(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. Antibody fragments include, e.g., but are not limited to. Fab, Fab' and F(ab )2, Fd, single-chain Fvs (scFv), single-chain antibodies, disulphide-linked Fvs (sdFv) and fragments comprising cither a V L or V H domain. Examples include: (i) a Fab fragment, a monovalent fragment consisting of the V L V H, C L and CH1 domains; (ii) a F(ab') 2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulphide bridge at the hinge region; (iii) a
Fd fragment consisting of the V and CH1 domains; (iv) a Fv fragment consisting of the V|, and Vn domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., Nature 341 : 544-
546, 1989; Muyldermans et a!., TIBS 24: 230-235, 2001), which consists of a V H domain; and (vi) an isolated complementarity determining region (CDR). The term ''antibody'' includes single domain antibodies, maxibodies, minibodies, intrabodies, diabodies, triabodies, telrabodies, v-NAR and bis-scFv (see, e.g., Hollinger & Hudson, Nature Biotechnology, 23, 9, 1126-1136 (2005)). Antigen binding portions of antibodies can be grafted into scaffolds based on polypeptides such as Fibronectin type Hl (Fn3) (see U.S. Pat. No. 6,703,199, which describes fibronectin polypeptide monobodies). Antigen binding portions can be incorporated into single chain molecules comprising a pair of tandem Fv segments (VH-CHl-VH-CHl ) which, together with complementary light chain polypeptides, form a pair of antigen binding regions (Zapata el at.. Protein Eng. 8(10): 1057-1062 (1995); and U.S. Pat No. 5,641,870).
Given that the antibodies used in the invention can bind to sclerostin and that antigen-binding specificity is provided primarily by the CDRl . 2 and 3 regions, the VH CDRl , 2 and 3 sequences and VL CDRl, 2 and 3 sequences can be "mixed and matched" (i.e., CDRs from different antibodies can be mixed and matched), although each antibody must contain a VH CDRl, 2 and 3 and a VL CDRl, 2 and 3 to create other antksclerostin antibodies. Sclerostin binding of such "mixed and matched" antibodies can be tested using the binding assays described in WO2009/047356. When VH CDR sequences are mixed and matched, the CDRl, CDR2 and/or CDR3 sequence from a particular VH sequence should be replaced with a structurally similar CDR sequence If an anti-sclcrostin antibody is administered, the dose may be from about 1 mg/kg to about 500 mg/kg, or about 10 mg/kg to about 400 mg/kg, or about 100 mg/kg to about 350 mg/kg, or about 200 mg/kg to about 300 mg/kg. For BPS8G4> the dose may be about 5 mg/kg to about 300 mg/kg, or about 10 mg/kg to about 200 mg/kg. mg/kg means nig drug per kg body weight of the patient to be treated. In one embodiment, the total dose of anii-sclerostin antibody given to a patient over the course of a year may be about SOOmg to about 50,000mg. Alternatively, the bone anabolic agent may be a RANKL antibody (such as denosumab), parathyroid hormone (PTH), a PTU fragment or a PTH derivative e.g. PTH (1-84) {such as Preos™), PTH (1-34) (such as Foiteo™), PTH (1-36), PTH (1-38), PTH (1-3DNH2 or PTS 893. If PTH is administered as the bone anabolic agent, the dosage will typically be 20µg or 40µg daily. In one embodiment the PTH is administered in a single daily dose. In a further embodiment, the PTH is administered in a twice daily dose. In certain embodiments, the PTH (e.g., PTH (1-36), PTH (1-38)) is administered orally in combination with a suitable oral carrier, such as those set forth in U.S. 5,773,647 (herein incorporated by reference in its entirety), e.g., N-(5~chlorosal-cyloyl)-8-aminocapryHe acid (5-CNAC) and pharmaceutically acceptable salts (e.g., the disodium salt of 5-CNAC) and esters thereof. Bone resorption inhibitors As referred to herein, bone resorption inhibitors include, but are not limited to, bisphosphonales (e.g. Fosamax' M (alendronate), Actonel™ (risedronate sodium), Boniva/Bonviva 1 (ibandronic acid), Zometa™ (zoledronic acid), Aclasta™/Reclast™ (zoledronic acid), olpadronate, neridronate, etidronate, ciodronate, skelid, bonefbs), Selected Estrogen Receptor Modulators (SERMs, such as raloxifene, lasofoxifene, bazedoxifene, arzoxifene, FC 1271 , Tibolone (Livial )X estrogen and calcitonin. Other variants of bone resorption inhibitors are disclosed in reference 13 and may be used in the invention, In one embodiment, the bone resorption inhibitor is a bisphosphonate. In a further embodiment, the bone resorption inhibitor is a nitrogen- containing bisphosphonate. In a fiirthcr embodiment, the bone resorption inhibitor is calcitonin (e.g., a salmon calcitonin (sCT), such as Miacalcin' M). In yel a further embodiment, the sCT is is administered orally in combination with a suitable oral carrier, such as those set forth in U.S. 5,773,647 (herein incorporated by reference in its entirely), e.g., 5-CNAC and pharmaceutically acceptable salts (e.g., the disodium salt of 5-CNAC) and esters thereof, ϊ n certain embodiments, sCT may be administered with PTH and the disodium salt of 5-CNAC. It is preferred that the bone resorption inhibitor is 'zoledronic acid, such as Aclasta 1M/Reclast I If a bone resorption inhibitor is administered, such as a bisphosphonate, the dose may be from about 1 mg/yr to about 10 mg/yr, or about 2 mg/yr to about 8 mg/yr, or about 4 mg/yr to about 6 mg/yr. Such dosages particularly apply to more potent bisphosphonates, such as zoledr αnic acid when administered intravenously. Other bone resorption inhibitors, such as bisphosphonates other than zoledronic acϊd are less potent (see table 1 of reference 2), but may be used in the co-treatment of the invention, albeit at higher doses (for example, zoledronic acid is 10,00Ox more potent than etidronate). In such cases the dose may be about 