CZ255393A3 - Mineral and vitamin preparation for bone building - Google Patents

Abstract

Nutritional mineral supplements comprising calcium citrate malate, salts of manganese, copper and zinc and a member or members selected from the group of vitamin D or its metabolites or precursors and drug therapies consisting of calcitonin, editronate, diphosphonates and amino-diphosphonates are disclosed. Estrogen can also be used with these supplements. These supplements, which provide at least 25 % RDA of the calcium, trace minerals and vitamins, are used in addition to the normal diet. These supplements are useful for increasing bone growth and for treating age-related bone loss in humans and animals. The supplements may be in the form of solid tablets, liquid unit dosage forms, or in a beverage.

Description

(57) The bone mineral and vitamin supplement comprises a unit dose composition comprising: a) 100 to 1000 mg of calcium (per element) in the form of a carboxylate selected from the group consisting of citrate, malate, lactate and mixtures thereof, preferably with a calcium: citrate: malate molar ratio of from 2: 1: 1 to 8: 2: 1, (b) from 0.5 to 5 mg of copper (based on the element, c) from 1.5 to 30 mg of zinc (based on the element d) from 1 to 8 mg of manganese (based on the element) and e) from 0.6 to 25 mg of vitamin D, preferably such that the D vitamin is present in an amount of 0.15 to 5 micrograms per supplement in in the form of vitamin D metabolites and precursors such as 1α, 25-di (OH) 2-vitamin D, 25-OH-vitamin, 1α-OH-vitamin D2 or D3 and / or dihydroxy compound analogs. These supplements, which provide at least 25% of the recommended daily dose of calcium, trace elements and vitamins, are used in addition to the normal diet. These supplements are useful for increasing bone growth and for treating bone loss associated with age and certain other diseases (eg, osteoporosis) in both humans and animals.

This invention relates to a mineral and vitamin supplement. for the construction of bone which contains trace elements, in particular copper, manganese and zinc, vitamin D, estrogen, calcitonin or Didronel or diphosphonate drugs. These supplements are useful for increasing bone growth and for treating age-related bone loss. They can be used with food and beverages, or can be taken as oral solid or liquid supplements. This invention also relates to a method of bone construction or treatment of bone loss in osteoporosis patients, postmenopausal women and / or elderly men.

BACKGROUND OF THE INVENTION

The use of vitamin supplements and supplements with elements is commonplace both in humans and in the veterinary field. Some diets, heavy physical exercise and disease states may require intake of substantial amounts of minerals and vitamins in addition to

age, which are usually obtained by a normal diet. Vitamin and mineral supplements are primarily important for those who do not have an adequate diet, including growing children. Older adults have an additional need for calcium to prevent bone loss that occurs as a normal consequence of the aging process. Especially women in postmenopause need additional calcium due to hormonal changes that can accelerate the rate of bone loss, leading to a further reduction in bone mass.

The trace elements that affect bone growth are copper, zinc and manganese. Supplementing the diet with these elements together with a highly available source of calcium is highly desirable. In many cases where increased intake of elements is desired, commercially available element additions are useful. Most of these multivitamin and multi-element tablets have a low calcium content, requiring separate supplementation with calcium sources. Moreover, in terms of biological additions, calcium sources are added. Moreover, not all sources of calcium are the same in terms of bioavailability and absorption capacity. The addition of vitamin D, calcitonin, estrogen and / or other treatments (editronate or diphosphonates) makes this supplement more complex as it may include three or more tablets. It would be more advantageous if all the elements and medicaments and / or vitamins could be administered together in a conventional and / or pleasant tasting form that would not require particular attention, planning and equipment for the user. This could be achieved by including said ingredients in food and beverage or tablets.

There are well-known problems associated with adding both elements and vitamins to foods and beverages. One is taste: calcium tends to taste chalk. In addition, the solubility of many calcium sources prevents their addition to many drinks. Other problems are the interaction of elements or vitamins with food or drink, which affects the stability and / or bioavailability of the product. The present invention provides methods of making such a product.

The present invention also relates to methods of bone formation in humans and other animals, i.e., treatment of age-related bone loss and related disorders. In particular, the present invention relates to methods of treatment by administering certain calcium salts and elements, copper, zinc and manganese, together with vitamin D and / or in the treatment of medicinal products.

Calcium is the fifth most abundant element in the human body. It plays an important role in many physiological processes, including nerve and muscle functions. Not surprisingly, nutritional and metabolic calcium deficiencies can have widespread adverse effects. Since about 98 to 99% of body calcium is found in bone tissues, many of these adverse effects are manifested by deficiencies in the structure, function and integrity of the skeletal system.

The most common metabolic bone disorder is osteoporosis. Osteoporosis can generally be defined as a reduction in the amount of bone, resulting either from a decrease in bone formation or from an accelerated bone resorption. In both cases, the result is a reduction in the amount of skeletal tissue. There are generally two types of osteoporosis: primary and secondary. Secondary osteoporosis is the result of an identifiable disease process or agent. However, approximately 90% of all osteoporosis cases are idiopathic primary osteoporosis. Primary osteoporosis includes postmenopausal oste ^? oporosis, age-related osteoporosis (affecting most individuals over 70 to 80 years of age) and idiopathic osteoporosis that affects middle-aged men and women or younger men and women. '~

In some individuals with osteoporosis, bone loss is large enough to cause mechanical damage to the bone structure. Bone fractures often occur, such as in the wrist, hip and spine of women often suffering from postmenopausal osteoporosis. This can also lead to kyphosis (abnormally increased distortion of the thoracic spine).

The bone loss mechanism in osteoporosis _t is believed to be due to an imbalance in the process of bone remodeling. K remodeloť. Bone remodeling occurs during life, when the skeleton is renewed and bone strength is maintained. In this process, there are two reactions, bone loss or resorption, and bone growth or growth. This remodeling occurs in a series of discrete vesicles of bone activity called osteoclasts and osteoblasts. Osteoclasts (cells responsible for dissolving or resorbing bones) are responsible for resorption of a portion of bone in the bone matrix during the resorption process. After resorption, osteoclasts (bone forming cells) appear after the osteoclasts, which then replenish the resorbed part with new bone.

In young healthy adults, the rate at which osteoclasts and osteoblasts are formed maintains a balance of bone resorption and bone formation. However, the normal consequence of aging is that there is an imbalance in the remodeling process, leading to bone loss at a faster rate than bone formation. If this imbalance continues for some time, then reducing bone mass and hence bone strength leads to fractures.

Numerous means and methods are described in the medical literature on the treatment of osteoporosis. See, for example, R. C. Haynes, Jr., et al .; Agents Affecting Calculation, The Pharmacological Basis of Therapeutics, 7th Edition (AG Gilman, LS Goodman et al., Eds., 1985) and GD Whedon et al .: An Analysis of Current Concepts and Research Interest in Osteoporosis, Current Advances in Skeletogenesis (A. Ornoy et al., Eds., 1985). Estrogen is often used to influence calcium metabolism by affecting osteoblast cells. Fluoride treatment has also been described. Due to the possible adverse side effects, the usefulness of these agents may be limited. See W. A. Peck et al., Physician ' s Resource Manual on Osteoporosis (1987), published by the National Osteoporosis Foundation.

Nutritional therapy has also been proposed for osteoporosis. Many calcium-containing compounds and substances have been described for use as food supplements. Many commercial compositions are also available, which typically include calcium carbonate or calcium phosphate. Other calcium salts have also been described for use as calcium supplements, including calcium lactate, calcium citrate, and calcium gluconate.

