Combination therapy of osteoporosis

Abstract

The present invention provides methods of treating and managing osteoporosis. Specifically, the invention provides treatment of osteoporosis by co-administering RANKE inhibitor such as denosumab and stabilized ACC.

Description

[0001] COMBINATION THERAPY OF OSTEOPOROSIS FIELD OF THE INVENTION

[0002] The present invention relates to improved management and treatment of osteoporosis implementing co-administration of stabilized amorphous calcium carbonate and denosumab.

[0003] BACKGROUND OF THE INVENTION

[0004] Osteoporosis is a systemic metabolic disease caused by bone resorption greater than bone remodeling imbalance due to bone formation. Osteoporosis can be classified into primary osteoporosis, secondary osteoporosis and idiopathic osteoporosis according to reason classification. Post-menopausal osteoporosis belongs to primary osteoporosis, which occurs for 5 to 10 years post-menopausal. The bone steady state of human body is maintained by osteoclast and osteoblast, the osteoclast is in charge of bone absorption, and the osteoblast is in charge of bone formation. Bone marrow monocytes (BMMs) are hematopoietic stem cells that can be differentiated into osteoclasts. When the bone is unbalanced, the BMMs form osteoclast cells are increased, causing bone metabolic diseases such as osteoporosis, and seriously affecting the living standard of the patient.

[0005] WO 2005 / 115414, WO 2008 / 041236, WO 2009 / 053967, and WO 2013088440 to the Applicant disclose use of amorphous calcium carbonate in prevention of bone resorption, increasing bone density and treating osteoporosis.

[0006] Denosumab is a fully human monoclonal IgG antibody that binds with high affinity and specificity to the receptor Activator of Nuclear Factor KB Ligand (RANKL). There are two commercial denosumab products, Prolia® and Xgeva® (Amgen Inc.), which contain 60 mg / ml and 70 mg / mL of denosumab, respectively. Prolia® and Xgeva® are both parenteral formulations suitable for administration by subcutaneous injection. The lower concentration denosumab product, Prolia®, is indicated for treatment of osteoporosis on a dosing schedule of one dose every six months, with each 1 mL dose containing 60 mg denosumab, 47 mg sorbitol, 1 mg acetate, 0.1 mg polysorbate 20, and sodium hydroxide for adjusting to pH 5.2, in water for injection. Xgeva® is indicated for the treatment of skeletal events associated with cancer, or cancerous tumors, on a dosing schedule of one dose every four weeks, with each 1.7 mL dose containing 120 mg denosumab, 78.1 mg sorbitol, 1.8 mg acetate, 0.17 mg polysorbate 20, and sodium hydroxide for adjusting to pH 5.2, in water for injection. Although denosumab effectively reduces bone resorption and increases BMD, the magnitude of hip BMD increase during the first year of therapy is typically limited(approximately 3% at the total hip). Cortical bone response remains clinically important and variable.

[0007] Treatment of osteoporosis is associated with calcium consumption. However, its necessity is not unequivocal. Jeong (J. Clin. Med. 2023, 12, 6904. https: / / doi.org / 10.3390 / jcml2216904) noticed that calcium supplementation did not change bone density, bone marker during treatment with denusomab. Several evidences of denosumab-induced was reported (Strickling and Wilkowski, Case Rep Nephrol Dial 2019;9:33-41).

[0008] There is still a need for improved methods of managing and treating osteoporosis.

[0009] SUMMARY OF THE INVENTION

[0010] In one aspect the present invention provides a composition comprising stabilized ACC, for use in enhancing the efficacy of a receptor Activator of Nuclear Factor KB Ligand (RANKL) therapy, the use comprises co-administering the composition comprising stabilized ACC and the RANKL inhibitor. In some embodiments, the denosumab therapy is selected from osteoporosis, cancer-related bone loss, bone metastases or giant cell tumor of bone. In some embodiments, the denosumab therapy is treatment of osteoporosis.

[0011] In another aspect, the present invention provides a pharmaceutical combination comprising a RANKL inhibitor and stabilized amorphous calcium carbonate (ACC), for use in treating osteoporosis, wherein the use comprises co-administering the RANKL inhibitor and stabilized ACC.

[0012] In another aspect, the present invention provides a composition comprising stabilized ACC, for use in enhancing a bone mineral density in a subject receiving a RANKL inhibitor, the use comprising co-administering to said subject stabilized amorphous calcium carbonate and RANKL inhibitor.

[0013] In some any one of the above embodiments, the RANKL inhibitor is denosumab. According to any one of aspects and embodiments of the present invention, the coadministering provides a synergistic effect.

[0014] According to any one of aspects and embodiments of the present invention, the subject suffers from oncology-associated bone disease or condition. In some embodiments, the oncology-associated bone disease or condition comprises metastatic cancer involving bone.

[0015] According to any one of aspects and embodiments of the present invention, the use or the method comprises at least one of (i) enhancing cortical bone density, (ii) increasing total hip bone mineral density by at least 4% after 12 months.According to any one of aspects and embodiments of the present invention, stabilized ACC is administered daily in a dose corresponding to from 200 to 2000 mg of calcium / day. In some embodiments, stabilized ACC is administered in a dose corresponding to from 600 to 1800 mg of calcium / day. According to any one of aspects and embodiments, the ACC is formulated as tablets, capsules, sachets, or controlled-release oral dosage forms.

[0016] DETAILED DESCRIPTION OF THE INVENTION

[0017] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. In case of conflict, the patent specification, including definitions, will control.

[0018] The present invention is based on an unexpected observation that stabilized ACC significantly enhances therapeutic efficacy of a RANKL inhibitor. Specifically, it was shown that co-administering of stabilized ACC and the RANKL inhibitor denosumab synergistically enhanced bone mineral density of hips and lumbar spine after 1 year. As shown in the examples, bone mineral density of hip increased by about 6.3% versus standard increase of about 3% when a subject is treated with denosumab in combination with standard crystalline calcium carbonate. Further a long-term increase in lumbar, neck and hip BMD was observed.

[0019] According to one aspect, the present invention provides a method of enhancing the efficacy of a therapy by a receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor, the method comprises co-administering RANKL inhibitor and stabilized amorphous calcium carbonate (ACC). In some embodiments, the RANKL inhibitor is denosumab. In some embodiments, the therapy comprises treating osteoporosis, cancer-related bone loss, bone metastases or giant cell tumor of bone. In some embodiments, the therapy is treating osteoporosis. In some embodiments, the method provides a synergistic effect. In some embodiments, the subject suffers from oncology-associated bone disease. In some embodiments, the oncology-associated bone disease comprises metastatic cancer involving bone such as metastatic breast cancer.

[0020] According to another aspect, the present invention provides a method for treating osteoporosis, the method comprises co-administering human monoclonal antibodies that target and inhibit receptor activator of nuclear factor kappa-B ligand (RANKL) and stabilized amorphous calcium carbonate. According to some embodiments, the human monoclonal antibody that targets and inhibits RANKL is denosumab.According to another aspect, the present invention provides a method for improving the efficacy of the treatment of osteoporosis by a RANKL inhibitor such as denosumab, the method comprises co-administering the RANKL inhibitor such as denosumab and stabilized amorphous calcium carbonate.

