Methods of treating or preventing osteoporosis and low bone mass

Abstract

The present application provides methods of use, specifically methods of treatment of a disease, disorder, or condition (e.g, a low bone mass condition such as osteoporosis) in a human individual, comprising administration of novel bispecific antibodies that bind to both sclerostin and DKK-1 (e.g, anti-Sclerostin x anti-DKK-1 bispecific antibodies). The present application also provides methods of increasing bone mineral density in a human individual comprising administration of novel anti-Scl erostin x anti-DKK-1 bispecific antibodies. The present application further provides methods of reducing risk of bone fracture (e.g., osteoporotic fracture) in a human individual comprising administration of novel anti-Sclerostin x anti-DKK-1 bispecific antibodies.

Description

Attorney Docket No. 21091-20003.40METHODS OF TREATING OR PREVENTING OSTEOPOROSIS AND LOW BONE MASSCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. provisional application 63 / 687,184, filed on August 26, 2024, the content of which is incorporated by reference in its entirety for all purposes.SUBMISSION OF SEQUENCE LISTING ON ASCII TEXT FILE

[0002] The contents of the electronic sequence listing (210912000340SEQLIST.xml; Size: 20,098 bytes; and Date of Creation: August 21, 2025) is herein incorporated by reference in its entirety.TECHNICAL FIELD

[0003] The present disclosure relates to methods of treating or preventing osteoporosis or conditions associated with low bone mass in an individual (e.g., human patient) by administration of a bispecific antibody that binds to both Sclerostin and Dickkopf-related protein 1 (DKK-1).BACKGROUND OF THE APPLICATION

[0004] Diseases or disorders associated with low bone mineral density, such as osteoporosis (OP), increased risk of bone fracture. These conditions can lead to decreased quality of life, particularly in elderly patients, relating to pain, immobility, discomfort, and increase in mortality. Methods to treat diseases or disorders associated with low bone mineral density such as osteoporosis are aimed to increase bone mineral density, and reduce skeletal fractures.

[0005] Currently, three classes of agents are commonly used for the treatment of OP: antiresorptive agents that target osteoclasts and inhibit bone resorption and destruction, anabolic agents that target osteoblasts and stimulate bone formation and rebuilding of bone mass, and dual-acting agents that can increase bone formation and reduce bone resorption with short term therapy. Approved antiresorptive agents include bisphosphonates, selective estrogen receptor modulators, a receptor activator of nuclear factor-K B ligand (RANKL) inhibitor, and others. Although some of these antiresorptive agents have shown reasonable efficacy in reducing bone resorption, increasing BMD, and decreasing the risk for skeletal fragility1MOFO-359878767Attorney Docket No. 21091-20003.40 fractures, there is no evidence that they can stimulate bone formation and restore strength to the levels similar to those observed in young, healthy adults.

[0006] The anabolic agents approved for OP are Forteo® (teriparatide, a parathyroid hormone analog [PTH 1-34]) and TYMLOS® (abaloparatide, a human parathyroid hormone related peptide [PTHrP 1-34] analog). Teriparatide causes an increase in bone mass and reduces vertebral fracture risk, but it is markedly less effective for the prevention of hip fractures in patients with OP. In addition, they must be injected daily, making patient compliance difficult.

[0007] Recently approved Evenity® (romosozumab, a humanized monoclonal IgG2 anti- sclerostin antibody) is a dual-acting agent that can increase bone formation and decrease bone resorption. Other anti-sclerostin antibodies including blosozumab (LY2541546) and setrusumab (BPS804) have also been investigated in humans for conditions such as OP (postmenopausal or male) and adult hypophosphatasia (setrusumab), and adult moderate osteogenesis imperfecta (setrusumab). Presently, romosozumab is the only dual -acting agent that has been approved for the treatment of OP. However, the anabolic effect of romosozumab wanes after 12 monthly doses of therapy. The duration of romosozumab use should be limited to 12 monthly doses. In addition, there was an increased risk of major adverse cardiovascular events observed with romosozumab in one of its registrational Phase 3 trials.

[0008] The disclosures of all publications, patents, patent applications and published patent applications referred to herein are hereby incorporated herein by reference in their entirety.BRIEF SUMMARY OF THE APPLICATION

[0009] The following summary is illustrative only and is not intended to be limiting in any way. That is, the following summary is provided to introduce highlights, benefits and advantages of the novel molecules and the uses thereof. Thus, the following summary is not intended to identify essential features of the claimed subject matter, nor is it intended for use in determining the scope of the claimed subject matter.

[0010] The present application in one aspect provides a method of treatment comprising administering a bispecific antibody that specifically binds to both sclerostin and DKK-1 to a human individual in need thereof, wherein the bispecific antibody comprises a) a first polypeptide comprising a first heavy chain variable region (VH-I), b) a second polypeptide comprising a first light chain variable region (VL-I), C) a third polypeptide comprising a second heavy chain variable region (VH-2), d) a fourth polypeptide comprising a second variable region (VL-2), wherein: 1) the VH-I comprises a HC-CDR1 comprising the amino acid sequence of2MOFO-359878767Attorney Docket No. 21091-20003.40SEQ ID NO: 1, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 3; 2) the VL-I comprises a LC- CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NOs: 6; 3) the VH-2 comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 9; and 4) the VL-2 comprises a LC- CDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12 (herein referred to as “BAP0063 polypeptides”), and wherein the bispecific antibody neutralizes both sclerostin and DKK1, and wherein the bispecific antibody is administered to the human individual at a dose of at least about Img / kg, preferably at a dose of at least 3 mg / kg. In some embodiments, the bispecific antibody reduces the risk of osteoporosis includes reducing the risk of developing osteoporosis, or reducing the severity of existing osteoporosis.

[0011] In some embodiments according to the method described above, the human individual is suffering from a bone-related disorder.

[0012] In some embodiments according to the method described above, the human individual is suffering from nonunion, a malunion, and / or a reoperation.

[0013] In some embodiments according to the method described above, the human individual is suffering from low bone mass.

[0014] When described hereafter, a bispecific antibody comprising “BAP0063 polypeptides” refers to a bispecific antibody comprising a) a first polypeptide comprising a first heavy chain variable region (VH-I), b) a second polypeptide comprising a first light chain variable region (VL-I), C) a third polypeptide comprising a second heavy chain variable region (VH-2), d) a fourth polypeptide comprising a second variable region (VL-2), wherein: 1) the VH-I comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3; 2) the VL-I comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NOs: 6; 3) the VH-2 comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 9; and 4) the VL-2 comprises a LC-CDR1 comprising the amino3MOFO-359878767Attorney Docket No. 21091-20003.40 acid sequence of SEQ ID NO: 10, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12.

[0015] When described hereafter, a bispecific antibody comprising “BAP0063 VH / VL” refers to a bispecific antibody comprising 1) a VH-I comprising a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3; 2) a VL-I comprising a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LC- CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NOs: 6; 3) a VH-2 comprising a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 9; and 4) a VL-2 comprising a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LC- CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12. When described hereafter, a bispecific antibody comprising “BAP0063 CDRs” comprises the CDRs comprised within the BAP0063 VH / VL. The BAP0063 polypeptides comprise the BAP0063 VH / VL. The BAP0063 VH / VL comprise the BAP0063 CDRs.

[0016] The present application in another aspect provides a method of treating a condition associated with low bone mass in a human individual comprising administering a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises a) a first polypeptide comprising a first heavy chain variable region (VH-I), b) a second polypeptide comprising a first light chain variable region (VL-I), C) a third polypeptide comprising a second heavy chain variable region (VH-2), d) a fourth polypeptide comprising a second variable region (VL-2), wherein: 1) the VH-I comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3; 2) the VL-I comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LC- CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NOs: 6; 3) the VH-2 comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 9; and 4) the VL-2 comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LC- CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12, and wherein the bispecific antibody is4MOFO-359878767Attorney Docket No. 21091-20003.40 administered to the human individual at a dose of at least about Img / kg, preferably at a dose of at least about 3 mg / kg.

[0017] The present application in another aspect provides a method of treating osteoporosis or reducing risk of osteoporosis in a human individual, comprising administering a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bi specific antibody comprises a) a first polypeptide comprising a first heavy chain variable region (VH-1), b) a second polypeptide comprising a first light chain variable region (VL-1), c) a third polypeptide comprising a second heavy chain variable region (VH-2), d) a fourth polypeptide comprising a second variable region (VL-2), wherein: 1) the VH-1 comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3; 2) the VL-1 comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LC- CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NOs: 6; 3) the VH-2 comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 9; and 4) the VL-2 comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12, and wherein the bispecific antibody is administered to the human individual at a dose of at least about 1 mg / kg, preferably at a dose of at least about 3 mg / kg.

[0018] The present application in another aspect provides a method of increasing bone mineral density in a human individual comprising administering a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises a) a first polypeptide comprising a first heavy chain variable region (VH-I), b) a second polypeptide comprising a first light chain variable region (VL-I), C) a third polypeptide comprising a second heavy chain variable region (VH-2), d) a fourth polypeptide comprising a second variable region (VL-2), wherein: 1) the VH-I comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3; 2) the VL-I comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LC- CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NOs: 6; 3) the VH-2 comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HC-CDR2 comprising the amino acid sequence of5MOFO-359878767Attorney Docket No. 21091-20003.40SEQ ID NO: 8, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 9; and 4) the VL-2 comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LC- CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12, and wherein the bispecific antibody is administered to the human individual at a dose of at least about Img / kg, preferably at a dose of at least about 3 mg / kg.

[0019] The present application in another aspect provides a method of increasing both cortical bone and trabecular bone in a human individual comprising administering a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises a) a first polypeptide comprising a first heavy chain variable region (VH-I), b) a second polypeptide comprising a first light chain variable region (VL-I), C) a third polypeptide comprising a second heavy chain variable region (VH-2), d) a fourth polypeptide comprising a second variable region (VL-2), wherein: 1) the VH-I comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3; 2) the VL-I comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LC- CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NOs: 6; 3) the VH-2 comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 9; and 4) the VL-2 comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LC- CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12, and wherein the bispecific antibody is administered to the human individual at a dose of at least about Img / kg, preferably at a dose of at least about 3 mg / kg.

[0020] The present application in another aspect provides a method of preventing or reducing risk of osteoporotic fracture or accelerating fracture healing in a human individual comprising administering a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises a) a first polypeptide comprising a first heavy chain variable region (VH-I), b) a second polypeptide comprising a first light chain variable region (VL-I), C) a third polypeptide comprising a second heavy chain variable region (VH-2), d) a fourth polypeptide comprising a second variable region (VL-2), wherein: 1) the VH-I comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HC-CDR3 comprising the amino6MOFO-359878767Attorney Docket No. 21091-20003.40 acid sequence of SEQ ID NO: 3; 2) the VL-I comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NOs: 6; 3) the VH-2 comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 9; and 4) the VL-2 comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12, and wherein the bispecific antibody is administered to the human individual at a dose of at least about Img / kg, preferably at a dose of at least about 3 mg / kg.

[0021] The present application in another aspect provides a method of reducing risk of vertebral fracture and / or non-vertebral fracture in a human individual comprising administering a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises a) a first polypeptide comprising a first heavy chain variable region (VH-I), b) a second polypeptide comprising a first light chain variable region (VL-I), C) a third polypeptide comprising a second heavy chain variable region (VH-2), d) a fourth polypeptide comprising a second variable region (VL-2), wherein: 1) the VH-I comprises a HC- CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3; 2) the VL-I comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LC- CDR3 comprising the amino acid sequence of SEQ ID NOs: 6; 3) the VH-2 comprises a HC- CDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 9; and 4) the VL-2 comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12, and wherein the bispecific antibody (subcutaneously) is administered to the human individual at a dose of at least about Img / kg. In some embodiments, the vertebral fracture is lumbar spine fracture. In some embodiments, the bispecific antibody is subcutaneously administered to the human individual at a dose of at least about 3 mg / kg. In some embodiments, the bispecific antibody is subcutaneously administered to the human individual at a dose of at least about 6 mg / kg. In some embodiments, the bispecific antibody is subcutaneously administered to the human individual at a dose of at least about 8 mg / kg. In some embodiments, the bispecific antibody is7MOFO-359878767Attorney Docket No. 21091-20003.40 subcutaneously administered to the human individual at a dose of at least about 10 mg / kg. In some embodiments, the bispecific antibody is subcutaneously administered to the human individual at a dose of at least about 12 mg / kg. In some embodiments, the bispecific antibody is subcutaneously administered to the human individual at a dose of at least about Img / kg, 3 mg / kg, 6 mg / kg, 8 mg / kg, or 10 mg / kg, 12 mg / kg or 15 mg / kg (e.g., a single injection within a one month, two months or three months period). In some embodiments, the bispecific antibody is subcutaneously administered to the human individual at a dose of at least about Img / kg, 3 mg / kg, 6 mg / kg, 8 mg / kg, or 10 mg / kg, 12 mg / kg monthly for at least about one month, two months or three consecutive months.

[0022] The present application in another aspect provides a method of reducing risk of hip fracture in a human individual comprising administering a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises a) a first polypeptide comprising a first heavy chain variable region (VH-I), b) a second polypeptide comprising a first light chain variable region (VL-I), C) a third polypeptide comprising a second heavy chain variable region (VH-2), d) a fourth polypeptide comprising a second variable region (VL-2), wherein: 1) the VH-I comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 3; 2) the VL-I comprises a LC- CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NOs: 6; 3) the VH-2 comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HC- CDR3 comprising the amino acid sequence of SEQ ID NO: 9; and 4) the VL-2 comprises a LC- CDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12, and wherein the bispecific antibody is administered (e.g., subcutaneously) to the human individual at a dose of at least about Img / kg, preferably at a dose of at least about 3 mg / kg. In some embodiments, wherein the hip fracture is femoral neck fracture.

[0023] In some embodiments according to any of the methods described above, the bispecific antibody is subcutaneously administered to the human individual at a dose of at least about 3 mg / kg. In some embodiments, the bispecific antibody is subcutaneously administered to the human individual at a dose of at least about 6 mg / kg. In some embodiments, the bispecific antibody is subcutaneously administered to the human individual at a dose of at least about 8 mg / kg. In some embodiments, the bispecific antibody is subcutaneously administered8MOFO-359878767Attorney Docket No. 21091-20003.40 to the human individual at a dose of at least about 10 mg / kg. In some embodiments, the bispecific antibody is subcutaneously administered to the human individual at a dose of at least about 12 mg / kg. In some embodiments, the bispecific antibody is subcutaneously administered to the human individual at a dose of at least about 1 mg / kg, 3 mg / kg, 6 mg / kg, 8 mg / kg, or 10 mg / kg, 12 mg / kg monthly for at least about one month, two months or three consecutive months.

[0024] In some embodiments according to any of the methods described above, the bispecific antibody is parenterally administered to the human individual. In some embodiments, the bispecific antibody is subcutaneously administered to the human individual. In some embodiments, the bispecific antibody is intravenously administered to the human individual.

[0025] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual in a single administration. In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual in a single injection. In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual for at least once. In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual for at least three times.

[0026] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual more than three times.

[0027] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual no more frequently than once every week.

[0028] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual no more frequently than once every two weeks.

[0029] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual every four weeks or monthly.

[0030] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual no more frequently than once every two months.

[0031] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual once every three months.9MOFO-359878767Attorney Docket No. 21091-20003.40

[0032] In some embodiments according to any of the methods described above, the human individual is treated with the bispecific antibody for at least one month.

[0033] In some embodiments according to any of the methods described above, the human individual is treated with the bispecific antibody for at least three months.

[0034] In some embodiments according to any of the methods described above, the human individual is treated with the bispecific antibody for at least six months.

[0035] In some embodiments according to any of the methods described above, the human individual is treated with the bispecific antibody at least for a year.

[0036] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of at least about 2 mg / kg.

[0037] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of at least about 3 mg / kg.

[0038] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of at least about 4 mg / kg.

[0039] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of at least about 6 mg / kg.

[0040] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of at least about 8 mg / kg.

[0041] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of at least about 10 mg / kg.

[0042] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of at least about 12 mg / kg.

[0043] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of about 1 mg / kg to about 15 mg / kg. (such as about 1 mg / kg to about 2 mg / kg, about 2 mg / kg to about 3 mg / kg, about 3 mg / kg to about 4 mg / kg, about 4 mg / kg to about 5 mg / kg, about 5 mg / kg to about 6 mg / kg, about 6 mg / kg to about 7 mg / kg, about 7 mg / kg to about 8 mg / kg, about 8 mg / kg to about 9 mg / kg, about 9 mg / kg to about 10 mg / kg, about 10 mg / kg to about 11 mg / kg, about 11 mg / kg to about 12 mg / kg, about 12 mg / kg to about 13 mg / kg, about 13 mg / kg to about 14 mg / kg, and / or about 14 mg / kg to about 15 mg / kg).10MOFO-359878767Attorney Docket No. 21091-20003.40

[0044] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of about 3 mg / kg to about 15 mg / kg.

[0045] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of about 1 mg / kg to about 12 mg / kg.

[0046] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of about 3 mg / kg to about 12 mg / kg.

[0047] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of about 4 mg / kg to about 12 mg / kg.

[0048] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of about 6 mg / kg to about 12 mg / kg.

[0049] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of about 8 mg / kg to about 12 mg / kg.

[0050] In some embodiments according to some of the methods described above, the bispecific antibody is administered to the human individual at a dose of less than about 10 mg / kg.

[0051] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of at least about 70 mg.

[0052] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of at least about 140 mg.

[0053] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of at least about 210 mg.

[0054] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of at least about 280 mg.

[0055] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of at least about 420 mg.

[0056] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of at least about 560 mg.11MOFO-359878767Attorney Docket No. 21091-20003.40

[0057] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of at least about 700 mg.

[0058] In some embodiments according to some of the methods described above, the bispecific antibody is administered to the human individual at a dose of at least about 840 mg.

[0059] In some embodiments according to some of the methods described above, the bispecific antibody is administered to the human individual at a dose of at least about 1050 mg.

[0060] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of about 70 mg to about 1050 mg (such as about 70 mg to about 140 mg, about 140 mg to about 210 mg, about 210 mg to about 280 mg, about 280 mg to about 350 mg, about 350 mg to about 420 mg, about 420 mg to about 490 mg, about 490 mg to about 560 mg, about 560 mg to about 630 mg, about 630 mg to about 700 mg, about 700 mg to about 770 mg, about 770 mg to about 840 mg, about 840 mg to about 910 mg, about 910 mg to about 980 mg, and / or about 980 mg to about 1050 mg).

[0061] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of about 140 mg to about 1050 mg.

[0062] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of about 210 mg to about 1050 mg.