U.S. Patent No. 3,949,098 to Bangerta (Nabisco, 1976) discloses a nutritional concentrate of an orange drink that contains a protein. This patent proposes the addition of small amounts of vitamins and other nutrients, including copper salts, manganese salts, zinc salts and also calcium salts.

Germany Patent Laid-Open No. 2,845,570 (E.R.E., Europe Representation Establishment, 1980) discloses a composition comprising copper. Copper contains low amounts of calcium, manganese and copper as well as trace amounts of magnesium, iron, phosphorus, silicon and nickel. The value of honey as a drug is undisputed according to this patent application. This application claims copper containing for ..... 5 .....

center with levorotatory ascorbic acid and citric acid. The Tanto patent was issued as US Patent No. 4,243,794 (1981).

U.S. Patent No. 4,497,800 to Larsen et al. (Mead Johnson and Company, 1985) discloses a nutritional, complete, ready-to-use liquid diet that provides the patient with overall nutrition. This diet includes free amino acids and small peptides, a source of hydrocarbons, and nutritionally significant amounts of all essential vitamins and elements, and stabilizing agents. Elements include, but are not limited to, zinc and manganese. Most of these elements are in the form of gluconate salts.

Dawson-Hughes, Seligson, and Hughes (Effect of calcium carbonate and hydroxyapatite on zinc and iron retention in postmenopausal women): American Journal of Clinical Nutrition 44, 83 (1986) describe the effect of calcium carbonate on zinc and iron retention throughout the body in thirteen healthy women after menopause. The test meal, including both dry food and prepared beverages, contained calcium, copper and zinc in amounts equal to one third of the usual daily requirement. These are the quantities that are nor.4 ».

small in the human diet.

U.S. Patent No. 3,992,555 to Kovacse (Vitamins, Inc., 1976) discloses food supplements prepared by mixing assimilatable iron compounds, vitamins, and elements with heated edible fat as carrier. Elements include, but are not limited to, calcium, zinc, copper, and manganese.

U.S. Patent No. 3,950,547 to Lamara et al. (Syntex Inc., 1976) discloses a dietary composition comprising peptides and / or amino acids, fats and hydrocarbons in an aqueous emulsion. Suitable elements for addition in low amounts include, but are not limited to, calcium, copper, and zinc.

U.S. Patent No. 4,107,346 to Kravitze (1978) discloses a dietary salt composition for use as a salt substitute in foods.

The role of copper is described as a component of several nutritional enzymes. This patent further discloses that spontaneous fractures are common in animals fed a copper deficient soil or in animals on an artificially depleted copper diet (column 4, lines 20-30). Zinc is described as promoting growth, wound healing and improving taste and smell. Clinical signs (symptoms) of manganese insufficiency have not been observed in humans. However, there is no doubt that manganese is essential for human nutrition. The main expressions of his lack are growth and skeletal abnormalities. Calcium is described as essential for blood coagulation, for calcium retention and for the removal of osteoporosis symptoms. Examples of salts containing these four trace elements are described.

U.S. Patent No. 4,070,488 to Davis (1978) discloses a highly stabilized, balanced nutritional composition useful for supplementing human and / or animal diet. The composition comprises gelatin. This patent discloses that suifhydryl groups of gelatin can cause copper to be inactive on ascorbic acid.

U.S. Patent No. 4,214,996 to Buddemeyer et al. (R.G.B. Laboratories, 1980) discloses mineral compositions which are highly soluble. These compositions include calcium, phosphorus, zinc and also manganese. Not all of the compositions described in this patent contain all four elements.

U.S. Patent No. 4,351,735 to Buddemeyer et al. (R.G.B. Laboratories, 1982) is similar to U.S. Patent No. 4,214,996.

The work of Ting (The Nutrients and Nutrition of Citrus Fruits in Citrus Nutrition and Quality: The American Chemical Society, 1980) describes the presence of some trace elements in orange juice. These include copper, zinc, iron and manganese. Calcium and magnesium are the two main divalent cations in orange juice. The amount of all these elements is low.

Hungerford et al (1983) describes the absorption of iron from various food substances. The diet, which contained small amounts of iron, also included calcium carbonate, manganese sulfate and copper sulfate.

U.S. Patent No. 4,419,369 to Nichols et al. (Baylor College of Medicine, 1983) describes an improved dietary protein mineral module for children. An approximate analysis of this material shows the presence of iron, zinc, copper and calcium.

The usefulness of these known supplements varies. In contrast to agents (such as estrogen ^- for example - which affect bone metabolism), nutritional supplements such as calcium are believed to only provide a source of nutrients (which may or may not be appropriately absorbed and metabolized). See, for example, B. Riis et al .: Does Calcium Supplementation Prevent Postmenopausal Bone Loss? ”, New England J. of Medicine 316, 173 (1987); L. Nilas et al .: Calcium Supplementation and Postmenopausal Bone Loss, British Medical Journal 289 , 1103 (1984) and H. Spencer et al., NIH Consensus Conference: Osteoporosis, Journal of Nutrition 116, 316 (1986).

However, it has now been discovered that the administration of a mixture of some calcium salts and trace elements is effective in retarding age-related bone loss (see the accompanying application of Smith et al. 07/562 773 published February 20, 1992 as WO 92/02235). ). Independently, it has also been found that the administration of mixtures of some calcium salts with vitamin D is also effective in altering age-related bone loss (see the accompanying application of Andon et al., U.S. Patent Application (P&G Cae 4394)). calcium, trace minerals, and vitamin D that are compatible and nutritionally available, as this method would provide greater efficacy compared to nutritional regimens known in the literature, and would be extremely useful as an adjunct or ancillary treatment in the treatment of bone diseases and bone loss associated with age-known drugs, i.e. calcitonin, estrogen and didronel, including salts of amine function compounds, in addition, it would be useful to have nutritional supplements that could be added to food and beverage compositions without adversely affecting them. organoleptic and aesthetic properties.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide calcium and trace element supplements which, in combination with vitamin D and / or calcitonin, Didronel or estrogen, provide bone growth and which can be used to treat age-related bone loss or to correct imbalances to which occurs in the formation and resorption of bones.

It is a further object of the present invention to provide foods, beverages, and beverage concentrates that are supplemented with calcium, trace minerals, vitamin D, and / or drug-like treatments.

These and other objects of the invention are apparent from the description herein.

Supplements use specific calcium salts of mixtures of citric acid and malic acid. Drug and / or vitamin therapies with which they are combined include vitamin D, Didronel (diphosphonates) and calcitonin. Mineral supplements contain zinc, copper and manganese. Estrogen may be used in conjunction with any of these therapies.

The present invention provides a method of constructing bones in a human or other animal comprising administering a safe and effective amount of vitamin D, didronel, estrogen, and / or calcitonin to a calcium salt of a mixture of citric and malic acid and copper, zinc salts and manganese to said animal or human. The mixture of calcium citric acid and malic acid comprises a complex or mixture of calcium salts in which the ratio of moles of citrate to moles of malate is from about 1: 0.16 to about 1: 13.5. Preferably, the combination of these elements and medicaments is administered in an oral dosage form containing pharmaceutically acceptable carriers and excipients.

All ratios, parts and percentages herein are by weight unless otherwise indicated. All mineral weights are element based unless otherwise noted.

The present invention relates to stable mineral / vitamin and / or medicinal supplements and supplemented foods and beverages including dry beverage compositions and a method of bone building.

The term comprising (including) as used herein means that the various ingredients may be used together in the mineral supplements, foods and beverages of the present invention. Accordingly, the terms consisting essentially of and consisting of are included in the term comprising.

