DESC:Technical Field:

The present invention relates to synergistic micronutrient enriched nutritional compositions for treating metabolic bone disorders.

Furthermore, the present invention provides synergistic, efficient, nutritional compositions comprising specific combination of Calcium-L-Threonate and Eldecalcitol along with pharmaceutically acceptable excipients or carriers.

The invention relates to micronutrient enriched nutritional composition, which is useful to control pathogenesis of osteoporosis, wherein it significantly increases bone mineral density (BMD) or bone strength in a subject in need thereof.

Background and Prior Art:

Metabolic bone disease is the third most common endocrine disorder after diabetes and thyroid diseases. The common metabolic bone diseases (MBD) include osteoporosis, rickets/osteomalacia, flurosis and primary hyperparathyroidism (PHPT), while the rare MBDs include Paget's disease, tumor-induced osteomalacia, fibrous dysplasia, and osteogenesis imperfecta. Most commonly these disorders are caused by abnormalities of minerals such as calcium, phosphorus, magnesium, or vitamin D leading to dramatic clinical disorders that are commonly recovered on proper treatment.

“Osteoporosis” is a condition characterized by a decrease in the density of bone, decreasing its strength and resulting in fragile bones. Osteoporosis literally leads to abnormally porous bone that is compressible, like a sponge. This disorder of the skeleton weakens the bone and results in frequent fractures (breaks) in the bones.

Normal bone is composed of protein, collagen, and calcium, all of which gives the bone its strength. Bones that are affected by osteoporosis can break (fracture) with relatively minor injury that normally would not cause a bone to fracture. The fracture can be either in the form of cracking (as in a hip fracture) or collapsing (as in a compression fracture of the vertebrae of the spine). The spine, hips, ribs, and wrists are common areas of bone fractures from osteoporosis although osteoporosis-related fractures can occur in almost any skeletal bone.

Osteoporotic bone fractures are responsible for considerable pain, decreased quality of life, lost workdays, and disability. Up to 30% of patients suffering a hip fracture will require long-term nursing-home care. Elderly patients can develop pneumonia and blood clots in the leg veins that can travel to the lungs (pulmonary embolism) due to prolonged bed rest after the hip fracture. Osteoporosis may limit mobility, which often leads to feelings of isolation or depression. Additionally, 20% of seniors who break a hip die within one year from either complication related to the broken bone itself or the surgery to repair it. Osteoporosis has even been linked with an increased risk of death.

In addition, once a person has experienced a spine fracture due to osteoporosis, he or she is at a very high risk of suffering another such fracture in the near future (next few years).

Currently, it has been estimated that more than 200 million people are suffering from osteoporosis. According to recent statistics from the International Osteoporosis Foundation, worldwide, 1 in 3 women over the age of 50 years and 1 in 5 men will experience osteoporotic fractures in their lifetime. It was estimated that the number of patients worldwide with osteoporotic hip fractures is more than 200 million.

It was reported that in both Europe and the United States, 30% women are osteoporotic, and it was estimated that 40% post-menopausal women and 30% men will experience an osteoporotic fracture in the rest of their lives [Eur J Rheumatol. 2017 Mar; 4(1): 46–56.]

Osteoporosis is a progressive systemic skeletal disease characterized by low bone mass and micro-architectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Changes in bone turnover with aging are responsible for bone loss and play a major role in osteoporosis. An imbalance in bone turnover impacts the bone strength as a result of reductions in bone volume and mineralization, loss of trabeculae, deterioration of trabecular connectivity, and the formation of resorption cavities and trabecular perforations. Therefore, an increase in bone turnover where resorption exceeds formation is not only inversely correlated with bone mineral density (BMD), but may also alter bone architecture and porosity, increasing the risk of fracture, and can therefore be an independent predictor of fracture risk.

Primary osteoporosis is mainly a disease of the elderly also known as age-related osteoporosis. The result of the cumulative impact of bone loss and deterioration of bone structure that occurs as people age [J Appl Physiol. 2003 Nov;95(5):2142–51]. Individuals who get the disease due to “outside” cause such as certain medications and toxic agents are said to have “secondary” osteoporosis.

Bone mass (bone density) is determined by the amount of bone present in the skeletal structure. Generally, bone density corresponds the bone strength; means higher the bone density, stronger are the bones.
After age 35, both men and women will normally lose 0.3-0.5% of their bone density per year as part of the aging process.
The bone density of the patient is compared to the average peak bone density of young adults of the same sex and race. This score is called the “T score” or “T-score”, and it expresses the bone density in terms of the number of standard deviations (SD) below peak young adult bone mass. Osteoporosis is defined as a bone density T scores of -2.5 or below.

Currently, most effective medications for osteoporosis that are approved by the FDA are anti-resorptive agents, which decrease the removal of calcium from bones. This process is an essential part of maintaining the normal calcium level in the blood and serves to repair tiny cracks in the bones that occur with normal daily activity and to remodel bone enriched on the physical stresses placed on the bone. Antiresorptive medications inhibit removal of bone (resorption), thus tipping the balance in favor of bone rebuilding and increasing bone density. The antiresorptive medications include alendronate, risendronate, raloxifene, ibandronate, zoledronate and denosumab.

However, the side effects for all the bisphosphonates (alendronate, ibandronate, risedronate and zoledronic acid) may include bone, joint or muscle pain, nausea, difficulty swallowing (Dysphagia), heartburn, irritation of the esophagus and gastric ulcer. All bisphosphonates can affect the kidneys work and should not be taken by patients who have poor kidney function or kidney failure.

Generally, calcium is good for human bones and helps to avert osteoporosis. The nutrient is essentially a building block of bone, and it helps to maintain bone strength throughout lifetime. But calcium can only reach its full bone-building potential if the body has enough vitamin D. Calcium and vitamin D work together to protect bones – calcium helps build and maintain bones; while vitamin D helps body to absorb calcium effectively.

One of the easiest and most effective methods of increasing the calcium intake is to take an oral calcium supplement. There are several over-the-counter forms of oral calcium that can help maintain healthy bones and prevent osteoporosis.

Additional calcium can be obtained by drinking more milk and eating more yogurt or cottage cheese or by taking calcium supplement tablets as well from calcium-fortified foods, such as orange juice.

It is also important to ameliorate calcium products with vitamin D, since this vitamin regulates the incorporation of calcium into the bones, and without it the bones would receive no benefits from the added calcium. Vitamin D also regulates phosphorous blood levels, regulates calcium reabsorption in the kidneys and participates in the inhibition of parathyroid hormone (PTH) secretion from the parathyroid gland, or influences the immune system due to its immunosuppressive action, promoting phagocytosis and antitumor activity. There are several compositions consisting calcium salts and vitamin D, which are reported and commercialized in the market.