[0063] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of about 70 mg to about 840 mg.

[0064] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of about 210 mg to about 840 mg.

[0065] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of about 280 mg to about 840 mg.

[0066] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of about 420 mg to about 840 mg.

[0067] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of about 560 mg to about 840 mg.12MOFO-359878767Attorney Docket No. 21091-20003.40

[0068] In some embodiments according to some of the methods described above, the bispecific antibody is administered to the human individual at a dose of less than about 700 mg.

[0069] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of about or at least about 70 mg about monthly or every four weeks.

[0070] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of about or at least about 140 mg about monthly or every four weeks.

[0071] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of about or at least about 210 mg about monthly or every four weeks.

[0072] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of about or at least about 280 mg about monthly or every four weeks.

[0073] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of about or at least about 560 mg about monthly or every four weeks.

[0074] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of about or at least about 840 mg about monthly or every four weeks.

[0075] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of about or at least about 70 mg about once every three months.

[0076] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of about or at least about 210 mg about once every three months.

[0077] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of about or at least about 280 mg about once every three months.

[0078] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of about or at least about 560 mg about once every three months.13MOFO-359878767Attorney Docket No. 21091-20003.40

[0079] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of about or at least about 840 mg about once every three months.

[0080] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a first dose of about 70 mg to about 840 mg about monthly or every four weeks for at least about one month, and then subsequently at a dose of about 70 mg to about 840 mg about every three months (e.g., for at least about three, six, nine or twelve months).

[0081] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a first dose of about 70 mg to about 840 mg about monthly or every four weeks for at least about three months, and then subsequently at a dose of about 70 mg to about 840 mg about every three months (e.g., for at least about three, six, nine or twelve months).

[0082] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a first dose of about 140 mg to about 840 mg about monthly or every four weeks for at least about one month, and then subsequently at a dose of about 140 mg to about 840 mg about every three months (e.g., for at least about three, six, nine or twelve months).

[0083] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a first dose of about 140 mg to about 840 mg about monthly or every four weeks for at least about three month, and then subsequently at a dose of about 140 mg to about 840 mg about every three months (e.g., for at least about three, six, nine or twelve months).

[0084] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a first dose of about 210 mg to about 840 mg about monthly or every four weeks for at least about one month, and then subsequently at a dose of about 210 mg to about 840 mg about every three months (e.g., for at least about three, six, nine or twelve months).

[0085] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a first dose of about 210 mg to about 840 mg about monthly or every four weeks for at least about three months, and then subsequently at a dose of about 210 mg to about 840 mg about every three months (e.g., for at least about three, six, nine or twelve months).14MOFO-359878767Attorney Docket No. 21091-20003.40

[0086] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a first dose of about 280 mg to about 840 mg about monthly or every four weeks for at least about one month, and then subsequently at a dose of about 280 mg to about 840 mg about every three months (e.g., for at least about three, six, nine or twelve months).

[0087] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a first dose of about 280 mg to about 840 mg about monthly or every four weeks for at least about three months, and then subsequently at a dose of about 280 mg to about 840 mg about every three months (e.g., for at least about three, six, nine or twelve months).

[0088] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a first dose of about 560 mg to about 840 mg about monthly or every four weeks for at least about one month, and then subsequently at a dose of about 560 mg to about 840 mg about every three months (e.g., for at least about three, six, nine or twelve months).

[0089] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a first dose of about 560 mg to about 840 mg about monthly or every four weeks for at least about three months, and then subsequently at a dose of about 560 mg to about 840 mg about every three months (e.g., for at least about three, six, nine or twelve months).

[0090] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a first dose of about 210 mg to about 1050 mg about monthly or every four weeks for at least about one month, and subsequently at a dose of about 210 mg to about 1050 mg about every three months (e.g., for at least about three, six, nine or twelve months).

[0091] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a first dose of about 280 mg to about 1050 mg about monthly or every four weeks (e.g., for at least about one, two or three months)s, and then subsequently at a dose of about 280 mg to about 1050 mg about every three months(e.g., for at least about three, six, nine or twelve months).

[0092] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a first dose of about 70 mg to about 840 mg about monthly or every four weeks (e.g., for at least about one, two or three15MOFO-359878767Attorney Docket No. 21091-20003.40 months), and subsequently at a dose of about 70 mg to about 840 mg about every three months (e.g., for at least about three, six, nine or twelve months).

[0093] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a first dose of about 210 mg to about 840 mg about monthly or every four weeks (e.g., for at least about one, two or three months), and subsequently at a dose of about 210 mg to about 840 mg about every three months (e.g., for at least about three, six, nine or twelve months).

[0094] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual at a dose of about 280 mg to about 840 mg about monthly or every four weeks (e.g., for at least about one, two or three months), and subsequently at a dose of about 280 mg to about 840 mg about every three months (e.g., for at least about three, six, nine or twelve months).

[0095] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual first at a dose of about 560 mg to about 840 mg about monthly or every four weeks(e.g., for at least about one, two or three months), and then subsequently at a dose of about 560 mg to about 840 mg about every three months (e.g., for at least about three, six, nine or twelve months).

[0096] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual first at a dose of at least about 70 mg about monthly or every four weeks (e.g., for at least about one, two or three months), and subsequently at a dose of at least about 70 mg about every three months (e.g., for at least about three, six, nine or twelve months).

[0097] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual first at a dose of at least about 210 mg about monthly or every four weeks (e.g., for at least about one, two or three months), and subsequently at a dose of at least about 210 mg about every three months (e.g., for at least about three, six, nine or twelve months).

[0098] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual first at a dose of at least about 280 mg about monthly or every four weeks (e.g., for at least about one, two or three months), and subsequently at a dose of at least about 280 mg about every three months (e.g., for at least about three, six, nine or twelve months).

[0099] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual first at a dose of at least about 42016MOFO-359878767Attorney Docket No. 21091-20003.40 mg about monthly or every four weeks (e.g., for at least about one, two or three months), and subsequently at a dose of at least about 420 mg about every three months (e.g., for at least about three, six, nine or twelve months).

[0100] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual first at a dose of at least about 560 mg about monthly or every four weeks (e.g., for at least about one, two or three months), and subsequently at a dose of at least about 560 mg about every three months (e.g., for at least about three, six, nine or twelve months).

[0101] In some embodiments according to any of the methods described above, the bispecific antibody is administered to the human individual first at a dose of at least about 840 mg about monthly or every four weeks (e.g., for at least about one, two or three months), and subsequently at a dose of at least about 840 mg about every three months (e.g., for at least about three, six, nine or twelve months).

[0102] In some embodiments according to any of the methods described above, the VH-1 comprises the amino acid sequence of SEQ ID NO: 13, or a variant comprising an amino acid sequence having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 13; and / or wherein VL-1 comprises the amino acid sequence of SEQ ID NO: 14, or a variant comprising an amino acid sequence having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 14.

[0103] In some embodiments according to any of the methods described above, the VH-2 comprises the amino acid sequence of SEQ ID NO: 15, or a variant comprising an amino acid sequence having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 15; and / or wherein VL-2 comprises the amino acid sequence of SEQ ID NO: 16, or a variant comprising an amino acid sequence having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 16.

[0104] In some embodiments according to any of the methods described above, the bispecific antibody is a full-length antibody comprising a Fc fragment comprising a first Fc domain and a second Fc domain. In some embodiments, the Fc fragment comprises an IgG fragment. In some embodiments, the IgG fragment is a IgG4 Fc Fragment, optionally wherein one of the first and the second Fc domains comprises a S228P mutation, and T366W mutation, and optionally a S354C mutation, and wherein the other Fc domain comprises a S228P mutation, T366S mutation, a L368A mutation, a Y407V mutation, and optionally a Y349C mutation, and optionally a H435R mutation, and optionally a Y436F mutation, wherein numbering is according to the EU index.17MOFO-359878767Attorney Docket No. 21091-20003.40

[0105] In some embodiments according to any of the methods described above, the third polypeptide comprises a CHI domain comprising a V173C mutation, and a C131S mutation; and the fourth polypeptide comprises a CL domain comprising a Q160C mutation and a C214S mutation, wherein numbering is according to the EU index.

[0106] In some embodiments according to any of the methods described above, the first polypeptide comprises the amino acid sequence of SEQ ID NO: 17, the second polypeptide comprises the amino acid sequence of SEQ ID NO: 18, the third polypeptide comprises the amino acid sequence of SEQ ID NO: 19, and the fourth polypeptide comprises the amino acid sequence of SEQ ID NO: 20.

[0107] In some embodiments according to any of the methods described above, the human individual is at high risk for fracture.

[0108] In some embodiments according to any of the methods described above, the human individual is at least about 18, 30, 35, 40, 45, 50, 55, or 60 years old.

[0109] In some embodiments according to any of the methods described above, the human individual is a male.

[0110] In some embodiments according to any of the methods described above, the human individual is a female. In some embodiments, the female is a postmenopausal woman.[OHl] In some embodiments according to any of the methods described above, the human individual has a history of osteoporotic fracture.

[0112] In some embodiments according to any of the methods described above, the human individual has a history of vertebral fracture.

[0113] In some embodiments according to any of the methods described above, the human individual has a history of non-vertebral fracture.

[0114] In some embodiments according to any of the methods described above, the human individual has a history of lumbar spine fracture.

[0115] In some embodiments according to any of the methods described above, the human individual has a history of femoral neck fracture.

[0116] In some embodiments according to any of the methods described above, the human individual has a history of total hip fracture.

[0117] In some embodiments according to any of the methods described above, the human individual has been subjected to, failed, or is intolerant to an osteoporosis therapy. In some embodiments, the osteoporosis therapy is selected from the group consisting of romosozumab, denosumab, etidronate, pamidronate, risedronate, alendronate, zoledronate, ibandronate, teriparatide, and abaloparatide.18MOFO-359878767Attorney Docket No. 21091-20003.40

[0118] In some embodiments according to any of the methods described above, the human individual has a history of a cardiovascular disease. In some embodiments, the cardiovascular disease is a myocardial infarction or stroke.

[0119] In some embodiments according to any of the methods described above, the human individual has a hip bone mineral density T-score measured by DXA a) that is between -1 and - 2.5; b) that is -2.5 or lower than -2.5; or c) that is -2.5 or lower than -2.5 and at least one fragility fracture.

[0120] In some embodiments according to any of the methods described above, at about one month, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the human individual has a) an increase in serum N-Terminal Propeptide of Type 1 Procollagen (P1NP) level, optionally wherein the increase is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% ,100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, or 200% as compared to the baseline; b) a decrease in serum C-terminal telopeptide of type 1 collagen (CTX-1) level, optionally wherein the decrease is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% as compared to the baseline; c) an increase in serum osteocalcin level, optionally wherein the increase is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% as compared to the baseline; d) an increase in serum bone-specific alkaline phosphatase (BSAP) level, optionally wherein the increase is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, or 150%as compared to the baseline; and / or e) an increase in serum intact human parathyroid hormone 1-84 (iPTH) level, optionally wherein the increase is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, or 150% as compared to the baseline.

[0121] In some embodiments according to any of the methods described above, at about one month, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the human individual has a) an increase in lumbar spine bone mineral density (BMD) by at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 10.5%, 11%, 11.5%, or 12%; b) an increase in total hip BMD by at least about 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, or 5.5%; and / or c) an increase in femoral neck BMD by at least about 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, or 5%.19MOFO-359878767Attorney Docket No. 21091-20003.40

[0122] In some embodiments according to any of the methods described above, the administration of the bispecific antibody does not result in a risk of more than 4%, 3%, 2% or 1% of developing osteonecrosis of the jaw. In some embodiments, the administration of the bispecific antibody does not result in osteonecrosis of the jaw.

[0123] In some embodiments according to any of the methods described above, the administration of the bispecific antibody reduces the risk of non-vertebral fracture.

[0124] In some embodiments according to any of the methods described above, the administration of the bispecific antibody reduces the risk of vertebral fracture.

[0125] In some embodiments according to any of the methods described above, the administration of the bispecific antibody reduced the risk of hip fracture.

[0126] In some embodiments according to any of the methods described above, the administration of the bispecific antibody reduced the risk of femoral neck fracture.

[0127] In some embodiments according to any of the methods described above, the administration of the bispecific antibody reduced the risk of lumbar spine fracture.

[0128] The present application in another aspect provides a unit dosage form of a bispecific antibody that specifically binds to both sclerostin and DKK-1 comprising a sealed vial containing a quantity of a bispecific antibody suitable for subcutaneous administration to a patient, wherein said quantity is sufficient to deliver a dose of about 70 mg to about 1050 mg, wherein the bispecific antibody comprises a) a first polypeptide comprising a first heavy chain variable region (VH-I), b) a second polypeptide comprising a first variable region (VL-I), C) a third polypeptide comprising a second heavy chain variable region (VH-2), d) a fourth polypeptide comprising a second variable region (VL-2), wherein: 1) the VH-I comprises a HC- CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3; 2) the VL-I comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LC- CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 6; 3) the VH-2 comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 9; and 4) the VL-2 comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12. In some embodiments, said quantity delivers a dose of at least about or about 70mg, 140mg, 210mg, 280 mg, 350 mg, 420 mg, 490 mg, 560 mg, 630 mg, 700 mg, 770 mg, 840 mg, 910 mg, 98020MOFO-359878767Attorney Docket No. 21091-20003.40 mg, 1050 mg. In some embodiments, said quantity delivers a dose of about 70mg to about 140mg, about 140mg to about 210mg, about 210mg to about 280mg, about 280 mg to about 350 mg, about 350 mg to about 420 mg, about 420 mg to about 490 mg, about 490 mg to about560 mg, about 560 mg to about 630 mg, about 630 mg to about 700 mg, about 700 mg to about770 mg, about 770 mg to about 840 mg, about 840 mg to about 910 mg, about 910 mg to about980 mg, and / or about 980 mg to about 1050 mg. In some embodiments, said quantity delivers a dose of about 280 mg to about 840 mg. In some embodiments, said quantity delivers a dose of about 560 mg to about 840 mg. In some embodiments, said quantity delivers a dose of about 280 mg to about 560 mg

[0129] The present application in another aspect provides an injection device comprising a quantity of a bispecific antibody suitable for subcutaneous administration, wherein said quantity is sufficient to deliver a dose of about 70 mg to about 1050 mg, wherein the bispecific antibody comprises a) a first polypeptide comprising a first heavy chain variable region (VH-I), b) a second polypeptide comprising a first variable region (VL-I), C) a third polypeptide comprising a second heavy chain variable region (VH-2), d) a fourth polypeptide comprising a second variable region (VL-2), wherein: 1) the VH-I comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3; 2) the VL-I comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LC- CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 6; 3) the VH-2 comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 9; and 4) the VL-2 comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12. In some embodiments, said quantity delivers a dose of at least about or about 70mg, 140mg, 210mg, 280 mg, 350 mg, 420 mg, 490 mg, 560 mg, 630 mg, 700 mg, 770 mg, 840 mg, 910 mg, 980 mg, 1050 mg. In some embodiments, said quantity delivers a dose of about 70mg to about 140mg, about 140mg to about 210mg, about 210mg to about 280mg, about 280 mg to about 350 mg, about 350 mg to about 420 mg, about 420 mg to about 490 mg, about 490 mg to about 560 mg, about 560 mg to about 630 mg, about 630 mg to about 700 mg, about 700 mg to about 770 mg, about 770 mg to about 840 mg, about 840 mg to about 910 mg, about 910 mg to about 980 mg, and / or about980 mg to about 1050 mg. In some embodiments, said quantity delivers a dose of about 28021MOFO-359878767Attorney Docket No. 21091-20003.40 mg to about 840 mg. In some embodiments, said quantity delivers a dose of about 560 mg to about 840 mg. In some embodiments, said quantity delivers a dose of about 280 mg to about 560 mg.BRIEF DESCRIPTION OF THE DRAWINGS

[0130] FIG. 1A shows two arms of BAP0063, a full-length antibody, separately bind to sclerostin and DKK-1. FIG. IB shows the percent increase from baseline of serum levels of procollagen type I N-terminal propeptide (P1NP) at three months following treatment of ovariectomized non-human primates with either romosozumab or BAP0063 anti-sclerostin x anti -DKK-1 bispecific antibody.

[0131] FIGs. 2A-2C show the clinical trial protocol and overall incidence of Treatment- Emergent Adverse Events (TEAE) in cohorts receiving subcutaneous (SC) or intravenous (IV) administration of BAP0063 compared to placebo groups. FIG. 2A provides an overview of the protocol for assessing TEAE in Single Ascending Dose (SAD) cohorts and Multiple Ascending Dose (MAD) cohorts. SAD cohorts received a single dose of BAP0063 per subject, with each subject receiving an increasing dose from 0.3, 1, 3, 10, and 15 mg / kg administered either through subcutaneously (SC) or intravenously (IV). MAD cohorts received one dose of BAP0063 a month for three total months, each subject receiving a dose of either 1, 3, 6, or 12 mg / kg through SC. FIG. 2B shows TEAE for SAD cohort. FIG. 2C shows TEAE for MAD cohorts.

[0132] FIGs. 3A-3B show bioavailability analysis of BAP0063 in SAD cohorts. FIG. 3A shows the mean plasma concentration (ng / mL) of BAP0063 in SAD cohort subjects up to 85 days following SC or IV. administration of either 0.3 or 3 mg / kg bodyweight BAP0063. FIG. 3B shows quantification of bioavailability for each dose concentration of BAP0063 in SAD cohorts. Ln(AUCinf) = Natural log of Area Under the Curve (from zero to infinity); Geomean LSM refers to Geometric Mean least squares mean.

[0133] FIGs. 4A-4C show the effects of BAP0063 treatment on bone mineral density (BMD) in SAD cohorts receiving SC or IV administration. Effect on BMD is shown as mean (+SD) percent change from baseline in BMD at 29, 57, and 85 days following administration. Cohorts received SC administration of placebo, 0.3, 1, 3, 10, or 15 mg / kg BAP0063, or IV administration of placebo, 0.3, or 3 mg / kg BAP0063. Changes in BMD were measured for lumbar spine (FIG. 4A), femoral neck (FIG. 4B), and total hip (FIG. 4C).

[0134] FIG. 5 shows a statistical summary of percent changes from baseline in BMD of left femur (total hip) following BAP0063 SAD treatment. The summary includes SC22MOFO-359878767Attorney Docket No. 21091-20003.40 administration of BAP0063 at 3, 10, and 15 mg / kg, and IV administration of either placebo or 3 mg / kg BAP0063 over the course of the 85-day trial.