As used herein, the term nutritional or nutritionally complementary means that the sources of elements and vitamins used in the practice of the present invention provide the amounts of trace elements, calcium and vitamin D needed for nutrition. This is an additional amount or an additional amount in addition to the amount found in the diet. This supplemental amount will contain at least 25 percent of the recommended dietary amount (RDA, recommended daily dose) of calcium, copper, manganese, zinc, and vitamin D. Preferably, this will provide at least 50% of the recommended daily dose (RDA). The RDA of elements and vitamins is defined in the US (see the Recommended Daily Dietary Allowance-Food and Nutrition Board, National Academy of Sciences-National Research Council).

The specific compounds and compositions to be used in these processes must be pharmaceutically acceptable. The term "pharmaceutically acceptable ingredient" as used herein means a ingredient that is suitable for use in humans and / or animals without undue adverse side effects (such as toxicity, irritation and allergic responses) with a reasonable benefit-risk balance. As used herein, the term safe and effective (effective) amount means an amount of a component sufficient to provide the desired therapeutic response without undue adverse side effects (such as toxicity, irritation and allergic response) with a reasonable ratio between beneficial effect and risk when used according to the method of the invention. The specific safe and effective amount will likely vary depending on such factors as the condition being treated, the patient's physical condition, the duration of treatment, the nature of the concurrent treatment (if any) and the specific means employed.

The term taste as used herein means both a fruity and botanical taste.

As used herein, sweeteners include sugars such as glucose, sucrose and fructose. Sugars also include solid corn syrups with high fructose content, invert sugar, sugar alcohols including sorbitol and mixtures thereof. Artificial sweeteners are also included in the term sweeteners.

The term trace elements, as used herein, means copper, manganese, and zinc. These elements play an important role in nutrition, but are only needed in small or trace amounts in the diet. All three of these elements are important enzymatic cofactors that are essential in bone and human development. The trace elements are administered herein in the form of pharmaceutically acceptable salts.

The carboxylate anion used in the preparation of the preferred mineral salts may be any edible carboxylate particles herein. However, there is a need for some appraisal of the contribution to appetite. For example, citrate, malate and ascorbate provide edible complexes whose flavors are judged to be quite acceptable, particularly as fruit juice drinks. Tartaric acid is acceptable, especially as a drink of grapefruit juice as well as lactic acid. Long-chain fatty acids may be used in solid mineral supplements but may affect taste and water solubility. For essentially all purposes, maleate (preferably), gluconate, citrate and ascorbate may be used, although other particles may be selected as desired by the formulator.

The anion for the trace elements may also be a phosphate, chloride, sulfate, nitrate or the like. However, these inorganic anions can interact undesirably with calcium ions, especially in beverages. At high concentrations, especially in the case of chloride and sulfate, these anions may contribute to the undesirable taste of the food or beverage containing them. Thus, the above-described carboxylate anions are preferred for use herein.

Calcitonin: Calcitonin is a 32 amino acid protein that is produced by thyroid C cells in higher mammals. It is known to block the stimulatory effects of PTH and other humoral agents in bone resorption. Calcitonin treatment reduces the rate of bone loss in patients with osteoporosis. It is also used to treat Paget's skeletal disease. It is used in combination with ethanedihydroxydiphosphonate. The term calcitonin as used herein means thyrocalcitonin, either natural or synthetic.

Vitamin D: Vitamin D includes vitamin D, cholecalciferol (D3), ergocalciferol (03) and its biologically active metabolites and precursors such as 1α, 25- (OH) 2-vitamin D, 25-OH-vitamin D, its a biological precursor; and 1α-hydroxyvitamin D and analogues of the dihydroxy compound. These materials promote intestinal calcium absorption, contribute to the regulation of plasma calcium by acting on bone density, and stimulate calcium reabsorption in the kidney.

Didronel: Didronel is the disodium salt of 1-hydroxyethylidene diphosphonic acid (EHDP or editronate). This compound and other similar diphosphonates and aminodiphosphonates are collectively referred to as diphosphonates.

Didronel and diphosphonates act primarily on bones. They inhibit the formation, growth and dissolution of hydroxyapatite crystals and their amorphous precursors by chemisorption on calcium phosphate surfaces. In general, they do not adversely affect parathyroid or calcium hormone levels.

Bone active drugs that are pharmaceutically acceptable salts of amine function compounds include pharmaceutically acceptable salts of diphosphonate compounds and phosphonoalkylphosphinate amine compounds, including esters of these prodrugs. Such compounds are described, for example, in U.S. Patent No. 3,683,080 to Francis of August 8, 1972, No. 4,304,734 to Jary, Řiháková and Zobac of December 8, 1981, No. 4,687,768 to Benedict and Johnson of August 18, 1987, No. 4,711,880 Stahl and Schmitz of

8 December 1987 and 4 711 203 Bosies and Galia of 12 January 1988, U.S. Patent Application Nos. 808,584 (published 29 July 1987 as European Patent No. 0 230 068) to Benedict and Perkins of 13 December 1985 No. 945,069 (published July 5, 1988 as European Patent No. 0 273 514) Ebetin, Buckingham and McOsker of December 19, 1986, No. 945,068 (published July 13, 1988 as European Patent No. 0 274 158) Ebetin and Benedict of 19 December 1986 and 069 666 (published January 11, 1989 as European Patent No. 0 298 553) Ebetina of 6 July 1987 and European Patent Applications No. 0 001 584 to Bluma, Hempel and Worms published May 2, 1979, No. 0 039 033 published April 11, 1981, No. 0 186 405 to Benedict and Perkins, published July 2, 1986; 0 243 173 Okua, Toda, Kasahara, Nakamury, Kayakiri and Hashimota published October 28, 1987. All of these references are incorporated herein by reference in their entirety. More preferred bone active drugs in the compositions of this invention include pharmaceutically acceptable salts of the following compounds or esters thereof: 6-amino-1-hydroxy-hexane-1,1-diphosphonic acid, 4-amino-1-hydroxy-butane-1, 1-diphosphonic acid, N, N-dimethyl-4-amino-1-hydroxy-butane-1,1-diphosphonic acid, N, N-diethyl-4-amino-1-hydroxy-butane-1,1-diphosphonic acid , 3-amino-1-hydroxy-propane-1,1-diphosphonic acid, N, N-dimethyl-3-amino-1-hydroxy-propane13

-1,1-diphosphonic acid, N, N-diethyl-3-amino-1-hydroxy-propane-1,1-diphosphonic acid, 6-aminohexane-1,1-diphosphonic acid, phenylaminomethanediphosphonic acid , N, N-dimethylaminoethane diphosphonic acid, N- (2-hydroxyethyl) -aminomethanediphosphonic acid, N-acetylaminomethanediphosphonic acid,