WO2011066880A2 discloses dietary product comprising tricalcium citrate and vitamin D, whereas WO2009095798A2 relates to composition of calcium, magnesium, zinc, and vitamin D3 for the prevention and amelioration of osteoporosis.

Further, EP1980255A1 discloses synergistic pharmaceutical composition comprising a synergistic combination of tibolone, calcium carbonate and the active metabolite of vitamin D3- calcitrol for the prevention and treatment of osteoporosis.

WO2013014654A2 discloses preparation of formulation containing calcium acetate, magnesium acetate, zinc acetate and vitamin D3.

Additionally, US7067154B2 describes a granular pharmaceutical composition consisting vitamin D3, calcium phosphate, propylene glycol, liquid paraffin, and silicone oil, for the prevention of osteoporosis.

US6447809 discloses a dietary supplement for benefitting human bone health and includes calcium, cholecalciferol, and an osteoblast stimulant-ipriflavone.

The various calcium supplements contain different amounts of elemental calcium (the actual amount of calcium in the supplement). For example, calcium carbonate, calcium citrate salts, etc. Calcium supplements are safe and generally well tolerated. However, there are certain side effects observed with calcium carbonate ingestion such as indigestion and constipation, and difficulty swallowing. Also, these salts have more limitations when applied to infants. Therefore, the need arises to find bioavailable salt of calcium that improves calcium serum level without any side effects.

Amino acid chelates of calcium are one of the selective and bioavailable complexes of calcium which contribute to maintain bone health.

L-threonate, a biocarrier for calcium, has specific influence in bone metabolism. It directs calcium passage through the intestine and deposits calcium in bones more efficiently. It also influences the biological activities or functions of vitamin C and provides optimum supply of dietary collagen and mineral to the body.

Further several clinical studies were indicated that, the bioavailability of calcium from calcium-L-threonate is higher than from other sources of calcium. Calcium-L-threonate has low oral acute toxicity, with no adverse effects observed.
It is further observed that, calcium-L-threonate could effectively control the loss of bone quantity, prevent the occurrence and development of rachitis and result in higher bone calcium sedimentation than calcium gluconate. [The EFSA Journal (2008) 866, 1-20].

L-threonic acid is an active metabolite of vitamin C. L-threonic acid may play a role in the mineralization process through its positive action on vitamin C. [Acta Pharmacol Sin. 2011 Dec; 32(12): 1555–1560].

Further, US6727288B2 relates to calcium-L-threonate composition for preventing or treating bone fracture.

US6077872A discloses method for treating, preventing and/or inhibiting osteoporosis, which comprises administration of an effective amount of calcium-L-threonate to individuals having an insufficient uptake of calcium or patients suffered from osteoporosis.

Conversely, deficiency/insufficiency of vitamin D causes a decrease in the serum concentration of calcium due to a reduction in intestinal absorption of calcium. This hypocalcaemia stimulates parathyroid hormone (PTH) secretion (secondary hyperparathyroidism), resulting in an increase in bone resorption and decrease of BMD. This may contribute to the cause of osteoporosis.

It is reported that very high bone turnover (bone loss) can result in high blood levels of calcium. Thus, the increased bone turnover is a risk factor for rapid bone loss and its inhibition by antiresorptive drugs can maintain BMD after menopause. Virtually anything that causes chronic inflammation will activate osteoclasts to break down and remove bone, so there is a need to control the amount of inflammation caused due to bone loss.

‘Vitamin D’ is a crucial factor for the intestinal absorption of calcium to maintain bone strength. Higher levels of Vitamin D are associated with lower levels of C-reactive protein. [PLoS One. 2015; 10(7): e0131740].

‘Vitamin D’ performs an equally essential role in maintaining a healthy mineralized skeleton for all ages. Vitamin D deficiency in children results in the bone-deforming disease rickets. In adults, vitamin D insufficiency and vitamin D deficiency has a more subtle effect on the skeleton. As the body becomes vitamin D insufficient, the efficiency of intestinal calcium absorption decreases from ~30-50% to no more than 15%. This results in a decrease in the ionized calcium concentration in the blood, which signals the calcium sensor in the parathyroid glands resulting in an increase in the synthesis and secretion of PTH.

PTH not only tries to conserve calcium by increasing renal tubular reabsorption of calcium but also plays an active role in mobilizing stem cells to become active calcium resorbing osteoclasts.
Vitamin D comes from the diet and the skin. Vitamin D production by the skin is dependent on exposure to sunlight. Sunlight is the main source of vitamin D for many people. However, staying in the sun without proper skin protection puts one at risk for skin cancer. Adequate levels of calcium and vitamin D are essential for optimal bone health, especially when used with prescribed medication for osteoporosis. Chronic excessive use of vitamin D can lead to toxic levels of vitamin D, elevated calcium levels in blood and urine, and may also cause kidney stones. Since various dietary supplements may also contain vitamin D, it is important to review vitamin D content in dietary supplements before taking additional vitamin D. An adequate intake of calcium and vitamin D are important foundations for maintaining bone density and strength. However, calcium and vitamin D alone are not sufficient to treat osteoporosis and should be given in conjunction with other treatments.

Therefore, to obviate the plausible adverse effects related to therapeutically poor calcium supplements and excessive vitamin D as disclosed above, the inventors of the present invention have come up with a non-toxic, bioavailable, dietary supplement having synergistic combination of bioavailable salt of calcium and active form of Vitamin D3 along with bioenhancer that suppress the bone turnover and subsequently improves the bone mineral density.

The present composition significantly improves bone health, wherein the active moieties produce synergy by increasing calcium absorption and mineralization and reducing bone resorption. The composition is therapeutically effective, cost-efficient, safe, and non-toxic.

Objective:

The primary objective of the invention is to provide micronutrient-enriched nutritional compositions for treating metabolic bone disorders.

Another objective of the invention is to provide bioavailable, safe, non-toxic, cost-effective antiresorptive composition for treating impaired bone functions.

Yet another objective of the invention is to provide synergistic, mineral and vitamin-enriched composition for treating osteoporosis.

Another objective of the invention is to provide synergistic combination of bioavailable chelates of macromineral and active form of fat-soluble vitamin along with bioenhancer for treating metabolic bone disorders.

Further objective of the invention is to provide efficient, dietary supplement for improving bone health by enhancing the bone mineral density.
Another objective of the invention is to provide synergistic therapeutically active remedy for treating osteoporosis through site specific action with no adverse effects.

Summary:

To meet the above objectives, the inventors of the present invention have performed thorough experiments to establish significant effects of the bioactive ingredients, micronutrients, minerals, vitamins or natural substances present in the composition that ameliorate bone health in a subject suffering from metabolic bone disorders like osteoporosis.

In a primary aspect of the invention, the invention relates to synergistic nutritional compositions comprising therapeutically active, bioavailable salts of macromineral and active forms of fat-soluble vitamin along with bioenhancer for treating impaired bone functions, preferably osteoporosis.