1mg/yr to about 50,000mg/yr, or about 10mg/yr to about 10OOϋnig/yr, or about 100mg/yr to about 1000mg/yr, Further methods of dosing with bisphosphonates are disclosed in the art, such as in reference 13. Bone loss Bone loss, as referred Io herein, can refer to any condition which results in a loss of bone. A loss of bone is understood to mean a decrease in bone mineral density over time and/or a decrease in bone strength over time. Various methods for measuring bone mineral density are known in the art and include Dual energy X-ray absorptiometry (DEXA) » peripheral Dual energy X-ray absorptiometry (P-DEXA), dual photon absorptiometry (DPA), ultrasound and quantitative computed tomography (QCT). Such bone loss may be due to a condition of abnormally increased bone turnover, for example due to osteoporosis (including postmenopausal osteoporosis, male osteoporosis, glucocorticosteroid induced osteoporosis and juvenile osteoporosis); osteopenia; hormone deficiency (vitamin D deficiency, tnalc and female hypogonadism); hormone excess (hyperprolactinaemia, excess glucocorticoid, hyperthyroidism hyperparathyroidism); nutritional factors (digestive abnormalities, malabsorption syndromes); Paget's disease; other forms of bone loss due to medication; osteoarthritis; Renal bone disease; inflammatory disorders (Crohn's disease, rheumatoid arthritis); immobilisation; space travel; osteoporosis caused through neoplastic bone marrow disorders; osteogenesis imperfecta; hypophosphatasia; osteoporosis following hormone replacement therapy and genetic disorders and inborn errors of metabolism that cause bone fragility (familial hypophosphatasia. Gaucher' s disease, osteogenesis imperfecta, collagen disorders). Other diseases and disorders that may be treated by the combination of the invention include achondroplasia, cleidocranial dysostosis, enchondromatosis, fibrous dysplasia, hypophosphatemic rickets, Marfan 1s syndrome, multiple hereditary exoioses, neurofibromatosis, osteopetrosis, osteopoikilosis, sclerotic lesions, fractures, periodontal disease, pseudoarthrosis, pyogenic osteomyelitis, periodontal disease, anti-epileptic drug induced bone loss, primary and secondary, renal osteodystrophy, infiltrative disorders of bone, oral bone loss, osteonecrosis of the jaw, juvenile Paget's disease, melorheostosis, metabolic bone diseases, mastocytosis, sickle cell anemia/disease, organ transplant related bone loss, kidney transplant related bone loss, systemic lupus erythematosus, ankylosing spondylitis, epilepsy, juvenile arthritides, thalassemia, mucopolysaccharidoses, fabry disease, turner syndrome, Down Syndrome, Klinefelter Syndrome, leprosy, Perthes' Disease, adolescent idiopathic scoliosis, infantile onset multi-system inflammatory disease, Winchester Syndrome, Menkes Disease, Wilson's Disease, ischemic bone disease (such as Legg-Calve-Perthes disease, regional migratory osteoporosis), anemic states, heparin-induccd bone loss, bone marrow disorders, scurvy, malnutrition, calcium deficiency, idiopathic os ope i o osteoporosis congenital osteopenia or osteoporosis alcoholism chrome liver disease, postmenopausal state, chronic inflammatory conditions, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, inflammatory colitis, oligomenorrhea, amenorrhea, pregnancy, diabetes mellitus, Cυshing's disease, acromegaly, hypogonadism, reflex sympathetic dystrophy syndrome, regional osteoporosis, osteomalacia, bone loss associated with joint replacement, HlV associated bone loss, bone loss associated with loss of growth hormone, bone loss associated with cystic fibrosis, fibrous dysplasia, chemotherapy associated bone loss, tumor induced bone loss, cancer-related bone loss, hormone ablative bone loss, multiple myeloma, anorexia nervosa, disease associated facial bone loss, disease associated cranial bone loss, disease associated bone loss of the jaw and disease associated bone loss of the skull. Further conditions relate to bone loss associated with aging, including facial bone loss associated with aging, cranial bone loss associated with aging, jaw bone loss associated with aging, and skull bone loss associated with aging. Combinations of the invention may also be useful for improving outcomes in orthopedic procedures, dental procedures, implant surgery, joint replacement, bone grafting, bone cosmetic surgery and bone repair such as fracture healing, nonunion healing, delayed union healing and facial reconstruction. The combination may be administered before, during and/or after the procedure, replacement, graft, surgery or repair. in one embodiment, die bone loss being treated is due to severe osteoporosis. Severe osteoporosis patients have bone density T-score of <-3. T-scores are measured by DHXA and compare a patient's bone density to the optimal peak bone density for their gender. It is reported as number of standard deviations below the average. A T-score of greater than minus 1 is considered normal. A T-score of minus 1 to minus 2.5 is considered osteopenia, and a risk for developing osteoporosis. A T-score of less than minus 2.5 is diagnostic of osteoporosis, while a T-score of less than minus 3 is considered to be diagnostic of severe osteoporosis. Preferably the type of bone loss being treated is bone loss due to osteoporosis. The terms ''treatment'' or "treat'' as used herein refer to both prophylactic (e.g., delaying the onset of symptoms) or preventative treatment as well as curative or disease modifying treatment, including treatment of patients at risk of contracting a disease which will result in bone loss or suspected to have contracted a disease which will result in bone loss as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition which results in bone loss. In one embodiment the invention may be used for the prophylactic treatment of osteoporosis. In a further embodiment the invention may be used for the treatment of patients at in one embodiment, the patient being treated is one who has been identified as being at risk of suffering from osteoporosis. his embodiment includes both (i) patients at risk of fractures, and (ii) patients not at risk of fractures. Such a patient may be identified by looking at, for example, nutritional intake, family history, genetic markers, medical examination, serological bone biomarkers, and bone mineral density by DEXA, and overall fracture assessment by FRAX™, In one embodiment, the patient is 40 years of age or older, 50 years of age or older. 