[0021] According to another aspect, the present invention provides a method of enhancing a bone mineral density in a subject receiving a RANKL inhibitor comprising administering to said subject stabilized amorphous calcium carbonate. In some embodiments, the method provides a synergistic effect.

[0022] According to another aspect, the present invention provides a composition comprising stabilized ACC, for use in enhancing the efficacy of RANKL inhibitor therapy, the use comprises co-administering the composition comprising stabilized ACC and a RANKL inhibitor. In some embodiments, the RANKL inhibitor is denosumab. In some embodiments, the therapy comprises treating osteoporosis, cancer-related bone loss, bone metastases or giant cell tumor of bone. In some embodiments, the therapy is treating osteoporosis. In some embodiments, the use provides a synergistic effect. Therefore, in some embodiments, the present invention provides a composition comprising stabilized ACC, for use in enhancing the efficacy of a RANKL inhibitor such as denosumab therapy, the use comprises coadministering the composition comprising stabilized ACC and a RANKL inhibitor such as denosumab. In some embodiments, the present invention provides composition comprising stabilized ACC, for use in enhancing treating osteoporosis by denosumab therapy, the use comprises co-administering the composition comprising stabilized ACC and denosumab. In some embodiments, the method provides a synergistic effect. In some embodiments, the subject suffers from oncology-associated bone disease. In some embodiments, the oncology-associated bone disease comprises metastatic cancer involving bone. In some embodiments, the oncology-associated bone disease comprises metastatic breast cancer involving bone.

[0023] According to some embodiments, the present invention provides a therapeutic combination comprising a RANKL inhibitor such as denosumab and stabilized amorphous calcium carbonate for use in improving the efficacy of the treatment of osteoporosis.

[0024] According to some embodiments, the present invention provides a pharmaceutical combination comprising denosumab and stabilized amorphous calcium carbonate (ACC), for use in treating osteoporosis, wherein the use comprises co-administering denosumab and a stabilized ACC.

[0025] According to other embodiments, the present invention provides a composition comprising stabilized ACC, for use in enhancing a bone mineral density in a subjectreceiving a RANKL inhibitor, the use comprising co-administering to said subject stabilized amorphous calcium carbonate and RANKL inhibitor. In some embodiments, the RANKL inhibitor is denosumab. In some embodiments, the use provides a synergistic effect.

[0026] The below provided embodiments and definitions refer to any one of the aspects of the present invention.

[0027] The terms "improving the efficacy" and "enhancing the efficacy" encompasses improving at least one parameter of a disease or condition such as osteoporosis in comparison to treatment with denosumab or in comparison to the treatment with denosumab and calcium supplement other than stabilized ACC.

[0028] According to some embodiments, the co-administering provides a synergistic effect. According to some embodiments, the co-administering provides an additive effect.

[0029] According to some embodiments, the stabilized ACC is administered in a dose corresponding to from 200 to 2000 mg of calcium / day. According to some embodiments, the stabilized ACC is administered in a dose corresponding to from 200 to 1800 mg of calcium / day. According to some embodiments, the stabilized ACC is administered in a dose corresponding to from 400 to 1600 mg of calcium / day. According to some embodiments, the stabilized ACC is administered in a dose corresponding to from 400 to 1200 mg of calcium / day. According to some embodiments, the stabilized ACC is administered daily in a dose corresponding to from 600 to 1200 mg of calcium / day. According to some embodiments, the stabilized ACC is administered in a dose corresponding to from 800 to 1200 mg of calcium / day. According to some embodiments, the stabilized ACC is administered in a dose corresponding to about 1000 mg of calcium / day. According to some embodiments, the stabilized ACC is administered in a dose corresponding to from 1000 to 2000 mg of calcium / day. According to some embodiments, the stabilized ACC is administered in a dose corresponding to from 800 to 2000 mg of calcium / day. According to some embodiments, the stabilized ACC is administered in a dose corresponding to from 1200 to 1800 mg of calcium / day. According to some embodiments, the stabilized ACC is administered in a dose corresponding to from 1000 to 1800 mg of calcium / day. According to some embodiment, stabilized ACC is formulated as a pharmaceutical, nutraceutical or cosmetic composition, as a food supplement or a medical food. According to some embodiments, the stabilized ACC is administered daily.

[0030] According to some embodiment, the method or use comprises administering at least two doses of denosumab. According to some embodiment, the method or use comprisesadministering at least 3 doses of denosumab. According to some embodiments, the method or use comprises administering at least 4 doses of denosumab.

[0031] According to some embodiment, the method or use comprises administering stabilized ACC for at least 1 year. According to some embodiment, the method or use comprises administering stabilized ACC for at least 1.5 years. According to some embodiment, the method or use comprises administering stabilized ACC for at least 2 years. According to some embodiment, the method or use comprises administering stabilized ACC for at least 2.5 years. According to some embodiment, the method or use comprises administering stabilized ACC for at least 3 years.

[0032] For purposes of this disclosure, “osteoporosis” refers to a systemic skeletal disease characterized by reduced bone mass, deterioration of bone microarchitecture, and increased susceptibility to fracture. Osteoporosis can be diagnosed using bone mineral density criteria, such as a T-score of < -2.5 relative to a young healthy adult reference population, and may include both primary and secondary forms of the disease.

[0033] The term “therapeutically effective amount” of a drug or agent is an amount of a drug or an agent that, when administered to a subject will have the intended therapeutic effect, e.g. antibacterial effect. The full therapeutic effect does not necessarily occur by the administration of one dose and may occur only after the administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. The precise effective amount needed for a subject will depend upon, for example, the subject's size, health and age, the nature and extent of the cognitive impairment, and the therapeutics or combination of therapeutics selected for administration, and the mode of administration. The skilled person can readily determine the effective amount for a given situation by routine experimentation.

[0034] The term “treating” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results include, but are not limited to, ameliorating, abrogating, substantially inhibiting, slowing or reversing the progression of a disease, condition or disorder, substantially ameliorating or alleviating clinical or esthetical symptoms of a condition, substantially preventing the appearance of clinical or esthetical symptoms of a disease, condition, or disorder, and protecting from harmful or annoying symptoms. Treating further refers to accomplishing one or more of the following: (a) reducing the severity of the disorder; (b) limiting the development of symptoms characteristic of the disorder(s) being treated; (c) limiting worsening of symptoms characteristic of the disorder(s) being treated; (d) limiting recurrence of the disorder(s) inpatients that have previously had the disorder(s); and / or (e) limiting recurrence of symptoms in patients that were previously asymptomatic for the disorder(s).

[0035] According to some embodiments, the use and method comprises administering the stabilized ACC to the subject. The term "administering” or “administration of’ a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. According to some embodiments, the compound or an agent can be administered locally and has a local effect. According to some embodiments, the compound or an agent may be administered systemically and have a systemic effect. For example, a compound or an agent can be administered intravenously, arterially, intradermally, intramuscularly, intraperitoneally, intravenously, subcutaneously, ocularly, sublingually, orally (by ingestion), topically, intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct). According to some embodiments, stabilized ACC is administered orally. According to some embodiments, stabilized ACC is administered sublingually. According to some embodiments, stabilized ACC is administered via inhalation. According to some embodiments, stabilized ACC is administered buccally. According to some embodiments, stabilized ACC is administered via enteric encapsulation (i.e., passing the stomach without being decomposed by the gastric acid). According to some embodiments, stabilized ACC is administered by a combination of two of oral, sublingual, buccal and via inhalation modes. A compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent. Administering can also be performed, for example, once, a plurality of times, and / or over one or more extended periods. According to some embodiments, the composition is administered 1, 2, 3, 4, 5 or 6 times a day. According to other embodiments, the composition is administered 1, 2, 3, 4, 5 or 6 times a month. In some embodiments, the administration includes both direct administration, including self-administration, and indirect administration, including the act of prescribing a drug. For example, as used herein, a physician who instructs a patient to self-administer a drug, or to have the drug administered by another and / or who provides a patient with a prescription for a drug is administering the drug to the patient.