[0135] FIGs. 6A-6C show the effects on BMD in MAD cohorts receiving once monthly SC doses of BAP0063 for three months. FIG. 6A shows mean % change from baseline + / - SEM of BMD in the lumbar spine of MAD cohort subjects receiving either placebo treatment or 1, 3, 6, or 12 mg / kg body weight BAP0063. FIG. 6B shows mean % change from baseline + / - SEM of BMD in the total hip (left femur) of MAD cohort subjects receiving either placebo treatment or 1, 3, 6, or 12 mg / kg bodyweight BAP0063. FIG. 6C shows mean % change from baseline + / - SEM of BMD in the femoral neck of MAD cohort subjects receiving either placebo treatment or 1, 3, 6, or 12 mg / kg bodyweight BAP0063.

[0136] FIG. 7 shows a statistical summary of percent changes from baseline in BMD of left femur (total hip) following BAP0063 MAD treatment. The summary includes SC administration of BAP0063 at 1, 3, 6, and 12 mg / kg over the course of the 169-day trial.

[0137] FIGs. 8A-8B show comparison in BMD gain in BAP0063 MAD cohorts relative to other treatments such as romosozumab (romo). FIG. 8A shows percent change in lumbar spine, total hip, and femoral neck BMD gain in BAP0063 MAD cohorts relative to romo phase 1 clinical trial. FIG. 8B shows percent change in lumbar spine, total hip, and femoral neck BMD gain in BAP0063 MAD cohorts relative to romo phase 2 clinical trial.

[0138] FIG. 9A shows changes to serum bone formation marker procollagen type I N- terminal propeptide (P1NP) and serum C-terminal telopeptide of type 1 collagen (CTX-1) in SAD cohort subjects receiving either placebo treatment, 0.3, 1, 3, 10, or 15 mg / kg bodyweight SC BAP0063, or 0.3 or 3 mg / kg bodyweight IV BAP0063 over 85 days. Changes were measured as mean % change from baseline + / - SEM of each marker in the plasma of subjects. FIG. 9B-9F shows the changes to PINP (FIG. 9B), CTX-1 (FIG. 9C), Osteocalcin (FIG. 9D), serum bone-specific alkaline phosphatase (BSAP) (FIG. 9E), and serum intact human parathyroid hormone 1-84 (iPTH) (FIG. 9F) in BAP0063 -treated subjects in SAD cohort.

[0139] FIG. 10A shows changes to serum bone formation marker procollagen type I N- terminal propeptide (PINP) and serum C-terminal telopeptide of type 1 collagen (CTX-1) in MAD cohort subjects receiving either placebo treatment or 1, 3, 6, or 12 mg / kg body weight SC BAP0063. FIG. 10B-10F shows the changes to PINP (FIG. 10B), CTX-1 (FIG. 10C), Osteocalcin (FIG. 10D), serum bone-specific alkaline phosphatase (BSAP) (FIG. 10E), and serum intact human parathyroid hormone 1-84 (iPTH) (FIG. 10F) in BAP0063 -treated subjects in MAD cohort.23MOFO-359878767Attorney Docket No. 21091-20003.40

[0140] FIG. 11 depicts summary of baseline coravirate data for the first-in-human (FIH) study for Example 6.

[0141] FIG. 12 depicts parameter estimates for the PK / PD final model.

[0142] FIG. 13 depicts comparison of predicted P1NP and CTX-1 profiles following QM and Q3M fixed subcutaneous dosing regimens.

[0143] FIG. 14 depicts integrated indirect PK / PD and BMD response model structures.

[0144] FIG. 15 depicts summary of baseline coravirate data for the first-in-human (FIH) study for Example 7.

[0145] FIG. 16 depicts Pop PK model structure and Pop PK model parameter estimates.

[0146] FIG. 17 depicts prediction-corrected visual predictive check.

[0147] FIG. 18 depicts predicted BAP0063 PK profiles following fixed and weight-based SC dosing.

[0148] FIG. 19 depicts predicted BAP0063 PK profiles following QM and Q3M fixed SC dosing.DETAILED DESCRIPTION OF THE APPLICATION

[0149] The present application provides methods of treating or preventing diseases or conditions associated with low bone mass or fracture. In one aspect, the present application provides methods of treating osteoporosis or reducing risk of osteoporosis (e.g. reducing the risk of developing osteoporosis, e.g. reducing the severity of existing osteoporosis) in a human individual. In another aspect, it provides methods of increasing bone mineral density in a human individual. In another aspect, it provides methods of increasing both cortical bone and trabecular bone in a human individual. In another aspect, it provides methods of preventing or reducing risk of osteoporotic fracture or accelerating fracture healing in a human individual. In another aspect, it provides methods of reducing risk of one or both of a vertebral fracture and, a non-vertebral fracture in a human individual. In yet another aspect, it provides methods of reducing risk of lumbar spine fracture in a human individual. In yet another aspect, it provides methods of reducing risk of hip fracture in a human individual. In yet another aspect, it provides methods of reducing risk of femoral neck fracture in a human individual. In yet another aspect, it provides methods of preventing or reducing the risk of fracture nonunion in a human individual. In yet another aspect, it provides methods of preventing or reducing the risk of delayed union in a human individual. In yet another aspect, it provides methods of reducing the need for reoperation following fracture repair surgery in a human individual. In some embodiments, the methods described above involve administering a bispecific antibody that24MOFO-359878767Attorney Docket No. 21091-20003.40 specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises a) a first polypeptide comprising a first heavy chain variable region (VH-I), b) a second polypeptide comprising a first light chain variable region (VL-I), C) a third polypeptide comprising a second heavy chain variable region (VH-2), d) a fourth polypeptide comprising a second variable region (VL-2), wherein: 1) the VH-I comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3; 2) the VL-I comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LC- CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NOs: 6; 3) the VH-2 comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 9; and 4) the VL-2 comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LC- CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12, wherein the bispecific antibody is administered to the human individual at a dose of at least about 1 mg / kg. In some embodiments, the bispecific antibody is administered to the human individual at a dose of at least about or about 3mg / kg, 4mg / kg, 6 mg / kg, 8 mg / kg, 10 mg / kg, or 12 mg / kg. In some embodiments, the bispecific antibody is administered to the human individual at a dose of at least about or about 70mg, 140mg, 210 mg, 280 mg, 420 mg, 560 mg, 700 mg, or 840 mg. In some cases, the bispecific antibody is administered about once every month. In some cases, the bispecific antibody is administered about once every three months. In some cases, the bispecific antibody is administered subcutaneously. In some cases, the bispecific antibody is administered intravenously.

[0150] The present application provides clinical trial data that demonstrated the safety and efficacy of using the bispecific antibodies with methods described herein for treating or reducing risk in diseases or conditions associated with low bone mass or fracture. As the first in human clinical trial for a sclerostin x DKK-1 bispecific antibody, the exemplary antibody BAP0063 was demonstrated as being safe at a dose of 0.3 mg / kg to 15 mg / kg without causing any serious adverse effect that is related to the treatment in a two-part trial that enrolled a total of sixty-six patients. See e.g., Example 2. Such safety profile shows that single doses of BAP0063 up to 15 mg / kg SC or 3 mg / kg IV and multiple doses of BAP0063 up to 12 mg / kg SC were safe and well-tolerated. Moreover, the administration of the exemplary antibody BAP0063 demonstrated a much more potent and durable response than romosozumab. See25MOFO-359878767Attorney Docket No. 21091-20003.40 e.g., Example 3 and 4. For example, an about monthly dose of 3mg / kg of BAP0063 for three months has a durable effect of increasing total hip BMD during at least the following three months after the final administration of the BAP0063. At the dose of 6 mg / kg, BAP0063 achieved an increase in femoral neck BMD from baseline that is 213% of the increase achieved by romosozumab at an equivalent dose of sclerostin (3mg / kg) at month 3, and 121% at month 6. See e.g., FIG. 6B and FIGs. 8A-8B. SC administration of BAP0063 achieved an increase in BMD for left femur (total hip) about three months after a single injection. See e.g., FIG. 5. The significant durable increase was demonstrated across the dosage of 3-15 mg / kg SC with a single injection, and further demonstrated across the dosage of 3-12 mg / kg with a monthly administration for three months. See FIG. 7. An increase of total hip BMD can reduce the risk of different bone fractures from forming. For example, total hip BMD of increase of 1.42% can reduce the risk of vertebral fractures, an increase of 2.13% can reduce the risk of non-vertebral fractures, and an increase of 3.18% can reduce the risk of hip fractures. See. e.g., FIG. 3, Lancet Diabetes Endocrinol. 2020 Aug;8(8):672-682. Bone fractures, such as hip fractures, can result in impaired mobility, reduced self-care abilities, and a 20-35% mortality rate within 12 months specifically for hip fractures. Reducing the risk, frequency, or severity of hip fractures decreases mortality at 1-year and beyond, thereby improving patient outcomes, including reducing pain, improving quality of life, and improving self-care ability.I. Definitions

[0151] The term “antibody” is used in its broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), full-length antibodies and antigen-binding fragments thereof, so long as they exhibit the desired antigen-binding activity. The term “antibody moiety” refers to a full-length antibody or an antigen-binding fragment thereof.

[0152] A full-length antibody comprises two heavy chains and two light chains. The variable regions of the light and heavy chains are responsible for antigen binding. The variable domains of the heavy chain and light chain may be referred to as “VH” and “VL”, respectively. The variable regions in both chains generally contain three highly variable loops called the complementarity determining regions (CDRs) (light chain (LC) CDRs including LC-CDR1, LC-CDR2, and LC-CDR3, heavy chain (HC) CDRs including HC-CDR1, HC-CDR2, and HC- CDR3). CDR boundaries for the antibodies and antigen-binding fragments disclosed herein may be defined or identified by the conventions of Kabat, Chothia, or Al-Lazikani (Al- Lazikani 1997; Chothia 1985; Chothia 1987; Chothia 1989; Kabat 1987; Kabat 1991). The three CDRs of the heavy or light chains are interposed between flanking stretches known as26MOFO-359878767Attorney Docket No. 21091-20003.40 framework regions (FRs), which are more highly conserved than the CDRs and form a scaffold to support the hypervariable loops. The constant regions of the heavy and light chains are not involved in antigen binding but exhibit various effector functions. Antibodies are assigned to classes based on the amino acid sequence of the constant region of their heavy chain. The five major classes or isotypes of antibodies are IgA, IgD, IgE, IgG, and IgM, which are characterized by the presence of a, 5, s, y, and p heavy chains, respectively. Several of the major antibody classes are divided into subclasses such as IgGl (yl heavy chain), lgG2 (y2 heavy chain), lgG3 (y3 heavy chain), lgG4 (y4 heavy chain), IgAl (al heavy chain), or lgA2 (a2 heavy chain).

[0153] The term “antigen-binding fragment” as used herein refers to an antibody fragment including, for example, a diabody, a Fab, a Fab’, a F(ab’)2, an Fv fragment, a disulfide stabilized Fv fragment (dsFv), a (dsFv)2, a bispecific dsFv (dsFv-dsFv’), a disulfide stabilized diabody (ds diabody), a single-chain Fv (scFv), a dsscFv, an scFv dimer (bivalent diabody), a multispecific antibody formed from a portion of an antibody comprising one or more CDRs, a camelized single domain antibody, a nanobody, a domain antibody, a bivalent domain antibody, or any other antibody fragment that binds to an antigen but does not comprise a complete antibody structure. An antigen-binding fragment is capable of binding to the same antigen to which the parent antibody or a parent antibody fragment (e.g., a parent scFv) binds. In some embodiments, an antigen-binding fragment may comprise one or more CDRs from a particular human antibody grafted to a framework region from one or more different human antibodies. In some embodiments, the antigen-binding fragment comprises a Fab.

[0154] As used herein, the term “CDR” or “complementarity determining region” is intended to mean the non-contiguous antigen combining sites found within the variable region of both heavy and light chain polypeptides. These particular regions have been described by Kabat el al., J. Biol. Chem. 252:6609-6616 (1977); Kabat el al., U.S. Dept, of Health and Human Services, “Sequences of proteins of immunological interest” (1991); Chothia et cd., J. Mol. Biol. 196:901-917 (1987); Al-Lazikani B. el cd., J. Mol. Biol., 273: 927-948 (1997); MacCallum et al., J. Mol. Biol. 262:732-745 (1996); Abhinandan and Martin, Mol. Immunol., 45: 3832-3839 (2008); Lefranc M.P. et al., Dev. Comp. Immunol., 27: 55-77 (2003); and Honegger and Pliickthun, J. Mol. BioL, 309:657-670 (2001), where the definitions include overlapping or subsets of amino acid residues when compared against each other. Nevertheless, application of either definition to refer to a CDR of an antibody or grafted antibodies or variants thereof is intended to be within the scope of the term as defined and used herein. The amino acid residues which encompass the CDRs as defined by each of the above-27MOFO-359878767Attorney Docket No. 21091-20003.40 cited references are set forth below in Table 1 as a comparison. CDR prediction algorithms and interfaces are known in the art, including, for example, Abhinandan and Martin, Mol.Immunol., 45: 3832-3839 (2008); Ehrenmann F. et al. , Nucleic Acids Res. , 38: D301-D307 (2010); and Adolf-Bryfogle J. et al., Nucleic Acids Res. , 43: D432-D438 (2015). The contents of the references cited in this paragraph are incorporated herein by reference in their entireties for use in the present application and for possible inclusion in one or more claims herein. In some embodiments, the CDR sequences provided herein are based on IMGT definition. For example, the CDR sequences may be determined by the VB ASE2 tool (http: / / www.vbase2.org / vbase2.php, see also Retter I, Althaus HH, Munch R, Muller W: VBASE2, an integrative V gene database. Nucleic Acids Res. 2005 Jan 1; 33 (Database issue): D671-4, which is incorporated herein by reference in its entirety).TABLE 1: CDR DEFINITIONSKabat1Chothia2MacCallum3IMGT4AHo5VH CDRI 31-35 26-32 30-35 27-38 25-40VH CDR2 50-65 53-55 47-58 56-65 58-77VH CDR3 95-102 96-101 93-101 105-117 109-137VL CDRI 24-34 26-32 30-36 27-38 25-40VL CDR2 50-56 50-52 46-55 56-65 58-77VL CDR3 89-97 91-96 89-96 105-117 109-137'Residue numbering follows the nomenclature of Kabat et al., supra2Residue numbering follows the nomenclature of Chothia et al., supra3Residue numbering follows the nomenclature of MacCallum et al. , supra4Residue numbering follows the nomenclature of Lefranc et al, supra5Residue numbering follows the nomenclature of Honegger and Pliickthun, supra

[0155] The expression “variable-domain residue-numbering as in Kabat” or “amino-acid- position numbering as in Kabat,” and variations thereof, refers to the numbering system used for heavy-chain variable domains or light-chain variable domains of the compilation of antibodies in Kabat et al., supra. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of, or insertion into, a FR or hypervariable region (HVR) of the variable domain. For example, a heavy-chain variable domain may include a single amino acid insert (residue 52a according to28MOFO-359878767Attorney Docket No. 21091-20003.40Kabat) after residue 52 of H2 and inserted residues (e.g. residues 82a, 82b, and 82c, etc. according to Kabat) after heavy-chain FR residue 82. The Kabat numbering of residues may be determined for a given antibody by alignment at regions of homology of the sequence of the antibody with a “standard” Kabat numbered sequence.

[0156] Unless indicated otherwise herein, the numbering of the residues in an immunoglobulin heavy chain is that of the EU index as in Kabat et al., supra. The “EU index as in Kabat” refers to the residue numbering of the human IgGl EU antibody.

[0157] “Framework” or “FR” residues are those variable-domain residues other than the CDR residues as herein defined.

[0158] “Percent (%) amino acid sequence identity” or “homology” with respect to the polypeptide and antibody sequences identified herein is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the polypeptide being compared, after aligning the sequences considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, Megalign (DNASTAR), or MUSCLE software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full-length of the sequences being compared. For purposes herein, however, % amino acid sequence identity values are generated using the sequence comparison computer program MUSCLE (Edgar, R.C., Nucleic Acids Research 32(5): 1792-1797, 2004; Edgar, R.C., BMC Bioinformatics 5(1): 113, 2004).

[0159] “Homologous” refers to the sequence similarity or sequence identity between two polypeptides or between two nucleic acid molecules. When a position in both of two compared sequences is occupied by the same base or amino acid monomer subunit, e.g., if a position in each of two DNA molecules is occupied by adenine, then the molecules are homologous at that position. The percent of homology between two sequences is a function of the number of matching or homologous positions shared by the two sequences divided by the number of positions compared times 100. For example, if 6 of 10 of the positions in two sequences are matched or homologous then the two sequences are 60% homologous. By way of example, the DNA sequences ATTGCC and TATGGC share 50% homology. Generally, a comparison is made when two sequences are aligned to give maximum homology.

[0160] The term “constant domain” refers to the portion of an immunoglobulin molecule having a more conserved amino acid sequence relative to the other portion of the29MOFO-359878767Attorney Docket No. 21091-20003.40 immunoglobulin, the variable domain, which contains the antigen-binding site. The constant domain contains the CHI, CH2 and CH3 domains (collectively, CH) of the heavy chain and the CHL (or CL) domain of the light chain.

[0161] The “light chains” of antibodies (immunoglobulins) from any mammalian species can be assigned to one of two clearly distinct types, called kappa (“K”) and lambda (“X”), based on the amino acid sequences of their constant domains.

[0162] The “CHI domain” (also referred to as “Cl” of “Hl” domain) usually extends from about amino acid 118 to about amino acid 215 (EU numbering system).

[0163] The “CH2 domain” of a human IgG Fc region (also referred to as “C2” domain) usually extends from about amino acid 231 to about amino acid 340. The CH2 domain is unique in that it is not closely paired with another domain. Rather, two N-linked branched carbohydrate chains are interposed between the two CH2 domains of an intact native IgG molecule. It has been speculated that the carbohydrate may provide a substitute for the domaindomain pairing and help stabilize the CH2 domain. Burton, Molec Immunol. 22: 161-206 (1985).

[0164] The “CH3 domain” (also referred to as “C3” domain) comprises the stretch of residues C-terminal to a CH2 domain in an Fc region (i.e. from about amino acid residue 341 to the C-terminal end of an antibody sequence, typically at amino acid residue 446 or 447 of an IgG).

[0165] The term “Fc region” or “fragment crystallizable region” herein is used to define a C- terminal region of an immunoglobulin heavy chain, including native- sequence Fc regions and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy-chain Fc region is usually defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl-terminus thereof. The C-terminal lysine (residue 447 according to the EU numbering system) of the Fc region may be removed, for example, during production or purification of the antibody, or by recombinantly engineering the nucleic acid encoding a heavy chain of the antibody. Accordingly, a composition of intact antibodies may comprise antibody populations with all K447 residues removed, antibody populations with no K447 residues removed, and antibody populations having a mixture of antibodies with and without the K447 residue. Suitable native-sequence Fc regions for use in the antibodies described herein include human IgGl, IgG2 (IgG2A, IgG2B), IgG3 and IgG4.