In another aspect, the invention relates to a synergistic, nutritional composition comprising a combination of chelated calcium and active form of vitamin D analogue, along with pharmaceutically acceptable excipients.

In a particular aspect, the present invention provides synergistic nutritional composition for improving bone mineral density and bone mineralization comprising specific combination of calcium-L-threonate and eldecalcitol along with pharmaceutically acceptable excipients.

According to the present invention, the micronutrients are present in specific amount, where it acts synergistically to improve bone mineral density; wherein L-threonate salt or chelate of calcium increases calcium serum level and bone calcium sedimentation; simultaneously or concomitantly eldecalcitol inhibits bone resorption, leads to improvement or enhancement in the overall bone mineral density.

In another aspect, the invention provides synergistic combination of naturally occurring nutrients as dietary supplements for maintaining bone architecture and porosity by increasing bone mineral density without any adverse effect, wherein a therapeutically effective amount of calcium-L-threonate is co-administered with lower dose of eldecalcitol along with pharmaceutically acceptable excipients.

In yet another aspect, the invention relates to synergistic nutritional compositions comprising combination of calcium-L-threonate which is present in the range of 100-2000 mg [elemental Ca2+ in the range of 5 to 500 mg]; and eldecalcitol present in the range of 0.1 to 10 micrograms; along with pharmaceutically acceptable excipients/carriers.

In yet one more aspect, the invention provides use of present synergistic composition for treating metabolic bone disorders. Particularly, the composition is useful for treating the disease conditions related to osteoporosis (postmenopausal osteoporosis, senile osteoporosis), bone fractures, hypocalcaemia, osteomalacia, rickets, osteitis fibrosa cystic, Paget's disease, tumor induced osteomalacia, fibrous dysplasia, osteogenesis imperfecta, osteopenia, hypocalcaemia, hypercalcaemia, marble bone disease, osteochondroma, bone demineralization, bone fracture and like thereof.

Abbreviations:

BMD: Bone Mineral Density
ELD: Eldecalcitol
CaLT: Calcium-L-threonate
PTH: Parathyroid Hormone
CRP: C-reactive protein

Brief description of figures:

Fig. 1 illustrates comparative BMD score with positive control
Fig. 2 illustrates BMD [T-score] of test samples in gm/cm3 [CaLT, ELD and Combination]

Detailed Description:

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be fully interpreted and comprehended. However, any skilled person in the art or artisan will appreciate the extent to which such embodiments could be generalized in practice.

It is further to be understood that all terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting in any manner or scope.

Unless defined otherwise, all technical and scientific expressions or terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which embodiments of the invention pertain.

In describing and claiming the embodiments of the present invention, the following terminologies will be used in accordance with the definitions set out below which are known in the art.
The singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise. Also, the term “composition” does not limit the scope of the invention, it may include multiple composition illustrations to establish best mode of the invention.

The term “pharmaceutically/nutraceutically acceptable salt” as use herein, represents those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and commensurate with a reasonable benefit/risk ratio. Particularly, the term “pharmaceutically-acceptable salts” refers to relatively non-toxic, inorganic and organic acid addition salts of compounds, alkali or alkaline earth metal salts, as well as solvates, co-crystals, polymorphs, isomers, enantiomers, congeners and the like of the salts.

All modifications and substitutions that come within the meaning of the description and the range of their legal equivalents are to be embraced within their scope. A description using the transition “comprising” allows the inclusion of other elements to be within the scope of the invention.

In a preferred embodiment, the invention discloses synergistic combination of micronutrients comprising bioavailable chelates of macrominerals and active form of fat-soluble vitamin for treating metabolic bone disorders.

In another embodiment, the invention provides more stable, non-toxic, safe, cost-effective, and efficient nutritional composition comprising bioavailable form of macromineral and fat-soluble vitamin for ameliorating bone loss.

Particularly, the invention provides synergistic combination of nutrients wherein one active moiety is bioavailable salt of a macromineral and another moiety is a fat-soluble vitamin, optionally along with bioenhancer.

According to the invention, the term “micronutrients” include combination of minerals and vitamins, wherein the vitamin is fat soluble, preferably, vitamin D analogue and macrominerals are selected from the group consisting of calcium, potassium, iron, sodium, and magnesium, preferably bioavailable chelates of calcium.

According to the invention, the term “chelate” relates to a chemical compound in which a metal molecule (mineral) and an organic molecule (ligand) are combined. The ligand is a critical component of a chelate that transforms the previously inorganic molecule into an organic mineral form, thus making it more bioavailable to the body.
In another embodiment, the bioavailable chelates or salts are selected from the group consisting of threonate, glutamate, succinate, carbonate, oxide, glycinate, acetate, citrate, aspartate, or combinations thereof.

The bioavailable organic salts of calcium are selected from the group consisting of calcium citrate, calcium maleate, calcium acetate, calcium gluconate, calcium lactate, calcium threonate or therapeutically active isomers or enantiomers thereof.

However, the organic salts of calcium are more bioavailable than the inorganic calcium salts like calcium carbonate, hence the inventors have selected bioavailable organic salts of calcium, i.e., chelated calcium mineral bound to threonic acid, called calcium-L-threonate.

It is noteworthy that, the bioavailability of calcium from calcium-L-threonate is higher than that from any other chelating agent. Further, acute oral toxicity studies have revealed that calcium-L-threonate is of low toxicity, with no adverse effects.

In another preferred embodiment, the invention provides synergistic micronutrient enriched nutritional compositions comprising specific combination of calcium-L-threonate and eldicalcitol, additionally bioenhancer.

In another embodiment, the invention discloses synergistic nutritional composition, wherein the active moiety called L-threonate chelated calcium ion enhances intestinal calcium absorption and increases calcium serum level.

Calcium-L-threonate is calcium (2R,3S)-2,3,4-trihydroxybutyric acid. In short, it is a calcium salt of L-threonic acid which is an L-enantiomer of threonic acid, that is used as a calcium supplement. It is present in a white crystalline form. It has molecular formula C8H14CaO10, represented by Formula-I.

Formula I

L-threonate is an active metabolite of vitamin C that mediates a stimulatory action on vitamin C uptake. Calcium threonate plays an important role in the mineralization process through its positive action on vitamin C.

In the present invention, L-threonate is used as chelating agent for calcium that improves intestinal mineral absorption.

In another embodiment, the invention discloses that the administration of an effective dose of calcium-L-threonate produces net increase of bone matrix and thus enhances the bone density and bone mechanical property.

Further it is manifested that calcium-L-threonate significantly raises the serum calcium level and decreases the serum ATP level and Tartrate resistant acid phosphatase (Tr-ACP) level, that consequently enhances the bone mineral density.