60 years of age or older, or 70 years of age or older, In one embodiment, the patient is a postmenopausal woman. n one embodiment, the patient is one who is non-responsive to treatment with parathyroid hormone, an analogue or fragment thereof. In one embodiment, the patient is one for whom treatment with parathyroid hormone, an analogue or fragment thereof is comraindicated. In such a case, the bone anabolic agent used is an anti-sclerostin antibody, preferably BPS804. Dosagefrequency As noted above, high doses of the bone anabolic agent and bone resorption inhibitor are administered to the subject. The administration may be simultaneous or sequential. If the bone anabolic agent and bone resorption inhibitor are administered sequentially, they may be administered in any order. In one embodiment, the time between administration of the bone anabolic agent and bone resorption inhibitor is about 24 hours or less, about 12 hours or less, about 6 hours or less, about 3 hours or less, or about one hour or less. In another embodiment, the time between administration of the bone anabolic agent and the bone resorption inhibitor may be about 1 month, about 3 months, or about 6 months. For example, in such cases the bone resorption inhibitor may be administered about 6 months (e.g., 6 months) after administration of the bone anabolic agent. Due to the high doses given, it will only be necessary to administer the medicaments infrequently. Thus the co-administration of the bone anabolic agent and anti-resorptive agent may take place about once annually, about once every 6 months or about once every 3 months. In one embodiment the co-administration may be a once-only treatment. If the co-administration of the bone anabolic agent and anti-rcsorptive agent is intended as a preventative measure, i.e. to treat a person at risk of suffering bone loss (for example, someone at risk of developing osteoporosis), then the medicaments may be administered about once a year, about once every two years, about once every five years or once only. Example dosage regimes include : 1) Quarterly administration Of course, it may be desirable Io give several doses of the bone anabolic agent before the first dose of bone resorption inhibitor is administered, and such dosage regimens are encompassed within the scope of the invention. Thus, a patient may receive several doses of a bone anabolic agent before receiving a dose of a bone resorption inhibitor. Thus, a patient may receive one, two, three or more doses of bone anabolic agent prior to receiving a dose of bone resorption inhibitor. IfPTH (or a fragment or analogue thereof, such as Forteo IM) is used as the bone anabolic agent, the PTH may be administered daily, while the bone resorption inhibitor is administered about once every 3 months, about once every 6 months, about once every 12 months or once only. The exact dosage frequency of the bone anabolic agent and bone resorption inhibitor may depend on various factors, such as effectiveness, speed of dosing and speed of action, Factors may also include the relative potency of the active ingredient, mode of administration, sex, age, weight and individual condition of the person being treated. Minor adjustments to the dosing frequency may be made by the attending physician to take into account these factors. Further co-treatments It has been recognized that mild to moderate vitamin D deficiency may contribute to bone loss and muscle weakness in osteoporosis patients, resulting in increased likelihood of falls and fractures. Clinical trials have shown that giving elderly patients a supplement of vitamin D and calcium resulted in a reduction in the hip fracture rate. In one embodiment, a co-administration of the invention may further comprise a dose of vitamin D. Typically, such a dose may be of about 10,000- about 600,000IU, about 50,000- about 300,000111 or about 100,000- about 20O5OOOIU with each administration of the bone anabolic agent and bone resorption inhibitor. The vitamin D may be parenterally administered in a single high dose (e. intravenously, intramuscularly, or subcutaneously; monthly, every 3 months, every 4 months, every 6 months or every 12 months). Alternatively, the vitamin D may be administered by a regular oral dose. If administered in a daily oral dose, the typical daily dose is 4G0-800IIK In one embodiment, the vitamin D may be provided separately to the bone anabolic agent and the bone resorption inhibitor, In another embodiment, the vitamin D may be provided as a single composition with a bisphosphonate, such as described in reference 14. Thus, if provided, the vitamin D may be co-administered with the bone anabolic agent and the bone resorption inhibitor in a simultaneous, sequential or separate manner. The term "vitamin D" as used herein defines any active form of vitamin D, such as 25- dihydroxyvitamin D, or a metabolite thereof, or a non-active precursor thereof, for example 25- hydroxyvitamin D3 (25-hydroxycholecalciferot, ealcifediol), vitamin D3 (cholecalciferol), vitamin D2 (ergoealciferol), l αHydroxycholecalciferol (alfacalcidol), 1,25- dihydroxycholecakiferol (cachriol), dihydroxytachysterol, doxercalciferol, provitamin D3 (7- dehydrocholestero!) and Vitamin D derivatives such as falecaicitriol, maxacalcitol and paricalcitol. In one embodiment of the invention, the vitamin D is provided as a non-activated precursor to 25-hydroxyvitamin D, for example in the form of cholecalciferol or ergoealciferol. In one embodiment the vitamin D is provided as cholecalciferol. Method of administration The bone anabolic agent and bone resorption inhibitor are preferably administered parenterally (e.g. intravenously, intramuscularly, or subcutaneously). They may be administered by injection or by infusion. If administered by infusion, the infusion may be administered over a period of 15 minutes or more. The bone anabolic agent and bone resorption inhibitor may be provided in separate containers and administered separately (but sliii simultaneously or sequentially). Alternatively, the bone anabolic agent and bone resorption inhibitor may be provided in (he same container. For example, the bone anabolic agent and bone resorption inhibitor may be provided in a two- or three-compartment infusion set (bag) such as described in references 15-18. The bone anabolic agent and bone resorption inhibitor may independently be provided as pre-concentrates, to be diluted prior to administration, or as ready-to-use solutions. Alternatively, the bone anabolic agent and bone resorption inhibitor may be provided as lyophilisates. Furthermore, if the bone resorption inhibitor is a bisphosphonate, it may be provided as a fat emulsion or a dispersion. If dilution is required, then this should be done with a pharmaceutically acceptable diluent. The anabolic agent and bone resorption inhibitor are preferably provided in one or more heat-sterilisable plastics containers. The particular mode of administration and the dosage may be adjusted by the attending physician taking into account the particulars of the patient, especially age, weight, lifestyle, activity level, hormonal status (e.g. postmenopausal) and bone mineral density as appropriate. As indicated above, the bone anabolic agent and bone resorption inhibitor (and optional vitamin D) may be administered in any order. Thus, the administration may take place in the order: ABC, BCA, CAB, ACB, BCA. BAC, wherein A is the bone anabolic agent, B is the bone resorption inhibitor and C is the optional vitamin D. The administration may be preceded, succeeded or interspersed with administration of PBS or another physiological buffer. Thus, in one embodiment, the bone anabolic agent is administered first, this is followed by administration of vitamin D or PBS, and lastly a bone resorption inhibitor is administered. Kits The invention provides kits, comprising a bone anabolic agent a bone resorption inhibitor and instructions for use. Such a kit may optionally further comprise vitamin I). In one embodiment, one or both of the bone anabolic agent and the bone resorption inhibitor may be provided in lyophilised form and the kit may further comprise a diluent and instructions for use. In one embodiment, the diluent for the bone anabolic agent may be a solution of the bone resorption inhibitor (tor example, a solution of zoledronic acid), Such kits may optionally further comprise infusion bags or syringes in order to administer the bone anabolic agent, bone resorption inhibitor and optional vitamin D. In one embodiment, the bone anabolic agent, bone resorption inhibitor and optional vitamin D may be in separate infusion bags. If in separate infusion bags, device may be provided to join the output of the infusion bags such that the patient receives the bone anabolic agent, bone resorption inhibitor and optional vitamin D simultaneously (i.e. through the same needle). In a further embodiment, the invention provides a kit comprising a bone anabolic agent and a bone resorption inhibitor in a pre-filled multi-compartment (e.g. two-compartment) infusion bag (e.g. Figure 4A), along with instructions for use. In a variant of this embodiment the multi¬ compartment infusion bag may comprise at least three compartments (e.g. Figure 4B), at least one compartment of which contains vitamin D. Multi-compartment infusion bags are known in the art, as described above. Thus, a prc-fiUed bag may contain a bone anabolic agent and an anti-resorptive agent in separate compartments. Once the agent in the first compartment has been administered, the seal between the two compartments may be ruptured (e.g. by pressure applied to the still filled compartment) so that the second agent is administered to the patient. In this case, the bone anabolic agent may be the first agent and the anti-resorptive agent may be the second agent, and vice versa. Such bags may optionally further comprise a third compartment containing vitamin D Thus, in such an embodiment, while the separate agents to be administered to the patient are prevented from being mixed (and thus simultaneously administered), they are conveniently available in a single infusion bag for sequential administration. As a further alternative, the multi-compartment infusion bag may contain the active ingredients in lyophilised form and suitable diluents, In such an embodiment, the multicompartment infusion bag would contain at least four compartments separated by ruptureable seals. Thus, for administration, the seal between the lyophilised first agent to be administered and its diluent would be ruptured to allow mixing. Once mixed, a further seal would be ruptured to allow administration. Following administration of the first agent, the seal between the lyophilised second agent