[0166] The term “epitope” as used herein refers to the specific group of atoms or amino acids on an antigen to which an antibody or antibody moiety binds. Two antibodies or antibody30MOFO-359878767Attorney Docket No. 21091-20003.40 moieties may bind the same epitope within an antigen if they exhibit competitive binding for the antigen.

[0167] As use herein, the terms “specifically binds,” “specifically recognizing,” and “is specific for” refer to measurable and reproducible interactions, such as binding between a target and an antibody or antibody moiety, which is determinative of the presence of the target in the presence of a heterogeneous population of molecules, including biological molecules. For example, an antibody or antibody moiety that specifically recognizes a target (which can be an epitope) is an antibody or antibody moiety that binds this target with greater affinity, avidity, more readily, and / or with greater duration than its bindings to other targets. In some embodiments, the extent of binding of an antibody to an unrelated target is less than about 10% of the binding of the antibody to the target as measured, e.g., by a radioimmunoassay (RIA). In some embodiments, an antibody that specifically binds a target has a dissociation constant (KD) of <10’5M, <10’6M, <10’7M, <10’8M, <10’9M, <1O’10M, <10-nM, or <10’12M. In some embodiments, an antibody specifically binds an epitope on a protein that is conserved among the protein from different species. In some embodiments, specific binding can include, but does not require exclusive binding. Binding specificity of the antibody or antigen-binding domain can be determined experimentally by methods known in the art. Such methods comprise, but are not limited to Western blots, ELISA-, RIA-, ECL-, IRMA-, EIA-, BLI-, BIACORE™ -tests and peptide scans.

[0168] As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results, including clinical results. For purposes of this application, beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviating one or more symptoms resulting from the disease, diminishing the extent of the disease, stabilizing the disease, preventing or delaying the recurrence of the disease, delaying or slowing the progression of the disease, ameliorating the disease state, providing a remission (partial or total) of the disease, decreasing the dose of one or more other medications required to treat the disease, delaying the progression of the disease, increasing or improving the quality of life, increasing weight gain, and / or prolonging survival. The methods of the application contemplate any one or more of these aspects of treatment.

[0169] The terms “inhibition” or “inhibit” refer to a decrease or cessation of any phenotypic characteristic or to the decrease or cessation in the incidence, degree, or likelihood of that characteristic. To “reduce” or “inhibit” is to decrease, reduce or arrest an activity, function, and / or amount as compared to that of a reference. In certain embodiments, by “reduce” or “inhibit” is meant the ability to cause an overall decrease of 20% or greater. In another31MOFO-359878767Attorney Docket No. 21091-20003.40 embodiment, by “reduce” or “inhibit” is meant the ability to cause an overall decrease of 50% or greater. In yet another embodiment, by “reduce” or “inhibit” is meant the ability to cause an overall decrease of 75%, 85%, 90%, 95%, or greater.

[0170] “Preventing” as used herein, includes providing prophylaxis with respect to the occurrence or recurrence of a disease in an human individual that may be predisposed to the disease but has not yet been diagnosed with the disease.

[0171] The terms “subject,” “individual,” and “patient” are used interchangeably herein to refer to a mammal, including, but not limited to, human, bovine, horse, feline, canine, rodent, or primate. In some embodiments, the individual is a human.

[0172] The terms “pharmaceutical formulation” and “pharmaceutical composition” refer to a preparation which is in such form as to permit the biological activity of the active ingredient(s) to be effective, and which contains no additional components which are unacceptably toxic to an individual to which the formulation would be administered. Such formulations may be sterile.

[0173] A “pharmaceutically acceptable carrier” refers to a non-toxic solid, semisolid, or liquid filler, diluent, encapsulating material, formulation auxiliary, or carrier conventional in the art for use with a therapeutic agent that together comprise a “pharmaceutical composition” for administration to an individual. A pharmaceutically acceptable carrier is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation. The pharmaceutically acceptable carrier is appropriate for the formulation employed. Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and / or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.

[0174] A “sterile” formulation is aseptic or essentially free from living microorganisms and their spores.

[0175] The term “concurrently” is used herein to refer to administration of two or more therapeutic agents, where at least part of the administration overlaps in time or where the administration of one therapeutic agent falls within a short period of time relative to administration of the other therapeutic agent. For example, the two or more therapeutic agents are administered with a time separation of no more than about 60 minutes, such as no more than about any of 30, 15, 10, 5, or 1 minutes.

[0176] The term “sequentially” is used herein to refer to administration of two or more therapeutic agents where the administration of one or more agent(s) continues after discontinuing the administration of one or more other agent(s). For example, administration32MOFO-359878767Attorney Docket No. 21091-20003.40 of the two or more therapeutic agents are administered with a time separation of more than about 15 minutes, such as about any of 20, 30, 40, 50, or 60 minutes, 1 day, 2 days, 3 days, 1 week, 2 weeks, or 1 month, or longer.

[0177] As used herein, “in conjunction with” refers to administration of one treatment modality in addition to another treatment modality. As such, “in conjunction with” refers to administration of one treatment modality before, during or after administration of the other treatment modality to the individual.

[0178] The term “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, combination therapy, contraindications and / or warnings concerning the use of such therapeutic products.

[0179] An “article of manufacture” is any manufacture (e.g., a package or container) or kit comprising at least one reagent, e.g., a medicament for treatment of a disease or disorder, or a probe for specifically detecting a biomarker described herein. In certain embodiments, the manufacture or kit is promoted, distributed, or sold as a unit for performing the methods described herein.

[0180] It is understood that embodiments of the application described herein include “consisting of’ and / or “consisting essentially of’ embodiments.

[0181] Reference to “about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”.

[0182] The term “about X-Y” used herein has the same meaning as “about X to about Y.”

[0183] As used herein and in the appended claims, the singular forms “a,” “or,” and “the” include plural referents unless the context clearly dictates otherwise.II. Methods of Treatment

[0184] The present application provides methods of treating a disease, disorder, or condition (such as osteoporosis or osteopenia) in a human individual comprising administering a bispecific antibody that specifically binds to both Sclerostin and DKK-1 as described herein. In other aspects, the present application provides a method of increasing bone mineral density in a human individual comprising administering a bispecific antibody that specifically binds to both Sclerostin and DKK-1 as described herein. In other aspects, the present application provides a method of treating or preventing diseases or conditions associated with low bone mass in a human individual comprising administering a bispecific antibody that specifically binds to both Sclerostin and DKK-1 as described herein.33MOFO-359878767Attorney Docket No. 21091-20003.40

[0185] In yet other aspects, the present application provides a method of reducing risk of developing osteoporosis and / or reducing the severity of existing osteoporosis in a human individual comprising administering a bispecific antibody that specifically binds to both Sclerostin and DKK-1 as described herein. In yet other aspects, the present application provides a method of preventing or reducing risk of bone fracture (such as osteoporotic fracture) in a human individual comprising administering a bispecific antibody that specifically binds to both Sclerostin and DKK-1 as described herein. In some embodiments, the present application provides a method of preventing or reducing the risk of a vertebral fracture and a non-vertebral fracture in a human individual comprising administering a bispecific antibody that specifically binds to both Sclerostin and DKK-1 as described herein. In some embodiments, the method prevents or reduces the risk of a vertebral fracture, a non-vertebral fracture, and a hip fracture in a human individual comprising administering a bispecific antibody that specifically binds to both Sclerostin and DKK-1 as described herein. In some embodiments, the method prevents or reduces the risk of a lumbar spine fracture and / or a femoral neck fracture in a human individual comprising administering a bispecific antibody that specifically binds to both Sclerostin and DKK-1 as described herein. In yet other aspects, the present application provides a method of accelerating bone fracture healing in a human individual comprising administering a bispecific antibody that specifically binds to both Sclerostin and DKK-1 as described herein. In yet other aspects, the present application provides a method of reducing one or more bone fracture-associated complications in a human individual comprising administering a bispecific antibody that specifically binds to both Sclerostin and DKK-1 as described herein. In some embodiments, the one or more complications comprise a nonunion, a malunion, and / or a reoperation. In yet other aspects, the present application provides a method of inhibiting bone resorption in a human individual comprising administering a bispecific antibody that specifically binds to both Sclerostin and DKK-1 as described herein.

[0186] In some embodiments, there is provided a method of treating a disease, disorder, or condition, comprising administering (e.g., subcutaneously or intravenously) a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises the BAP0063 polypeptides. In some embodiments, the bispecific antibody is administered at a dose of about 70 mg to about 140 mg, of about 140 mg to about 210 mg, of about 210 mg to about 280 mg, of about 280 mg to about 350 mg, of about 350 mg to about 420 mg, of about 420 mg to about 490 mg, of about 490 mg to about 560 mg, of about 560 mg to about 630 mg, of about 630 mg to about 700 mg, of about 700 mg to about 770 mg, of about34MOFO-359878767Attorney Docket No. 21091-20003.40770 mg to about 840 mg, of about 840 mg to about 910 mg, of about 910 mg to about 980 mg, or of about 980 mg to about 1050mg. In some embodiments, the bispecific antibody is administered at a dose of about 70 mg to about 1050 mg. In some embodiments, the bispecific antibody is administered at a dose of about 210 mg to about 1050 mg. In some embodiments, the bispecific antibody is administered at a dose of about 280 mg to about 840 mg. In some embodiments, the bispecific antibody is administered at a dose of about 560 mg to about 840 mg. In some embodiments, the bispecific antibody is administered at a dose of about 70 mg. In some embodiments, the bispecific antibody is administered at a dose of about 210 mg. In some embodiments, the bispecific antibody is administered at a dose of about 280 mg. In some embodiments, the bispecific antibody is administered at a dose of about 420 mg. In some embodiments, the bispecific antibody is administered at a dose of about 560 mg. In some embodiments, the bispecific antibody is administered at a dose of about 840 mg. In some embodiments, the bispecific antibody is administered about every week (weekly), about every two weeks, about every month (monthly), about every 2 months, about every 3 months, about every 4 months, about every 5 months, or about every 6 months. In some embodiments, the bispecific antibody is administered about every week (weekly). In some embodiments, the bispecific antibody is administered about every two weeks. In some embodiments, the bispecific antibody is administered about every month (monthly). In some embodiments, the bispecific antibody is administered about every 2 months. In some embodiments, the bispecific antibody is administered about every 3 months. In some embodiments, the bispecific antibody is administered about every 4 months. In some embodiments, the bispecific antibody is administered about every 5 months. In some embodiments, the bispecific antibody is administered about every 6 months. In some embodiments, the bispecific antibody is administered for a duration of at least 1 month, of at least 2 months, of at least 3 months, of at least 4 months, of at least 5 months, of at least 6 months, of at least 7 months, of at least 8 months, of at least 9 months, of at least 10 months, of at least 11 months, of at least 12 months, of at least 13 months, of at least 14 months, of at least 15 months, of at least 16 months, of at least 17 months, of at least 18 months, of at least 19 months, of at least 20 months, of at least 21 months, of at least 22 months, of at least 23 months, or of at least 24 months, or of at least 3 years, or of at least 4 years, or of at least 5 years, or of at least 6 years, or of at least 7 years, or of at least 8 years, or of at least 9 years, or of at least 10 years. In some embodiments, the bispecific antibody is administered for a duration of at least 12 months. In some embodiments, the bispecific antibody is administered for a duration of at least 15 months. In some embodiments, the bispecific antibody is administered for a duration of at least 18 months. In35MOFO-359878767Attorney Docket No. 21091-20003.40 some embodiments, the bispecific antibody is administered for a duration of at least 24 months. In some embodiments, the bispecific antibody is administered for a duration of at least 3 years. In some embodiments, the bispecific antibody is administered for a duration of at least 5 years. In some embodiments, the bispecific antibody is administered for a duration of at least 10 years. In some embodiments, the bispecific antibody is administered at two or more different frequencies comprising a first frequency and a second frequency. In some embodiments, the first frequency is more frequent than the second frequency. In some embodiments, the first frequency comprises administration of the bispecific antibody about every week (weekly), every two weeks, about every month (monthly), or about every 2 months; and the second frequency comprises administration of the bispecific antibody about every 3 months, or about every 6 months. In some embodiments, the first frequency lasts for a duration of at least 1 month, of at least 2 months, of at least 3 months, of at least 4 months, of at least 5 months, of at least 6 months, of at least 7 months, of at least 8 months, of at least 9 months, of at least 10 months, of at least 11 months, of at least 12 months, of at least 13 months, of at least 14 months, of at least 15 months, of at least 16 months, of at least 17 months, of at least 18 months, of at least 19 months, of at least 20 months, of at least 21 months, of at least 22 months, of at least 23 months, or of at least 24 months; and the second frequency lasts for a duration of at least 1 month, of at least 2 months, of at least 3 months, of at least 4 months, of at least 5 months, of at least 6 months, of at least 7 months, of at least 8 months, of at least 9 months, of at least 10 months, of at least 11 months, of at least 12 months, of at least 13 months, of at least 14 months, of at least 15 months, of at least 16 months, of at least 17 months, of at least 18 months, of at least 19 months, of at least 20 months, of at least 21 months, of at least 22 months, of at least 23 months, or of at least 24 months, or of at least 3 years, or of at least 4 years, or of at least 5 years, or of at least 6 years, or of at least 7 years, or of at least 8 years, or of at least 9 years, or of at least 10 years. In some embodiments, the bispecific antibody is administered about four weeks or about every month for at least one month, then is administered about every three months for at least 6 months. In some embodiments, the bispecific antibody is administered about four weeks or about every month for at least one month, then is administered about every three months for at least 9 months. In some embodiments, the bispecific antibody is administered about four weeks or about every month for at least one month, then is administered about every three months for at least 12 months. In some embodiments, the bispecific antibody is administered about four weeks or about every month for at least three months, then is administered about every three months for at least 6 months. In some embodiments, the bispecific antibody is administered about four36MOFO-359878767Attorney Docket No. 21091-20003.40 weeks or about every month for at least three months, then is administered about every three months for at least 9 months. In some embodiments, the bispecific antibody is administered about four weeks or about every month for at least three months, then is administered about every three months for at least 12 months. In some embodiments, the bispecific antibody is administered about four weeks or about every month for at least 4 months, then is administered about every 4 months for at least 8 months. In some embodiments, the bispecific antibody is administered about every 2 months for at least 4 months, then is administered about every three months for at least 6 months. In some embodiments, the bispecific antibody is administered about every 2 months for at least 4 months, then is administered about every three months for at least 9 months. In some embodiments, the bispecific antibody is administered about every 2 months for at least 4 months, then is administered about every three months for at least 12 months. In some embodiments, the bispecific antibody is administered at a first dose with the first frequency followed by an administration at a second dose with the second frequency. In some embodiments, the first dose and the second dose are the same. In some embodiments, the first dose and the second dose are different. In some embodiments, the bispecific antibody is administered at two or more distinct doses comprising a first dose and a second dose, wherein 1) the first dose is a dose of at least about 70 mg, of at least about 140 mg, of at least about 210 mg, of at least about 280 mg, of at least about 350 mg, of at least about 420 mg, of at least about 490 mg, of at least about 560 mg, of at least about 630 mg, of at least about 700 mg, of at least about 770 mg, of at least about 840 mg, of at least about 910 mg, of at least about 980 mg, or of at least about 1050mg, and 2) the second dose is a different dose to the first dose and is a dose of at least about 70 mg, of at least about 140 mg, of at least about 210 mg, of at least about 280 mg, of at least about 350 mg, of at least about 420 mg, of at least about 490 mg, of at least about 560 mg, of at least about 630 mg, of at least about 700 mg, of at least about 770 mg, of at least about 840 mg, of at least about 910 mg, of at least about 980 mg, or of at least about 1050mg. In some embodiments, the bispecific antibody is administered at two or more distinct doses comprising a first dose and a second dose, wherein 1) the first dose is a dose of about 70 mg to about 140 mg, about 140 mg to about 210 mg, about 210 mg to about 280 mg, of about 280 mg to about 350 mg, of about 350 mg to about 420 mg, of about 420 mg to about 490 mg, of about 490 mg to about 560 mg, of about 560 mg to about 630 mg, of about 630 mg to about 700 mg, of about 700 mg to about 770 mg, of about 770 mg to about 840 mg, of about 840 mg to about 910 mg, of about 910 mg to about 980 mg, or of about 980 mg to about 1050mg, and 2) the second dose is a different dose to the first dose and is a dose of about 70 mg to about 140 mg, about 140 mg to about 21037MOFO-359878767Attorney Docket No. 21091-20003.40 mg, about 210 mg to about 280 mg, of about 280 mg to about 350 mg, of about 350 mg to about 420 mg, of about 420 mg to about 490 mg, of about 490 mg to about 560 mg, of about 560 mg to about 630 mg, of about 630 mg to about 700 mg, of about 700 mg to about 770 mg, of about 770 mg to about 840 mg, of about 840 mg to about 910 mg, of about 910 mg to about 980 mg, or of about 980 mg to about 1050mg. In some embodiments, the first dose is less than the second dose (ascending dosing). In some embodiments, the first dose is about 280 mg and the second dose is about 560 mg. In some embodiments, the first dose is about 280 mg and the second dose is about 840 mg. In some embodiments, the two or more distinct doses comprises a third dose. In some embodiments, the third dose is greater than the first dose and / or the second dose.

