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WO 2010/115932 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 14 October 2010 (14.10.2010) WO 2010/115932 Al (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, A61K 31/675 (2006.01) A61K 45/06 (2006.01) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, A61K 38/00 (2006.01) A61P 19/08 (2006.01) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, A61K 39/395 (2006.01) A61P 19/10 (2006.01) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (21) International Application Number: ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, PCT/EP20 10/054605 NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (22) International Filing Date: SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, 7 April 2010 (07.04.2010) TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, (30) Priority Data: ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, 61/167,688 8 April 2009 (08.04.2009) US TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (71) Applicant (for all designated States except US): NO- MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM, VARTIS AG [CH/CH]; Lichtstrasse 35, CH-4056 Basel TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, (CH). ML, MR, NE, SN, TD, TG). (72) Inventors; and Declarations under Rule 4.17: (75) Inventors/Applicants (for US only): JUNKER, Uwe — as to applicant's entitlement to apply for and be granted [DE/CH]; Novartis Pharma AG, Postfach, CH-4002 Basel a patent (Rule 4.1 7(U)) (CH). KNEISSEL, Michaela [AT/CH]; Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel (CH). Published: (74) Agent: SPINNER, David, Richard; Novartis Pharma — with international search report (Art. 21(3)) AG, Patent Department, CH-4002 Basel (CH). — with amended claims (Art. 19(1)) (81) Designated States (unless otherwise indicated, for every — with sequence listing part of description (Rule 5.2(a)) kind of national protection available): AE, AG, AL, AM, (54) Title: COMBINATION FOR THE TREATMENT OF BONE LOSS (57) Abstract: The invention provides a novel treatment regime for bone loss, such as that which occurs in osteoporosis patients. In said regime the patients arc provided with a single high dose of a bone anabolic agent and a single high dose of a bone resorp- tion inhibitor. COMBINATION FOR THE TREATMENT OF BONE LOSS TECHNICAL FIELD This invention is in the field of combinations for the treatment of bone loss. Particularly the invention is in the field of osteoporosis treatment. BACKGROUND Patient compliance is a major problem with any chronic condition. After time, patients forget to take their medicine, do not have time to take their medicine, or do not want to take their medicine. This obviously has consequences for recovery and such patients often suffer from relapses. Osteoporosis is one such chronic disease where this occurs. Bone is not a static structure. It is continually shaped, reformed and rebuilt by cells called osteoblasts and osteoclasts. These cells continuously deposit and remove calcium and phosphorous, stored in a protein network that makes up the structure of the bone. Old bone is broken down by the osteoclasts and new bone is formed by the osteoblasts. At the moment, the only therapeutic on the market thai is anabolic and actually induces the build up of new bone is human parathyroid hormone (PTH). However, this can only be administered for limited periods (maximum 2 years) due Io a possible link with bone cancer [1], Furthermore, it usually needs to be administered daily by injection. The only other current treatments available are bone resorption inhibitors thai prevent the resorption of bone. Such treatments include btsphosphonates (such as zoledronic acid) and SERMs. Problems with oral administration of bisphosphonates include low bioavailability, requiring high doses which exacerbate gasttoesophageal corrosion, Furthermore, research has shown that patient compliance is very low when taking oral bisphosphonates on a daily or weekly basis, leading to much reduced efficacy. In addition, long term administration of bisphosphonates has been implicated in osteonecrosis of the jaw [2,3]. There is therefore a need for a combination that induces bone anabolism with a long lasting effect. DISCLOSURE OF THE INVENTION U has been discovered that a single high dose of a bone anabolic agent can stimulate bone growth for an extended period, although the effect reduces over time. This reduction can be counteracted by providing co-treatment with a single high dose of an anti-resorptive agent. Such high dose co-treatments would need to be administered less frequently than conventional treatments (for example, only once every 3 months, once every 6 months, or once a year). Sυch an infrequent dosage requirement would therefore likely greatly increase patient compliance. Therefore, the invention provides a method of reducing bone loss in a subject comprising co-administering a high dose of a bone anabolic agent and a high dose of a bone resorption inhibitor. The dosages referred to herein are considered to be ''high" doses ibr the purposes of the invention. The invention further provides a method of inducing bone growth in a subject suffering from bone loss comprising co-administering a high dose of a bone anabolic agent and a high dose of a bone resorption inhibitor, The invention further provides use of a high dose of a bone anabolic agent co-administered with a high dose of a bone resorption inhibitor for the treatment of bone loss. The invention further provides use of a bone anabolic agent in the manufacture of a medicament for the treatment of bone loss, wherein the medicament is used in conjunction with a bone resorption inhibitor. The invention further provides use of a bone resorption inhibitor in the manufacture of a medicament for the treatment of bone o ss , wherein the medicament is used in conjunction with a bone anabolic agent. The invention further provides use of a bone anabolic agent in the manufacture of a medicament for the treatment of bone loss i a patient, wherein said patient has been pre-treated with a bone resorption inhibitor. The invention further provides use of a bone resorption inhibitor in the manufacture of a medicament for the treatment of bone loss in a patient, wherein said patient has been pre-treated with a bone anabolic agent. Bone anabolic agents Bone anabolic agents are agents which cause the active build up of new bone, rather than inhibiting the resorption of bone. The bone anabolic agent may be an anti-sclerostin antibody. Various anti-sclerostin antibodies have been disclosed in references 4-1 1. Any of the antibodies disclosed in these references may be used in the invention. In particular, an antibody comprising a heavy chain comprising SEQ ID NOs:245, 246 and 247 and a light chain comprising SEQ ID NOs:78, 79 and 80 of reference 1 may be used in the invention. A preferred antibody for use with the invention is an anti-sclerostin antibody as disclosed in reference 12 (the complete contents of which are incorporated herein by reference). Particularly preferred is the antibody MOR05813. MOR05813 (referred to herein as 'BPS804') has a VH domain with amino acid SEQ ID NO: 1 and a V L domain with amino acid SEQ ID NO: 2. Other anti-sclerostin antibodies useful with the present invention may include one or more (1, 2, 3, 4, S or 6) CDRs from MOR05813. The CDRs in the heavy chain are SEQ ID NOs: 3, 4 & 5. The CDRs in the light chain are SEQ ID NOs: 6, 7 & 8. The MOR05813 variable domains may be expressed as SEQ ID NOs: 9 and 10 to give a functional antibody, the MOR05813 VH CDRs may be expressed along with V H framework regions (e.g., V H human framework regions) to give a functional antibody, the MOR05813 V L CDRs may be expressed along with V L framework regions (e.g., V L human framework regions) to give a functional antibody, and MOR05813 V H and V L CDRS may be expressed along with V H and V L framework regions (e.g., V H and V L human framework regions) to give a functional antibody (e.g., human or humanized). As used herein, the term ""antibody" means a polypeptide comprising a framework region from an immunoglobulin gene or fragments thereof that specifically binds and recognizes an epitope, e.g. an epitope found on scierostin, as described above. Thus, the term antibody includes whole antibodies (such as monoclonal, chimeric, humanised and human antibodies), including single- chain whole antibodies, and antigen-binding fragments thereof. The term "antibody" includes antigen-binding antibody fragments, including single-chain antibodies, which can comprise the variable regions alone, or in combination, with all or part of the following polypeptide elements: hinge region, CH1, CH2, and CH3 domains of an antibody molecule. Also included within the definition are any combinations of variable regions and hinge region, CH1, CH2, and CH3 domains.
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