to be administered and its diluent would be ruptured to allow mixing. Once mixed, a further seal would be ruptured to allow administration. In one embodiment, pre- filled infusion bags contain about 300 to about 18000mg BPS804, about 600 to about 6000mg BPS804 or about 800 to about 3000mg BPS804. In a further embodiment, pre-filled infusion bags contain about 0.5 to about 4.5mg Aclasta t M, about 1.5 to about 3.5mg Aclasta™, or about 2 to about 2.5mg Aclasta' M (i.e. about 0.5 to about 4.5mg z.oledron.ic acid, about 1.5 to about 3.5mg zoledronic acid, or about 2 to about 2.5mg zoledronic acid). In a further embodiment, a mulli -compartment infusion bag contains (i) about lOOOmg BPS804 and about 1.5mg Aclasta™, (ii) about 3000mg BPS804 and about 2.5mg Aclasta 1M, or (iii) about 6000mg BPS804 and about 4.5mg Aclasla™ (i.e. (i) about lOOOmg BPS804 and about 1.5mg zoledronic acid, (H) about 3000mg BPS804 and about 2.5mg zoledronic acid, or (iii) about όOOOmg BPS804 and about 4.5mg zoledronic acid). In such an embodiment, the BPS804 and zoledronic acid would be found in separate compartments of the multi-compartment infusion bag. In these embodiments, the BPS804 and zoledronic acid are provided as aqueous solutions. General The practice of the present invention will employ, unless otherwise indicated, conventional methods of chemistry biochemistry molecular biology immunology pharmacy posology and pharmacology, within the skill of the art. Such techniques are explained fully in the literature. See, e.g., references 19-25, etc. The term comprising' * encompasses "including -' as well as "consisting" e.g. a composition '"comprising" X may consist exclusively of X or may include something additional e.g. X - Y. The term "about" in relation to a numerical value x is optional and means, for example, x±l 0%. BRIEF DKSCRIPTION OF DRAWINGS Figure I shows the change in (A) bone mineral density and (B) bone mineral content over baseline in mouse tibia following a weekly dose of O, 1, 10 or 100 mg/kg BPS804 or a single 300mg/kg treatment with BPS804. Figure 2 shows the change in (A) bone mineral density and (B) bone mineral content over baseline in mouse tibia following four monthly treatments of 0. 1, 10 or 100mg/kg BPS804 with and without subsequent administration of a single iv dose of 100 µg/kg zoledronic acid. Figure 3 shows percent change from baseline value in cross-sectional total bone mineral density of the distal femur metaphysis of aged intact or ovariectomized (OVX) O I/IC mice as evaluated by pQCT. Mean +/- SEM. ANOVA, Dunnett, p < .05, ** p < .01 versus OVX control; x p < .05, xx p < .01 single treatment versus combination treatment. Figure 4 illustrates the 2 (A) or 3 (B) compartment infusion bag. The arrow indicates the outlet to the patient, the dashed lines indicate ruptυreabte seals and the numbers indicate the compartments which may contain a bone anabolic, a bone anti-rcsorptive and/or vitamin D. MODES FOR CARRYING OUT THE INVENTION Example J Female aged nude mice (7-month-old) were treated intravenously either weekly (n !!! 16 / group) with increasing doses of the anti-SOST antibody (1, 10, 100 mg/kg) for 4 months or they received a single dose of the anti-SOST antibody (300 mg/kg) (n !!! 8 / group). Changes in bone mineral density and content were monitored at monthly intervals in the proximal tibia mctaphysis by peripheral quantitative computed tomography (pQCT). Weekly treatment with the anti-SOST antibody induced dose-related increases in bone mineral density from the 10 mg/kg dose onwards (Figure 1 A, B). Single application of 300 mg/kg was sufficient to increase bone mineral density and bone mineral content significantly above control levels for up to 2 and 3 months respectively (Figure 1 A, B). The highest increase was observed at the 1 month scanning time point, while values reverted towards control levels by 4 months. The animals, which had received weekly treatment were subdivided into two groups (n = 8 / group) and received either no treatment or a single intravenous dose of anti-catabolic zoledronic acid treatment ( 100 microg/kg). Changes in bone mineral density and content in the cross-section of the proximal tibia metaphysis were monitored for another two months by pQCT. Animals, which received no anti-catabolic treatment, lost the bone gained during anabolic treatment, while those animals* which had received a single dose of zoledronic acid maintained or slightly increased bone mineral density and content F e 2 A, B). Example 2 It has been shown previously that co-treatment of multiple bone anabolic doses of the anti-SOST antibody with single dose zoledronic acid protected estrogen deprived mice entirely from bone loss and instead induced bone gain (reference 12). Based on this previous evidence and the present data, we conclude that combination of a single bone anabolic dose of anti-SOST antibody with a single dose of zoledronic acid will induce bone gain due to the anabolic treatment, which will be sustained for an extended time period due to the anti-resoφ tive protective treatment. In order to demonstrate that combination of a single bone anabolic dose of anti-SOST antibody with a single dose of zoledronic acid induces bone gain due to the anabolic treatment, we apply now a single dose of either treatment or the combination thereof to skeletally mature mice. Female skeletally mature mice are treated with vehicle, a single iv. dose 300 mg/kg anti-SOST antibody, a single iv. dose of zoledronic acid (100 microg/kg), a combination thereof or with vehicle (n 10 / group). Changes in bone mineral density and content in the cross-section of the proximal tibia metaphysis are monitored in alt 4 groups monthly by pQCT for 6 months. Example 2a Female