In another embodiment, the invention provides that calcium-L-threonate not only suppresses bone turnover but also promotes proliferation, differentiation and mineralization functions of osteoblast. It also improves the calcification and tenacity of the bones.

Further, calcium-L-threonate facilitates bone fracture healing, and increases bone density and mechanical performance, to prevent bone fracture, especially pathological fracture (such as caused by senile osteoporosis).

In yet another embodiment, the invention provides synergistic nutritional composition comprising therapeutically effective amount of calcium L-threonate, which is present in the range of 10-2000 mg; wherein elemental Ca2+ is present in the range of 5 to 500 mg of total composition.

In a further embodiment, the invention provides synergistic nutritional composition, wherein elemental Ca is present in the range of 9-15% by weight of total amount of calcium-L-threonate.

According to the invention, another active moiety of the present nutritional composition is fat-soluble vitamin, preferably vitamin D.

In another embodiment, the invention provides synergistic combination of active nutrients, wherein the second active moiety is active form vitamin D analogue called ‘eldecalcitol’, which reduces osteo¬clastic bone resorption and lowers the level of inflammatory markers.

Eldecalcitol, or ELD is chemically known as (1S,2S,3S,5Z,7E)-2-(3-Hydroxypropoxy)-9,10-secocholesta-5,7,10-triene-1,3,25-triol. It has molecular formula C30H50O5, represented by Formula-II.

Formula-II

It is an analogue of calcitriol, i.e., 1-alpha,25-dihydroxy-2beta-(3-hydroxypropoxy) vitamin D3; it is a hydroxycalciol that is calcitriol with a 3-hydroxypropoxy group at position 2. It is a tetrol, a member of D3 vitamins and a hydroxycalciol.

In another embodiment, eldecalcitol synergistically improves bone health in combination with L-threonic acid chelated calcium.

In a particular manner, ELD suppresses osteoclastic bone resorption and increases bone mass density to a greater extent than other active metabolites of Vitamin D. Further, it improves BMD or bone strength by significantly reducing inflammatory biomarkers like C-reactive protein (CRP).

Eldecalcitol is even more effective than its counterparts, other vitamin D analogues in preventing vertebral and wrist fractures, and even falls, with osteoporotic patients with vitamin D insufficiencies.

Therefore, ELD has shown promising potential in treatment of osteoporosis when combined with calcium-L-threonate.

In yet another embodiment, the invention provides synergistic nutritional composition comprising therapeutically effective amount of eldecalcitol, which is present in the range of 0.1 to 10.0 mcg or µgm of total composition. The mcg or µgm unit can be interchanged with ‘IU’ unit (1 IU is the biological equivalent of 0.025 mcg eldecalcitol).

In another embodiment, the invention provides synergistic nutritional composition comprising therapeutically effective amount of eldecalcitol, which is present in the range of 0.0001 to 0.01 mg of total composition.

In another optional embodiment, the invention provides synergistic nutritional composition, wherein the synergy may improve by adding bioenhancer, which is mostly organic salt of magnesium, magnesium salts added to the composition are preferably organic acid salts including but not limited to aspartate, citrate, lactate, orotate, arginate, glycinate, malate. Magnesium aspartate is a chelated magnesium salt of aspartic acid, which exhibits high oral bioavailability and water solubiltiy compared to other magnesium salts.

It is evaluated that when calcium level is elevated in the blood, it stimulates the secretion of a hormone called calcitonin and suppresses the secretion of the parathyroid hormone (PTH). Secretion of parathyroid hormone is determined chiefly by serum ionized calcium concentration through negative feedback. Parathyroid cells express calcium-sensing receptors on the cell surface. PTH is secreted when calcium level is decreased, and calcitonin is secreted when serum calcium levels are elevated. PTH draws calcium out of the bones and deposits it in the soft tissues, while calcitonin increases calcium in bones and keeps it from being absorbed in soft tissues.

These hormones regulate the levels of calcium in the human bones and soft tissues therefore, directly related to bone function.

According to the invention the effective amount of magnesium regulates the homeostasis of calcium metabolism by suppressing PTH and stimulating calcitonin, it helps put calcium into the bones and preventing osteoporosis.

In another optional embodiment, the invention provides synergistic nutritional composition optionally comprising therapeutically effective amount of magnesium aspartate, present in the range of 1-500 mg of total composition.

In another voluntary embodiment, the invention provides synergistic nutritional composition optionally comprising therapeutically effective amount of magnesium aspartate, present in the range of 0.1 to 10% by weight of the total composition.

In a preferred embodiment, the invention provides synergistic micronutrient enriched nutritional composition(s) for treating metabolic bone disorders comprising a therapeutic blend of bioavailable chelates of macromineral and active form of fat-soluble vitamin along with pharmaceutically acceptable excipients, wherein the chelates of macromineral is calcium-L-threonate enriched with elemental calcium and the fat-soluble vitamin is eldecalcitol.

In another embodiment, the invention provides an antiresorptive synergistic nutritional composition for treating metabolic bone disorders comprising an exogenous blend of therapeutically effective amount of calcium-L-threonate enriched with elemental calcium and eldecalcitol along with pharmaceutically acceptable excipients.

In another embodiment, the invention provides antiresorptive synergistic micronutrients enriched nutritional composition, wherein the calcium-L-threonate is present in the range of 80-99% by weight of total composition and eldecalcitol is present in the range of 0.00005 to 0.001% by weight of total composition.

In another embodiment, the invention provides synergistic nutritional composition comprising calcium-L-threonate enriched with elemental calcium which is present in the range of 9-15% by weight of the total calcium-L-threonate.

In some embodiment, the invention provides antiresorptive synergistic micronutrients enriched nutritional composition, wherein the calcium-L-threonate is in present in the range of 100-1500 mg and eldecalcitol is present in the range of 0.0001 to 0.01 mg.

In another embodiment, the invention provides an oral anti-osteoporotic nutritional composition comprising synergistic combination of calcium-L-threonate present in the range of 80-99% and eldecalcitol present in the range of 0.00005 to 0.001% by weight of total composition.

In another embodiment, the invention provides stable, nutrient enriched, dietary supplement composed of synergistic combination of calcium-L-threonate and eldecalcitol and additionally magnesium aspartate; wherein the active moieties are working synergistically to control osteoporosis, particularly calcium-L-threonate enhances calcium serum level through optimal intestinal calcium absorption; In short, L-threonate chelate of calcium promotes proliferation, differentiation and mineralization functions of osteoblast; simultaneously or concomitantly active form of vitamin D analogue, i.e., eldecalcitol reduces osteo¬clastic bone resorption and inflammation thereof, whereas magnesium salt managing the synergy by regulating homeostasis of calcium metabolism. This overall synergistic effect increases bone mineral density and suppresses bone turnover or loss, result in fast recovery from bone diseases like osteoporosis.