3- (2-acetylaminocyclohexyl) -1-hydroxypropane-1,1-diphosphonic acid, 2- (2-aminomethylcyclohexyl) -1-hydroxyethane-1,1-diphosphonic acid, cis-3- (2-aminocyclohexyl) -1-hydroxypropane-1,1-diphosphonic acid, 3- (1-aminocyclohexyl) -1-hydroxypropane-1,1-diphosphonic acid, 3- (2-aminocyclohexyl) -1-hydroxypropane-1,1- diphosphonic acid, 3- (2-aminocyclohexyl) -1-tert-hydroxy-propane-1,1-diphosphonic acid, 1-aminoindan-2,2-diphosphonic acid, 4- (aminomethyl) -indan-2 , 2-diphosphonic acid, 1- (aminomethyl) -dihydro-2-pyridine-6,6-diphosphonic acid, 4-aminohexahydroindan-2,2-diphosphonic acid, 4- (aminomethyl) -hexahydroindan-2,2-diphosphonic acid Osphonic acid, octahydro-1-pyridine-5,5-diphosphonic acid, octahydro-2-pyridine-5,5-diphosphonic acid, octahydro-1-pyridine-6,6-diphosphonic acid, octahydro-2 -pyridine-6,6-diphosphonic acid, octahydro-1-pyridine-7,7-diphosphonic acid, octahydro-2-pyridine-7,7-diphosphonic acid, 2-methyl-octahydro-1-pyridine din-5,5-diphosphonic acid, 1,3-diethyl-octahydro-2-pyridine-5,5-diphosphonic acid, 7-hydroxy-octahydro-1-pyridine-6,6-diphosphonic acid, 4-methoxy -octahydro-2-pyridine-6,6-diphosphonic acid, 5-vinyl-octahydro-1-pyridine-7,7-diphosphonic acid, 1- (dimethylamino) -octahydro-2-pyridine-7,7-diphosphonic acid, N-acetyl-octahydro-2-pyridine-6,6-diphosphonic acid, N-benzyl-octahydro-1-pyridine-5,5-diphosphonic acid, N- (p-methoxyphenyl) -octahydro-2-pyridine-7, 7-diphosphonic acid, 2- (3,4-dichlorophenyl) -octahydro-1-pyridine-7,7-diphosphonic acid, 2- (p-dimethylaminophenyl) -octahydro-1-pyridine-7,7-diphosphonic acid, 4 -chloro-octahydro-1-pyridine-6,6-diphosphonic acid, 4-amino-octahydro-1-pyridine-6,6-diphosphonic acid, 7-carboxy-octahydro-1-pyridine-6,6-diphosphonic acid, 5-carboxy (methyl ester) -octahydro-1-pyridine-6,6-diphosphonic acid, 4-hydroxy-octahydro-2-pyridine-6,6-diphosphonic acid propanoate ester,

4- (Ν, Ν-dimethylamino) -octahydro-1-pyridine-6,6-diphosphonic acid14, 5- (N-acetamido) -octahydro-1-pyridine-7,7-diphosphonic acid, 7- (ethylketone) -octahydro-2-pyridine-5,5-diphosphonic acid and 4-nitro-octahydro-1-pyridine-6,6-diphosphonic acid, (2'-piperidinyl) -methanediphosphonic acid, (3'-piperidinyl) -methanediphosphonic acid (4'-piperidinyl) -methanediphosphonic acid, 2- (2'-piperidinyl) -ethane-1,1-diphosphonic acid,

2- (3'-piperidinyl) -ethan-1,1-diphosphonic acid, 2- (4'-piperidinyl) -ethan-1,1-diphosphonic acid, 2- (2'-piperidinyl) -1-hydroxy -ethane-1,1-diphosphonic acid, 2- (3'-piperidinyl) -1-hydroxy-ethane-1,1-diphosphonic acid, 2- (4'-piperidinyl) -1-hydroxy-ethane-1,1 -diphosphonic acid, 2- (2 '- (3'-methyl) -piperidinyl) -ethan-1,1-diphosphonic acid, 2- (2' - (5'-methyl) -piperidinyl) -ethan-1,1 - diphosphonic acid, 2- (2 '- (3'-methyl) -piperidinyl) -1-hydroxy-ethane-1,1-diphosphonic acid,

3- (2'-piperidinyl) -propane-1,1-diphosphonic acid, 3- (3'-piperidinyl) -propane-1,1-diphosphonic acid, 3- (4'-piperidinyl) -propane-1,1 diphosphonic acid, 3- (2'-piperidinyl) -1-hydroxy-propane-1,1-diphosphonic acid, 3- (3'-piperidinyl) -1-hydroxy-propane-1,1-diphosphonic acid, 3- (4'-piperidinyl) -1-hydroxy-propane-1,1-diphosphonic acid, 3- (2'-piperidinyl) -propane-2,2-diphosphonic acid, 3- (3'-piperidinyl) -propan-2 2-diphosphonic acid, 3- (4'-piperidinyl) -propane-2,2-diphosphonic acid, 2- (2 '- (N-methyl) -piperidinyl) -1-hydroxy-ethane-1,1-diphosphonic acid acid, 2- (2'-piperidinyl) -1-amino-ethane-1,1-diphosphonic acid,

-ethane-1,1-diphosphonic acid,

-ethane-1,1-diphosphonic acid, nyl) -1-amino-ethane-1,1-diphosphonic acid, 2- (2'-piperidinyl) -1-hydroxy-propane-1,1-diphosphonic acid, 3- (2'-piperidinyl) -propionic acid-2,2-diphosphonic acid, 2- (2'-piperidinyl) -1- (N-methyl) amino-ethane-1,1-diphosphonic acid, 4- (2'- piperidinyl) -1-hydroxy-butane-1,1-diphosphonic acid, 2- (2 '- (5'-amino) -piperidinyl) -1-hydroxy-ethane-1,1-diphosphonic acid, 2- (2 * - (3'-ethyl) -piperidinyl) -1-hydroxy-ethane-1,1-diphosphonic acid, 2- (2 '- (3'-carboxy) -piperidinyl) -1-hydroxy-ethane-1,1- diphosphonic acid, 2- (25'-carboxy) -piperidinyl) -1-hydroxy-ethane-1,1-diphosphonic acid, 2- (2 * - (1 ', 4' 2- (3'-piperidinyl) -1) -amino2- (4'-piperidinyl) -1-amino2- (2 '- (3'-methyl) -piperidine15

-diazinyl) -1-ethane-1,1-diphosphonic acid, 2- (2 '- (1', 5'-diazinyl)) - 1-hydroxy-ethane-1,1-diphosphonic acid, 2- (2 ' - (1 ', 4'-diazinyl)) -1-hydroxy-ethane-1,1-diphosphonic acid, 2- (2'- (1', 3'-diazinyl)) -ethane-1,1 -diphosphonic acid, 2- (3 '- (1', 2'-diazinyl)) - ethane-1,1-diphosphonic acid, N- (2'-piperidinylidene) -amino-methane-diphosphonic acid, N- (3'-piperidinyl) -amino-methane-diphosphonic acid, N- (4'-piperidinyl) -amino-methane-diphosphonic acid, N- (2 '- (3'-methyl) -piperidinylidene) -amino- methane-diphosphonic acid, N- (2 '- (5'-methyl) -piperidinylidene) -amino-methane-diphosphonic acid, 2- (N- (2'-piperazinyl) -4-amino') ^ ethane diphosphonic acid — 1- (N- (2'-piperidinylidene) amino) -ethane-1,1-diphosphonic acid, N- (2 '(1', 3'-diazinylidene)) -aminomethane-diphosphonic acid, N- (2 * (1 ', 4'-diazinylidene)) -aminomethane-diphosphonic acid, N- (2' - (1 ', 3', 5'-triazinylidene)) -aminomethan- diphosphonic acid, N- (4 '- (1', 2'-diazinyl)) - aminomethane diphosphonic acid, O- (3'-piperidinyl) -oxamethane-diphosphonic acid, O- (4'-piperidinyl) -oxamethane-diphosphonic acid, 2- (O- (3'-piperidinyl) -oxa) -ethan-1,1-diphosphonic acid, 1- (0- (3'-piperidinyl) -oxa) -ethan -1,1-diphosphonic acid, O- (4 '- (1', 2'-diazinyl)) -oxamethanediphosphonic acid, S- (3'-piperidinyl) -thiomethanediphosphonic acid, S- (4'- piperidinyl) -thiomethanediphosphonic acid, 2- (S- (3'-piperidinyl) -thio) -ethane-1,1-diphosphonic acid, 1- (S- (3'-piperidinyl) -thio) -ethane-1 , 1-diphosphonic acid, S- (4 '- (1', 2'-diazinyl)) - thiomethanediphosphonic acid, N- (2-pyridyl) -aminomethanediphosphonic acid, N- (2- (5-amino) -pyridyl) -aminomethanediphosphonic acid, N- (2- (5-chloro) -pyridyl) -aminomethanediphosphonic acid, N- (2- (5-nitro) -pyridyl)) - aminomethanediphosphonic acid, N- (2- (3,5) -dichloro-pyridyl) -aminomethanediphosphonic acid, N- (4-p N- (2- (3-picolyl)) - aminomethanediphosphonic acid, N- (2- (4-picolyl)) - aminomethanediphosphonic acid, N- (2- (5-picolyl)) N - (2- (6-picolyl)) - aminomethanediphosphonic acid, N- (2- (3,4-lutidin)) -aminomethanediphosphonic acid, N- (2- (4,6-picolyl)) N- (2-pyrimidyl) -aminomethanediphosphonic acid, N- (4- (2,6-dimethyl) -pyrimidyl) 16