[0036] According to some embodiments, the use and method comprise co-administering the stabilized ACC or the composition comprising stabilized ACC and RANKL inhibitor, e.g. denosumab. According to some embodiments, the use and method comprise co-administering the stabilized ACC or the composition comprising stabilized ACC and denosumab.

[0037] Co-administration of the compounds is performed in a regimen selected from a single combined composition, separate individual compositions administered substantially at the same time, and separate individual compositions administered under separate schedules and include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term “sequential manner” refers to an administration of two compounds at different times, and optionally in different modes of administration. The agents can be administered sequentially in either order. The term “coadministration” encompasses the administration of a first and second agent within the same therapy regimen,.

[0038] The terms "pharmaceutical combination" and "therapeutic combination" used herein interchangeably and refer to a product that results from the mixing or combining of two or more active ingredients or compositions comprising active ingredients and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, e.g. a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, or compositions comprising thereof are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient.

[0039] The terms "receptor Activator of Nuclear Factor KB Ligand inhibitor" and "RANKL inhibitor" are used herein interchangeably and refer to monoclonal antibodies that binds with high affinity and specificity to the receptor Activator of Nuclear Factor KB Ligand (RANKL). According to some embodiments, the RANKL is denosumab. According to any one of the aspects and embodiments of the invention, There denosumab is administered in a dose of from 50 to 80 mg every 6 months. In some embodiments, denosumab is administered in a dose of 60 or 70 mg of denosumab. As used here, the term "denosumab" refers to a human monoclonal IgG2 antibody that targets and inhibits receptor activator of nuclear factor kappa-B ligand (RANKL inhibitor) and to any active fragment thereof. The sequence of the denosumab is as disclosed in US6740522. According to some embodiments, denosumab is administered every 6 months. According to some embodiments, denosumab is administered is administered in a dose of from 50 to 80 per administration. According tosome embodiments, denosumab is administered is administered in a dose of 60 mg / per administration. According to some embodiments, denosumab is administered is administered in a dose of 70 mg.

[0040] According to any one of the aspects and embodiments of the present invention, the terms "stabilized ACC" and "stabilized amorphous calcium carbonate" refer to an amorphous calcium carbonate comprising a stabilizing agent as part of the stabilized ACC and wherein the calcium carbonate is present in an amorphous form. The term "stable" as used herein indicates that the calcium carbonate is maintained in the amorphous form for a long period of time, for example for about at least 7 days in the solid form having less than or about 30% crystalline calcium carbonate. According to any one of the above embodiments, the composition is stable for at least 7 days. According to some embodiments, the composition is stable for at least 1 month. According to other embodiments, the composition is stable for at least 3 months. According to a further embodiment, the composition is stable for 6 months. According to certain embodiments, the composition is stable for at least 1 year. According to a particular embodiment, the composition is stable for at least 2 years. According to some embodiments, ACC is stable in amorphous form for at least 7 days, at least 1 month, at least 3 months or 6 months in an aqueous solution.

[0041] In some embodiments, the stabilized ACC is formulated as tablets, capsules, sachets, or controlled-release oral dosage forms.

[0042] According to any one of the above embodiments, the subject suffers from oncology-associated bone disease. The term "oncology-associated bone disease or condition" refers to condition selected from bone metastases, cancer treatment-induced bone loss, malignancy-related hypercalcemia, primary bone tumors and Structural bone weakness from cancer. According to some embodiments, the oncology-associated bone disease or condition comprises metastatic cancer involving bone. According to some embodiments, the oncology-associated bone disease or condition comprises metastatic breast cancer involving bone.

[0043] According to any one of the embodiments of the invention, the use or the method comprises enhancing cortical bone density. According to any one of the embodiments of the invention, the use or the method comprises enhancing cortical bone density. According to any one of the embodiments of the invention, the use or the method comprises increasing total hip bone mineral density by at least 4% after 12 months. According to any one of the embodiments of the invention, the use or the method comprises increasing total hip bone mineral density by at least 5% after 12 months. According to any one of the embodimentsof the invention, the use or the method comprises increasing total hip bone mineral density by at least 5.5% after 12 months.

[0044] According to any one of the embodiments of the invention, the use or the method comprises increasing total lumbar spine bone mineral density by at least 3% after 12 months. According to any one of the embodiments of the invention, the use or the method comprises increasing total lumbar spine bone mineral density by at least 3.5% after 12 months. According to any one of the embodiments of the invention, the use or the method comprises increasing total lumbar spine bone mineral density by at least 4% after 12 months. According to any one of the embodiments of the invention, the use or the method comprises increasing total lumbar spine bone mineral density by at least 4.5% after 12 months.

[0045] According to any one of the embodiments of the invention, the use or the method comprises increasing total lumbar spine bone mineral density by at least 10% after 24 months. According to some embodiments, the use or the method comprises increasing total lumbar spine BMD by at least 10% after 24 months. According to some embodiments, the use or the method comprises increasing total lumbar spine BMD by at least 15% after 24 months. According to some embodiments, the use or the method comprises increasing total lumbar spine BMD by at least 20% after 24 months. According to some embodiments, the use or the method comprises increasing total lumbar spine BMD by at least 25% after 24 months. According to some embodiments, the use or the method comprises increasing total lumbar spine BMD by at least 30% after 24 months.

[0046] According to any one of the embodiments of the invention, the use or the method comprises increasing total lumbar spine bone mineral density by at least 10% after 36 months. According to some embodiments, the use or the method comprises increasing total lumbar spine BMD by at least 10% after 24 months. According to some embodiments, the use or the method comprises increasing total lumbar spine BMD by at least 15% after 36 months. According to some embodiments, the use or the method comprises increasing total lumbar spine BMD by at least 20% after 36 months. According to some embodiments, the use or the method comprises increasing total lumbar spine BMD by at least 25% after 36 months. According to some embodiments, the use or the method comprises increasing total lumbar spine BMD by at least 30% after 36 months.As used herein, the term “synergistic” refers to a combination of a compound described herein and another therapeutic agent, which, when taken together, is more effective than the additive effects of the individual therapies. In addition, a synergistic effect can result in improved efficacy of agents in the prevention, management or treatment of a disease or disorder. Finally, a synergistic effect of a combination of therapies may avoid or reduce adverse or unwanted side effects associated with the use of either therapeutic agent alone. As used herein, “synergistic effect,” “synergism,” or “synergy” can refer to an effect arising between two or more molecules, compounds, substances, factors, or compositions that is greater than or different from the sum of their individual effects.