The composition of the present invention can also include various minerals known to positively affect the health of bone. Such minerals include magnesium, copper, zinc, manganese, boron, fluoride, silicon, and chromium. These minerals can be present as pharmaceutically acceptable salts or, in the form of, as bioavailable chelates.

In another embodiment, the invention provides synergistic bioactive composition which is useful for treating metabolic bone disorders. Particularly the composition is useful for treating the disease conditions related to osteoporosis (postmenopausal osteoporosis, senile osteoporosis), bone fractures, hypocalcaemia, osteomalacia, rickets, osteitis fibrosa cystic, Paget's disease, tumor induced osteomalacia, fibrous dysplasia, osteogenesis imperfecta, osteopenia, hypocalcaemia, hypercalcaemia, marble bone disease, osteochondroma, bone demineralization, bone fracture, dysfunctional kidneys and like thereof.

As used herein, the term “therapeutically effective amount” is intended to mean the amount of active compounds of the present invention to be effective for treating osteoporosis through synergistic effect.

The term “pharmaceutically acceptable salt” refers to a salt prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic or organic acids preferably bioavailable forms, such as amino acid, or sugar acid chelates, which are well known in the art.

As used herein, the term “pharmaceutically acceptable carriers, diluents or excipients” is intended to mean, without limitation, any adjuvant, carrier, excipient, sweetening agent, diluents, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, or encapsulating agent, encapsulating polymeric delivery systems or polyethyleneglycol matrix, which is acceptable for use in the subject, preferably humans. Excipients may also include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, fragrances, glidants (flow enhancers), lubricants, preservatives, sorbents, suspending or dispersing agents, sweeteners, surfactant, anticaking agent, food additives, or waters of hydration.

As used herein, “comprising,” “including,” “containing,” “characterized by,” and grammatical equivalents thereof are inclusive or open-ended terms that do not exclude additional, unrecited elements or method steps.

In the context of the present invention, the terms “treatment” and the like refer to alleviate, mitigate, prophylaxis, attenuate, manage, regulate, modulate, reduce, control, moderate, reverse, prevent, inhibit, stabilize, or cure the pre-existing or occurrence of metabolic bone disorders like osteoporosis.

The present composition is used to maintain adequate bone mineralization in the subject in need thereof, means either the administration of the remedy to prevent occurrence or pre-existing cause of metabolic bone disorders like osteoporosis.

The “subject in need thereof” pertains to subject preferably mammal, more preferably human victimised with pre-existing or onset symptoms of metabolic bone disorders, like bone damage, bone fracture, bone loss, decalcification of bone, softening of bones, bone demineralization and like thereof.

Remarkably, the present synergistic composition is non-hazardous, non-toxic, stable, cost-effective, nutrient enriched and safe for human consumption without any side effects, therefore, the present synergistic nutritional composition can also be administered under preventive therapy by healthy subjects.

The therapeutically effective amount of such actives will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.

Thus, a "therapeutically effective" amount is an amount that reduces the risk, potential, possibility or occurrence of a disease or disorder, or provides advanced alleviation, mitigation, and/or reduction or restoration of at least one indicator/biomarker (e.g., blood or serum CRP level), and/or decrease in at least one clinical symptom of metabolic bone disorders (e.g., osteoporosis). Moreover, the present composition significantly improves BMD.

In another embodiment, the invention relates to synergistic composition, which can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. The preferable route of administration includes but not limited to sublingual, rectal, topical, parenteral, or oral.

Therapeutic (prescription) supplements are generally administered by the oral or parenteral or topical routes for curing osteoporosis. The therapeutic administration of materials of the present invention may be in conjunction with other therapies.

Further, the present synergistic nutritional composition can be administered to subject in a form suitable for oral use, such as a tablet, capsule (in the form of delayed release, extended release, sustained release, enteric coated release); hard gelatin capsules, soft gelatin capsules in an oily vehicle, granulate for sublingual use, effervescent tablets, aqueous or oily solution, suspension or emulsion, encapsulate, matrix, coat, beadlets, nanoparticles, caplet, granule, particulate, agglomerate, spansule, chewable tablet, lozenge, troche, solution, suspension, rapidly dissolving film, elixir, gel, as tablets, pellets, granules, capsules, lozenges, aqueous or oily solutions, suspensions, emulsions, sprays or reconstituted dry powdered form with a liquid medium or syrup. It can be applied topically in the form of cream, lotion, foam, powder, transdermal patch, ointment, gel, balm, paste, tincture. Further, the composition can be formulated for parenteral use including intravenous, subcutaneous, intramuscular, intravascular, infusion, intraperitoneal, or intradermal.

In some embodiment, the pharmaceutically acceptable carriers, diluents or excipients are selected from the group consisting of adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, or encapsulating agent, such as a liposome, cyclodextrins, encapsulating polymeric delivery systems or polyethylene glycol matrix, which is acceptable for use in the subject, preferably humans. Excipients may also include, for example: anti-adherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, fragrances, glidants (flow enhancers), lubricants, preservatives, sorbents, suspending or dispersing agents, sweeteners, surfactant, anticaking agent, food additives, or waters of hydration.

In some embodiment of the invention, the diluents are selected from starches, hydrolyzed starches, and partially pregelatinized starches, anhydrous lactose, cellulose powder, lactose monohydrate, and sugar alcohols such as sorbitol, xylitol and mannitol, silicified microcrystalline cellulose, ammonium alginate, calcium carbonate, calcium lactate, dibasic calcium phosphate (anhydrous/ dibasic dehydrate/ tribasic), calcium silicate, calcium sulfate, cellulose acetate, corn starch, pregelatinized starch, dextrin, ß-cyclodextrin, dextrates, dextrose, erythritol, ethyl cellulose, fructose, fumaric acid, glyceryl palmitostearate, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium-chain triglycerides, polydextrose, polymethacrylates, sodium alginate, sodium chloride, sterilizable maize, sucrose, sugar spheres, talc, trehalose, xylitol, vehicles like petrolatum, dimethyl sulfoxide and mineral oil or the like.

In some embodiment of the invention, the amount of diluent is present in the range of 1% to 30% of total weight of the composition/formulation.