-aminomethanediphosphonic acid, N- (2 (4,6-dihydroxy) -pyrimidyl) -aminomethanediphosphonic acid, N- (2- (5-methoxy) -pyridyl) -aminomethanediphosphonic acid, N- (2-pyridyl) 2-Aminoethane-1,1-diphosphonic acid, N- (2- (3-picolyl)) -2-aminoethan-1,1-diphosphonic acid, N- (3-pyridyl) -2-amino -1-chloroethane-1,1-diphosphonic acid, N- (3-pyridyl) -2-amino-1-chloroethane-1,1-diphosphonic acid, N- (2- (4-picolyl)) -2-amino-1-hydroxy-ethane-1,1-diphosphonic acid, (3-pyridyl) -aminomethanediphosphonic acid, 2- (2-pyridyl) -1-amino-ethane-1,1-diphosphonic acid, O- (4-pyridyl) -1-amino-2-oxa-ethane-1,1-diphosphonic acid, N- (phenyl) thiocarbamoylmethanediphosphonic acid, N- (4-chlorophenyl) carbamyolmethanediphosphonic acid, N- (4-chlorophenyl) thiocarbamyolmethanediphosphonic acid, N- (2-benzoyl [b] thienyl) thiocarbamoylmethanediphosphonic acid, N- (4-trifluoromethylphenyl) thiocarbamyolmethanediphosphonic acid, N- (3-trifluoromethylphenyl) thiocarbamoylmethanediphosphonic acid acid, N- (4-chloro-3-trifluoromethylphenyl) thiokarbamyolmethandif phosphonic acid, (4-chlorophenyl) sulfonylaminomethandifosfonová acid and N- (3-mesylaminofenyl) thiokarbamyolmethandif phosphonic acid. Bone active compounds that are more preferred in the compositions of this invention include pharmaceutically acceptable salts of the following compounds or esters thereof: 6-amino-1-hydroxy-hexane-1,1-diphosphonic acid, 3-amino-1 -hydroxy-hexane-1,1-diphosphonic acid, octahydro-1-pyridine-6,6-diphosphonic acid, 2- (2'-piperidinyl) -ethane-1,1-diphosphonic acid, 2- (3 ' -piperidinyl) -ethane-1,1-diphosphonic acid, 2- (2'-piperidinyl) -1-hydroxy-ethane-1,1-diphosphonic acid, 2- (3'-piperidinyl) -1-hydroxy-ethane- 1,1-diphosphonic acid, N- (2 '- (3'-methyl) -piperidinylidene) -aminomethanediphosphonic acid, N- (2' - (1 ', 3'-diazinylidene)) -aminomethanediphosphonic acid and N- (2- (3-methylpiperidinylidene)) -aminomethane-1,1-diphosphonic acid. Other bone-active compounds for use in the compositions of this invention include phosphonomethylphosphinic acid compounds that are analogous to the above diphosphonic acid compounds.

A pharmaceutically acceptable amine function salt of a compound, as used herein, means an addition salt of a compound with similar pharmacological activity (potency and safety) to the compound as a base. A preferred compound addition salt has substantially the same pharmacological activity as the base of the compound. The compound addition salt can be formed by associating the amine functional drug compound in base form with the appropriate acid. Acids known to form pharmaceutically acceptable acid addition salts with certain amine-functional drugs in the form of bases include, but are not limited to, the following acids: hydrochloric, hydrobromic, hydroiodic, malonic, succinic, tartaric , fumaric, milky, lemon, ascorbic, oxalic, gluconic, phosphoric, nitric, sulfuric, methanesulfonic, ethanesulfonic and 2-naphthalenesulfonic.

Estrogen: Estrogen therapy can be used in conjunction with any of these regimens. The method herein also comprises co-administering from about 0.3 mg to about 6 mg of estrogen together with calcium, trace elements and vitamin D, calcitonin or editronate (or diphosphonates). Preferably, about 0.625 mg to about 1.25 mg of estrogen is administered daily. Any estrogen hormone can be used.

In the supplements described above, the nutritional supplemental amount of minerals will generally comprise more than 50% RDA, preferably 80 to 100% RDA, most preferably 100% RDA, per unit portion of the final supplement. It will be appreciated, however, that the preferred daily dosage of any element may vary according to the user.

The RDA of calcium will range from 360 mg per 6 kg for a child to 800 mg per 54 to 58 kg for a woman, the dose being partly dependent on age. In addition, it may be difficult to supplement beverages with more than 20 to 30% RDA of calcium (based on the amount administered) without precipitating and / or without causing organoleptic problems. However, this amount of supplement is equivalent to cow's milk in terms of calcium and is therefore acceptable.

The zinc RDA is 15 milligrams (mg) per day for men and 12 mg per day for women. There is no specific RDA for manganese and copper. A safe and adequate amount was determined to be 2-5 mg of manganese and 1.5-3 mg of copper per day.

Any soluble trace element salt may be used, for example, zinc chloride, zinc sulfate, manganese sulfate, manganese gluconate, copper sulfate, and copper gluconate are useful. A nutritionally complementary amount of these elements is used. However, what salt is used and in what amount depends on their interaction with the other ingredients of the supplement.

The following inorganic ions are useful for the production of trace element salts: sulfate, nitrate, phosphate, dibasic phosphate and carbonate. Mexi organic anions include carboxylate anions such as citrate, malate, tartrate, acetate and gluconate.

In this supplement, it is essential that the calcium salts are soluble in the stomach. Solubility helps make calcium more readily bioavailable. Equally important, the trace elements are dissolved and absorbed in the stomach or intestines. Thus, the choice of calcium salts and trace elements depends on the interaction of these salts in acidic solutions (gastric pH) or basic solutions (intestinal pH).

Solubility also plays an important role in the preparation of foods and beverages containing these supplements.

Compositions comprising citrate and calcium malate: The methods of the invention include administering a mixture of calcium salts, wherein the citrate and calcium malate comprises calcium salts of citric acid and malic acid. The calcium citrate and malate may comprise a mixture of calcium citrate and calcium malate, a complex comprising citrate and malate ligands, a mixture of calcium salt of citric acid and malic acid, or a combination thereof. Mixtures of calcium salts and malic and citric acid may be used to prepare citrate and calcium malate in beverages in drinks. Preferred are mixtures of citrate and calcium malate prepared by adding calcium carbonate, calcium hydroxide or other suitable source to the mixture of citric acid and lactic acid.