[0187] In some embodiments, there is provided a method of treating a disease, disorder, or condition, comprising administering (e.g., subcutaneously or intravenously) a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises the BAP0063 polypeptides, wherein the bispecific antibody is administered at a dose of at least about or about 70 mg (e.g., about 70 mg), wherein the bispecific antibody is administered about every month (every four weeks). In some embodiments, the bispecific antibody is administered for a duration of at least 1 month, of at least 2 months, of at least 3 months, of at least 4 months, of at least 5 months, of at least 6 months, of at least 7 months, of at least 8 months, of at least 9 months, of at least 10 months, of at least 11 months, of at least 12 months, of at least 13 months, of at least 14 months, of at least 15 months, of at least 16 months, of at least 17 months, of at least 18 months, of at least 19 months, of at least 20 months, of at least 21 months, of at least 22 months, of at least 23 months, or of at least 24 months, or of at least 3 years, or of at least 4 years, or of at least 5 years, or of at least 6 years, or of at least 7 years, or of at least 8 years, or of at least 9 years, or of at least 10 years. In some embodiments, the VH-I, VL-I, VH-2, and VL-2 comprise the amino acid sequences of SEQ ID NO: 13, 14, 15, and 16 respectively. In some embodiments, the bispecific antibody is a full- length antibody comprising an IgG (e.g., IgG4) Fc fragment. In some embodiments, the first, second, third and fourth polypeptides comprise the amino acid sequences of SEQ ID NO: 17, 18, 19, and 20 respectively. In some embodiments, the method treats osteoporosis or reduces the risk of osteoporosis in a human individual. In some embodiments, the method reduces the risk of developing osteoporosis. In some embodiments, the method reduces the severity of existing osteoporosis. In some embodiments, the method treats or prevents diseases or conditions associated with low bone mass. In some embodiments, the method increases bone mineral density in a human individual. In some embodiments, the method reduces the risk of38MOFO-359878767Attorney Docket No. 21091-20003.40 osteoporotic fracture in a human individual. In some embodiments, the method accelerates fracture healing in a human individual. In some embodiments, the method prevents or reduces the risk of fracture nonunion, and / or prevents or reduces the risk of delayed union, and / or prevents the need for reoperation following fracture repair surgery. In some embodiments, the method prevents or reduces the risk of a vertebral fracture, a non-vertebral fracture and / or a hip fracture, or any combination thereof, in a human individual. In some embodiments, the method prevents or reduces the risk of a lumbar spine fracture and / or a femoral neck in a human individual. In some embodiments, the individual is at high risk for fracture. In some embodiments, the individual is at least about 18, 30, 35, 40, 45, 50, 55, or 60 years old. In some embodiments, the individual is a male. In some embodiments, the individual is a female. In some embodiments, the female is a postmenopausal woman. In some embodiments, the method treats osteoporosis in a postmenopausal female individual. In some embodiments, the individual has a history of osteoporotic fracture. In some embodiments, the individual has been subjected to, failed, or is intolerant to an osteoporosis therapy. In some embodiments, the osteoporosis therapy is selected from the group consisting of romosozumab, denosumab, etidronate, pamidronate, risedronate, alendronate, zoledronate, ibandronate, teriparatide, and abaloparatide. In some embodiments, the individual has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90% or 95% probability of fraction in the next five or ten years as determined by a clinician or under Fracture Risk Assessment Tool (FRAX®). In some embodiments, the individual has a history of a cardiovascular disease, optionally the cardiovascular disease is a myocardial infarction or stroke. In some embodiments, the individual has a hip bone mineral density T-score measured by DXA a) that is between -1 and - 2.5; b) that is -2.5 or lower than -2.5; or c) that is -2.5 or lower than -2.5 and at least one fragility fracture. In some embodiments, the individual has a history of fracture (e.g., a vertebral or non-vertebral fracture). In some embodiments, the individual is subject to a supplement (e.g., daily supplement) comprising Vitamin D (e.g., Vitamin D2 or Vitamin D3) and / or calcium. In some embodiments, the individual is subject to calcium at a dose of about 100, 250, 500, 750 or 1000 mg / day or more daily and / or Vitamin D at a dose of about 100, 250, 500, 750 or 1000 lU / day or more.

[0188] In some embodiments, there is provided a method of treating a disease, disorder, or condition, comprising administering (e.g., subcutaneously or intravenously) a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises the BAP0063 polypeptides, wherein the bispecific antibody is administered at a dose of at least about or about 70 mg (e.g., 70 mg), wherein the bispecific antibody is39MOFO-359878767Attorney Docket No. 21091-20003.40 administered about every 3 months. In some embodiments, the bispecific antibody is administered for a duration of at least 3 months, of at least 4 months, of at least 5 months, of at least 6 months, of at least 7 months, of at least 8 months, of at least 9 months, of at least 10 months, of at least 11 months, of at least 12 months, of at least 13 months, of at least 14 months, of at least 15 months, of at least 16 months, of at least 17 months, of at least 18 months, of at least 19 months, of at least 20 months, of at least 21 months, of at least 22 months, of at least 23 months, or of at least 24 months, or of at least 3 years, or of at least 4 years, or of at least 5 years, or of at least 6 years, or of at least 7 years, or of at least 8 years, or of at least 9 years, or of at least 10 years.. In some embodiments, the VH-I, VL-I, VH-2, and VL-2 comprise the amino acid sequences of SEQ ID NO: 13, 14, 15, and 16 respectively. In some embodiments, the bispecific antibody is a full-length antibody comprising an IgG (e.g., IgG4) Fc fragment. In some embodiments, the first, second, third and fourth polypeptides comprise the amino acid sequences of SEQ ID NO: 17, 18, 19, and 20 respectively. In some embodiments, the method treats osteoporosis or reduces the risk of osteoporosis in a human individual. In some embodiments, the method reduces the risk of developing osteoporosis. In some embodiments, the method reduces the severity of existing osteoporosis. In some embodiments, the method treats or prevents diseases or conditions associated with low bone mass. In some embodiments, the method increases bone mineral density in a human individual. In some embodiments, the method reduces the risk of osteoporotic fracture in a human individual. In some embodiments, the method accelerates fracture healing in a human individual. In some embodiments, the method prevents or reduces the risk of fracture nonunion, and / or prevents or reduces the risk of delayed union, and / or prevents the need for reoperation following fracture repair surgery. In some embodiments, the method prevents or reduces the risk of a vertebral fracture, a non-vertebral fracture and / or a hip fracture, or any combination thereof, in a human individual. In some embodiments, the method prevents or reduces the risk of a lumbar spine fracture and / or a femoral neck in a human individual. In some embodiments, the individual is at high risk for fracture. In some embodiments, the individual is at least about 18, 30, 35, 40, 45, 50, 55, or 60 years old. In some embodiments, the individual is a male. In some embodiments, the individual is a female. In some embodiments, the female is a postmenopausal woman. In some embodiments, the method treats osteoporosis in a postmenopausal female individual. In some embodiments, the individual has a history of osteoporotic fracture. In some embodiments, the individual has been subjected to, failed, or is intolerant to an osteoporosis therapy. In some embodiments, the osteoporosis therapy is selected from the group consisting of romosozumab, denosumab,40MOFO-359878767Attorney Docket No. 21091-20003.40 etidronate, pamidronate, risedronate, alendronate, zoledronate, ibandronate, teriparatide, and abaloparatide. In some embodiments, the individual has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90% or 95% probability of fraction in the next five or ten years as determined by a clinician or under Fracture Risk Assessment Tool (FRAX®). In some embodiments, the individual has a history of a cardiovascular disease, optionally the cardiovascular disease is a myocardial infarction or stroke. In some embodiments, the individual has a hip bone mineral density T-score measured by DXA a) that is between -1 and - 2.5; b) that is -2.5 or lower than -2.5; or c) that is -2.5 or lower than -2.5 and at least one fragility fracture. In some embodiments, the individual has a history of fracture (e.g., a vertebral or non-vertebral fracture). In some embodiments, the individual is subject to a supplement (e.g., daily supplement) comprising Vitamin D (e.g., Vitamin D2 or Vitamin D3) and / or calcium. In some embodiments, the individual is subject to calcium at a dose of about 100, 250, 500, 750 or 1000 mg / day or more daily and / or Vitamin D at a dose of about 100, 250, 500, 750 or 1000 lU / day or more.

[0189] In some embodiments, there is provided a method of treating a disease, disorder, or condition, comprising administering (e.g., subcutaneously or intravenously) a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises the BAP0063 polypeptides, wherein the bispecific antibody is administered at a dose of at least about or about 140 mg (e.g., about 140 mg), wherein the bispecific antibody is administered about every month (every four weeks). In some embodiments, the bispecific antibody is administered for a duration of at least 1 month, of at least 2 months, of at least 3 months, of at least 4 months, of at least 5 months, of at least 6 months, of at least 7 months, of at least 8 months, of at least 9 months, of at least 10 months, of at least 11 months, of at least 12 months, of at least 13 months, of at least 14 months, of at least 15 months, of at least 16 months, of at least 17 months, of at least 18 months, of at least 19 months, of at least 20 months, of at least 21 months, of at least 22 months, of at least 23 months, or of at least 24 months, or of at least 3 years, or of at least 4 years, or of at least 5 years, or of at least 6 years, or of at least 7 years, or of at least 8 years, or of at least 9 years, or of at least 10 years. In some embodiments, the VH-I, VL-I, VH-2, and VL-2 comprise the amino acid sequences of SEQ ID NO: 13, 14, 15, and 16 respectively. In some embodiments, the bispecific antibody is a full- length antibody comprising an IgG (e.g., IgG4) Fc fragment. In some embodiments, the first, second, third and fourth polypeptides comprise the amino acid sequences of SEQ ID NO: 17, 18, 19, and 20 respectively. In some embodiments, the method treats osteoporosis or reduces the risk of osteoporosis in a human individual. In some embodiments, the method reduces the41MOFO-359878767Attorney Docket No. 21091-20003.40 risk of developing osteoporosis. In some embodiments, the method reduces the severity of existing osteoporosis. In some embodiments, the method treats or prevents diseases or conditions associated with low bone mass. In some embodiments, the method increases bone mineral density in a human individual. In some embodiments, the method reduces the risk of osteoporotic fracture in a human individual. In some embodiments, the method accelerates fracture healing in a human individual. In some embodiments, the method prevents or reduces the risk of fracture nonunion, and / or prevents or reduces the risk of delayed union, and / or prevents the need for reoperation following fracture repair surgery. In some embodiments, the method prevents or reduces the risk of a vertebral fracture, a non-vertebral fracture and / or a hip fracture, or any combination thereof, in a human individual. In some embodiments, the method prevents or reduces the risk of a lumbar spine fracture and / or a femoral neck in a human individual. In some embodiments, the individual is at high risk for fracture. In some embodiments, the individual is at least about 18, 30, 35, 40, 45, 50, 55, or 60 years old. In some embodiments, the individual is a male. In some embodiments, the individual is a female. In some embodiments, the female is a postmenopausal woman. In some embodiments, the method treats osteoporosis in a postmenopausal female individual. In some embodiments, the individual has a history of osteoporotic fracture. In some embodiments, the individual has been subjected to, failed, or is intolerant to an osteoporosis therapy. In some embodiments, the osteoporosis therapy is selected from the group consisting of romosozumab, denosumab, etidronate, pamidronate, risedronate, alendronate, zoledronate, ibandronate, teriparatide, and abaloparatide. In some embodiments, the individual has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90% or 95% probability of fraction in the next five or ten years as determined by a clinician or under Fracture Risk Assessment Tool (FRAX®). In some embodiments, the individual has a history of a cardiovascular disease, optionally the cardiovascular disease is a myocardial infarction or stroke. In some embodiments, the individual has a hip bone mineral density T-score measured by DXA a) that is between -1 and - 2.5; b) that is -2.5 or lower than -2.5; or c) that is -2.5 or lower than -2.5 and at least one fragility fracture. In some embodiments, the individual has a history of fracture (e.g., a vertebral or non-vertebral fracture). In some embodiments, the individual is subject to a supplement (e.g., daily supplement) comprising Vitamin D (e.g., Vitamin D2 or Vitamin D3) and / or calcium. In some embodiments, the individual is subject to calcium at a dose of about 100, 250, 500, 750 or 1000 mg / day or more daily and / or Vitamin D at a dose of about 100, 250, 500, 750 or 1000 lU / day or more.42MOFO-359878767Attorney Docket No. 21091-20003.40

[0190] In some embodiments, there is provided a method of treating a disease, disorder, or condition, comprising administering (e.g., subcutaneously or intravenously) a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises the BAP0063 polypeptides, wherein the bispecific antibody is administered at a dose of at least about or about 140 mg (e.g., 140 mg), wherein the bispecific antibody is administered about every 3 months. In some embodiments, the bispecific antibody is administered for a duration of at least 3 months, of at least 4 months, of at least 5 months, of at least 6 months, of at least 7 months, of at least 8 months, of at least 9 months, of at least 10 months, of at least 11 months, of at least 12 months, of at least 13 months, of at least 14 months, of at least 15 months, of at least 16 months, of at least 17 months, of at least 18 months, of at least 19 months, of at least 20 months, of at least 21 months, of at least 22 months, of at least 23 months, or of at least 24 months, or of at least 3 years, or of at least 4 years, or of at least 5 years, or of at least 6 years, or of at least 7 years, or of at least 8 years, or of at least 9 years, or of at least 10 years.. In some embodiments, the VH-I, VL-I, VH-2, and VL-2 comprise the amino acid sequences of SEQ ID NO: 13, 14, 15, and 16 respectively. In some embodiments, the bispecific antibody is a full-length antibody comprising an IgG (e.g., IgG4) Fc fragment. In some embodiments, the first, second, third and fourth polypeptides comprise the amino acid sequences of SEQ ID NO: 17, 18, 19, and 20 respectively. In some embodiments, the method treats osteoporosis or reduces the risk of osteoporosis in a human individual. In some embodiments, the method reduces the risk of developing osteoporosis. In some embodiments, the method reduces the severity of existing osteoporosis. In some embodiments, the method treats or prevents diseases or conditions associated with low bone mass. In some embodiments, the method increases bone mineral density in a human individual. In some embodiments, the method reduces the risk of osteoporotic fracture in a human individual. In some embodiments, the method accelerates fracture healing in a human individual. In some embodiments, the method prevents or reduces the risk of fracture nonunion, and / or prevents or reduces the risk of delayed union, and / or prevents the need for reoperation following fracture repair surgery. In some embodiments, the method prevents or reduces the risk of a vertebral fracture, a non-vertebral fracture and / or a hip fracture, or any combination thereof, in a human individual. In some embodiments, the method prevents or reduces the risk of a lumbar spine fracture and / or a femoral neck in a human individual. In some embodiments, the individual is at high risk for fracture. In some embodiments, the individual is at least about 18, 30, 35, 40, 45, 50, 55, or 60 years old. In some embodiments, the individual is a male. In some embodiments, the individual is a female. In some43MOFO-359878767Attorney Docket No. 21091-20003.40 embodiments, the female is a postmenopausal woman. In some embodiments, the method treats osteoporosis in a postmenopausal female individual. In some embodiments, the individual has a history of osteoporotic fracture. In some embodiments, the individual has been subjected to, failed, or is intolerant to an osteoporosis therapy. In some embodiments, the osteoporosis therapy is selected from the group consisting of romosozumab, denosumab, etidronate, pamidronate, risedronate, alendronate, zoledronate, ibandronate, teriparatide, and abaloparatide. In some embodiments, the individual has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90% or 95% probability of fraction in the next five or ten years as determined by a clinician or under Fracture Risk Assessment Tool (FRAX®). In some embodiments, the individual has a history of a cardiovascular disease, optionally the cardiovascular disease is a myocardial infarction or stroke. In some embodiments, the individual has a hip bone mineral density T-score measured by DXA a) that is between -1 and - 2.5; b) that is -2.5 or lower than -2.5; or c) that is -2.5 or lower than -2.5 and at least one fragility fracture. In some embodiments, the individual has a history of fracture (e.g., a vertebral or non-vertebral fracture). In some embodiments, the individual is subject to a supplement (e.g., daily supplement) comprising Vitamin D (e.g., Vitamin D2 or Vitamin D3) and / or calcium. In some embodiments, the individual is subject to calcium at a dose of about 100, 250, 500, 750 or 1000 mg / day or more daily and / or Vitamin D at a dose of about 100, 250, 500, 750 or 1000 lU / day or more.

[0191] In some embodiments, there is provided a method of treating a disease, disorder, or condition, comprising administering (e.g., subcutaneously or intravenously) a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises the BAP0063 polypeptides, wherein the bispecific antibody is administered at a dose of at least about or about 210 mg (e.g., about 210 mg), wherein the bispecific antibody is administered about every month (every four weeks). In some embodiments, the bispecific antibody is administered for a duration of at least 1 month, of at least 2 months, of at least 3 months, of at least 4 months, of at least 5 months, of at least 6 months, of at least 7 months, of at least 8 months, of at least 9 months, of at least 10 months, of at least 11 months, of at least 12 months, of at least 13 months, of at least 14 months, of at least 15 months, of at least 16 months, of at least 17 months, of at least 18 months, of at least 19 months, of at least 20 months, of at least 21 months, of at least 22 months, of at least 23 months, or of at least 24 months, or of at least 3 years, or of at least 4 years, or of at least 5 years, or of at least 6 years, or of at least 7 years, or of at least 8 years, or of at least 9 years, or of at least 10 years. In some embodiments, the VH-I, VL-I, VH-2, and VL-2 comprise the amino acid sequences of SEQ ID44MOFO-359878767Attorney Docket No. 21091-20003.40NO: 13, 14, 15, and 16 respectively. In some embodiments, the bispecific antibody is a full- length antibody comprising an IgG (e.g., IgG4) Fc fragment. In some embodiments, the first, second, third and fourth polypeptides comprise the amino acid sequences of SEQ ID NO: 17, 18, 19, and 20 respectively. In some embodiments, the method treats osteoporosis or reduces the risk of osteoporosis in a human individual. In some embodiments, the method reduces the risk of developing osteoporosis. In some embodiments, the method reduces the severity of existing osteoporosis. In some embodiments, the method treats or prevents diseases or conditions associated with low bone mass. In some embodiments, the method increases bone mineral density in a human individual. In some embodiments, the method reduces the risk of osteoporotic fracture in a human individual. In some embodiments, the method accelerates fracture healing in a human individual. In some embodiments, the method prevents or reduces the risk of fracture nonunion, and / or prevents or reduces the risk of delayed union, and / or prevents the need for reoperation following fracture repair surgery. In some embodiments, the method prevents or reduces the risk of a vertebral fracture, a non-vertebral fracture and / or a hip fracture, or any combination thereof, in a human individual. In some embodiments, the method prevents or reduces the risk of a lumbar spine fracture and / or a femoral neck in a human individual. In some embodiments, the individual is at high risk for fracture. In some embodiments, the individual is at least about 18, 30, 35, 40, 45, 50, 55, or 60 years old. In some embodiments, the individual is a male. In some embodiments, the individual is a female. In some embodiments, the female is a postmenopausal woman. In some embodiments, the method treats osteoporosis in a postmenopausal female individual. In some embodiments, the individual has a history of osteoporotic fracture. In some embodiments, the individual has been subjected to, failed, or is intolerant to an osteoporosis therapy. In some embodiments, the osteoporosis therapy is selected from the group consisting of romosozumab, denosumab, etidronate, pamidronate, risedronate, alendronate, zoledronate, ibandronate, teriparatide, and abaloparatide. In some embodiments, the individual has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90% or 95% probability of fraction in the next five or ten years as determined by a clinician or under Fracture Risk Assessment Tool (FRAX®). In some embodiments, the individual has a history of a cardiovascular disease, optionally the cardiovascular disease is a myocardial infarction or stroke. In some embodiments, the individual has a hip bone mineral density T-score measured by DXA a) that is between -1 and - 2.5; b) that is -2.5 or lower than -2.5; or c) that is -2.5 or lower than -2.5 and at least one fragility fracture. In some embodiments, the individual has a history of fracture (e.g., a vertebral or non-vertebral fracture). In some embodiments, the individual is subject to a45MOFO-359878767Attorney Docket No. 21091-20003.40 supplement (e.g., daily supplement) comprising Vitamin D (e.g., Vitamin D2 or Vitamin D3) and / or calcium. In some embodiments, the individual is subject to calcium at a dose of about 100, 250, 500, 750 or 1000 mg / day or more daily and / or Vitamin D at a dose of about 100, 250, 500, 750 or 1000 lU / day or more.