aged OR/IC mice (6-month-old) were ovariectomized (OVX). The animals received 2-3 days after OVX intravenously a single dose of the anti-SOST antibody MOR05813 (100 mg/kg), or a single dose of zoledronic acid (100 microg/kg), or a combination thereof (n = 7-10 / group). Changes in bone mineral density (BMD) were monitored at monthly intervals in the distal femur metaphysis by peripheral quantitative computed tomography (pQCT). Animals were sacrificed after 5 months. Ovariectomy induced rapid BMD loss as expected (Figure 3). Single application of 100 mg/kg bone forming anti-SOST antibody was sufficient to inhibit significantly bone loss for up to 3 months. Single dose application of anti-resorptive zoledronic acid provided significant protection from BMD loss for the entire monitoring period. Combination of the two single dose treatments resulted not only in protection from BMD loss, but induction of gain and a significantly better effect than the individual treatments at all lime points which suggested a synergistic interaction. Example 3 Example dosage regimes for humans In each case, the active agents are administered by iv infusion, sequentially. BPS804 is administered first, followed by Aclasta IM (zoledronic acid). Assuming no adverse reactions to BPS804 treatment, Aclasta1M (zoledronic acid) is administered within 24 hours of the BPS804 being administered. 1) Quarterly administration: 5 to 50 mg/kg BPS804 with 0.5 to 1.5 mg Aclasta™ (zoledronic acid) 2) Half-yearly administration: 10 to 100 mg/kg BPS804 with 1.5 Io 2.5 mg Aclasta™ (zoledronic acid) 3) Yearly administration: 30 to 300 mg/kg BPS804 with 3 5 to 4.5 mg Aclasta™ (zoledronic acid) It will be understood that the invention will be described by way of example only, and that modifications may be made whilst remaining within the scope and spirit of the invention. REFERENCES [I ] Honeywell et al. Physical Therapy, 2003, 28(11):713-716 [2] Shaw & Bishop. Arch. DLs. Child, 2005, 90:494-499 [3] Woo et al. Ann. Intern. Med., 2006, 144:753-761 [4] WO00/32773 [5] WO2005/014650 [6] WO2005/003158 [7] WO2006/119107 [8] WO2008/06 1013 [9] WO2008/133722 [10] WO2008/115732 [ 1 1] US7592429 B2 [12] WO2009/047356 [13] WOO 1/97788 [14] WO2008/116809 [15] WO2007/040010 [16] WO2008/08I023 [17] EPO87523 l [18] WO97/37628 {19] Methods In Enzymology (S. Colowick and N . Kaplan, eds., Academic Press, Inc.) [20] Handbook of Experimental Immunology, VoIs. I-IV (D.M. Weir and CC. Blackwell, eds, 1986, Blackwell Scientific Publications) [21] Sambrook et al. (2001) Molecular Cloning: A Laboratory Manual, 3rd edition (Cold Spring Harbor Laboratory Press), [22] Handbook of Surface and Colloidal Chemistry (Birdi, K.S. ed., CRC Press, 1997) 123] Ausubel et al. (eds) (2002) Short protocols in molecular biology, 5th edition (Current Protocols). [24] Molecular Biology Techniques: An Intensive Laboratory Course, (Ream et al., eds., 1998, Academic Press) [25] PCR {Introduction to Biotechniques Series), 2nd ed. (Newton & Graham eds., 1997, Springer Verlag) CLAIMS 1. 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. 2. 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, 3. 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. 4. 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. 5. Use of a bone resorption inhibitor in the manufacture of a medicament for the treatment of bone loss, wherein the medicament is used in conjunction with a bone anabolic agent. 6. Use of a bone anabolic agent 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 resorption inhibitor. 7. of a bone resorption inhibitor in the manufacture of medicament for the treatment of bone loss in a patient, wherein said patient has been pre-treated with a bone anabolic agent. 8. The method or use of any one of claims 1-7 wherein the bone loss is caused by asteoporosis. 9. The method or use of any previous claim wherein said bone anabolic agent is (a) an anti-sclerostin antibody or functional fragment thereof, or (b) denosumab. 10. The method or use of claim 9, wherein said anti-sclerostin antibody is selected from the group consisting of BPS804, an antibody comprising the three CDRs of the V domain of BPS804, an antibody comprising the three CDRs of the V] domain of BPS804, and an antibody comprising the three CDRs of the V domain and the three CDRs of the Vi. domain of BPS804 . 1. The method or use of claim 10, wherein said antibody is administered in a dose of about 5mg/kg to about 200mg/kg. 12. The method or use of claim 10, wherein said antibody is administered in a dose of about 500mg to about 50,000mg per year. 13. The method or use of any previous claim, wherein said bone resorption inhibitor is a bisphosphonate. 14. The method or use of claim 13, wherein said bisphosphonate is /oledronic acid. 15. The method or use of claim 14, wherein said zoledronic acid is administered in a dose of about 2ing/yr to about 10mg/yr. 16. The method or use of any previous claim wherein the co-treatment is administered once every 3 months, once every 6 months or once every 12 months. 17. The method or use according to claim 16, wherein the co-treatment is administered once every 3 months. 18. The method or use of any previous claim, wherein the bone anabolic agent and bone resorption inhibitor are administered simultaneously or sequentially. 19. The method or use of claim 18, wherein the bone anabolic agent and bone resorption inhibitor are administered sequentially, wherein the time between administration of the bone anabolic agent and bone resorption inhibitor is 24 hours or less, 12 hours or less, 6 hours or less, 3 hours or less, or one hour or less. 20. The method or use of any previous claim wherein a high dose of vitamin D is co-administered. 