The molar ratio of citrate to malate is from about 1: 0.16 to about 1: 13.5, preferably from about 1: 0.5 to about 1: 4.5, more preferably from about 1: 0.75 to about 1: 3. The ratio of moles of calcium to total moles of citrate and total moles of malate is from about 2: 1: 1 to about 8: 2: 1, preferably from about 4: 2: 3 to about 6: 3: 4. Calcium citrate and malate may contain other anionic acids. Such anions include, for example, carbonate, hydroxide, phosphate, and mixtures thereof, depending on the source of calcium.

Preferably, the citrate and calcium malate are neutral, containing only citrate and malate anions. Thus, the number of calcium equivalents (2 x number of moles of calcium) is preferably equal to the total number of equivalents of citrate (3 x number of moles of citrate) plus malate (2 x number of moles of malate). Preferred citrate and calcium malate are compositions with a calcium: citrate: malate molar composition of about 6: 2: 3 and 4: 2: 3.

The calcium citrate and malate used in the methods of the invention may be prepared in solid or liquid form. For example, citrate and calcium malate for use in solid forms may be prepared by first dissolving citric acid and malic acid in the desired molar ratio in water. Thereafter, calcium carbonate may be added to the solution in an amount such that the ratio of moles of calcium to moles of citrate and moles of malate is as desired. Carbon dioxide will be released. The solution may then be dried (for example by freeze drying or oven drying at temperatures above 100 ° C). Calcium citrate and malate are obtained. Methods for producing calcium citrate and malate are described in the following documents: Japanese Patent Publication No. SHO 56-97248 (Kawai, published August 5, 1981) and U.S. Patent No. 4,722,847 (Heckert, 1988); Accompanying Application Foxe et al., US Patent Application 07/537313 (published

On December 26, 1991 as World Patent Patent WO91-19692) of July 14, 1980.

Calcium carbonate may be used as the calcium source. Other sources are calcium oxide and calcium hydroxide. Calcium chloride, calcium phosphate and calcium sulfate are suitable for use herein, but these compounds may form an acidic solution that could adversely affect the taste of beverages and aqueous solutions of citrate and calcium malate.

Solids are formed as the calcium oxide or calcium hydroxide is mixed with citric acid and malic acid. If these materials are used, the solution should be stirred until all the calcium is clearly dissolved. If the solubility of citrate and calcium malate is exceeded, then this mixture begins to precipitate.

A preferred method of preparation is to prepare a highly concentrated solution of citrate and calcium malate that rapidly and efficiently displaces metastable citrate and calcium malate from solution. A concentration of from 20 to 75% is preferred. More preferably, the concentration is from 40 to 65%.

The reaction temperature may be room temperature (20 ° C) or higher. The reaction temperature is preferably in the range of from 30 to 80 ° C. The most preferred temperature is from 40 ° C to 60 ° C.

Flavor component: The flavor component according to the invention comprises flavors selected from natural flavors, botanical flavors and mixtures thereof. The term fruit tastes refers to those tastes which are derived from the edible reproductive portion of the seed of plants, particularly those having a sweet pulp associated with the seed. The term fruit flavor also includes synthetically prepared flavors that simulate fruit flavors derived from natural sources.

The term botanical taste refers to flavors that are derived from parts of the plant other than the fruit, ie derived from beans, nuts, bark, roots and leaves. The term botanical flavors also includes synthetically prepared flavors that are made to simulate botanical flavors that are derived from natural sources. Examples of such tastes include cocoa, chocolate, vanilla, coffee, cola, tea and the like. Botanical flavors can be derived from natural sources such as essential oils and extracts or can be prepared synthetically.

The appropriate amount of flavor component that is effective to impart flavor properties to the food or beverage compositions of the present invention (flavor enhancer) depends on the flavor (s) selected, the desired flavor and the form of the flavor component. The flavor component may be present at a concentration of at least about 0.05% by weight of the beverage composition, preferably from 0.05 to about 10%. The amount of flavor component to be added to the food, beverage or supplement depends on the skill of the artisan and the desired flavor intensity.

In the case of chocolate or cocoa, from about 0.05 to about 20% of the flavor component is added. In the case of artificial or synthetic chocolate flavor components, lower amounts are used than for cocoa.

The drinks may be flavored with fruit or other botanical flavors, such as vanilla, strawberry, sour cherry, pineapple, banana, and mixtures thereof.

Calcium, citric acid and malic acid, together with trace elements and vitamin D, may be added to 100% fruit juice or diluted fruit juice. The sugars present in the juice are useful sweeteners. Juice can serve directly as a flavoring component. Such beverages may contain from 5 to 100% juice. Preferred diluted juice drinks contain from 10 to 40% juice. Preferred juices for 100% juice products or for diluted products are orange, cranberry, apple, pear, wine, raspberry, lemon, grapefruit, pineapple, banana, blackberry, blueberry and bitter fruit juices and mixtures thereof.

Sweetening component: The sweetening component is usually a monosaccharide or disaccharide. These include sucrose, fructose, dextrose, maltose and lactose. If less sweetener is desired, other sweeteners may also be used. Mixtures of these sweeteners may also be used.

In addition to sugar, other natural or artificial sweeteners may be used in the present invention. Other sweeteners include saccharin, cyclamates, acetosulfam, L-aspartyl-L-phenylalanine lower alkyl ester sweeteners (eg, aspartame), L-aspartyl-D-alanine amides described in U.S. Patent No. 4,411,925 to Brennan et al. October 23, 1983), L-aspartyl-D-serine-amides disclosed in U.S. Patent No. 4,399,163 (Brenna et al., Aug. 16, 1983), L-aspartyl-11-hydroxymethyl-alkanamide. No. 4,338,346 (Brand, Dec. 21, 1982), L-aspartyl-1-hydroxyethylalkanamide sweeteners disclosed in U.S. Patent No. 4,423,029 (Rizzi, Dec. 27, 1983), L-aspartyl-D-phenylglycine ester, and amide sweeteners described in European Patent Application 168,112 (JM Janusz, published January 15, 1986) and the like. A particularly preferred sweetener is aspartame.

The amount of sweetener that is effective in the food, beverage, compositions or supplements of the invention depends on the particular sweetener used and the desired sweetness intensity. For non-caloric sweeteners, this amount depends on the sweetness of the sweetener in question. For sugar (e.g. sucrose), this amount is from 10 to 85% by weight (typically from 55 to 70%). Any sugar or any other sweetener present in the flavor component should also be considered when determining the amount of sugar. Combinations of low-calorie sweeteners containing a non-caloric sweetener such as aspartame and a sugar such as solid corn syrup or sugar alcohols may also be used in the beverage compositions. The amount of sweetener is usually from about 0.5 to about 85%.

Other ingredients: Supplements, food and beverages often contain other minor ingredients. These additives include preservatives such as benzoic acid and its salts, sulfur dioxide, butylated hydroxyanisole, butylated hydroxytoluene, etc. Also included are dyes that are either naturally derived or synthetically prepared.

Salt, such as sodium chloride, and other flavoring agents may be used to improve the taste of the food, beverage or supplement.

Emulsifying agents may also be included in the ingredients. Any suitable food emulsifier may be used. The preferred emulsifier is lecithin. Other edible emulsifying agents include long-chain mono- and diglycerides of fatty acids, preferably saturated fatty acids, most preferably stearic and palmitic mono- and diglycerides. Propylene glycol esters are also useful for beverage compositions.

Fats or oils may also be added to the supplements or foods to improve taste.

pH and other beverage ingredients: The pH of the beverages and beverage concentrates of the present invention depends on the weight ratios of acids, the total amount of acids and the desired acidity impression. The pH is typically in the range of 2.5 to 6.5. Preferred carbonated drinks have a pH of from 3.0 to 4.5.