[0192] In some embodiments, there is provided a method of treating a disease, disorder, or condition, comprising administering (e.g., subcutaneously or intravenously) a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises the BAP0063 polypeptides, wherein the bispecific antibody is administered at a dose of at least about or about 210 mg (e.g., 210 mg), wherein the bispecific antibody is administered about every 3 months. In some embodiments, the bispecific antibody is administered for a duration of at least 3 months, of at least 4 months, of at least 5 months, of at least 6 months, of at least 7 months, of at least 8 months, of at least 9 months, of at least 10 months, of at least 11 months, of at least 12 months, of at least 13 months, of at least 14 months, of at least 15 months, of at least 16 months, of at least 17 months, of at least 18 months, of at least 19 months, of at least 20 months, of at least 21 months, of at least 22 months, of at least 23 months, or of at least 24 months, or of at least 3 years, or of at least 4 years, or of at least 5 years, or of at least 6 years, or of at least 7 years, or of at least 8 years, or of at least 9 years, or of at least 10 years.. In some embodiments, the VH-I, VL-I, VH-2, and VL-2 comprise the amino acid sequences of SEQ ID NO: 13, 14, 15, and 16 respectively. In some embodiments, the bispecific antibody is a full-length antibody comprising an IgG (e.g., IgG4) Fc fragment. In some embodiments, the first, second, third and fourth polypeptides comprise the amino acid sequences of SEQ ID NO: 17, 18, 19, and 20 respectively. In some embodiments, the method treats osteoporosis or reduces the risk of osteoporosis in a human individual. In some embodiments, the method reduces the risk of developing osteoporosis. In some embodiments, the method reduces the severity of existing osteoporosis. In some embodiments, the method treats or prevents diseases or conditions associated with low bone mass. In some embodiments, the method increases bone mineral density in a human individual. In some embodiments, the method reduces the risk of osteoporotic fracture in a human individual. In some embodiments, the method accelerates fracture healing in a human individual. In some embodiments, the method prevents or reduces the risk of fracture nonunion, and / or prevents or reduces the risk of delayed union, and / or prevents the need for reoperation following fracture repair surgery. In some embodiments, the method prevents or reduces the risk of a vertebral fracture, a non-vertebral fracture and / or a hip fracture, or any combination thereof, in a human individual. In some embodiments, the method prevents or46MOFO-359878767Attorney Docket No. 21091-20003.40 reduces the risk of a lumbar spine fracture and / or a femoral neck in a human individual. In some embodiments, the individual is at high risk for fracture. In some embodiments, the individual is at least about 18, 30, 35, 40, 45, 50, 55, or 60 years old. In some embodiments, the individual is a male. In some embodiments, the individual is a female. In some embodiments, the female is a postmenopausal woman. In some embodiments, the method treats osteoporosis in a postmenopausal female individual. In some embodiments, the individual has a history of osteoporotic fracture. In some embodiments, the individual has been subjected to, failed, or is intolerant to an osteoporosis therapy. In some embodiments, the osteoporosis therapy is selected from the group consisting of romosozumab, denosumab, etidronate, pamidronate, risedronate, alendronate, zoledronate, ibandronate, teriparatide, and abaloparatide. In some embodiments, the individual has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90% or 95% probability of fraction in the next five or ten years as determined by a clinician or under Fracture Risk Assessment Tool (FRAX®). In some embodiments, the individual has a history of a cardiovascular disease, optionally the cardiovascular disease is a myocardial infarction or stroke. In some embodiments, the individual has a hip bone mineral density T-score measured by DXA a) that is between -1 and - 2.5; b) that is -2.5 or lower than -2.5; or c) that is -2.5 or lower than -2.5 and at least one fragility fracture. In some embodiments, the individual has a history of fracture (e.g., a vertebral or non-vertebral fracture). In some embodiments, the individual is subject to a supplement (e.g., daily supplement) comprising Vitamin D (e.g., Vitamin D2 or Vitamin D3) and / or calcium. In some embodiments, the individual is subject to calcium at a dose of about 100, 250, 500, 750 or 1000 mg / day or more daily and / or Vitamin D at a dose of about 100, 250, 500, 750 or 1000 lU / day or more.

[0193] In some embodiments, there is provided a method of treating a disease, disorder, or condition, comprising administering (e.g., subcutaneously or intravenously) a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises the BAP0063 polypeptides, wherein the bispecific antibody is administered at a dose of at least about or about 280 mg (e.g., about 280 mg), wherein the bispecific antibody is administered about every month (every four weeks). In some embodiments, the bispecific antibody is administered for a duration of at least 1 month, of at least 2 months, of at least 3 months, of at least 4 months, of at least 5 months, of at least 6 months, of at least 7 months, of at least 8 months, of at least 9 months, of at least 10 months, of at least 11 months, of at least 12 months, of at least 13 months, of at least 14 months, of at least 15 months, of at least 16 months, of at least 17 months, of at least 18 months, of at least 19 months, of at least 2047MOFO-359878767Attorney Docket No. 21091-20003.40 months, of at least 21 months, of at least 22 months, of at least 23 months, or of at least 24 months, or of at least 3 years, or of at least 4 years, or of at least 5 years, or of at least 6 years, or of at least 7 years, or of at least 8 years, or of at least 9 years, or of at least 10 years. In some embodiments, the VH-I, VL-I, VH-2, and VL-2 comprise the amino acid sequences of SEQ ID NO: 13, 14, 15, and 16 respectively. In some embodiments, the bispecific antibody is a full- length antibody comprising an IgG (e.g., IgG4) Fc fragment. In some embodiments, the first, second, third and fourth polypeptides comprise the amino acid sequences of SEQ ID NO: 17, 18, 19, and 20 respectively. In some embodiments, the method treats osteoporosis or reduces the risk of osteoporosis in a human individual. In some embodiments, the method reduces the risk of developing osteoporosis. In some embodiments, the method reduces the severity of existing osteoporosis. In some embodiments, the method treats or prevents diseases or conditions associated with low bone mass. In some embodiments, the method increases bone mineral density in a human individual. In some embodiments, the method reduces the risk of osteoporotic fracture in a human individual. In some embodiments, the method accelerates fracture healing in a human individual. In some embodiments, the method prevents or reduces the risk of fracture nonunion, and / or prevents or reduces the risk of delayed union, and / or prevents the need for reoperation following fracture repair surgery. In some embodiments, the method prevents or reduces the risk of a vertebral fracture, a non-vertebral fracture and / or a hip fracture, or any combination thereof, in a human individual. In some embodiments, the method prevents or reduces the risk of a lumbar spine fracture and / or a femoral neck in a human individual. In some embodiments, the individual is at high risk for fracture. In some embodiments, the individual is at least about 18, 30, 35, 40, 45, 50, 55, or 60 years old. In some embodiments, the individual is a male. In some embodiments, the individual is a female. In some embodiments, the female is a postmenopausal woman. In some embodiments, the method treats osteoporosis in a postmenopausal female individual. In some embodiments, the individual has a history of osteoporotic fracture. In some embodiments, the individual has been subjected to, failed, or is intolerant to an osteoporosis therapy. In some embodiments, the osteoporosis therapy is selected from the group consisting of romosozumab, denosumab, etidronate, pamidronate, risedronate, alendronate, zoledronate, ibandronate, teriparatide, and abaloparatide. In some embodiments, the individual has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90% or 95% probability of fraction in the next five or ten years as determined by a clinician or under Fracture Risk Assessment Tool (FRAX®). In some embodiments, the individual has a history of a cardiovascular disease, optionally the cardiovascular disease is a myocardial infarction or stroke. In some embodiments, the48MOFO-359878767Attorney Docket No. 21091-20003.40 individual has a hip bone mineral density T-score measured by DXA a) that is between -1 and - 2.5; b) that is -2.5 or lower than -2.5; or c) that is -2.5 or lower than -2.5 and at least one fragility fracture. In some embodiments, the individual has a history of fracture (e.g., a vertebral or non-vertebral fracture). In some embodiments, the individual is subject to a supplement (e.g., daily supplement) comprising Vitamin D (e.g., Vitamin D2 or Vitamin D3) and / or calcium. In some embodiments, the individual is subject to calcium at a dose of about 100, 250, 500, 750 or 1000 mg / day or more daily and / or Vitamin D at a dose of about 100, 250, 500, 750 or 1000 lU / day or more.

[0194] In some embodiments, there is provided a method of treating a disease, disorder, or condition, comprising administering (e.g., subcutaneously or intravenously) a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises the BAP0063 polypeptides, wherein the bispecific antibody is administered at a dose of at least about or about 280 mg (e.g., 280 mg), wherein the bispecific antibody is administered about every 3 months. In some embodiments, the bispecific antibody is administered for a duration of at least 3 months, of at least 4 months, of at least 5 months, of at least 6 months, of at least 7 months, of at least 8 months, of at least 9 months, of at least 10 months, of at least 11 months, of at least 12 months, of at least 13 months, of at least 14 months, of at least 15 months, of at least 16 months, of at least 17 months, of at least 18 months, of at least 19 months, of at least 20 months, of at least 21 months, of at least 22 months, of at least 23 months, or of at least 24 months, or of at least 3 years, or of at least 4 years, or of at least 5 years, or of at least 6 years, or of at least 7 years, or of at least 8 years, or of at least 9 years, or of at least 10 years.. In some embodiments, the VH-I, VL-I, VH-2, and VL-2 comprise the amino acid sequences of SEQ ID NO: 13, 14, 15, and 16 respectively. In some embodiments, the bispecific antibody is a full-length antibody comprising an IgG (e.g., IgG4) Fc fragment. In some embodiments, the first, second, third and fourth polypeptides comprise the amino acid sequences of SEQ ID NO: 17, 18, 19, and 20 respectively. In some embodiments, the method treats osteoporosis or reduces the risk of osteoporosis in a human individual. In some embodiments, the method reduces the risk of developing osteoporosis. In some embodiments, the method reduces the severity of existing osteoporosis. In some embodiments, the method treats or prevents diseases or conditions associated with low bone mass. In some embodiments, the method increases bone mineral density in a human individual. In some embodiments, the method reduces the risk of osteoporotic fracture in a human individual. In some embodiments, the method accelerates fracture healing in a human individual. In some embodiments, the method prevents or reduces the risk of fracture49MOFO-359878767Attorney Docket No. 21091-20003.40 nonunion, and / or prevents or reduces the risk of delayed union, and / or prevents the need for reoperation following fracture repair surgery. In some embodiments, the method prevents or reduces the risk of a vertebral fracture, a non-vertebral fracture and / or a hip fracture, or any combination thereof, in a human individual. In some embodiments, the method prevents or reduces the risk of a lumbar spine fracture and / or a femoral neck in a human individual. In some embodiments, the individual is at high risk for fracture. In some embodiments, the individual is at least about 18, 30, 35, 40, 45, 50, 55, or 60 years old. In some embodiments, the individual is a male. In some embodiments, the individual is a female. In some embodiments, the female is a postmenopausal woman. In some embodiments, the method treats osteoporosis in a postmenopausal female individual. In some embodiments, the individual has a history of osteoporotic fracture. In some embodiments, the individual has been subjected to, failed, or is intolerant to an osteoporosis therapy. In some embodiments, the osteoporosis therapy is selected from the group consisting of romosozumab, denosumab, etidronate, pamidronate, risedronate, alendronate, zoledronate, ibandronate, teriparatide, and abaloparatide. In some embodiments, the individual has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90% or 95% probability of fraction in the next five or ten years as determined by a clinician or under Fracture Risk Assessment Tool (FRAX®). In some embodiments, the individual has a history of a cardiovascular disease, optionally the cardiovascular disease is a myocardial infarction or stroke. In some embodiments, the individual has a hip bone mineral density T-score measured by DXA a) that is between -1 and - 2.5; b) that is -2.5 or lower than -2.5; or c) that is -2.5 or lower than -2.5 and at least one fragility fracture. In some embodiments, the individual has a history of fracture (e.g., a vertebral or non-vertebral fracture). In some embodiments, the individual is subject to a supplement (e.g., daily supplement) comprising Vitamin D (e.g., Vitamin D2 or Vitamin D3) and / or calcium. In some embodiments, the individual is subject to calcium at a dose of about 100, 250, 500, 750 or 1000 mg / day or more daily and / or Vitamin D at a dose of about 100, 250, 500, 750 or 1000 lU / day or more.

[0195] In some embodiments, there is provided a method of treating a disease, disorder, or condition, comprising administering (e.g., subcutaneously or intravenously) a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises the BAP0063 polypeptides, wherein the bispecific antibody is administered at a dose of at least about or about 420 mg (e.g., 420 mg), wherein the bispecific antibody is administered about every month (every four weeks). In some embodiments, the bispecific antibody is administered for a duration of at least 1 month, of at least 2 months, of at least 350MOFO-359878767Attorney Docket No. 21091-20003.40 months, of at least 4 months, of at least 5 months, of at least 6 months, of at least 7 months, of at least 8 months, of at least 9 months, of at least 10 months, of at least 11 months, of at least 12 months, of at least 13 months, of at least 14 months, of at least 15 months, of at least 16 months, of at least 17 months, of at least 18 months, of at least 19 months, of at least 20 months, of at least 21 months, of at least 22 months, of at least 23 months, or of at least 24 months, or of at least 3 years, or of at least 4 years, or of at least 5 years, or of at least 6 years, or of at least 7 years, or of at least 8 years, or of at least 9 years, or of at least 10 years.. In some embodiments, the VH-I, VL-I, VH-2, and VL-2 comprise the amino acid sequences of SEQ ID NO: 13, 14, 15, and 16 respectively. In some embodiments, the bispecific antibody is a full- length antibody comprising an IgG (e.g., IgG4) Fc fragment. In some embodiments, the first, second, third and fourth polypeptides comprise the amino acid sequences of SEQ ID NO: 17, 18, 19, and 20 respectively. In some embodiments, the method treats osteoporosis or reduces the risk of osteoporosis in a human individual. In some embodiments, the method reduces the risk of developing osteoporosis. In some embodiments, the method reduces the severity of existing osteoporosis. In some embodiments, the method treats or prevents diseases or conditions associated with low bone mass. In some embodiments, the method increases bone mineral density in a human individual. In some embodiments, the method reduces the risk of osteoporotic fracture in a human individual. In some embodiments, the method accelerates fracture healing in a human individual. In some embodiments, the method prevents or reduces the risk of fracture nonunion, and / or prevents or reduces the risk of delayed union, and / or prevents the need for reoperation following fracture repair surgery. In some embodiments, the method prevents or reduces the risk of a vertebral fracture, a non-vertebral fracture and / or a hip fracture, or any combination thereof, in a human individual. In some embodiments, the method prevents or reduces the risk of a lumbar spine fracture and / or a femoral neck in a human individual. In some embodiments, the individual is at high risk for fracture. In some embodiments, the individual is at least about 18, 30, 35, 40, 45, 50, 55, or 60 years old. In some embodiments, the individual is a male. In some embodiments, the individual is a female. In some embodiments, the female is a postmenopausal woman. In some embodiments, the method treats osteoporosis in a postmenopausal female individual. In some embodiments, the individual has a history of osteoporotic fracture. In some embodiments, the individual has been subjected to, failed, or are intolerant to an osteoporosis therapy. In some embodiments, the osteoporosis therapy is selected from the group consisting of romosozumab, denosumab, etidronate, pamidronate, risedronate, alendronate, zoledronate, ibandronate, teriparatide, and abaloparatide. In some embodiments, the individual has at least 5%, 10%, 20%, 30%, 40%,51MOFO-359878767Attorney Docket No. 21091-20003.4050%, 60%, 70%, 80%, 85%, 90% or 95% probability of fraction in the next five or ten years as determined by a clinician or under Fracture Risk Assessment Tool (FRAX®). In some embodiments, the individual has a history of a cardiovascular disease, optionally the cardiovascular disease is a myocardial infarction or stroke. In some embodiments, the individual has a hip bone mineral density T-score measured by DXA a) that is between -1 and - 2.5; b) that is -2.5 or lower than -2.5; or c) that is -2.5 or lower than -2.5 and at least one fragility fracture. In some embodiments, the individual has a history of fracture (e.g., a vertebral or non-vertebral fracture). In some embodiments, the individual is subject to a supplement (e.g., daily supplement) comprising Vitamin D (e.g., Vitamin D2 or Vitamin D3) and / or calcium. In some embodiments, the individual is subject to calcium at a dose of about 100, 250, 500, 750 or 1000 mg / day or more daily and / or Vitamin D at a dose of about 100, 250, 500, 750 or 1000 lU / day or more.

