects occurred in white women and black men.Further evidence came from clinical studies (six observationstudies and three controlled intervention trials), of which theprimary focus was the calcium effect on bone mass, from studiesrelating nutrient intake to body composition and from somerecently controlled intervention trials explicitly testing thecalcium effect on body weight, fat and the efficacy of weightreduction diets (Table 1). These studies consistently revealed, thata high calcium intake in childhood and adulthood as well assupplemental calcium is associated with a lower body weight (or BMI), less body fat due to a shift from fat to lean body massand a slower age-dependent weight gain in midlife. Furthermore,calcium increased the efficacy of energy-reduced weightreduction diets. And last but not least, all studies together show,that calcium has an own anti-obesity effect which is independentfrom other components of the diet.

Fighting obesity with calcium GERHARD GERSTNER

Jungbunzlauer Ladenburg GmbHDr.-Albert-Reimann-Str. 18 - D-68526 Ladenburg - Germany

Weig

ht C

on

trol

AgroFOO

Dindustry hi-tech

■ January/Feb

ruary 2005

3

fatty acid soaps and bile salts36-40. By the same mechanismcalcium may enhance the cholesterol-lowering effect of plantsterols41. A third possible mechanism, which may slightlycontribute to weight reduction as well, has recently beenpublished42. In a randomised, blind, controlled cross-over studywith a sequential-meal design, 11 overweight or obese subjects(mean BMI 31 kg/m2) consumed isocaloric high (543 mg Ca and349 IU vitamin D) and low (248 mg Ca and 12 IU vitamin D)dairy calcium breakfasts followed by a very low calcium (48 mgCa and 25 IU vitamin D) standard lunch. High calcium intake didnot affect hunger and satiety immediately after meal, but didsignificantly reduce spontaneous food intake over the

subsequent 24h.

CONCLUSIONAlthough the contribution of the differentmechanisms to the overall anti-obesity effectof calcium is not clear, there is much evidencefrom animal and human studies, that a high-calcium diet and/or calcium supplementationdecreases body weight and fat. High calcium

in some studies the expression of uncoupling protein 2 andthereby thermogenesis. At the same time lipogenic geneexpression and fatty acid synthase activity are inhibited, but acontribution of de novo lipogenesis in the development ofobesity in human remains doubtful35. All these effects result indecreased adipocyte lipid accumulation29, weight and body fatreduction and an overall shift of dietary energy from adiposetissue to lean body mass. An overview of the proposedmechanism had been compiled in Figure 1.Another reasonable idea may be, that the divalent cation calciumprevents the intestinal absorption of part of the dietary fat andincreases faecal lipid loss and sterol excretion forming insoluble

Table 2: Effect of a 300 mg (one serving) increment in regular calciumintake on body weight and body fat

Table 1. Human studies showing significant anti-obesity effect of high calcium uptake.

Wei

gh

t C

on

tro

lJa

nuar

y/Fe

bru

ary

2005

■ Ag

roFO

OD

indu

stry

hi-t

ech

4

15. Carruth BR, Skinner JD. The role of dietary calcium and othernutrients in moderating body fat in preschool children. Int JObes Relat Metab Disord 2001;25:559-66

16. Skinner JD, Bounds W, Carruth BR, Ziegler P. Longitudinalcalcium intake is negatively related to children’s body fatindexes. J Am Diet Assoc 2003;103:1626-31

17. Buchowski MS, Semenya J, Johnson AO. Dietary calcium intakein lactose maldigesting intolerant and tolerant African-Americanwomen. J Am Coll Nutr 2002 ;21 :47-54

18. Lelovics Z. Relation between calcium and magnesium intake andobesity. Asia Pac J Clin Nutr 2004;13:S144

19. Melanson EL, Sharp TA, Schneider J, Donahoo WT, GrunwaldGK, Hill JO. Relation between calcium intake and fat oxidationin adult humans. Int J Obes 2003 ;27 :196-203

20. Zemel MB, Thompson W, Milstead A, Morris K, Campbell P.Calcium and dairy acceleration of weight and fat loss duringenergy restriction in obese adults. Obes Res 2004;12:582-90

21. Zhang Q, Tordoff MG. No effect of dietary calcium on bodyweight of lean and obese mice and rats. Am J Physiol RegulIntegr Comp Physiol 2004;286:R669-77

22. Wosje KS, Kalkwarf HJ.Lactation, weaning, and calciumsupplementation: effects on body composition in postpartumwomen. Am J Clin Nutr 2004;80:423-9.