2 1. The method or use of claim 20, wherein vitamin D is administered in a dose of about 10,000 to about 600,000 IU. 22. The method or use according to any previous claim, wherein the subject is human. 23. The method or use according to any previous claim, wherein the subject is a human suffering from severe osteoporosis, as determined by having a T-score of <-3. 24. The method or use according to claim 23, wherein the subject has suffered from one or more bone fractures. 25. Λ kit comprising a bone anabolic agent, a bone resorption inhibitor and instructions for administration. 26. The kit of claim 25, further comprising vitamin D. 27. The kit of claim 25 or claim 26, wherein said bone anabolic agenl is an anti-scierostin antibody. 28. The kit of claim 27, wherein said bone anabolic agent is BPS804. 29. the kit of claim 27, wherein said bone anabolic agent is denosumab. 30. The kit of any one of claims 25-29,. wherein said bone resorption inhibitor is a bisphosphonate. 31. The kit of claim 30, wherein said bone resorption inhibitor is /oledronic acid, 32. The kit of claim 31, comprising about 500 to about 50,000 mg BPS804, about 2 to about 10 mg zoledronic acid, instructions for use and optionally vitamin D. 33. A kit according to any one of claims 25-32. wherein one or more of the active agents is provided in lyophilised form and the kit optionally further comprises a pharmaceutically acceptable diluent, 34. A kit according to any one of claims 25-33 wherein said kit comprises a multi-compartment infusion bag, said bag containing, in separate compartments, a bone anabolic agent, a bone resorption inhibitor and optionally vitamin D. AMENDED CLAIMS rece ived by the Inte rnational Bureau on 03 August 2010 (03.08.2010) A method of reducing bone loss in a subject comprising co-administering an anti-sclerostin antibody or functional fragment thereof and zoledronic acid. A method of inducing bone growth in a subject suffering from bone loss comprising co-administering an anti-sclerostin antibody or functional fragment thereof and zoledronic acid. Use of an anti-sclerostin antibody or functional fragment thereof co-administered with zoledronic acid for the treatment of bone loss. Use of an anti-sclerostin antibody or functional fragment thereof in the manufacture of a medicament for the treatment of bone loss, wherein the medicament is used in conjunction with zoledronic acid. Use of zoledronic acid in the manufacture of a medicament for the treatment of bone loss, wherein the medicament is used in conjunction with an anti-sclerostin antibody or functional fragment thereof. Use of an anti-sclerostin antibody or functional fragment thereof in the manufacture of a medicament for the treatment of bone loss in a patient, wherein said patient has been pre-treated with zoledronic acid. Use of zoledronic acid in the manufacture of a medicament for the treatment of bone loss in a patient, wherein said patient has been pre-treated with an anti-sclerostin antibody or functional fragment thereof. The method or use of any one of claims 1-7 wherein the bone loss is caused by osteoporosis. The method or use of any previous claim, wherein the anti-sclerostin antibody or functional fragment thereof comprises the three CDRs of the V H domain set forth as SEQ ID NO:1 and the three CDRs of the VL domain set forth as SEQ ID NO:2. The method or use of claim 9, wherein said antibody is administered in a dose of about 10 mg/kg to about 100 mg/kg. The method or use of claim 9, wherein said antibody is administered in a dose of about 500 mg to about 50,000 mg per year. The method or use of any previous claim, wherein said zoledronic acid is administered in a dose of about 2 mg/yr to about 10 mg/yr. The method or use of any previous claim, wherein the co-treatment is administered once every 3 months, once every 6 months or once every 12 months. The method or use according to claim 13, wherein the co-treatment is administered once every 3 months. The method or use of any previous claim, wherein the anti-sclerostin antibody or functional fragment thereof and zoledronic acid are administered simultaneously or sequentially. The method or use of claim IS, wherein the anti-sclerostin antibody or functional fragment thereof and zoledronic acid are administered sequentially, wherein the time between administration of the anti-sclerostin antibody or functional fragment thereof and zoledronic acid is 24 hours or less, 12 hours or less, 6 hours or less, 3 hours or less, or one hour or less. The method or use any previous claim, wherein vitamin D is co-administered at dose of about 10,000 to about 600,000 IU. The method or use according to any previous claim, wherein the subject is human. The method or use according to any previous claim, wherein the subject is a human suffering from severe osteoporosis, as determined by having a T-score of <-3. The method or use according to claim 19, wherein the subject has suffered from one or more bone fractures. A kit comprising about 2 to about 10 mg of zoledronic acid, about 500 to about 50,000 mg of an anti-sclerostin antibody or functional fragment thereof and instructions for administration. The kit of claim 21, further comprising vitamin D. A kit according to claim 2 1 or 22, wherein one or more of the zoledronic acid and the anti-sclerostin antibody or functional fragment thereof is provided in lyophilised form and the kit optionally further comprises a pharmaceutically acceptable diluent. A kit according to any one of claims 21, 22 or 23, wherein said kit comprises a multi-compartment infusion bag, said bag containing, in separate compartments, an anti-sclerostin antibody or functional fragment thereof, zoledronic acid and optionally vitamin D. A method or use according to any