[0196] In some embodiments, there is provided a method of treating a disease, disorder, or condition, comprising administering (e.g., subcutaneously or intravenously) a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises the BAP0063 polypeptides, wherein the bispecific antibody is administered at a dose of at least about or about 420 mg (e.g., 420 mg), wherein the bispecific antibody is administered about every 3 months. In some embodiments, the bispecific antibody is administered for a duration of at least 3 months, of at least 4 months, of at least 5 months, of at least 6 months, of at least 7 months, of at least 8 months, of at least 9 months, of at least 10 months, of at least 11 months, of at least 12 months, of at least 13 months, of at least 14 months, of at least 15 months, of at least 16 months, of at least 17 months, of at least 18 months, of at least 19 months, of at least 20 months, of at least 21 months, of at least 22 months, of at least 23 months, or of at least 24 months, or of at least 3 years, or of at least 4 years, or of at least 5 years, or of at least 6 years, or of at least 7 years, or of at least 8 years, or of at least 9 years, or of at least 10 years.. In some embodiments, the VH-I, VL-I, VH-2, and VL-2 comprise the amino acid sequences of SEQ ID NO: 13, 14, 15, and 16 respectively. In some embodiments, the bispecific antibody is a full-length antibody comprising an IgG (e.g., IgG4) Fc fragment. In some embodiments, the first, second, third and fourth polypeptides comprise the amino acid sequences of SEQ ID NO: 17, 18, 19, and 20 respectively. In some embodiments, the method treats osteoporosis or reduces the risk of osteoporosis in a human individual. In some embodiments, the method reduces the risk of developing osteoporosis. In some embodiments, the method reduces the severity of existing osteoporosis. In some embodiments, the method treats or prevents diseases or conditions associated with low bone52MOFO-359878767Attorney Docket No. 21091-20003.40 mass. In some embodiments, the method increases bone mineral density in a human individual. In some embodiments, the method reduces the risk of osteoporotic fracture in a human individual. In some embodiments, the method accelerates fracture healing in a human individual. In some embodiments, the method prevents or reduces the risk of fracture nonunion, and / or prevents or reduces the risk of delayed union, and / or prevents the need for reoperation following fracture repair surgery. In some embodiments, the method prevents or reduces the risk of a vertebral fracture, a non-vertebral fracture and / or a hip fracture, or any combination thereof, in a human individual. In some embodiments, the method prevents or reduces the risk of a lumbar spine fracture and / or a femoral neck in a human individual. In some embodiments, the individual is at high risk for fracture. In some embodiments, the individual is at least about 18, 30, 35, 40, 45, 50, 55, or 60 years old. In some embodiments, the individual is a male. In some embodiments, the individual is a female. In some embodiments, the female is a postmenopausal woman. In some embodiments, the method treats osteoporosis in a postmenopausal female individual. In some embodiments, the individual has a history of osteoporotic fracture. In some embodiments, the individual has been subjected to, failed, or is intolerant to an osteoporosis therapy. In some embodiments, the osteoporosis therapy is selected from the group consisting of romosozumab, denosumab, etidronate, pamidronate, risedronate, alendronate, zoledronate, ibandronate, teriparatide, and abaloparatide. In some embodiments, the individual has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90% or 95% probability of fraction in the next five or ten years as determined by a clinician or under Fracture Risk Assessment Tool (FRAX®). In some embodiments, the individual has a history of a cardiovascular disease, optionally the cardiovascular disease is a myocardial infarction or stroke. In some embodiments, the individual has a hip bone mineral density T-score measured by DXA a) that is between -1 and - 2.5; b) that is -2.5 or lower than -2.5; or c) that is -2.5 or lower than -2.5 and at least one fragility fracture. In some embodiments, the individual has a history of fracture (e.g., a vertebral or non-vertebral fracture). In some embodiments, the individual is subject to a supplement (e.g., daily supplement) comprising Vitamin D (e.g., Vitamin D2 or Vitamin D3) and / or calcium. In some embodiments, the individual is subject to calcium at a dose of about 100, 250, 500, 750 or 1000 mg / day or more daily and / or Vitamin D at a dose of about 100, 250, 500, 750 or 1000 lU / day or more.

[0197] In some embodiments, there is provided a method of treating a disease, disorder, or condition, comprising administering (e.g., subcutaneously or intravenously) a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody53MOFO-359878767Attorney Docket No. 21091-20003.40 comprises the BAP0063 polypeptides, wherein the bispecific antibody is administered at a dose of at least about or about 560 mg (e.g., 560 mg), wherein the bispecific antibody is administered about every month (every four weeks). In some embodiments, the bispecific antibody is administered for a duration of at least 1 month, of at least 2 months, of at least 3 months, of at least 4 months, of at least 5 months, of at least 6 months, of at least 7 months, of at least 8 months, of at least 9 months, of at least 10 months, of at least 11 months, of at least 12 months, of at least 13 months, of at least 14 months, of at least 15 months, of at least 16 months, of at least 17 months, of at least 18 months, of at least 19 months, of at least 20 months, of at least 21 months, of at least 22 months, of at least 23 months, or of at least 24 months, or of at least 3 years, or of at least 4 years, or of at least 5 years, or of at least 6 years, or of at least 7 years, or of at least 8 years, or of at least 9 years, or of at least 10 years.. In some embodiments, the VH-I, VL-I, VH-2, and VL-2 comprise the amino acid sequences of SEQ ID NO: 13, 14, 15, and 16 respectively. In some embodiments, the bispecific antibody is a full- length antibody comprising an IgG (e.g., IgG4) Fc fragment. In some embodiments, the first, second, third and fourth polypeptides comprise the amino acid sequences of SEQ ID NO: 17, 18, 19, and 20 respectively. In some embodiments, the method treats osteoporosis or reduces the risk of osteoporosis in a human individual. In some embodiments, the method reduces the risk of developing osteoporosis. In some embodiments, the method reduces the severity of existing osteoporosis. In some embodiments, the method treats or prevents diseases or conditions associated with low bone mass. In some embodiments, the method increases bone mineral density in a human individual. In some embodiments, the method reduces the risk of osteoporotic fracture in a human individual. In some embodiments, the method accelerates fracture healing in a human individual. In some embodiments, the method prevents or reduces the risk of fracture nonunion, and / or prevents or reduces the risk of delayed union, and / or prevents the need for reoperation following fracture repair surgery. In some embodiments, the method prevents or reduces the risk of a vertebral fracture, a non-vertebral fracture and / or a hip fracture, or any combination thereof, in a human individual. In some embodiments, the method prevents or reduces the risk of a lumbar spine fracture and / or a femoral neck in a human individual. In some embodiments, the individual is at high risk for fracture. In some embodiments, the individual is at least about 18, 30, 35, 40, 45, 50, 55, or 60 years old. In some embodiments, the individual is a male. In some embodiments, the individual is a female. In some embodiments, the female is a postmenopausal woman. In some embodiments, the method treats osteoporosis in a postmenopausal female individual. In some embodiments, the individual has a history of osteoporotic fracture. In some embodiments, the individual has been54MOFO-359878767Attorney Docket No. 21091-20003.40 subjected to, failed, or is intolerant to an osteoporosis therapy. In some embodiments, the osteoporosis therapy is selected from the group consisting of romosozumab, denosumab, etidronate, pamidronate, risedronate, alendronate, zoledronate, ibandronate, teriparatide, and abaloparatide. In some embodiments, the individual has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90% or 95% probability of fraction in the next five or ten years as determined by a clinician or under Fracture Risk Assessment Tool (FRAX®). In some embodiments, the individual has a history of a cardiovascular disease, optionally the cardiovascular disease is a myocardial infarction or stroke. In some embodiments, the individual has a hip bone mineral density T-score measured by DXA a) that is between -1 and - 2.5; b) that is -2.5 or lower than -2.5; or c) that is -2.5 or lower than -2.5 and at least one fragility fracture. In some embodiments, the individual has a history of fracture (e.g., a vertebral or non-vertebral fracture). In some embodiments, the individual is subject to a supplement (e.g., daily supplement) comprising Vitamin D (e.g., Vitamin D2 or Vitamin D3) and / or calcium. In some embodiments, the individual is subject to calcium at a dose of about 100, 250, 500, 750 or 1000 mg / day or more daily and / or Vitamin D at a dose of about 100, 250, 500, 750 or 1000 lU / day or more.

[0198] In some embodiments, there is provided a method of treating a disease, disorder, or condition, comprising administering (e.g., subcutaneously or intravenously) a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises the BAP0063 polypeptides, wherein the bispecific antibody is administered at a dose of at least about or about 560 mg, wherein the bispecific antibody is administered about every 3 months. In some embodiments, the bispecific antibody is administered for a duration of at least 3 months, of at least 4 months, of at least 5 months, of at least 6 months, of at least 7 months, of at least 8 months, of at least 9 months, of at least 10 months, of at least 11 months, of at least 12 months, of at least 13 months, of at least 14 months, of at least 15 months, of at least 16 months, of at least 17 months, of at least 18 months, of at least 19 months, of at least 20 months, of at least 21 months, of at least 22 months, of at least 23 months, or of at least 24 months, or of at least 3 years, or of at least 4 years, or of at least 5 years, or of at least 6 years, or of at least 7 years, or of at least 8 years, or of at least 9 years, or of at least 10 years.. In some embodiments, the VH-I, VL-I, VH-2, and VL-2 comprise the amino acid sequences of SEQ ID NO: 13, 14, 15, and 16 respectively. In some embodiments, the bispecific antibody is a full- length antibody comprising an IgG (e.g., IgG4) Fc fragment. In some embodiments, the first, second, third and fourth polypeptides comprise the amino acid sequences of SEQ ID NO: 17, 18, 19, and 20 respectively. In some embodiments, the method treats osteoporosis or reduces55MOFO-359878767Attorney Docket No. 21091-20003.40 the risk of osteoporosis in a human individual. In some embodiments, the method reduces the risk of developing osteoporosis. In some embodiments, the method reduces the severity of existing osteoporosis. In some embodiments, the method treats or prevents diseases or conditions associated with low bone mass. In some embodiments, the method increases bone mineral density in a human individual. In some embodiments, the method reduces the risk of osteoporotic fracture in a human individual. In some embodiments, the method accelerates fracture healing in a human individual. In some embodiments, the method prevents or reduces the risk of fracture nonunion, and / or prevents or reduces the risk of delayed union, and / or prevents the need for reoperation following fracture repair surgery. In some embodiments, the method prevents or reduces the risk of a vertebral fracture, a non-vertebral fracture and / or a hip fracture, or any combination thereof, in a human individual. In some embodiments, the method prevents or reduces the risk of a lumbar spine fracture and / or a femoral neck in a human individual. In some embodiments, the individual is at high risk for fracture. In some embodiments, the individual is at least about 18, 30, 35, 40, 45, 50, 55, or 60 years old. In some embodiments, the individual is a male. In some embodiments, the individual is a female. In some embodiments, the female is a postmenopausal woman. In some embodiments, the method treats osteoporosis in a postmenopausal female individual. In some embodiments, the individual has a history of osteoporotic fracture. In some embodiments, the individual has been subjected to, failed, or are intolerant to an osteoporosis therapy. In some embodiments, the osteoporosis therapy is selected from the group consisting of romosozumab, denosumab, etidronate, pamidronate, risedronate, alendronate, zoledronate, ibandronate, teriparatide, and abaloparatide. In some embodiments, the individual has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90% or 95% probability of fraction in the next five or ten years as determined by a clinician or under Fracture Risk Assessment Tool (FRAX®). In some embodiments, the individual has a history of a cardiovascular disease, optionally the cardiovascular disease is a myocardial infarction or stroke. In some embodiments, the individual has a hip bone mineral density T-score measured by DXA a) that is between -1 and - 2.5; b) that is -2.5 or lower than -2.5; or c) that is -2.5 or lower than -2.5 and at least one fragility fracture. In some embodiments, the individual has a history of fracture (e.g., a vertebral or non-vertebral fracture). In some embodiments, the individual is subject to a supplement (e.g., daily supplement) comprising Vitamin D (e.g., Vitamin D2 or Vitamin D3) and / or calcium. In some embodiments, the individual is subject to calcium at a dose of about 100, 250, 500, 750 or 1000 mg / day or more daily and / or Vitamin D at a dose of about 100, 250, 500, 750 or 1000 lU / day or more.56MOFO-359878767Attorney Docket No. 21091-20003.40

[0199] In some embodiments, there is provided a method of treating a disease, disorder, or condition, comprising administering (e.g., subcutaneously or intravenously) a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises the BAP0063 polypeptides, wherein the bispecific antibody is administered at a dose of at least about or about 840 mg, wherein the bispecific antibody is administered about every month (every four weeks). In some embodiments, the bispecific antibody is administered for a duration of at least 1 month, of at least 2 months, of at least 3 months, of at least 4 months, of at least 5 months, of at least 6 months, of at least 7 months, of at least 8 months, of at least 9 months, of at least 10 months, of at least 11 months, of at least 12 months, of at least 13 months, of at least 14 months, of at least 15 months, of at least 16 months, of at least 17 months, of at least 18 months, of at least 19 months, of at least 20 months, of at least 21 months, of at least 22 months, of at least 23 months, or of at least 24 months, or of at least 3 years, or of at least 4 years, or of at least 5 years, or of at least 6 years, or of at least 7 years, or of at least 8 years, or of at least 9 years, or of at least 10 years.. In some embodiments, the VH-I, VL-I, VH-2, and VL-2 comprise the amino acid sequences of SEQ ID NO: 13, 14, 15, and 16 respectively. In some embodiments, the bispecific antibody is a full-length antibody comprising an IgG (e.g., IgG4) Fc fragment. In some embodiments, the first, second, third and fourth polypeptides comprise the amino acid sequences of SEQ ID NO: 17, 18, 19, and 20 respectively. In some embodiments, the method treats osteoporosis or reduces the risk of osteoporosis in a human individual. In some embodiments, the method reduces the risk of developing osteoporosis. In some embodiments, the method reduces the severity of existing osteoporosis. In some embodiments, the method treats or prevents diseases or conditions associated with low bone mass. In some embodiments, the method increases bone mineral density in a human individual. In some embodiments, the method reduces the risk of osteoporotic fracture in a human individual. In some embodiments, the method accelerates fracture healing in a human individual. In some embodiments, the method prevents or reduces the risk of fracture nonunion, and / or prevents or reduces the risk of delayed union, and / or prevents the need for reoperation following fracture repair surgery. In some embodiments, the method prevents or reduces the risk of a vertebral fracture, a non-vertebral fracture and / or a hip fracture, or any combination thereof, in a human individual. In some embodiments, the method prevents or reduces the risk of a lumbar spine fracture and / or a femoral neck in a human individual. In some embodiments, the individual is at high risk for fracture. In some embodiments, the individual is at least about 18, 30, 35, 40, 45, 50, 55, or 60 years old. In some embodiments, the individual is a male. In some embodiments, the individual is a female.57MOFO-359878767Attorney Docket No. 21091-20003.40In some embodiments, the female is a postmenopausal woman. In some embodiments, the method treats osteoporosis in a postmenopausal female individual. In some embodiments, the individual has a history of osteoporotic fracture. In some embodiments, the individual has been subjected to, failed, or are intolerant to an osteoporosis therapy. In some embodiments, the osteoporosis therapy is selected from the group consisting of romosozumab, denosumab, etidronate, pamidronate, risedronate, alendronate, zoledronate, ibandronate, teriparatide, and abaloparatide. In some embodiments, the individual has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90% or 95% probability of fraction in the next five or ten years as determined by a clinician or under Fracture Risk Assessment Tool (FRAX®). In some embodiments, the individual has a history of a cardiovascular disease, optionally the cardiovascular disease is a myocardial infarction or stroke. In some embodiments, the individual has a hip bone mineral density T-score measured by DXA a) that is between -1 and - 2.5; b) that is -2.5 or lower than -2.5; or c) that is -2.5 or lower than -2.5 and at least one fragility fracture. In some embodiments, the individual has a history of fracture (e.g., a vertebral or non-vertebral fracture). In some embodiments, the individual is subject to a supplement (e.g., daily supplement) comprising Vitamin D (e.g., Vitamin D2 or Vitamin D3) and / or calcium. In some embodiments, the individual is subject to calcium at a dose of about 100, 250, 500, 750 or 1000 mg / day or more daily and / or Vitamin D at a dose of about 100, 250, 500, 750 or 1000 lU / day or more.

[0200] In some embodiments, there is provided a method of treating a disease, disorder, or condition, comprising administering (e.g., subcutaneously or intravenously) a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises the BAP0063 polypeptides, wherein the bispecific antibody is administered at a dose of at least about or about 840 mg, wherein the bispecific antibody is administered about every three months. In some embodiments, the bispecific antibody is administered for a duration of at least 3 months, of at least 4 months, of at least 5 months, of at least 6 months, of at least 7 months, of at least 8 months, of at least 9 months, of at least 10 months, of at least 11 months, of at least 12 months, of at least 13 months, of at least 14 months, of at least 15 months, of at least 16 months, of at least 17 months, of at least 18 months, of at least 19 months, of at least 20 months, of at least 21 months, of at least 22 months, of at least 23 months, or of at least 24 months, or of at least 3 years, or of at least 4 years, or of at least 5 years, or of at least 6 years, or of at least 7 years, or of at least 8 years, or of at least 9 years, or of at least 10 years.. In some embodiments, the VH-I, VL-I, VH-2, and VL-2 comprise the amino acid sequences of SEQ ID NO: 13, 14, 15, and 16 respectively. In some embodiments, the58MOFO-359878767Attorney Docket No. 21091-20003.40 bispecific antibody is a full-length antibody comprising an IgG (e.g., IgG4) Fc fragment. In some embodiments, the first, second, third and fourth polypeptides comprise the amino acid sequences of SEQ ID NO: 17, 18, 19, and 20 respectively. In some embodiments, the method treats osteoporosis or reduces the risk of osteoporosis in a human individual. In some embodiments, the method reduces the risk of developing osteoporosis. In some embodiments, the method reduces the severity of existing osteoporosis. In some embodiments, the method treats or prevents diseases or conditions associated with low bone mass. In some embodiments, the method increases bone mineral density in a human individual. In some embodiments, the method reduces the risk of osteoporotic fracture in a human individual. In some embodiments, the method accelerates fracture healing in a human individual. In some embodiments, the method prevents or reduces the risk of fracture nonunion, and / or prevents or reduces the risk of delayed union, and / or prevents the need for reoperation following fracture repair surgery. In some embodiments, the method prevents or reduces the risk of a vertebral fracture, a non-vertebral fracture and / or a hip fracture, or any combination thereof, in a human individual. In some embodiments, the method prevents or reduces the risk of a lumbar spine fracture and / or a femoral neck in a human individual. In some embodiments, the individual is at high risk for fracture. In some embodiments, the individual is at least about 18, 30, 35, 40, 45, 50, 55, or 60 years old. In some embodiments, the individual is a male. In some embodiments, the individual is a female. In some embodiments, the female is a postmenopausal woman. In some embodiments, the method treats osteoporosis in a postmenopausal female individual. In some embodiments, the individual has a history of osteoporotic fracture. In some embodiments, the individual has been subjected to, failed, or is intolerant to an osteoporosis therapy. In some embodiments, the osteoporosis therapy is selected from the group consisting of romosozumab, denosumab, etidronate, pamidronate, risedronate, alendronate, zoledronate, ibandronate, teriparatide, and abaloparatide. In some embodiments, the individual has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90% or 95% probability of fraction in the next five or ten years as determined by a clinician or under Fracture Risk Assessment Tool (FRAX®). In some embodiments, the individual has a history of a cardiovascular disease, optionally the cardiovascular disease is a myocardial infarction or stroke. In some embodiments, the individual has a hip bone mineral density T-score measured by DXA a) that is between -1 and -2.5; b) that is -2.5 or lower than - 2.5; or c) that is -2.5 or lower than -2.5 and at least one fragility fracture. In some embodiments, the individual has a history of fracture (e.g., a vertebral or non-vertebral fracture). In some embodiments, the individual is subject to a supplement (e.g., daily59MOFO-359878767Attorney Docket No. 21091-20003.40 supplement) comprising Vitamin D (e.g., Vitamin D2 or Vitamin D3) and / or calcium. In some embodiments, the individual is subject to calcium at a dose of about 100, 250, 500, 750 or 1000 mg / day or more daily and / or Vitamin D at a dose of about 100, 250, 500, 750 or 1000 lU / day or more.