[0047] ACC Stabilizers

[0048] The stabilizer may comprise an organic molecule having one or more functional groups selected from, but not limited to, hydroxyl, carboxyl, ester, amine, phosphino, phosphono, phosphate, sulfonyl, sulfate or sulfino groups. The hydroxy bearing compounds, combined with the hydroxide, optionally also bear other functions like carboxyl, etc. but with the hydroxyl not being esterified.

[0049] According to some embodiments, the stabilizer has low toxicity or no toxicity to mammalian cells or organism, and in particular to a human being. According to some embodiment, the stabilizer is of food, nutraceutical or pharmaceutical grade.

[0050] In certain embodiments, the ACC stabilizing agent is independently at each occurrence, an organic acid, phosphorylated, phosphonated, sulfated or sulfonated organic compound, phosphoric or sulfuric ester of a hydroxyl carboxylic acid, an organoamine compound, an organic compound comprising a hydroxyl, an organophosphorous compound or salts thereof, phosphorylated amino acids and derivatives thereof, a bisphosphonate, triphosphonate, or tetraphosphonate compound, an organophosphate compound (e.g., phytic acid, AMP, ADP and ATP), an organophosphonate compound, an inorganic phosphorous acid, an organic compound having multiple functional groups as defined above, an inorganic phosphate and polyphosphate compound, an organic compound having a polyphosphate chain, an organic surfactant, a bio-essential inorganic ion, salts thereof or any combination thereof.

[0051] According to some embodiments, the stabilizer is an organic acid or salt thereof. According to certain embodiments, the organic acid is selected from ascorbic acid, citric acid, lactic acid, acetic acid, oxalic acid, malonic acid, glutaconic acid, succinic acid, maleic acid, lactic acid, aconitic acid, or salts thereof and optionally include compounds having at least two carboxylic groups and molecular weight not larger than 250g / mol, such as citricacid, tartaric acid, malic acid, etc. According to one particular embodiment, the stabilizer is citric acid or a citrate salt

[0052] In another embodiment, the phosphoric ester of hydroxyl carboxylic acids is a phosphoenolpyruvate. In another embodiment, the phosphoric or sulfuric esters of hydroxyl carboxylic acids comprise amino acids. Examples of such esters are phosphoserine, phosphothreonine, sulfoserine, sulfothreonine and phosphocreatine.

[0053] The hydroxyl bearing compounds combined with hydroxide may comprise, for example, mono-, di- tri-, oligo-, and polysaccharides like sucrose or other polyols like glycerol. The hydroxyl bearing compounds may further comprise hydroxy acids like citric acid, tartaric acid, malic acid, etc., or hydroxyl-bearing amino acids such as serine or threonine and salts thereof. Each possibility represents a separate embodiment, of the present invention.

[0054] Some specific unlimited examples of such ACC stabilizers that include phytic acid, citric acid, and salts thereof, sodium pyrophosphate dibasic, adenosine 5 '-monophosphate (AMP) sodium salt, adenosine 5 '-diphosphate (ADP) sodium salt and adenosine 5'-triphosphate (ATP) disodium salt hydrate, phosphoserine, phosphorylated amino acids, food-grade surfactants, sodium stearoyl lactylate, and combinations thereof.

[0055] According to some embodiments, the stabilizer comprises at least one component selected from phosphoric or sulfuric esters of hydroxyl carboxylic acids, such as phosphoenolpyruvate, phosphoserine, phosphothreonine, sulfoserine or sulfothreonine and hydroxyl bearing organic compounds, selected from mono-, di-, tri-, oligo- and polysaccharides, for example, sucrose, mannose, glucose.

[0056] The hydroxyl bearing compound may further comprise at least one alkali hydroxide, such as sodium hydroxide, potassium hydroxide and the like. The phosphorylated acids may be present in oligopeptides and polypeptides. In other embodiments, of the invention, the stabilizer is an organic acid selected from monocarboxylic acid or multiple carboxylic acid, e.g., dicarboxylic acid or tricarboxylic acid. Each possibility represents a separate embodiment of the invention. The organic acid may be as defined above.

[0057] In some embodiments of the invention, the ACC stabilizer is selected from phosphorylated amino acids, polyols and combinations thereof. In some embodiments, the stable ACC comprises a phosphorylated compound as a stabilizer wherein the phosphorylation is performed on the hydroxyl group of an organic compound. In some embodiments, the stable ACC comprises a stabilizer selected from the group consisting of citric acid, phosphoserine, phospho threonine and combinations thereof. The non-limitingexamples of stabilizers containing phosphate, phosphite, phosphonate groups and salts or esters thereof include phytic acid, dimethyl phosphate, trimethyl phosphate, sodium pyrophosphate, tetraethyl pyrophosphate, ribulose bisphosphate, etidronic acid and other medical bisphosphonates, 3 -phosphoglyceric acid salt, glyceraldehyde 3-phosphate, 1-deoxy-D-xylulose-5-phosphate sodium salt, diethylene triamine pentakis(methylphosphonic acid), nitrilo tri(methylphosphonic acid), 5-phospho-D-ribose 1-diphosphate pentasodium salt, adenosine 5 '-diphosphate sodium salt, adenosine 5 '-triphosphate disodium salt hydrate, a-D-galactosamine 1 -phosphate, 2-phospho-L-ascorbic acid trisodium salt, a-D-galactose 1-phosphate dipotassium salt pentahydrate, a-D-galactosamine 1 -phosphate, O-phosphorylethanolamine, disodium salt hydrate, 2,3-diphospho-D-glyceric acid pentasodium salt, phospho(enol)pyruvic acid monosodium salt hydrate, D-glyceraldehyde 3-phosphate, sn-glycerol 3-phosphate lithium salt, D-(-)-3-phosphoglyceric acid disodium salt, D-glucose 6-phosphate sodium salt, phosphatidic acid, ibandronate sodium salt, phosphonoacetic acid, DL-2-amino-3-phosphonopropionic acid or combinations thereof.

[0058] In some embodiments, the stabilizers can be bio-essential inorganic ions including, inter alia, Na, K, Mg, Zn, Fe, P, S, N, P, or S in the phase of oxides, or N as ammonia or nitro groups.

[0059] The stabilized ACC may be stabilized by more than one stabilizer, e.g., 2, 3, or more stabilizers. The stabilizers can be added during the synthesis and precipitation of the ACC primary particles and they are defined as “internal stabilizer”. Stabilizers can be added after the synthesis and bind to the external surface of the particles. They are defined as “external stabilizers”. In some embodiments, where both internal and external stabilizers are used, the internal stabilizer and the external stabilizer are similar. In other embodiments, the internal stabilizer and the external stabilizer are different stabilizers. The internal and the external stabilizers may be each independently as defined hereinabove and each can be a combination of more than one type of stabilizer.

[0060] The stable ACC can comprise more than two stabilizers, wherein one or more stabilizers are added to the ACC during the formation and precipitation of the ACC, or added after the precipitation, or added in both steps.

[0061] According to some embodiments, the stabilizer is selected from the group consisting of a phosphate, polyphosphate, polyphosphonate, bisphosphonate, phosphorylated amino acid, citric acid, salts thereof and any combination thereof. In some embodiments, more than one stabilizer, e.g., 2, 3, or 4 stabilizers are added.According to one embodiment, ACC is stabilized by a combination of phosphoserine and citric acid. According to another embodiment, ACC is stabilized by a combination of tripolyphosphate (also defined as triphosphate) and citric acid.