In some embodiment, the binder is selected from disaccharides such as sucrose, lactose, polysaccharides and their derivatives like starches, cellulose or modified cellulose such as microcrystalline cellulose and cellulose ethers such as hydroxypropyl cellulose (HPC); hydroxypropyl methyl cellulose (HPMC); sugar alcohols such as xylitol, sorbitol or mannitol; protein like gelatin; synthetic polymers such as polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), starch, acacia, agar, alginic acid, calcium carbonate, calcium lactate, carbomers, carboxymethylcellulose sodium, carrageenan, cellulose acetate phthalate, chitosan, copovidone, corn starch, pregelatinized starch, cottonseed oil, dextrates, dextrin, dextrose, ethylcellulose, guar gum, hydrogenated vegetable oil, mineral oil, hydroxyethyl cellulose, hydroxymethyl cellulose hydroxyl ethylmethyl cellulose, hydroxypropyl cellulose, inulin, cellulose, methyl cellulose, polyvinylpyrrolidone and polyethylene glycol, lactose, liquid glucose, hypromellose, magnesium aluminum silicate, maltodextrin, maltose, methyl-cellulose, microcrystalline cellulose, pectin, poloxamer, polydextrose, polymethacrylates, povidone, sodium alginate, stearic acid, sucrose, sunflower oil, various animal vegetable oils, and white soft paraffin, paraffin, flavorants, colourants and wax.

In some embodiment of the invention, the amount of binder is present in the range of 0.1 to 25% of total weight of the composition/formulation.

In further embodiment, the lubricant is selected from magnesium stearate, ascorbyl palmitate zinc stearate, calcium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium lauryl sulfate, medium-chain triglycerides, mineral oil, myristic acid, palmitic acid, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, potassium, or sodium benzoate or the like.

In some embodiment of the invention, the amount of lubricant in the composition/formulation is present in the range of 0.1% to 5.0% of the total weight of the composition/formulation.

In another embodiment, the solubilizing agent is selected from polysorbate 80, sodium lauryl sulfate, anionic emulsifying wax, nonionic emulsifying wax, glyceryl monooleate, phospholipids, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, polyoxylglycerides, sorbitan esters, triethyl citrate, vitamin E, polyethylene glycol succinate, microcrystalline cellulose, carboxymethylcellulose sodium, diethanolamine, ethylene glycol palmitostearate, glycerin monostearate, hypromellose, hypromellose, acetate succinate, lecithin, polyethylene alkyl ethers, aluminum oxide, poly(methylvinyl ether/maleic anhydride), calcium carbonate, crospovidone, cyclodextrins, fructose, hydroxpropyl betadex, oleyl alcohol, povidone, benzalkonium chloride, benzethonium chloride, benzyl alcohol, benzyl benzoate, cetylpyridinium chloride, inulin, meglumine, poloxamer, pyrrolidone, sodium bicarbonate, starch, stearic acid, sulfobutylether beta cyclodextrin, tricaprylin, triolein, docusate sodium, glycine, alcohol, self-emulsifying glyceryl monooleate, cationic benzethonium chloride, cetrimide, xanthan gum, lauric acid, myristyl alcohol, butylparaben, ethylparaben, methylparaben, propylparaben, sorbic acid or the like.

In some embodiment of the invention, the amount of solubilizing agent or surfactant is present in the range of 0.1% to 10%, preferably 0.1% to 5.0% of the total weight of the composition/formulation

In some embodiment, the glidant is selected from colloidal silicon dioxide, magnesium stearate, fumed silica (colloidal silicon dioxide), starch, talc, calcium phosphate tribasic, cellulose powdered, hydrophobic colloidal silica, magnesium oxide, zinc stearate, magnesium silicate, magnesium trisilicate, silicon dioxide or the like.

In some embodiment of the invention, the amount of glidant present in the composition/formulation ranges from 0.1% to 5.0% of the total weight of the composition/formulation.

In some embodiment, the complexing/chelating agent is selected from dimercaprol, penicillamine, trientine, edetate, ethylenediaminetetraacetic acid, trisodiumnitrilotriacetate, ethylenediamine tetra methylenephosphonicacid, hexamethylenediamine tetra methylenephosphonic acid, diethylenetriamine penta methylenephosphonic acid, diethylenetriaminepentaacetic acid, diazoaminobenzene, ethyleneglycol-bis-(aminoethylether)tetra-acetic acid, cyclodextrin, zinc, trientine or the like.

In some embodiment of the invention, the amount of complexing/chelating agent present in the composition/formulation ranges from 0.1% to 5.0% of the total weight of the composition/formulation.

In some embodiment of the inventions, the stabilizers are selected from the group consisting of alginate, agar, carrageen, gelatin, guar gum, gum arabic, locust bean gum, pectin, starch, xanthan gum, trehalose and likewise.

In some embodiment of the invention, the amount of stabilizers in the composition/formulation ranges from 0.1% to 5.0% of the total weight of the composition/formulation.

In some embodiment, the solvent is selected from water, alcohol, isopropyl alcohol, propylene glycol, mineral oil, benzyl alcohol, benzyl benzoate, flavored glycol, carbon dioxide, castor oil, corn oil (maize), cottonseed oil, dimethyl ether, albumin, dimethylacetamide, ethyl acetate, ethyl lactate, medium-chain triglycerides, methyl lactate, olive oil, peanut oil, polyethylene glycol, polyoxyl, castor oil, propylene carbonate, pyrrolidone, safflower oil, sesame oil, soybean oil, sunflower oil, water-miscible solvents, organic polar or non-polar solvents or mixtures thereof.

In some embodiment of the invention, the amount of solvent in the composition/formulation is used in a quantity sufficient to make the weight of the composition/ formulation 100% by weight.

The additional additives include polymer, a plasticizer, a sweetener, and a powdered flavor, preservative, colorant, surfactant, and other excipients. The powdered flavor composition includes a flavourant associated with a solid carrier, coating materials are used, for example synthetic polymers, shellac, corn protein (zein) or other polysaccharides, gelatin, fatty acids, waxes, shellac, plastics, and plant fibers and like thereof. The additives are used in the range of 1 to 20% w/w of unit dose.

In another embodiment, the invention provides the oral antiresorptive composition comprising synergistic combination of calcium-L-threonate and eldecalcitol along with pharmaceutical excipients, wherein the pharmaceutically acceptable excipients are selected from the group consisting of a diluent present in a range of 1 to 30%; a binder present in a range of 0.1 to 25%; a lubricant present in a range of 0.1 to 5.0 %; a glidant present in a range of 0.1 to 5.0%; a complexing agent/chelating agent present in the range of 0.1 to 5.0 %; an additive present in a range of 0.1 to 10%; a surfactant present in a range of 0.1 to 5.0%; a stabilizer present in a range of 0.1 to 5.0% by weight of total composition.

In some embodiment, the present antiresorptive composition/formulation is formulated for oral administration. Specifically, the solid medicinal compositions, for example, can be in the form of tablets, capsules, pills, hard capsules filled with liquids or solids, soft capsules, sachets, powders, granules, suspensions, solutions, or modified release formulations. Formulations of the present invention suitable for oral administration can be presented as discrete units such as capsules (e.g., soft-gel capsules, hard-gel capsule), cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid, syrup; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.

Further the present composition can be formulated in the form of age-appropriate pediatric oral dosage forms such as syrup, minitablets, chewable formulations, orodispersible films orodispersible tablets.