23. Shapses SA, Heshka S, Heymsfield SB. Effect of calciumsupplementation on weight and fat loss in women. J ClinEndocrinol Metab 2004;89:632-7

24. Kamycheva E, Joakimsen RM, Jorde R. Intakes of calcium andvitamin D predict body mass index in the population ofNorthern Norway. J Nutr 2003;133:102-6.

25. Zemel MB, Zemel PC, Bryg RJ, Sowers JR. Dietary calciuminduces regression of left ventricular hypertrophy in hypertensivenon-insulin-dependent duiabetric blacks. Am J Hypertens1990;3:468-63

26. Heaney RP, Davies KM, Barger-Lux MJ. Calcium and weight:clinical studies. J Am Coll Nutr 2002;21:S152-5.

27. Heaney RP. Normalizing calcium intake: projected populationeffects for body weight. J Nutr 2003;133:S268-70

28. Jones BH, Kim JH, Zemel MB et al. Upregulation of adipocytemetabolism by agouti protein: possible paracrine actions inyellow mouse obesity. Am J Physiol 1996;20:E192-6

29. Shi H, DiRienzo D, Zemel MB. Effects of dietary calcium onadipocyte lipid metabolism and body weight regulation inenergy-restricted aP2-agouti transgenic mice. FASEB J2001;15:291-3

30. Xue B, Greenberg AG, Kraemer FB, Zemel MB. Mechanism ofintracellular calcium inhibition of lipolysis in human adipocytes.FASEB J 2001;015:2527-29

31. Xue B, Moustaid-Moussa N, Wilkison WO, Zemel MB.The agoutigene product inhibits lipolysis in human adipocytes via a Ca2+

dependent mechanism. FASEB J 1998;12:1391-632. Zemel MB, Kim JH. Woychik RP, Michaud EJ, Kadwell SH, Patel

IR, Wilkison WO. Agouti regulation of intracellular calcium: Rolein the insulin resistance of viable yellow mice. Proc Natl Acad SciUSA 1995;92:4733-7

33. FujitaT, Palmieri GMA. Calcium paradox disease: calciumdeficiency prompting secondary hyperparathyroidism andcellular calcium overload. J Bone Miner Metab 2000;18:109-25

34. Palmieri GMA, Nutting DF, Bhattacharya SK, Bertorini TE,Williams JC. Parathyroid ablation in dystrophic hamsters. J ClinInvest 1998;68 :646-54

35. Hellerstein MK. De novo lipogenesis in humans:metabolic andregulatory aspects. Eur J Clin Nutr 1999;53:S53-65

36. Denke MA, Fox MM, Schulte MC. Short-term dietary calciumfortification increases fecal saturated fat content and reducesserum lipids in men. J Nutr 1993;123:1047-53

37. Papakonstantinou E, Flatt WP, Huth PJ, Harris RBS. High dietarycalcium reduces body fat content, digestibility of fat and serumvitamin D in rats. Obes Res 2003;11:387-94

38. Vaskonen T, Mervaala E, Sumuvuori V, Seppanen-Laakso T,Karppanen H. Effects of calcium and plant sterols on serumlipids in obese Zucker rats on a low-fat diet. Br J Nutr2002;87:239-45

39. Vaskonen T. Dietary minerals and modification of cardiovascularrisk factors. J Nutr Biochem. 2003;14:492-506

40. Welberg JW, Monkelbaan JG, de Vries EG, Muskiet FA, Cats Aet al. Effects of supplemental dietary calcium on quantitativeand qualitative fecal fat excretion in man. Ann Nutr Metab1994;38:185-91

41. Vaskonen T, Mervaala E, Seppanen-Laakso T, Karppanen H. Dietenrichment with calcium and magnesium enhances thecholesterol-lowering effect of plant sterols in obese Zucker rats.Nutr Metab Cardiovasc Dis 2001;11:158-67.