[0062] According to some embodiments, the stabilizer is phosphate and / or a polyphosphate or pharmaceutically acceptable salts thereof. According to some embodiments, the polyphosphate is physiologically compatible, water-soluble polyphosphate salt selected from the group consisting of sodium, potassium, and any other essential cation of polyphosphate. In one embodiment, the polyphosphate is organic or inorganic polyphosphate. The term “polyphosphate” as used herein refers to (1) polymeric unhydrates of PO4 or a (2) phosphorylated organic compound containing more than 1 phosphorylated groups via C-O-P (ether) bonding. An example for Type 2 polyphosphate is phytic acid or salts thereof, which contains 6-phosphorylated groups.

[0063] According to some embodiments, the polyphosphate is a physiologically compatible water-soluble polyphosphate salt selected from the group consisting of sodium and potassium polyphosphate. In some embodiments, the polyphosphate is an inorganic polyphosphate or pharmaceutically acceptable salts thereof. Not-limiting examples of such salt are Na, K, Mg, Mn, and Zn. According to some embodiments, the polyphosphate such as an inorganic polyphosphate comprises 2 to 10 phosphate groups, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 phosphate groups. According to some embodiments, the inorganic polyphosphate is selected from pyrophosphate, triphosphate, and hexametaphosphate. According to one embodiment, the stabilizer is pyrophosphate or pharmaceutically acceptable salts thereof such as sodium pyrophosphate. According to another embodiment, the stabilizer is triphosphate (tripolyphosphate) or pharmaceutically acceptable salts thereof such as sodium triphosphate. The term “triphosphate” and “tripolyphosphate” are used herein interchangeably. According to a further embodiment, the stabilizer is hexametaphosphate or a pharmaceutically acceptable salt thereof such as sodium hexametaphosphate.

[0064] According to some embodiments, the stabilizer is a polyphosphonate such as bisphosphonate or tetraphosphonate or pharmaceutically acceptable salts thereof. The nonlimiting examples of salt are Na, K, Mg, Mn and Zn.

[0065] The term “bisphosphonate” as used herein refers to organic compounds having two phosphonate (PO(OH)2) groups. The term further relates to compounds having a backbone of PCh-organic-POs. Most typical is a series of bisphosphonates that are used as pharmaceuticals for treating osteoporosis. According to some embodiments, the bisphosphonate is selected from the group consisting of etidronic acid, zoledronic acid,medronic acid, alendronic acid, and a pharmaceutically acceptable salt thereof. According to some embodiments, the stabilizer is an etidronic acid or a pharmaceutically acceptable salt thereof. According to another embodiment, the stabilizer is a zoledronic acid or a pharmaceutically acceptable salt thereof. According to a further embodiment, the stabilizer is a medronic acid or a pharmaceutically acceptable salt thereof. According to certain embodiments, the stabilizer is alendronic acid or a pharmaceutically acceptable salt thereof.

[0066] According to certain embodiments, the stabilizer is a phosphorylated amino acid. According to one embodiment, the phosphorylated amino acid is phosphoserine. According to another embodiment, the phosphorylated amino acid is phospho threonine.

[0067] According to certain embodiments, the stabilizer is phytic acid or salts thereof.

[0068] According to some embodiments, the ACC composition comprises a combination of the stabilizers disclosed above.

[0069] According to some embodiments, the stabilizer is an inorganic polyphosphate or a bisphosphonate as defined hereinabove, and the molar ratio between P atoms of the stabilizer and Ca atoms of the ACC (P:Ca molar ratio) is about 1:90 to 1:1. In one embodiment, the P:Ca molar ratio is about 1:40 to about 1: 1. In a further embodiment, the P:Ca molar ratio is about 1:35 to about 1:2. In certain embodiments, the P:Ca molar ratio is about 1:30 to about 1:3. In certain embodiments, the P:Ca molar ratio is about 1:28 to about 1:3. In other embodiments, the P:Ca molar ratio is about 1:25 to about 1:4. In further embodiment, the P:Ca molar ratio is about 1:20 to about 1:5. In another embodiment, the P:Ca molar ratio is about 1:20 to about 1:6. In a particular embodiment, the P:Ca molar ratio is about 1:15 to about 1:5. In another particular embodiment, the P:Ca molar ratio is about 1:25 to about 1:5. According to some embodiments, such inorganic polyphosphate is pyrophosphate, triphosphate, hexametaphosphate or a pharmaceutically acceptable salt thereof. According to another embodiment, the bisphosphonate is alendronic acid, etidronic acid, zoledronic acid or medronic acid and the P:Ca molar ratio is as defined hereinabove.

[0070] According to some embodiments, the calcium content (Ca content) of such compositions comprising stabilizers is about 1 wt% to about 39 wt%, about 5 wt% to about 39 wt%, about 10% to about 39 wt%, about 15% to about 39 wt%, about 20 wt% to about 38 wt%, about 25 wt% to about 38 wt%, or about 30 wt% to about 38 wt% of the dry ACC particles The terms “Ca content” and “calcium content” is used herein interchangeably and refer to the content of calcium of the ACC in the final composition.

[0071] In certain embodiments, the P:Ca molar ratio is about 1:40 to about 1:1, and the Ca content is about 20 wt% to about 39 wt%. In some embodiments, the molar ratio is 1:28 toabout 1:3, and the Ca content is about 30 wt% to about 38 wt% of the dry ACC particles. In another embodiment, the molar ratio is 1:25 to about 1:5, and the Ca content is about 30 wt% to about 36 wt% of the dry ACC particles.

[0072] According to some embodiments, the stabilizer is an inorganic polyphosphate or a bisphosphonate as defined hereinabove, and the molar ratio between P atoms of the stabilizer and Mg atoms of amorphous magnesium carbonate (AMC) (P:Mg molar ratio) is about 1:90 to 1:1. In one embodiment, the P:Mg molar ratio is about 1:40 to about 1:1. In a further embodiment, the P:Mg molar ratio is about 1:35 to about 1:2. In certain embodiments, the P:Mg molar ratio is about 1:30 to about 1:3. In certain embodiments, the P:Mg molar ratio is about 1:28 to about 1:3. In other embodiments, the P:Mg molar ratio is about 1:25 to about 1:4. In further embodiment, the P:Mg molar ratio is about 1:20 to about 1:5. In another embodiment, the P:Mg molar ratio is about 1:20 to about 1:6. In a particular embodiment, the P:Mg molar ratio is about 1: 15 to about 1:5. In another particular embodiment, the P:Mg molar ratio is about 1:25 to about 1:5. According to some embodiments, such inorganic polyphosphate is pyrophosphate, triphosphate, hexametaphosphate or a pharmaceutically acceptable salt thereof. According to another embodiment, the bisphosphonate is alendronic acid, etidronic acid, zoledronic acid or medronic acid and the P:Mg molar ratio is as defined hereinabove.

[0073] According to some embodiments, the stabilizer is selected from the group consisting of a polyphosphate, phosphorylated amino acid, bisphosphonate, citric acid, tartaric acid and any combination thereof. According to one embodiment, the polyphosphate is selected from the group consisting of triphosphate, pyrophosphate, and hexametaphosphate, the phosphorylated amino acid is phosphoserine or phosphothreonine, and the bisphosphonate is selected from the group consisting of alendronate, etidronic acid, zoledronic acid and medronic acid. According to some embodiments, the polyphosphate is an inorganic polyphosphate.