The magnitude of a prophylactic or therapeutic dose typically varies with the nature and severity of the condition to be treated and the route of administration. The dose, and perhaps the dose frequency, will also vary according to the age, body weight and response of the individual patient. In general, the total daily dose (in single or divided doses) ranges from about 1 mg per day to about 5000 mg per day, preferably about 50 mg per day to about 3000 mg per day.

The synergistic nutritional compositions, comprising specific combination of calcium-L-threonate and eldecalcitol and salts thereof along with pharmaceutically acceptable excipients or carriers, wherein the effective unit dose for oral administration is formulated in the range of 100 to 800 mg.

It is further recommended that children, patients over 60 years old, initially receive low doses and that the dosage be titrated enriched on individual physiological responses and/or pharmacokinetics. It can be necessary to use dosages outside these ranges in some cases, as will be apparent to those in the art.

The present composition can be used as infant formula as well as adult formula by varying the concentration of active ingredients.

Further, it is noted that the dietician or nutritionist or certified physician knows how and when to
interrupt, adjust or terminate therapy in conjunction with an individual patient's response.

Further, it is noted that the dietician or nutritionist or certified physician knows how and when to interrupt, adjust or terminate therapy in conjunction with an individual patient's response.

The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention, and does not pose a limitation on the scope of the invention unless otherwise claimed.

While in the foregoing specification this invention has been described in relation to certain embodiments thereof, and many details have been put forth for the purpose of illustration, it will be apparent to those skilled in the art that the invention is susceptible to additional embodiments and that certain of the details described herein can be varied considerably without departing from the basic principles of the invention.

The present invention is not to be limited in terms of the particular embodiments described in this application, which are intended as single illustrations of individual aspects of the invention. Functionally equivalent compositions and treatments within the scope of the invention, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing description and examples. Such modifications and variations are intended to fall within the scope of the appended claims. The contents of each reference, patent and patent application cited in this application is hereby incorporated by reference in its entirety.

Examples:

Example 1:
Composition 1: Synergistic Blend
Blend
Calcium-L-threonate
[Elemental Ca- 9-15%] 250-1000mg
Eldecalcitol 0.0001 – 0.01mg

Composition 2: Tablet/Capsule
Ingredient % w/w unit dose
Calcium-L-threonate
[Elemental Ca- 10-13%] 80-99%
Eldecalcitol 0.00005 - 0.001%
Excipient 1-20%
Average Weight 100%
Average weight in mg 500-800 mg

Composition 3: Tablet/Capsule
Ingredient mg unit dose
Calcium-L-threonate
[Elemental Ca- 10-13%] 500
Eldecalcitol 0.0001
Diluents 1-10
Binders 0.5-5
Glidants 0.5-10
Lubricants 0.5-10
Stabilizers 0.5-10
Additives 0.5-10
Solvents QS
Average weight 510-600

Composition 4: Tablet/Capsule
Ingredient mg per unit dose
Calcium-L-threonate
[Elemental Ca- 10-13%] 800
Eldecalcitol 0.00025
Silicon dioxide 1-10
Hydroxypropyl Methylcellulose 1-10
Microcrystalline Cellulose 1-20
Zinc Stearate 1-10
PVP K-30 5-10
Cyclodextrin 1-10
Polysorbate 80 1-10
Ascorbyl palmitate 1-10
Mannitol 1-20
Propylene Glycol QS
Water QS
Average weight 850-900 mg

Composition 5: Tablet/Capsule
Ingredient mg per unit dose
Calcium-L-threonate
[Elemental Ca- 12%] 775
Eldecalcitol 0.0005
Sodium ascorbate 1-10
Microcrystalline Cellulose 2-20
Silicon dioxide 5-15
Hydroxypropyl Methylcellulose 2-10
Magnesium aspartate 2-10
PVP K-30 5-10
Talc 1-10
Tween 80 1-10
Stearic acid 1-5
hydroxypropyl-ß-cyclodextrin 1-10
Mannitol 5-20
Alcohol QS
Water QS
Average weight 725-800 mg

Composition 6: Tablet/Capsule
Ingredient mg per unit dose
Calcium-L-threonate
[Elemental Ca- 10-13%] 500
Eldecalcitol 0.00075
Sodium ascorbate 1-10
Microcrystalline Cellulose 2-20
Silicon dioxide 5-15
Hydroxypropyl Methylcellulose 2-10
Magnesium stearate 2-10
PVP K-30 5-10
Talc 1-10
Tween 80 1-10
Mannitol 5-20
Alcohol QS
Water QS
Average weight 510-600 mg

Composition 7: Tablet/Capsule
Ingredient mg per unit dose
Calcium-L-threonate
[Elemental Ca- 10-13%] 250
Eldecalcitol 0.0001
Microcrystalline Cellulose 1-10
Silicon dioxide 1-10
Hydroxypropyl Methylcellulose 1-10
Sodium ascorbate 1-10
Magnesium aspartate 1-20
Polyvinylpyrrolidone 1-10
Talc 1-10
Polysorbate 20 1-10
Starch 1-10
Mannitol 1-10
IPA QS
Water QS
Average weight 250-300mg

Composition 8: Tablet/Capsule
Ingredient mg per unit dose
Calcium-L-threonate
[Elemental Ca- 10-13%] 500
Eldecalcitol 0.0002
Microcrystalline Cellulose 1-10
Silicon dioxide 1-10
Hydroxypropyl Methylcellulose 1-10
Magnesium Stearate 2-10
Polyvinylpyrrolidone 1-10
Talc 1-10
Polysorbate 20 1-10
Mannitol 1-10
IPA QS
Water QS
Average weight 520-550 mg

Example 2:
Bone Mineral Density Study
A randomized double blinded case-controlled study of the effects of Shelcal, Placebo, Calcium L-threonate, Eldecalcitol individually and in combination therapy (Calcium-L-threonate + Eldecalcitol) on bone mineral density in Osteopenia/Osteoporotic chronic spinal cord injury patients.

Study Design: Randomized, Parallel Group, Placebo Controlled Trial
Sample Size: 225
Indication: Bone Mineral Density
Treatment Duration: 60 days
Investigational Product: Calcium-L-threonate, Eldecalcitol
Treatment Regimen:

Table 1
Treatment Group Number of Subject
Control (Placebo) 45
Reference (Shelcal) 45
Test 1 (Calcium L Threonate) 45
Test 2 (Eldecalcitol) 45
Combination (Calcium-L- threonate + Eldecalcitol) 45

Table 2: Group, dose and treatment
Group Dose and Treatment Parameters Analysed
Control (Placebo) Placebo

BMD

Reference (Shelcal) Treated with shelcal 500mg
Test 1- Calcium L- threonate CaLT-775 mg
Test-2 – Eldecalcitol ELD-0.5 mcg
Combination- CaLT+ ELD CaLT-775 mg + ELD-0.5 mcg
Number of Visits: 2 visits (Screening [Baseline visit], 45 days, after 60 days follow-up visit)
Primary Objective: Change in bone mineral density as measured by DEXA scan 45 days after administration of test group regimen.
Secondary Objective: To assess the safety profile of test groups in osteopenia and osteoporosis and overall compliance to the drug treatment.
Inclusion Criteria: Adult male and female, in between 18 years to 55 years old both inclusive; Patients recently diagnosed with osteopenia and osteoporosis, with the signs and symptoms like pain in bone.
Exclusion Criteria: Features of non traumatic spinal cord injury, renal failure, heterotrophic ossification, pressure sores with osteomyelitis or history of treatment for osteoporosis.

