CHAPTER 6 The Health Benefits of Calcium Citrate Malate: A Review of the Supporting Science Susan Reinwald,* Connie M. Weaver,* and Jeffrey J. Kester† Contents I. Why Focus on Calcium Citrate Malate? 221 II. Ca Needs and Current Intakes 222 A. The role of Ca in the body 222 B. General Ca requirements 223 C. Specific Ca needs 224 D. Current intakes 226 E. Implications 231 III. Description and Properties of CCM 232 A. Chemical formula of CCM and its component anions 232 B. Ca content 232 C. How CCM is made 234 D. Aqueous solubility 235 E. CCM in fortified foods and beverages 237 F. CCM in dietary supplements 242 IV. Studies of Ca Bioavailability from CCM 244 A. Ca absorption 244 B. Factors that influence Ca absorption 256 C. How CCM fits with the influencing factors — human studies with CCM 257 D. Animal studies with CCM 269 *Department of Foods and Nutrition, Purdue University, West Lafayette, Indiana 47907 {Coffee & Snacks Technology Division, The Procter & Gamble Company, Miami Valley Innovation Center, Cincinnati, Ohio 45252 Advances in Food and Nutrition Research, Volume 54 # 2008 Elsevier Inc. ISSN 1043-4526, DOI: 10.1016/S1043-4526(07)00006-X All rights reserved. 219 220 Susan Reinwald et al. V. Studies of Ca Retention and Bone Building in Children and Adolescents 276 A. Ca balance studies 278 B. Bone density studies (2–3 years) 280 C. Long-term bone density studies (4–7 years) 283 VI. Studies of Bone Maintenance in Adults 289 A. Studies in postmenopausal women 290 B. Studies in elderly men and women — including effects on fracture risk and risk of falls 294 VII. Other Health Benefits 298 A. Oral health 298 B. Blood pressure reduction 304 C. No increase in the risk of kidney stones 306 D. No effect on the status of other minerals (Fe, Zn, Se, and Mg) 308 E. Effect on serum lipids 319 F. Colon health 321 VIII. Limitations of CCM 323 IX. Conclusion 324 References 328 Abstract There has been considerable investigation into the health benefits of calcium citrate malate (CCM) since it was first patented in the late 1980s. This chapter is a comprehensive summary of the sup- porting science and available evidence on the bioavailability and health benefits of consuming CCM. It highlights the important roles that CCM can play during various life stages. CCM has been shown to facilitate calcium retention and bone accrual in children and adolescents. In adults, it effectively promotes the consolidation and maintenance of bone mass. In conjunction with vitamin D, CCM also decreases bone fracture risk in the elderly, slows the rate of bone loss in old age, and is of benefit to the health and well-being of postmenopausal women. CCM is exceptional in that it confers many unique benefits that go beyond bone health. Unlike other calcium sources that necessitate supplementation be in conjunc- tion with a meal to ensure an appreciable benefit is derived, CCM can be consumed with or without food and delivers a significant nutritional benefit to individuals of all ages. The chemistry of CCM makes it a particularly beneficial calcium source for individuals with hypochlorydia or achlorydia, which generally includes the elderly and those on medications that decrease gastric acid secretion. CCM is also recognized as a calcium source that does not increase the risk of kidney stones, and in fact it protects against stone-forming potential. The versatile nature of CCM makes it a convenient and practical calcium salt for use in moist foods and beverages. The major factor that may preclude selection of CCM as The Health Benefits of Calcium Citrate Malate: A Review of the Supporting Science 221 a preferred calcium source is the higher cost compared to other sources of calcium commonly used for fortification (e.g., calcium carbonate and tricalcium phosphate). However, formation of CCM directly within beverages or other fluid foods and/or preparations, and the addition of a concentrated CCM solution or slurry, are rela- tively cost-effective methods by which CCM can be incorporated into finished food and beverage products. I. WHY FOCUS ON CALCIUM CITRATE MALATE? Regul ar inge stion of adequa te calcium (Ca), particul arly by way of con- sum ption of foo ds natur ally hig h in Ca, re quires a deli berate approa ch to balance d nutr ition for a large number of individual s. Ev eryday exposur e to an increasin gly wide varie ty of appe aling foo d and bever age choices can diver t the emphasi s and preferen ce away from in herentl y Ca- rich food s that all too often are large ly undercon sumed by those mos t in nee d of them. Und er certain circumst ances, such a s lac tose intol