[0074] According to one embodiment, the stabilizer is selected from the group consisting of organic acids, phosphorylated, phosphonated, sulfated or sulfonated organic compound, phosphoric or sulfuric esters of hydroxy carboxylic acids, phosphorylated amino acids, bisphosphonate, organic polyphosphate, hydroxyl bearing organic compounds, derivatives thereof, proteins and any combinations thereof.

[0075] According to another embodiment, the stabilizer is selected from the group consisting of phosphoserine, adenosine triphosphate, adenosine diphosphate, phytic acid, citric acid,etidronic acid, pyrophosphate, polyphosphate, inorganic triphosphate, hexamethaphosphate, ethanol, and any combination thereof.

[0076] According to some embodiments, the wherein the stabilizer is selected from the group consisting of polyphosphates, organic acids, phosphorylated amino acids, phosphorylated, phosphonated, sulfated or sulfonated organic compounds, phosphoric or sulfuric esters of hydroxy carboxylic acids, bisphosphonates, organic polyphosphates, polyphosphates, hydroxyl bearing organic compounds, derivatives thereof, proteins and any combinations thereof.

[0077] According to some embodiments, wherein the stabilizer is selected from the group consisting of tripolyphosphate or a salt thereof, phosphoserine, citric acid, sodium triphosphate and citric acid, adenosine triphosphate, adenosine diphosphate, phytic acid, etidronic acid, pyrophosphate, polyphosphate, hexamethaphosphate, a salt thereof, ethanol, and any combination thereof.

[0078] The invention will now be illustrated by the following non-limiting Examples.

[0079] Having now generally described the invention, the same will be more readily understood through reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present invention.

[0080] The terms “a,” “an,” and “the” are used herein interchangeably and mean one or more. The term “and / or” is used to indicate one or both stated cases may occur, for example A and / or B includes, (A and B) and (A or B).

[0081] The term “or,” as used herein, denotes alternatives that may, where appropriate, be combined; that is, the term “or” includes each listed alternative separately as well as their combination if the combination is not mutually exclusive.

[0082] The terms “comprising”, "comprise(s)", "include(s)", "having", "has" and "contain(s)," are used herein interchangeably and have the meaning of “consisting at least in part of’. When interpreting each statement in this specification that includes the term “comprising”, features other than that or those prefaced by the term may also be present. Related terms such as “comprise” and “comprises” are to be interpreted in the same manner. The terms “have”, “has”, having” and “comprising” may also encompass the meaning of “consisting of’ and “consisting essentially of’, and may be substituted by these terms. The term “consisting of’ excludes any component, step or procedure not specifically delineated or listed. The term “consisting essentially of’ means that the composition or component may include additional ingredients, but only if the additional ingredients do not materially alter the basic and novel characteristics of the claimed compositions or methods.As used herein, the term “about”, when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of + / -10%, or + / -5%, + / -1%, or even + / -0.1% from the specified value.

[0083] Having now generally described the invention, the same will be more readily understood through reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present invention.

[0084] Clauses

[0085] Clause 1. A method of enhancing the efficacy of a RANKL inhibitor, such as denosumab, therapy, the method comprises co-administering RANKL inhibitor such as denosumab and stabilized ACC.

[0086] Clause 2. The method of Clause 1, wherein the a RANKL inhibitor therapy comprises osteoporosis, cancer-related bone loss, bone metastases or giant cell tumor of bone.

[0087] Clause 3. A method for treating osteoporosis, the method comprises co-administering a RANKL inhibitor such as denosumab and a stabilized amorphous calcium carbonate.

[0088] Clause 4. A method of enhancing a bone mineral density in a subject receiving a RANKL inhibitor comprising administering to said subject stabilized amorphous calcium carbonate.

[0089] Clause 5. The method of any clauses herein, particularly clause 4, particularly clause any one of clauses 1 to 4, wherein the co-administering provides a synergistic effect.

[0090] Clause 6. The method of any clauses herein, particularly clauses 1 to 5, wherein the subject suffers from oncology-associated bone disease

[0091] Clause 7. The method of any clauses herein, particularly clause 6, wherein the oncology-associated bone disease comprises metastatic breast cancer involving bone.

[0092] Clause 8. The method of any clauses herein, particularly clauses 1 to 7, wherein the method comprises at least one of (i) enhancing cortical bone mineral density (BMD), (ii) increasing total hip BMD by at least 4% after 12 months, and (iii) increasing total lumbar spine BMD.Clause 9. The method of any clauses herein, particularly clauses 1 to 8, wherein stabilized ACC is administered daily in a dose corresponding to from 600 to 2000 mg of calcium / day.

[0093] Clause 10. The method of any clauses herein, particularly clauses 1 to 9, wherein stabilized ACC is administered daily in a dose corresponding to from 800 to 1600 mg of calcium / day.

[0094] Clause 11. The method of any clauses herein, particularly clauses 1 to 10, wherein the method comprises administering at least two doses of denosumab.

[0095] Clause 12. The method of any clauses herein, particularly clause 12, wherein denosumab is administered every 6 months.

[0096] Clause 13. The method of any clauses herein, particularly clauses 1 to 12, wherein the ACC is formulated as tablets, capsules, sachets, or controlled-release oral dosage forms.

[0097] EXAMPLES

[0098] Example 1.

[0099] Test product:

[0100] 1. Name: stabilized ACC ( DENSITY™, 200mg Calcium per tablet) lOOOmg Calcium per day.

[0101] 2. Prolia (Denosumab)

[0102] Dosing schedule:

[0103] Subjects with a bone mineral density (BMD) T-score between -4.0 to -2.5 and no fractures receive only ACC tablet supplements. Subjects with BMD T-score between -4.0 to -2.5 having one or more fractures, are treated with Denosumab in addition to ACC tablet supplements. The usual oral dose of ACC is 5 ACC tablets (lOOOmg Ca) daily, recommended to be taken after meals.

[0104] Subjects with a baseline 25-hydroxy vitamin D level of 12 to 20 ng / ml were given at least 800 IU of vitamin D daily, and those with a baseline level above 20 ng / ml were given at least 400 IU daily.

[0105] Endpoints

[0106] Primary Endpoints

[0107] Mean change from baseline of BMD at the lumbar spine.Secondary Endpoint(s)

[0108] • Mean change from baseline of BMD at spine (LI, L2, L3, L4), total hip, Femoral neck, Trochanter

[0109] • Bone turnover markers (BTMs):

[0110] ■ P1NP (total procollagen type 1 N-terminal propeptide)

[0111] ■ CTX (C-terminal telopeptide of type 1 collagen)

[0112] Inclusion Criteria:

[0113] 1. Women 60-90 years of age

[0114] 2. With BMD T-score of at least -2.5 but not lower than -4.0 at the lumbar spine and / or total hip

[0115] 3. Willingness to limit additional Vitamin D3 intake to 400IU or 800IU per day during the study period

[0116] 4. Ability to complete the entire procedure and to comply with study instructions 5. Wiliness to provide completed and signed written informed consents

[0117] Exclusion Criteria:

[0118] 1. Subjects previously administered with intravenous bisphosphonate, fluoride or strontium therapy within the past 5 years.

[0119] 2. Subjects who had conditions that influence bone metabolism or had taken oral bisphosphonates for more than 3 years.