Beverages and concentrates often contain other minor beverage ingredients. Typically, dyes are also included which either originate from natural sources or are synthetically prepared. For preservatives and dyes used in beverages, see L. F. Green: Developments in Soft Drinks Technology, Vol. 1 (Applied Science Publishers Ltd., 1978), p. 185 (incorporated herein by reference).

Beverage Preparation: The beverages and concentrates of the present invention can be prepared by standard beverage preparation methods. However, it is to be understood that, after appropriate treatment, the carbonated beverage production techniques are also applicable to non-carbonated beverages. While the following description is given on sugar-containing beverages, dietary beverages containing non-caloric sweeteners may also be prepared by appropriate treatment. Beverages include dry beverage compositions which are prepared by mixing flavorings, sweeteners and other optional ingredients as well as fruit juices and diluted fruit juices.

When preparing sugar-sweetened beverages containing carbon dioxide, a beverage concentrate containing from 30 to 70% by weight of water is usually prepared. This beverage concentrate typically comprises emulsified or water-soluble flavoring agents, emulsion stabilizing agents, and adjuvants, if desired, the desired colorant and suitable preservatives. When the concentrate is produced, sugar and water are added to produce a beverage syrup. The beverage syrup is then mixed with an appropriate amount of water to form the final beverage. The weight ratio of water to syrup is from about 3: 1 (3 x syrup) to about 5: 1 (5 x syrup). In the manufacture of a beverage that contains carbon dioxide, the carbon dioxide may be introduced either into water that is mixed with the beverage syrup or into a dilute beverage ready to drink to achieve the desired saturation. The beverage may then be sealed from a container such as a bottle or can. For a further description of beverage production, particularly for the carbonation process, see L. F. Green: Developments in Soft Drinks Technology, Volume 1 (Applied Science Publishers Ltd., 1978), p. 102 (incorporated herein by reference).

The amount of carbon dioxide in the beverage depends on the particular flavor system used and the desired amount of carbon dioxide. The carbon dioxide drinks of the present invention typically contain from 1.0 to 4.5 volumes of carbon dioxide. Preferred carbonated beverages contain from 2 to 3.5 volumes of carbon dioxide.

A source of calcium and acid (citric, malic, phosphoric) may be added at various points in the process. Sources of lime. , 25

The nicotine and acids are preferably added at the same time of the process, but can be added at different times. Sources of calcium and acid are usually added during the preparation of the beverage concentrate or syrup. The trace elements are preferably added after the source of calcium and acids has been added. Vitamin D may be added with oily flavoring agents or supplementary oils.

When a dry beverage is produced, it is preferable to mix powdered citrate and calcium malate and trace element salts with sugar or non-white sweeteners, vitamin D and flavoring agents. Dyes and colored sugar can be added. The dry chocolate milk beverages are preferably dry beverage compositions. These mixtures may be diluted with either water or milk. Milk provides additional vitamin D and calcium citrate. A typical prescription for chocolate mixtures is:

(a) from 0 to 25% of milk powder, preferably from 5 to 20% of non-fat milk powder;

(b) from 0.05% to 20% of a flavoring component, preferably cocoa;

c) from about 0.5 to about 85% of a sweetener, preferably sucrose;

d) from about 0.6 to about 0.15% calcium citrate and malate and from about 0.60 to about 30 micrograms of vitamin D.

Supplement Forms: Solid forms include tablets, capsules, granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flowability agents and fluxes. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions prepared from non-effervescent granules and effervescent compositions prepared from effervescent granules. Such liquid oral dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, fluxes, coloring agents and flavoring agents. A preferred liquid dosage form comprises calcium citrate and malate and trace elements in a juice-containing beverage or other beverage.

In treatment, the trace elements, calcium citrate and malate, vitamin D and / or drugs may be co-administered in a single tablet, liquid, food or beverage, or may be administered separately. A capsule containing salts of trace elements, a second tablet with citrate and calcium malate and a third containing vitamin D and / or drug treatment are easy to prepare and swallow. The elemental supplement and vitamin D can also be administered together with a beverage containing calcium.

Specific examples of pharmaceutically acceptable carriers and excipients that may be used in the preparation of the oral dosage forms of the invention are described in U.S. Patent No. 3,903,297 (Robert, Sep. 2, 1975). Methods and compositions for making dosage forms useful in the methods of the invention are described in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker and Rhodes, Editors, 1979), Lieberman et al .: Pharmaceutical Dosage Forms: Tablets (1981) and Ansel: Introduction to Pharmaceutical Dosage Forms, second edition (1976).

Bone Construction Method: Various oral dosage forms of calcium citrate and malate treatment, trace elements, vitamin D and / or drug can be used in accordance with the present invention. The dosage forms comprise a safe and effective amount of calcium citrate and malate, trace elements, vitamin D and / or medicaments, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier is preferably present in an amount of from about 0.1 to about 99%, preferably from about 0.1 to about 75% by weight of the composition. Unit dosage forms (i.e., dosage forms containing an amount of citrate and calcium malate suitable for administration in a single dose, according to medical practice) preferably contain from about 100 mg to about 1000 mg, preferably from about 100 mg to 500 mg, more preferably from about 200 mg to about 300 mg of calcium (based on the element). Unit dosage forms of copper (per element) contain 0.5 to 5 mg, preferably 0.5 to 4.0 mg, unit dosage forms of manganese (per element) contain 1 to 8 mg, preferably 2 to 7 mg of manganese , and unit dosage forms of zinc contain (per element) 1.5 to 30 mg, preferably 7.5 to 20 mg of zinc.

Preferably, from about 175 mg to about 2000 mg of calcium (per element) is administered per day. More preferably, from about 250 mg to about 1500 mgs are administered, most preferably from about 350 mg to about 1000 mg of calcium per day. The appropriate amount of citrate and calcium malate to be administered depends on the relative weight percent of calcium in the respective citrate and calcium malate used.

The recommended daily dose of vitamin D is 200-400 J international ednotek by ^- 'ďtaří tdhdT ^ ^ ^ whom the vitamin-D-podává.-ins that are used herein have a unit dosage amount of from about 25 IU to about 1000 IU units, or from about 0.6 to 25 micrograms.

The effective amount of calcitonin is about 100 international units per day. Together with citrate and calcium malate, trace elements and vitamin D, from about 25 to 120 international units may be administered.

The effective amount of the diphosphonate is from about 200 mg to about 1000 mg. The usual safe and effective amount of Didronel and diphosphonates is from 1 mg / kg / day to 20 mg / kg / day. Preferably, from 5 to 10 mg / kg / day is used. This dose can be administered in two dosage units, one in the morning and one in the evening. Didronel and bisphosphonates for treating age-related bone loss are typically administered in an intermittent cyclic fashion.

Specifically, the present invention provides a method of bone formation in humans or other animals, comprising administering to said human or animal a safe and effective amount of calcium citrate and malate, copper, zinc, manganese, vitamin D and / or either calcitonin, editronate or estrogen for a period of time sufficient to achieve an increase in the net skeletal mass of said human or animal. The term bone building as used herein means a reduction in the net bone loss of the treated human or animal and thus a net increase in skeletal weight. The rate of bone loss is slowed and the rate of growth is increased simultaneously so that the net bone density can remain the same. The weight gain can be at any point in the skeleton including the spine, hip, long bones of the hands or feet, or throughout the skeleton. Preferably, the net mass of the carcass is increased by at least about 0.1%, more preferably by at least about 1%.