The efficacy has been evaluated with the improvement bone marrow density with respective of treatment groups and reduction in severity assessed by Visual Analog Scale (VAS) relief from clinical symptoms of Osteopenia/Osteoporosis.

Study Procedure:
All eligible subjects who meet the Inclusion and Exclusion Criteria were enrolled into the study. They visited the study site on screening (Baseline Day) and Day 45 (end of treatment), safety follow-up done by Physician at day 60.
Total 225 subjects were enrolled. Subjects BMD was recorded at the baseline and day 45 to compare improvement of BMD. Subjects in study were equally divided into 5 groups and received respective investigational product as listed in Table 1 and advised to take prescribed dose once in day. Physical examination and demographics were recorded at the screening time and day 45.

Vitals were recorded on screening time and day 45. Adverse events were monitored up to 60 days and recorded on day 30 and day 60. A buffer period of ±3 days was allowed for every visit and beyond which it was considered as a protocol deviation.

Discussion:
All the subjects who meet the eligibility criteria and had received at least one dose of study medication were included in the safety and efficacy analysis. Patient data from all the centers was pooled together and analyzed using paired t-test.
Demographic data such as age, gender, weight, vitals was summarized using descriptive statistics. Changes in VAS score from (Screening) baseline to end of treatment were analyzed using paired t-test. All other secondary efficacy and safety end points were summarized using descriptive statistics. All statistical tests were performed at 5% level of significance.

Result:
It was observed that T-score for control group indicated osteoporotic condition, where the combination of CaLT and ELD showed synergistic effect with significant fall in T-score as compared with individual ingredients. Further the combination found to be more effective than the marketed sample i.e., Shelcal for enhancing bone mineral density.

Table 3: Total Comparative BMD values
Control Shelcal CaLT ELD CaLT+ELD
Mean -2.54 -1.27 -1.31 -1.32 -0.65
Standard Error 0.07 0.09 0.08 0.09 0.07
Median -2.80 -1.58 -1.60 -1.63 -0.73
Standard Deviation 0.48 0.58 0.53 0.58 0.45
Sample Variance 0.23 0.34 0.28 0.33 0.20
Kurtosis -1.59 -1.54 -1.56 -1.56 0.33
Skewness 0.47 0.47 0.49 0.46 0.97
Range 1.35 1.76 1.57 1.70 1.64
Minimum -3.10 -2.01 -2.02 -2.07 -1.28
Maximum -1.75 -0.25 -0.45 -0.36 0.36
Sum -114.15 -56.95 -58.95 -59.44 -29.20
Count 45.00 45.00 45.00 45.00 45.00

Table 4: Observed BMD values in g/cm3
Control Shelcal Calcium
L Threonate Eldecalcitol Calcium
L-Threonate + Eldecalcitol
BMD (T-Score) -2.54 -1.27 -1.31 -1.32 -0.65
Standard Error 0.07 0.09 0.08 0.09 0.07
Median -2.80 -1.58 -1.60 -1.63 -0.73
Standard Deviation 0.48 0.58 0.53 0.58 0.45

Conclusion:
The T-score observed for individual ingredients CaLT and ELD indicated low bone density (Osteopenia), where combination surprisingly improved bone strength with value -0.65 g/cm3. It is concluded that the present composition shows significant results with synergistic effect, the composition administration ameliorates recovery of bone mass and normalization of bone turnover. Moreover, the present composition arrest bone loss better than marketed sample (shelcal).
,CLAIMS:1. An antiresorptive synergistic nutritional composition for treating metabolic bone disorders comprising: an exogenous blend of a therapeutically effective amount of calcium-L-threonate and eldecalcitol along with pharmaceutically acceptable excipients.

2. The antiresorptive synergistic nutritional composition as claimed in claim 1, wherein the calcium-L-threonate is present in a range of 80-99% and the eldecalcitol is present in a range of 0.00005 to 0.001% by weight of the total composition.

3. The antiresorptive synergistic nutritional composition as claimed in claim 1, wherein elemental calcium is present in a range of 9-15% by weight of the total calcium-L-threonate.

4. The antiresorptive synergistic nutritional composition as claimed in claim 1, wherein the calcium-L-threonate is present in a range of 100-1500 mg.

5. The antiresorptive synergistic nutritional composition as claimed in claim 1, wherein the eldecalcitol is present in a range of 0.0001 to 0.01 mg.

6. The antiresorptive synergistic nutritional composition as claimed in claim 1, wherein the pharmaceutically acceptable excipients are selected from a group consisting of a diluent present in a range of 1 to 30%; a binder present in a range of 0.1 to 25%; a lubricant present in a range of 0.1 to 5.0%; a glidant present in a range of 0.1 to 5.0%; a complexing agent/chelating agent present in a range of 0.1 to 5.0%; an additive present in a range of 0.1 to 10%; a surfactant present in a range of 0.1 to 5.0%; and a stabilizer present in a range of 0.1 to 5.0%, by weight of the total composition.

7. The antiresorptive synergistic nutritional composition as claimed in claim 1, wherein a bone mineral density T-score is -0.65 gm/cm3.

8. The antiresorptive synergistic nutritional composition as claimed in claim 1, wherein the composition comprises magnesium aspartate present in a range of 0.1 to 10% by weight of the total composition.

9. The antiresorptive synergistic nutritional composition as claimed in claim 1, wherein an effective unit dose for oral administration is formulated in a range of 100 to 800 mg.

10. The antiresorptive synergistic nutritional composition as claimed in claim 9, wherein the oral formulation comprises tablets, enteric coated tablets, modified release/sustained release/extended release tablets, capsules, soft-gel capsules, hard-gel capsules, pills, hard capsules filled with liquids or solids, caplets, sachets, powders, granules, pellets, suspensions, syrup, solutions, liquid emulsion, minitablets, chewable tablets, candies, orodispersible films, orodispersible tablets, agglomerates, spansules, lozenges, troche, solution, suspension, rapidly dissolving film, elixir, gel, sprays or reconstituted dry powdered form with a liquid medium.