[0120] (If subjects had taken oral bisphosphonates therapy for less than 3 months, they could be enrolled in the study. If their cumulative exposure was more than 3 months but less than 3 years and treatment had been discontinued for 12 months, they were also eligible for inclusion.)

[0121] 3. Subject with other osteoporosis therapies, parathyroid hormone or its derivatives, corticosteroids, systemic hormone-replacement therapy, selective estrogen-receptor modulators, tibolone, calcitonin or calcitriol.

[0122] If subjects undergo a 6-week wash-out period, they could be enrolled

[0123] 4. Subjects had a serum 25-hydroxy vitamin D level of less than 12 ng / ml.

[0124] 5. Subjects had a BMD T-score of less than -4.0 at the lumbar spine or total hip.

[0125] 6. Subjects with any severe or more than two moderate vertebral fractures on spinal x-ray at entry.7. If total hip BMD decreased by more than 7% during a 12-month period or by 10% or more during the study or if the T-score dropped below -4.0, the subject was again counseled by the study clinician about using alternative treatments in lieu of continuing to participate in the study.

[0126] 8. Known hypersensitivity to any component of the study drug product.

[0127] 9. Any previous or ongoing clinically significant illness that may interfere with the study conduct, as judged by the investigator.

[0128] 10. Participation in any other investigational study within 30 days prior to receiving study medication.

[0129] 11. Any condition that in the opinion of the investigator would jeopardize the evaluation of efficacy or safety.

[0130] I Study Procedures:

[0131] In this study, we aim to evaluate the efficacy of ACC in enhancing BMD by utilizing two external comparators. The Prolia + ACC arm is compared with the active arm of the FREEDOM sub-study as an external comparator. On the other hand, the ACC alone arm is independently compared with the Placebo arm of the FREEDOM sub-study. FREEDOM was an international, multicenter, randomized, double-blinded, placebo-controlled study in 7808 postmenopausal women with osteoporosis. Subjects were randomized to receive either 60 mg denosumab or placebo subcutaneously every 6 months for 36 months. All subjects received daily calcium (>1000 mg) and vitamin D (> 400 IU) supplements.

[0132] A total of 205 eligible subjects enrolled in this study. 142 subjects receive injections of 60mg of Denosumab every 6 months at study sites. Additionally, prior to the commencement of the study, 205 subjects receive ACC tablets and Vitamin D3. The schematic presentation of the study is shown in scheme I.Scheme I

[0133]

[0134] The study product, ACC, containing 200mg of Calcium per tablet, is administered as follows: 5 tablets taken after meal throughout the 24-month treatment period. Subjects with a baseline 25-hydroxy vitamin D level of 12 to 20 ng / ml were given 800 IU of vitamin D3 daily, while those with a baseline level above 20 ng / ml received 400 IU of vitamin D3, both administered after breakfast.

[0135] After signed ICF, eligible subject who meet NHI reimbursement criteria for use of denosumab is assigned to A arm, and subject who does not meet NHI reimbursement criteria for use of denosumab, or who is no willing to receive denosumab treatment during study period, even meet NHI reimbursement criteria is assigned to B arm. A total of 205 subjects are enrolled into this study, in which 142 subjects in A arm and 63 subjects in B arm.

[0136] In A arm, subject receives 5 DensityTM tablets (equal to 1000 mg calcium element) daily with injections of 60 mg of Prolia™ (denosumab) every 6 months at study site, while in B arm, eligible subject receives 5 DensityTM tablets (equivalent to 1000 mg calcium element) daily only. DensityTM tablets are administered as follows: 5 tablets are taken after meal. In addition, all subjects with a baseline 25-hydroxy vitamin D level of 12 to 20 ng / ml are given 800 IU of vitamin D3 daily, while those with a baseline level above 20 ng / ml received 400 IU of vitamin D3, both administered after meal.

[0137] The study consists of 7 clinical visits. Subjects come to the clinics at Visit 1 (screening visit, Month -1), Visit 2 (regimen start, Day 0 in Month 0), and Visit 3 to 7 (follow-up visits, Month 1, 6, 12, 18, 24). BMD assessment and blood drawing are performed before study medication administration and at Month 1, 6, 12, and 24.Mean change from baseline of BMD

[0138] Bone mineral density was assessed via dual energy x-ray absorptiometry at baseline, 1, 6, 12, and 24 months for both the spine (LI, L2, L3, L4, Total), Femoral neck, Trochanter and hip.

[0139] BTMs

[0140] Concentrations of CTX and P1NP were measured in all subjects using serum samples collected before the injection on day 1, at 1 -month post-baseline injection, and prior to injections at months 6, 12 and 24.

[0141] I Concomitant treatment:

[0142] The following medications and dietary supplements should be prohibited from the regimen start to the end of study: Anti-osteoporotic drugs other than Denosumab

[0143] Calcium supplements other than study product

[0144] Vitamin D3 other than study supplements

[0145] Other dietary supplements for osteoporosis

[0146] 1. Sample size:

[0147] In the Prolia+ACC arm compared to the FREEDOM sub- study active arm, the mean change from baseline in total spine BMD is expected to be more than 0.3. Considering a standard deviation of 0.8 and a dropout rate of 20%, the total number of subjects is 142. In the ACC alone arm, the mean change from baseline in total spine BMD compared to the FREEDOM sub-study control arm is expected to be more than 0.4. Considering a standard deviation of 0.7 and a dropout rate of 20%, the total number of subjects is 63.

[0148] The two different arms in this study (Prolia + ACC arm and ACC alone arm) were compared with the active arm and control arm of the FREEDOM sub-study respectively.

[0149] I Flow chart

[0150]

[0151]

[0152] a: One month in this study refers to 4 weeks.

[0153] b: The day of regimen start is day 1 of month 0.

[0154] c: Prolia+ACC arm only

[0155] In the A arm compared to the FREEDOM sub- study active arm, the percent change in BMD from baseline to Month 24 at lumbar spine from active arm in FREEDOM sub-study is 7.7%. The results of the A and B arm outperform the corresponding BMD change of the FREEDOM sub-study by at least 1.3%.

[0156] The two different arms in this study (A arm and B arm) are compared with the active arm and control arm of the FREEDOM substudy, respectively.

[0157] Efficacy Evaluation

[0158] The percent change from baseline of BMD at lumbar spine, total hip, femoral neck, trochanter, 1 / 3 radius and total body is summarized with descriptive statistics and the 95% CI. One sample t-test is adopted to test the superiority between A arm and FREEDOM substudy active arm and the superiority between B arm and FREEDOM sub-study control arm.

[0159] The absolute values and percent changes from baseline of P1NP and CTX at different timepoints are summarized with the descriptive statistics for A arm and B arm, respectively. The line chart and box-and-whisker plot is drawn to display the trend via timepoints.