Bone loss is cumulative over a longer period of time. The typical loss of bone mass during life is about 35% for men and 50% for women. Thus, although a net skeletal enlargement of 0.5% in one year is not critical, in ten years it leads to a 5% increase in bone mass compared to the condition if bone loss continues at the normal rate.

The term administration means any method by which, according to medical practice, vitamin D and / or the drug, calcium citrate and malate and the trace elements used in the present invention are delivered to a human or animal to be treated in such a way as to be effective for bone building.

The time that is sufficient to achieve an increase in the net skeletal weight of a human or animal depends on various factors. These factors include, for example, the particular device used, the amount of elements administered, the age and sex of the human or animal, the specific disorder being treated, the concurrent treatment (if any), the overall physical health of the human or animal (including the presence other disorders), the extent of individual bone loss and nutritional habits. Although administration of even small amounts of calcium citrate and malate, trace elements, vitamin D and / or drugs may build bone, a net increase in bone weight may be undetectable at shorter administration times.

In the treatment of age-related bone loss, calcium citrate and malate, trace elements and vitamin D and / or calcitonin, bisphosphonates or estrogen are administered according to medical practice for at least six months, preferably for at least twelve29 months. However, such administration may continue without restriction, according to medical practice.

The methods of the invention can be used in the treatment of any of a variety of disorders in which bone formation is desired. Thus, a human or other animal according to the methods of the invention preferably needs a method of bone building, i.e., the human or animal has a disorder for which bone formation or reducing bone resorption would be beneficial, according to known medical practice. Such disorders include, for example, bone fractures, decreased bone mass, and disorders caused by bone loss _n such as age-related bone loss and osteoporosis (both primary and secondary forms).

A preferred method of the invention is to treat age-related bone loss.

The following example illustrates compositions of the type used in the practice of this invention, but is not intended to be limiting thereof.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Several postmenopausal women are treated by administering a composition comprising citrate and calcium malate having a molar ratio of calcium to citrate to malate in the composition of about 6: 2: 3. The citrate and calcium malate are prepared by first dissolving about 384.2 grams of citric acid and about 402.3 grams of malic acid in about two liters of water. This citrate-maltate solution is then heated to about 55 ° C with stirring. Separately with stirring, about 600.6 grams of calcium carbonate is added to about 1.2 liters of water. This creates a slurry.

The citrate / malate solution is then removed from the heat source and a calcium carbonate slurry is added slowly with stirring. The rate of addition was controlled so that the reaction contained carbon dioxide evolved. Finally, an additional amount of water, about 0.4 liters, is added. The reaction mixture is then stirred for about 1 to 1.5 hours. The reaction is substantially complete when the pH of the solution has stabilized at about 4.3.

In this way, a citrate and calcium malate precipitate is formed. Excess reaction liquid was filtered off. The citrate and calcium malate are dried for about 12 hours at about 105 ° C, thereby reducing the moisture content to less than about 1%. The dried product is then milled to a size of approximately 2.00 to 0.84 mm for the tablets to be swallowed. Each tablet contains 250 mg.

Thereafter, a dosage form of a swallowable tablet is prepared comprising:

% by weight component of citrate and calcium malate * 99.73 magnesium stearate 0.27 * molar ratio calcium: citrate: malate of the composition is about 6: 2: 3; this composition is produced as above

The tablet is made by thoroughly mixing the powders and forming tablets, each weighing approximately 1104 milligrams, on a standard tablet press. The tablets are then coated with a coating comprising about 11% hydroxypropylmethylcellulose, about 2% polyethylene glycol and about 3.5% dye. The rest is water.

Each patient is also given a capsule containing 15 mg of zinc (from zinc sulfate), 5 mg of manganese (from manganese gluconate) and 2.5 mg of copper (from copper gluconate) and 10 micrograms of vitamin D.

Example 2

Powdered mineral supplement containing 2000 g of calcium citrate and malt, 6.3 mg of copper sulphate (2.5 mg of copper), 31.3 mg of zinc chloride (15 mg of zinc) and 5 mg of manganese (15.4 mg of manganese sulfate monohydrate) ) is prepared by tableting a mixture of powders. This tablet is taken on a daily basis with 2 mg per kg of Didronel for 6 months.

Example 3

Tablet containing 200 mg of calcium (from citrate and calcium malate), 1 mg of copper (from copper gluconate), 1.5 mg of manganese (from manganese gluconate), 3 mg of zinc (from zinc gluconate) and 3 micrograms of vitamin D (from cholecalciferol) is taken 4 times a day with a single dose of 0.625 mg conjugated estrogen in the form of a tablet taken once daily for 2 years.

Claims (8)

1. A mineral and vitamin supplement for bone building, characterized by: comprising a unit dose composition comprising: (a) 100 to 1000 mg of calcium (per element) in the form of a carboxylate selected from the group consisting of citrate, malate, lactate and mixtures thereof, preferably with a molar ratio of calcium: citrate: malate of from 2: 1: 1 to 8 : 2: 1, (b) from 0,5 to 5 mg of copper (based on the element), (c) from 1,5 to 30 mg of zinc (based on the element), (d) from 1 to 8 mg of manganese (per element); and e) from 0.6 to 25 micrograms of vitamin D, preferably such that the D vitamin is present in an amount of 0.15 to 5 micrograms per supplement in the form of vitamin D metabolites and precursors such as 1of, 25-di (OH) 2-vitamin D, 25-OH-vitamin, 1d-OH-vitamin D 2 or D 3 and / or dihydroxy compound analogs. Supplement according to claim 1, characterized in that the copper, zinc and manganese are in the form of salts anions selected from the group consisting of chloride, sulfate, aluconate, citrate, malate, lactate, tartrate, nitrate and mixtures thereof. 3. A bone-building supplement comprising a unit dose composition comprising: (a) 100 to 1000 mg of calcium (per element) in the form of carboxylate, selected from the group consisting of citrate, malate, lactate and mixtures thereof; (b) from 0,5 to 5 mg of copper (based on the element), (c) from 1,5 to 30 mg of zinc (based on the element), d) from 1 to 8 m of manganese (based on the element) and iodine 200 mg to 1000 mg of diphosphonate, which is preferably Didronel or aminodiphosphonate. A bone-building supplement according to claims 1 to 3 comprising calcium citrate and malate, zinc, manganese and copper salts and a member or members selected from the group consisting of calcitonin, vitamin D,. of editronate and diosionates, the calcium citrate and the malate being in the amount of 175 mg to 2000 mg (based on the element), zinc 1.5 to 30 mg, manganese in the amount of 1 to 8 mg and copper in the amount of 0.5 to 5 0 mg, vitamin D at 0.6 to 25 micrograms and diosionate at 200 to 1000 mg. A bone construction supplement according to claim 4, characterized in that the citrate and calcium malate have a molar ratio of citrate to malate from 1: 0.5 to 1: 4.5, zinc from 7.5 to 20 mg, copper from 0.5 to 5 mg, and manganese from 2 to 7 mg, wherein the zinc is preferably in the form of zinc sulfate and the manganese and the copper are preferably in the form of manganese gluconate and copper gluconate. A bone building supplement according to claim 4 or 5, characterized in that it is in a fixed dosage form. A bone-building supplement according to claim 4 or 5, characterized in that it is in a liquid dosage form, preferably in the form of a beverage, the beverage preferably comprising a juice selected from the group consisting of orange , cider, pear, burgundy, lemon and cranberry juices. 8. A supplement according to claim 6, wherein the solid dosage form comprises a tablet of calcium citrate and malate and vitamin D and a separate tablet or capsule of zinc, copper and manganese salts. Bone-building supplement according to claim 1, characterized in that it also contains a safe and effective amount of estrogen from 0.6 to 6 mg.