erance, allergi es, strict vegeta rianism, and personal dislik es, da iry foo ds are not even co nsidere d as a viable option or are consumed in insufficie nt quantity to meet Ca requ irements by many subgr oups. In situat ions such as thes e, Ca suppl e- menta tion and/or fortif ication of regu larly consumed food s and bever ages is an ideal adjunctive appr oach, conf erring bene fits to those bot h intereste d in reducing the risk for chro nic diseas e and seeking to pro mote optim al heal th. Alth ough there are ofte n claims to the contr ary, differen t Ca salt s are not, in effect, bioe quiva lent. Whi le a nu mber of common ly used Ca salt s are currentl y avai lable in the market place, each one is distin ct in terms of its chemic al co mposition , the func tional and aestheti c pro perties it im parts to variou s food matric es, and its efficacy wh en it co mes to deli vering health bene fits. In man y res pects, the attr ibutes of cal cium citrat e mal ate (CCM) , a comp ound salt of citrate and mal ate, set it apa rt from other Ca salt pre- paratio ns. Othe r Ca sa lts do not matc h CC M’s combi nation of qualitie s that inclu de: co mparativ ely high aqueous solu bility, enhance d absorbab ility and bioavai lability und er a wide range of circumst ances for all age groups, compositional flexibility (i.e., adjustable molar ratios and mineral content), convenient and practical compatibility with food systems, and an imper- ceptible presence as a fortificant in foods and beverages at concentrations that make a discernable contribution to health. The choice of a source of Ca is best made from an informed perspective. Recognizing that other Ca salt s can also be effective ly utilize d a s fortif icants (Rafferty et .,al 2007), there has been a wealth of investigation into the bioavailability and health benefits of CCM since it was first patented in the late 1980s. The purpose of this chapter is to present a comprehensive summary of the supporting science and available evidence on the bioavailability and health benefits of consuming CCM. 222 Susan Reinwald et al. II. Ca NEEDS AND CURRENT INTAKES A. The role of Ca in the body Ca is a mineral essential to the optimal functioning of virtually every cell in the body. It is required by nonskeletal cells for functions such as muscle contraction, neurotransmission, signal transduction, enzyme secretion, vas- cular function, blood coagulation, and glandular secretion. There is 1gof Ca in plasma and extracellular fluids (ECFs), 6–8 g is found in body tissues and within cells, and over 99% of total body Ca is found in bones and teeth, primarily in the form of hydroxyapatite Ca10(OH)(PO4)3 (Weaver and Heaney, 2006a). The main functional roles played by Ca in the skeleton can be summarized as structural and metabolic. Ca provides the mineral material that principally contributes to growth and development of a dynamic skeletal framework that facilitates stature, posture, is a lever system for locomotion, mechanical strength, provides protection for vital organs, and simultaneously serves as a labile reservoir to enable effective Ca homeostasis in the body. Ca normally circulates in the bloodstream, within a 2.25–2.50 mmol concentration range, bound to proteins (40–45%), complexed with ions (8– þ 10%), and ionized as Ca2 (45–50%) (Weaver and Heaney, 2006a). Circulat- ing Ca in excess of that required for maintenance of plasma levels is ideally transferred from the blood to be deposited in bone via the bone formation process. The Ca concentration outside of blood vessels in the ECF that bathes cells is tightly regulated close to 1.25 mmol (Weaver and Heaney, 2006a), almost to the point of invariance. It is this ECF Ca pool that cells are immediately reliant upon to sustain vital cellular functions that are immi- nently critical to the maintenance of life (e.g., cardiac muscle contraction). Circulating Ca is constantly utilized to replenish ECF pools, and when Ca derived from dietary intake is insufficient to replace the amount of Ca used for replenishment, Ca in bone is transferred to the blood via a bone resorp- tion process. A regular adequate dietary intake of Ca is required to promote the maintenance of Ca balance in tissues and to attenuate undue resorption and subsequent bone loss that can lead to skeletal fragility and fractures. Bidirectional Ca fluxes between the blood and bone are mediated by parathyroid hormone (PTH) and vitamin D (1,25(OH)2 D3)(Awuney and Bukoski, 2006). Homeostatic regulation of Ca is via an orchestrated interplay among three main organs, the intestines, the kidney, and bones (Fleet, 2006).