42. Ping-Delfos WC, Soares MJ, Cummings NK. Acute suppressionof spontaneous food intake following dairy calcium and vitaminD. Asia Pac J Clin Nutr 2004;13:S82

uptake can be attributed to an increased lipolysis and fatty acidoxidation and to a lower intake of digestible energy caused byincreased fecal lipid loss and (possibly) a reduction in food andenergy intake. These positive effects can be achieved by a dietrich in calcium and also by consuming calcium supplements andcalcium fortified food, paving the way for new nutritionalconcepts to fight obesity.

REFERENCES1. Zemel MB. Regulation of adiposity and obesity risk by dietary

calcium: mechanisms and implications. J Am Coll Nutr2002;21:S146-51

2. Teegarden D. Calcium intake and reduction in weight or fatmass. J Nutr 2003;133:S249-51

3. Zemel MB, Miller SL. Dietary calcium and dairy modulation ofadiposity and obesity risk. Nutrition Reviews 2004;62:125-31

4. Draznin B, Sussman KE, Eckel RH, Kao M, Yost T, Sherman NA.Possible role of cytosolic free calcium concentrations inmediating insulin resistance of obesity and hyperinsulinemia. JClin Invest 1988;82:1848-52

5. Zemel MB, Shi H, Greer B, DiRienzo D, Zemel PC. Regulation ofadiposity by dietary calcium. FASEB J 2000; 14:1132-8.

6. Albertson AM, Good CK, Holschuh NM, Eldridge EL. Therelationship between dietary calcium intake and body massindex in adult women: data from the Continuing Survey of FoodIntake by Individuals 1994-96. FASEB J 2003;17:A289

7. Pereia MA, Jacobs DR Jr, Van Horn L, Slattery ML, Kartashov AI,Ludwig DS. Dairy consumption, obesity, and the insulinresistance syndrome in young adults: the CARDIA Study. JAMA2002;287:2081-9

8. Jacqmain M, Doucet E, Despres J-P, Bouchard C. Calcium intake,body composition, and lipoprotein-lipid concentrations inadults. Am J Clin Nutr 2003 ;77 :1448-52

9. Loos RJ, Rankinen T, Leon AS, Skinner JS, Wilmore JH, Rao DC,Bouchard C. Calcium intake is associated with adiposity in Blackand White men and White women of the HERITAGE FamilyStudy. J Nutr 2004;134:1772-8.

10. Davies KM, Heaney RP, Recker RR, Lappe JM, Barger-Lux MJ,Rafferty K, Hinders S. Calcium intake and body weight. J ClinEndocrinol Metab 2000;85:4635-8

11. Barger-Lux MJ, Davies KM, Heaney RP, Cvhin BK, Rafferty.Calcium supplementation may attenuate accumulation of fat inyoung women. J Bone Miner Res 2001;16 :S219

12. Lin YC, Lyle RM, McCabe LD, McCabe GP, Weaver CM,Teegarden D. Dairy calcium is related to changes in bodycomposition during a two-year exercise intervention in youngwomen. J Am Coll Nutr 2000;19:754-60

13. Lovejoy JC, Champagne CM, Smith SR, de Jonge L, Xie H.Ethnic differences in dietary intakes, physical activity, and energyexpenditure in middle-aged, premenopausal women: theHealthy Transitions study. Am J Clin Nutr 2001;74:90-5

14. Tanaseku M, Ferris AM, Himmelgreen DA, Rodriguez P, Perez-Escamilla R. Biobehavioral factors are associated with obesity inPuerto Rican children. J Nutr 2000;130:1734-42

Figure 1. Oneof the threeproposedmechanismsabout the anti-obesity effectof calcium,based on thehypothesis ofZemel and co-workers5: Highcalcium uptakeleads to weightloss due to theinfluence ofhighintracellularlevels ofcalcium on fatmetabolism.