one of claims 1-8, wherein the anti-sclerostin antibody is substituted by denosumab. A. CLASSIFICATION OF SUBJECT MATTER INV. A61K31/675 A61K38/00 A61K39/395 A61K45/06 A61P19/08 A61P19/10 ADD. According Io International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) A61K A61P Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted duπng the international search (name of data base and, where practical, search terms used) EPO-Internal , BIOSIS, EMBASE, WPI Data C. DOCUMENTS CONSIDERED TO BE RELEVANT Category * Citation of document, with indication, where appropnate, of the relevant passages Relevant to claim No US 2008/160060 A l (ELLIES DEBRA L [US]) 1-34 3 July 2008 (2008-07-03) page 2 , paragraph 22-28 page 5 , paragraph 46 page 8 , paragraph 83-84 page 9 , paragraph 93 claims 23-34 WO 03/039534 A l (MERCK & CO INC [US]; 1-12, STOCH SELWYN AUBREY [US]; ORLOFF JOHN 16-29, [US]) 15 May 2003 (2003-05-15) 33,34 claims 1,210,11, page 18, lines 13-23 -/-- Further documents are listed in the continuation of Box C See patent family annex * Special categones of cited documents "T" later document published after the international filing date or pπonty date and not in conflict with the application but "A" document defining the general state of the art which is not cited to understand the pnnciple or theory underlying the considered to be of particular relevance invention "E" earlier document but published on or after the international "X" document of particular relevance, the claimed invention filing date cannot be considered novel or cannot be considered to "L" document which may throw doubts on priority claιm(s) or involve an inventive step when the document is taken alone which is cited to establish the publication date of another "Y" document of particular relevance, the claimed invention citation or other special reason (as specilied) cannot be considered to involve an inventive step when the "O" document referπng to an oral disclosure, use, exhibition or document is combined with one or more other such docu¬ other means ments, such combination being obvious to a person skilled "P" document published prior to the international filing date but in the art later than the priority date claimed "&" document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 4 June 2010 23/06/2010 Name and mailing address of the ISA/ Aulhonzed officer European Patent Oflice P B 5818 Patentlaan 2 NL - 2280 HV Rijswijk TeI (+31-70) 340-2040, Fax (+31-70) 340-3016 Nyeki , Agnes Form PCT/ISA/210 (second sheel) (April 2005) C(Conlinuation). DOCUMENTS CONSIDERED TO BE RELEVANT Category * Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X US 2007/238769 Al (OCHI YASUO [JP] ET AL ) 1-8, 11 October 2007 (2007-10-11 ) 16-26, 33,34 page 2 , paragraph 19-22 page 11 , paragraph 157-160 c l aims 1-3 , 7 , 5 X WO 98/57656 Al (ASTRA AB [SE] ; DIETRICH 1-5,7,8, JOHN [CA] ; LJUNGHALL SVERKER [SE] ; 13-26, SJOEGREN SV ) 23 December 1998 ( 1998-12-23) 30, 3 1 , 33 , 34 the whol e document X PAPAPOULOS SOCRATES ET AL : "Sel ection of 1-5,7,8, antiresorpti ve or anabol i c treatments for 13-26, postmenopausal osteoporosi s . " 30, 3 1 , NATURE CLINICAL PRACTICE . ENDOCRINOLOGY & 33, 34 METABOLISM SEP 2008 LNKD- PUBMED : 18714329 , vol . 4 , no . 9 , September 2008 (2008-09) , pages 514-523 , XP002585731 ISSN: 1745-8374 abstract "Combi nati on therapy" ; page 519, r i ght-hand col umn - page 521 , right-hand col umn Y L I XIAODONG ET AL : "Sclerostin anti body 1-34 treatment increases bone formati on , bone mass , and bone strength i n a rat model of postmenopausal osteoporosi s . " JOURNAL OF BONE AND MINERAL RESEARCH : THE OFFICIAL JOURNAL OF THE AMERICAN SOCIETY FOR BONE AND MINERAL RESEARCH APR 2009 LNKD- PUBMED : 19049336, vol . 24 , no . 4 , 1 December 2008 (2008-12-01 ) , pages 578-588, XP002585732 ISSN: 1523-4681 abstract Y REID ET AL : "Anti-resorpti ve therapi es 1-34 for osteoporosi s " SEMINARS I N CELL AND DEVELOPMENTAL BIOLOGY, ACADEMIC PRESS , GB LNKD- DOI : 10 . 1016/J . SEMCDB . 2008. 08. 002, vol . 19, no. 5 , 1 October 2008 (2008-10-01 ) , pages 473-478, XP025561443 ISSN : 1084-9521 [retrieved on 2008-08-07] the whol e document -/-- Form PCT/ISA/210 (continuation ol second sheet) (April 2005) C(Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT Category- Citation ol document, with indication, where approp πate, ol the relevant passages Relevant to claim No X ,P WO 2009/047356 A l (NOVARTIS AG [CH]; 1-34 KNEISSEL MICHAELA [CH]; HALLEUX CHRISTINE [CH]; HU S ) 16 April 2009 (2009-04-16) page 2 , paragraph 5 - page 3 , paragraph 5 pages 85-86; example 13 figure 2 1 Form PCT/lSA/210 (continuation of second sheet) {April 2005) Patent document Publication Patent family Publication cited in search report date member(s) date US 2008160060 Al 03-07-2008 EP 2144613 A2 20-01-2010 WO 2009131553 A2 29-10-2009 WO 03039534 Al 15-05-2003 CA 2465499 Al 15-05-2003 EP 1446114 Al lfr-08-2004 J P 2005511593 T 28-04-2005 US 2007238769 Al 11-10-2007 EP 1741441 Al 10-01-2007 UO 2005102381 Al 03-11-2005 WO 9857656 Al 23-12-1998 AT 447410 T 15-11-2009 AT 275419 T 15-09-2004 AU 753477 B2 17-10-2002 CA 2294101 Al 23-12-1998 CA 2698626 Al 23-12-1998 DE 69826132 Dl 14-10-2004 DE 69826132 T2 15-09-2005 DK 1473040 T3 15-03-2010 DK 1001802 T3 17-01-2005 EP 1473040 Al 03-11-2004 EP 1001802 Al 24-05-2000 ES 2335404 T3 26-03-2010 ES 2229511 T3 16-04-2005 HK 1029738 Al 24-03-2005 J P 2002504140 T 05-02-2002 PT 1473040 E 02-02-2010 PT 1001802 E 31-01-2005 US 6284730 Bl 04-09-2001 US 2009118192 Al 07-05-2009 ZA 9804947 A 04-01-1999 WO 2009047356 Al 16-04-2009 A R 068767 Al 02-12-2009 AU 2008309514 Al 16-04-2009 PE 12212009 Al 11-09-2009 US 2009130113 Al 21-05-2009 Form PCT/ISA/210 (palenl family annex) (April 2005)