[0160] Percentage of Subjects with P1NP and CTX values below the premenopausal reference interval at Month 0, 1, 6, 12, and 24 are summarized by number and percentage for A arm and B arm, respectively. Premenopausal reference interval is defined as CTX values <0.20 ng / mL and P1NP values <17.4 ng / mL.Example 2

[0161] Clinical observational data

[0162] Three female patients diagnosed with osteoporosis were treated for 12 months with:

[0163] • Denosumab (standard dosing)

[0164] • ACC equivalent of 1500 mg elemental calcium / day orally

[0165] All Dual-Energy X-ray Absorptiometry (DEXA) measurements were performed:

[0166] • At the same clinical center

[0167] • Using the same DEXA device

[0168] • Under consistent measurement protocols

[0169] Patient 1

[0170] Age: 48

[0171] Diagnosis: Severe osteoporosis

[0172] 12-month BMD change:

[0173] • Total Hip: +7.6%

[0174] • Lumbar Spine: +4.3%

[0175] Patient 2

[0176] Age: 69

[0177] Diagnosis: Severe osteoporosis

[0178] Comorbidity: Metastatic breast cancer with bone involvement

[0179] 12-month BMD change:

[0180] • Total Hip: +7.0%

[0181] Patient 3

[0182] Age: 58

[0183] Diagnosis: Advanced osteoporosis

[0184] 12-month BMD change:

[0185] • Total Hip: +4.3%

[0186] • Lumbar Spine: +5.2%

[0187] Summary of the results

[0188] Mean increase in bone mineral density of Hip: 6.3% (n=3).Mean increase in bone mineral density of Lumbar Spine: 4.75% (n=2)

[0189] The observed mean total hip BMD increase of 6.3% within 12 months exceeds the typical ~3% first-year increase reported for denosumab (as disclosed e.g. in Cummings et al The New England journal of medicine 361;8, 759-765 (e.g. fig 2 there). It should be noted that in that publication, denosumab was administered in parallel to 1000 mg calcium and vitamin D (if the basic level was 10-20 ng / ml). According to applicant experience, treatment of osteoporosis by only ACC in the dose corresponding to 800-1500 mg calcium a day results in improvement of 1.5-2% increase in the first year in BMD of hip. Considering that the effect of different treatments on the improvement in BMD of subjects suffering from osteoporosis is not always linear and is not a simple sum of effects, 2 time increase in BMD of hip after treatment of ACC+ denosumab in comparison to denosumab+ crystalline calcium carbonate indicates for a synergistic effect of ACC+ denosumab.

[0190] The 7% increase observed in a 69-year-old patient with metastatic breast cancer involving bone indicates enhanced cortical bone response even in a high-turnover metastatic bone environment.

[0191] These findings indicate that co-administration of stabilized ACC and RANKL inhibition provide:

[0192] • Synergistic interaction between stabilized ACC and RANKL inhibition

[0193] • Enhanced mineral accrual during suppressed bone resorption

[0194] • Improved cortical bone response

[0195] • Potential stabilization of bone in oncology-associated bone disease

[0196] Administration of ACC, therefore, amplifies BMD gains beyond those achieved with denosumab alone.

[0197] Example 3. Long term administration of ACC+ denosumab

[0198] In an additional example, a long-term effect of ACC+ denosumab was further tested. Denosumab was administered in standard dose and ACC was administered as a powder formulation in the amount corresponding to 1500 mg calcium. Results of five case are presented in Table 1.Table 1

[0199]

[0200] Table 2 shows the effect of denosumab+ crystalline calcium carbonate on BMD after 12 and 36 months as tested on women and reported from clinical trial either Prolia Package insert to FDA or in scientific publications.

[0201] Table 2

[0202]

[0203] 1. Miller et al., J Clin Endocrinol Metab. 2016 Jun 6; 1O1(8):3163- 3170. doi: 10.1210 / jc.2016-1801

[0204] 2. PROLIA safely and effectively on FDA site https: / / www.accessdata.fda.gov / See full prescribing information for PROLIA.

[0205] It can be clearly seen that the effect of the combined treatment of ACC+denosumab is much higher than observed for a denosumab therapy alone or in combination with crystalline calcium carbonate.

[0206] Example 4. Case report of a combinational therapy of denosumab (Prolia™) and stabilized ACC

[0207] A female patient, age 47 with prior BMD decline was monitored after initiation of a combination treatment with denosumab and stable ACC. DXA was measured before the beginning of the treatment and after about 12 months.Treatment:

[0208] • Denosumab 60 mg subcutaneously every 6 months, initiated March 2023 and continued through follow up (time from initiation to follow up ~17 months).

[0209] • PH Direct Amorphous Calcium Carbonate (sublingual powder): 5 sachets daily corresponding to 1500 mg elemental calcium (and 2250 mg carbonate) for ~12 months.

[0210] DXA results (15 Aug 2023 — 18 Aug 2024; DXA interval ~12 months) Results

[0211] Lumbar spine (L1-L4): BMD 1.050 — 1.095 g / cm2; T score -2.5 — -2.3. Absolute change +0.045 g / cm2; relative change +4.3%.

[0212] Left femoral neck: BMD 0.610 — 0.656 g / cm2;; T score -3.5 — -3.2. Absolute change +0.046 g / cm2; relative change +7.6%.

[0213] Overall, lumbar spine and left femoral neck BMD increased by 4.3% and 7.6%, respectively; changes exceed the reported least significant change (LSC) and are clinically meaningful.

[0214] Although the present invention has been described herein above by way of preferred embodiments thereof, it can be modified, without departing from the spirit and nature of the subject invention as defined in the appended claims.

Claims

CLAIMS1. A composition comprising stabilized ACC, for use in enhancing the efficacy of receptor activator of nuclear factor KB ligand (RANKL) inhibitor therapy, the use comprises co-administering the composition comprising stabilized ACC and the RANKL inhibitor.

2. The composition for use of claim 1, wherein the denosumab therapy is selected from osteoporosis, cancer-related bone loss, bone metastases or giant cell tumor of bone.

3. The composition for use of claim 1, wherein the denosumab therapy is treatment of osteoporosis.

4. A pharmaceutical combination comprising a RANKL inhibitor and stabilized amorphous calcium carbonate (ACC), for use in treating osteoporosis, wherein the use comprises co-administering the RANKL inhibitor and stabilized ACC.

5. A composition comprising stabilized ACC, for use in enhancing a bone mineral density in a subject receiving a RANKL inhibitor, the use comprising co-administering to said subject stabilized amorphous calcium carbonate and RANKL inhibitor.

6. The subject matter of any one of claims 1 to 5, wherein the RANKL inhibitor is denosumab.

7. The subject matter of any one of claims 1 to 6, wherein the co-administering provides a synergistic effect.

8. The subject matter of any one of claims 1 to 7, wherein the subject suffers from oncology-associated bone disease or condition.

9. The subject matter of claim 8, wherein the oncology-associated bone disease or condition comprises metastatic cancer involving bone.

10. The subject matter of any one of claims 1 to 9, wherein the method comprises at least one of (i) enhancing cortical bone density, (ii) increasing total hip bone mineral density by at least 4% after 12 months.

11. The subject matter of any one of claims 1 to 9, wherein stabilized ACC is administered daily in a dose corresponding to from 200 to 2000 mg of calcium / day.

12. The subject matter of claim 11, wherein stabilized ACC is administered in a dose corresponding to from 600 to 1800 mg of calcium / day.

13. The subject matter of any one of claims 1 to 12, wherein the use comprises administering at least two doses of denosumab.

14. The subject matter of any one of claims 1 to 13, wherein denosumab is administered every 6 months.

15. The subject matter of any one of claims 1 to 14, wherein the ACC is formulated as tablets, capsules, sachets, or controlled-release oral dosage forms.

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