[0201] In some embodiments, there is provided a method of treating a disease, disorder, or condition, comprising administering e.g., subcutaneously or intravenously) a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises the BAP0063 polypeptides, wherein the bispecific antibody is administered at a first dose of about 70 mg to about 840 mg at a first frequency of about every month, then at the second dose of about 70 mg to about 840 mg at a second frequency of about every 3 months. In some embodiments, the first frequency lasts for a duration of at least 1 month, of at least 2 months, of at least 3 months, of at least 4 months, of at least 5 months, of at least 6 months, of at least 7 months, of at least 8 months, of at least 9 months, of at least 10 months, of at least 11 months, of at least 12 months, of at least 13 months, of at least 14 months, of at least 15 months, of at least 16 months, of at least 17 months, of at least 18 months, of at least 19 months, of at least 20 months, of at least 21 months, of at least 22 months, of at least 23 months, or of at least 24 months; and the second frequency lasts for a duration of at least 1 month, of at least 2 months, of at least 3 months, of at least 4 months, of at least 5 months, of at least 6 months, of at least 7 months, of at least 8 months, of at least 9 months, of at least 10 months, of at least 11 months, of at least 12 months, of at least 13 months, of at least 14 months, of at least 15 months, of at least 16 months, of at least 17 months, of at least 18 months, of at least 19 months, of at least 20 months, of at least 21 months, of at least 22 months, of at least 23 months, or of at least 24 months, or of at least 3 years, or of at least 4 years, or of at least 5 years, or of at least 6 years, or of at least 7 years, or of at least 8 years, or of at least 9 years, or of at least 10 years. In some embodiments, the VH-I, VL-I, VH-2, and VL-2 comprise the amino acid sequences of SEQ ID NO: 13, 14, 15, and 16 respectively. In some embodiments, the bispecific antibody is a full-length antibody comprising an IgG (e.g., IgG4) Fc fragment. In some embodiments, the first, second, third and fourth polypeptides comprise the amino acid sequences of SEQ ID NO: 17, 18, 19, and 20 respectively. In some embodiments, the method treats osteoporosis or reduces the risk of osteoporosis in a human individual. In some embodiments, the method reduces the risk of developing osteoporosis. In some embodiments, the method reduces the severity of existing osteoporosis. In some embodiments, the method treats or prevents diseases or conditions associated with low bone mass. In some embodiments, the method increases bone mineral density in a human individual.60MOFO-359878767Attorney Docket No. 21091-20003.40In some embodiments, the method reduces the risk of osteoporotic fracture in a human individual. In some embodiments, the method prevents or reduces the risk of a lumbar spine fracture and / or a femoral neck in a human individual. In some embodiments, the method accelerates fracture healing in a human individual. In some embodiments, the method prevents or reduces the risk of a vertebral fracture, a non-vertebral fracture and / or a hip fracture, or any combination thereof, in a human individual. In some embodiments, the individual is at high risk for fracture. In some embodiments, the individual is at least about 18, 30, 35, 40, 45, 50, 55, or 60 years old. In some embodiments, the individual is a male. In some embodiments, the individual is a female. In some embodiments, the female is a postmenopausal woman. In some embodiments, the method treats osteoporosis in a postmenopausal female individual. In some embodiments, the individual has a history of osteoporotic fracture. In some embodiments, the individual has been subjected to, failed, or is intolerant to an osteoporosis therapy. In some embodiments, the osteoporosis therapy is selected from the group consisting of romosozumab, denosumab, etidronate, pamidronate, risedronate, alendronate, zoledronate, ibandronate, teriparatide, and abaloparatide. In some embodiments, the individual has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90% or 95% probability of fraction in the next five or ten years as determined by a clinician or under Fracture Risk Assessment Tool (FRAX®). In some embodiments, the individual has a history of a cardiovascular disease, optionally the cardiovascular disease is a myocardial infarction or stroke. In some embodiments, the individual has a hip bone mineral density T-score measured by DXA a) that is between -1 and -2.5; b) that is -2.5 or lower than -2.5; or c) that is -2.5 or lower than -2.5 and at least one fragility fracture. In some embodiments, the individual has a history of fracture (e.g., a vertebral or non-vertebral fracture). In some embodiments, the individual is subject to a supplement (e.g., daily supplement) comprising Vitamin D (e.g., Vitamin D2 or Vitamin D3) and / or calcium. In some embodiments, the individual is subject to calcium at a dose of about 100, 250, 500, 750 or 1000 mg / day or more daily and / or Vitamin D at a dose of about 100, 250, 500, 750 or 1000 lU / day or more.

[0202] In some embodiments, there is provided a method of treating a disease, disorder, or condition, comprising administering (e.g., subcutaneously or intravenously) a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises the BAP0063 polypeptides, wherein the bispecific antibody is administered at a first dose of about 280 mg to about 840 mg at a first frequency of about every month, then at the second dose of about 280 mg to about 840 mg at a second frequency of about every 3 months. In some embodiments, the first frequency lasts for a duration of at least 1 month, of at least 261MOFO-359878767Attorney Docket No. 21091-20003.40 months, of at least 3 months, of at least 4 months, of at least 5 months, of at least 6 months, of at least 7 months, of at least 8 months, of at least 9 months, of at least 10 months, of at least 11 months, of at least 12 months, of at least 13 months, of at least 14 months, of at least 15 months, of at least 16 months, of at least 17 months, of at least 18 months, of at least 19 months, of at least 20 months, of at least 21 months, of at least 22 months, of at least 23 months, or of at least 24 months; and the second frequency lasts for a duration of at least 1 month, of at least 2 months, of at least 3 months, of at least 4 months, of at least 5 months, of at least 6 months, of at least 7 months, of at least 8 months, of at least 9 months, of at least 10 months, of at least 11 months, of at least 12 months, of at least 13 months, of at least 14 months, of at least 15 months, of at least 16 months, of at least 17 months, of at least 18 months, of at least 19 months, of at least 20 months, of at least 21 months, of at least 22 months, of at least 23 months, or of at least 24 months, or of at least 3 years, or of at least 4 years, or of at least 5 years, or of at least 6 years, or of at least 7 years, or of at least 8 years, or of at least 9 years, or of at least 10 years. In some embodiments, the VH-I, VL-I, VH-2, and VL-2 comprise the amino acid sequences of SEQ ID NO: 13, 14, 15, and 16 respectively. In some embodiments, the bispecific antibody is a full-length antibody comprising an IgG (e.g., IgG4) Fc fragment. In some embodiments, the first, second, third and fourth polypeptides comprise the amino acid sequences of SEQ ID NO: 17, 18, 19, and 20 respectively. In some embodiments, the method treats osteoporosis or reduces the risk of osteoporosis in a human individual. In some embodiments, the method reduces the risk of developing osteoporosis. In some embodiments, the method reduces the severity of existing osteoporosis. In some embodiments, the method treats or prevents diseases or conditions associated with low bone mass. In some embodiments, the method increases bone mineral density in a human individual. In some embodiments, the method reduces the risk of osteoporotic fracture in a human individual. In some embodiments, the method prevents or reduces the risk of a lumbar spine fracture and / or a femoral neck in a human individual. In some embodiments, the method accelerates fracture healing in a human individual. In some embodiments, the method prevents or reduces the risk of a vertebral fracture, a non-vertebral fracture and / or a hip fracture, or any combination thereof, in a human individual. In some embodiments, the individual is at high risk for fracture. In some embodiments, the individual is at least about 18, 30, 35, 40, 45, 50, 55, or 60 years old. In some embodiments, the individual is a male. In some embodiments, the individual is a female. In some embodiments, the female is a postmenopausal woman. In some embodiments, the method treats osteoporosis in a postmenopausal female individual. In some embodiments, the individual has a history of62MOFO-359878767Attorney Docket No. 21091-20003.40 osteoporotic fracture. In some embodiments, the individual has been subjected to, failed, or is intolerant to an osteoporosis therapy. In some embodiments, the osteoporosis therapy is selected from the group consisting of romosozumab, denosumab, etidronate, pamidronate, risedronate, alendronate, zoledronate, ibandronate, teriparatide, and abaloparatide. In some embodiments, the individual has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90% or 95% probability of fraction in the next five or ten years as determined by a clinician or under Fracture Risk Assessment Tool (FRAX®). In some embodiments, the individual has a history of a cardiovascular disease, optionally the cardiovascular disease is a myocardial infarction or stroke. In some embodiments, the individual has a hip bone mineral density T-score measured by DXA a) that is between -1 and -2.5; b) that is -2.5 or lower than - 2.5; or c) that is -2.5 or lower than -2.5 and at least one fragility fracture. In some embodiments, the individual has a history of fracture (e.g., a vertebral or non-vertebral fracture). In some embodiments, the individual is subject to a supplement (e.g., daily supplement) comprising Vitamin D (e.g., Vitamin D2 or Vitamin D3) and / or calcium. In some embodiments, the individual is subject to calcium at a dose of about 100, 250, 500, 750 or 1000 mg / day or more daily and / or Vitamin D at a dose of about 100, 250, 500, 750 or 1000 lU / day or more.

[0203] In some embodiments, there is provided a method of treating a disease, disorder, or condition, comprising administering (e.g., subcutaneously or intravenously) a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises the BAP0063 polypeptides, wherein the bispecific antibody is administered at a first dose of about 560 mg to about 840 mg at a first frequency of about every month, then at the second dose of about 560 mg to about 840 mg at a second frequency of about every 3 months. In some embodiments, the first frequency lasts for a duration of at least 1 month, of at least 2 months, of at least 3 months, of at least 4 months, of at least 5 months, of at least 6 months, of at least 7 months, of at least 8 months, of at least 9 months, of at least 10 months, of at least 11 months, of at least 12 months, of at least 13 months, of at least 14 months, of at least 15 months, of at least 16 months, of at least 17 months, of at least 18 months, of at least 19 months, of at least 20 months, of at least 21 months, of at least 22 months, of at least 23 months, or of at least 24 months; and the second frequency lasts for a duration of at least 1 month, of at least 2 months, of at least 3 months, of at least 4 months, of at least 5 months, of at least 6 months, of at least 7 months, of at least 8 months, of at least 9 months, of at least 10 months, of at least 11 months, of at least 12 months, of at least 13 months, of at least 14 months, of at least 15 months, of at least 16 months, of at least 17 months, of at least 1863MOFO-359878767Attorney Docket No. 21091-20003.40 months, of at least 19 months, of at least 20 months, of at least 21 months, of at least 22 months, of at least 23 months, or of at least 24 months, or of at least 3 years, or of at least 4 years, or of at least 5 years, or of at least 6 years, or of at least 7 years, or of at least 8 years, or of at least 9 years, or of at least 10 years. In some embodiments, the VH-I, VL-I, VH-2, and VL-2 comprise the amino acid sequences of SEQ ID NO: 13, 14, 15, and 16 respectively. In some embodiments, the bispecific antibody is a full-length antibody comprising an IgG (e.g., IgG4) Fc fragment. In some embodiments, the first, second, third and fourth polypeptides comprise the amino acid sequences of SEQ ID NO: 17, 18, 19, and 20 respectively. In some embodiments, the method treats osteoporosis or reduces the risk of osteoporosis in a human individual. In some embodiments, the method reduces the risk of developing osteoporosis. In some embodiments, the method reduces the severity of existing osteoporosis. In some embodiments, the method treats or prevents diseases or conditions associated with low bone mass. In some embodiments, the method increases bone mineral density in a human individual. In some embodiments, the method reduces the risk of osteoporotic fracture in a human individual. In some embodiments, the method accelerates fracture healing in a human individual. In some embodiments, the method prevents or reduces the risk of fracture nonunion, and / or prevents or reduces the risk of delayed union, and / or prevents the need for reoperation following fracture repair surgery. In some embodiments, the method prevents or reduces the risk of a vertebral fracture, a non-vertebral fracture and / or a hip fracture, or any combination thereof, in a human individual. In some embodiments, the method prevents or reduces the risk of a lumbar spine fracture and / or a femoral neck in a human individual. In some embodiments, the individual is at high risk for fracture. In some embodiments, the individual is at least about 18, 30, 35, 40, 45, 50, 55, or 60 years old. In some embodiments, the individual is a male. In some embodiments, the individual is a female. In some embodiments, the female is a postmenopausal woman. In some embodiments, the method treats osteoporosis in a postmenopausal female individual. In some embodiments, the individual has a history of osteoporotic fracture. In some embodiments, the individual has been subjected to, failed, or is intolerant to an osteoporosis therapy. In some embodiments, the osteoporosis therapy is selected from the group consisting of romosozumab, denosumab, etidronate, pamidronate, risedronate, alendronate, zoledronate, ibandronate, teriparatide, and abaloparatide. In some embodiments, the individual has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90% or 95% probability of fraction in the next five or ten years as determined by a clinician or under Fracture Risk Assessment Tool (FRAX®). In some embodiments, the individual has a history of a cardiovascular disease, optionally the64MOFO-359878767Attorney Docket No. 21091-20003.40 cardiovascular disease is a myocardial infarction or stroke. In some embodiments, the individual has a hip bone mineral density T-score measured by DXA a) that is between -1 and - 2.5; b) that is -2.5 or lower than -2.5; or c) that is -2.5 or lower than -2.5 and at least one fragility fracture. In some embodiments, the individual has a history of fracture (e.g., a vertebral or non-vertebral fracture). In some embodiments, the individual is subject to a supplement (e.g., daily supplement) comprising Vitamin D (e.g., Vitamin D2 or Vitamin D3) and / or calcium. In some embodiments, the individual is subject to calcium at a dose of about 100, 250, 500, 750 or 1000 mg / day or more daily and / or Vitamin D at a dose of about 100, 250, 500, 750 or 1000 lU / day or more.

[0204] In some embodiments, there is provided a method of treating a disease, disorder, or condition, comprising administering (e.g., subcutaneously or intravenously) a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises the BAP0063 polypeptides, wherein the bispecific antibody is administered at a first dose of about 280 mg every month for a duration of at least 1 month, of at least 2 months, of at least 3 months, of at least 4 months, of at least 5 months, of at least 6 months, of at least 7 months, of at least 8 months, of at least 9 months, of at least 10 months, of at least 11 months, of at least 12 months, then at a second dose of about 560 mg every month for a duration of at least 1 month, of at least 2 months, of at least 3 months, of at least 4 months, of at least 5 months, of at least 6 months, of at least 7 months, of at least 8 months, of at least 9 months, of at least 10 months, of at least 11 months, of at least 12 months, of at least 13 months, of at least 14 months, of at least 15 months, of at least 16 months, of at least 17 months, of at least 18 months, of at least 19 months, of at least 20 months, of at least 21 months, of at least 22 months, of at least 23 months, or of at least 24 months, or of at least 3 years, or of at least 4 years, or of at least 5 years, or of at least 6 years, or of at least 7 years, or of at least 8 years, or of at least 9 years, or of at least 10 years . In some embodiments, the VH-I, VL-I, VH-2, and VL-2 comprise the amino acid sequences of SEQ ID NO: 13, 14, 15, and 16 respectively. In some embodiments, the bispecific antibody is a full-length antibody comprising an IgG (e.g., IgG4) Fc fragment. In some embodiments, the first, second, third and fourth polypeptides comprise the amino acid sequences of SEQ ID NO: 17, 18, 19, and 20 respectively. In some embodiments, the method treats osteoporosis or reduces the risk of osteoporosis in a human individual. In some embodiments, the method reduces the risk of developing osteoporosis. In some embodiments, the method reduces the severity of existing osteoporosis. In some embodiments, the method treats or prevents diseases or conditions associated with low bone mass. In some embodiments, the method increases bone mineral density in a human individual.65MOFO-359878767Attorney Docket No. 21091-20003.40In some embodiments, the method reduces the risk of osteoporotic fracture in a human individual. In some embodiments, the method accelerates fracture healing in a human individual. In some embodiments, the method prevents or reduces the risk of fracture nonunion, and / or prevents or reduces the risk of delayed union, and / or prevents the need for reoperation following fracture repair surgery. In some embodiments, the method prevents or reduces the risk of a vertebral fracture, a non-vertebral fracture and / or a hip fracture, or any combination thereof, in a human individual. In some embodiments, the method prevents or reduces the risk of a lumbar spine fracture and / or a femoral neck in a human individual. In some embodiments, the individual is at high risk for fracture. In some embodiments, the individual is at least about 18, 30, 35, 40, 45, 50, 55, or 60 years old. In some embodiments, the individual is a male. In some embodiments, the individual is a female. In some embodiments, the female is a postmenopausal woman. In some embodiments, the method treats osteoporosis in a postmenopausal female individual. In some embodiments, the individual has a history of osteoporotic fracture. In some embodiments, the individual has been subjected to, failed, or is intolerant to an osteoporosis therapy. In some embodiments, the osteoporosis therapy is selected from the group consisting of romosozumab, denosumab, etidronate, pamidronate, risedronate, alendronate, zoledronate, ibandronate, teriparatide, and abaloparatide. In some embodiments, the individual has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90% or 95% probability of fraction in the next five or ten years as determined by a clinician or under Fracture Risk Assessment Tool (FRAX®). In some embodiments, the individual has a history of a cardiovascular disease, optionally the cardiovascular disease is a myocardial infarction or stroke. In some embodiments, the individual has a hip bone mineral density T-score measured by DXA a) that is between -1 and - 2.5; b) that is -2.5 or lower than -2.5; or c) that is -2.5 or lower than -2.5 and at least one fragility fracture. In some embodiments, the individual has a history of fracture (e.g., a vertebral or non-vertebral fracture). In some embodiments, the individual is subject to a supplement (e.g., daily supplement) comprising Vitamin D (e.g., Vitamin D2 or Vitamin D3) and / or calcium. In some embodiments, the individual is subject to calcium at a dose of about 100, 250, 500, 750 or 1000 mg / day or more daily and / or Vitamin D at a dose of about 100, 250, 500, 750 or 1000 lU / day or more.

[0205] In some embodiments, there is provided a method of treating a disease, disorder, or condition, comprising administering (e.g., subcutaneously or intravenously) a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises the BAP0063 polypeptides, wherein the bispecific antibody is administered at a first66MOFO-359878767Attorney Docket No. 21091-20003.40 dose of about 280 mg every month for a duration of at least 1 month, of at least 2 months, of at least 3 months, of at least 4 months, of at least 5 months, of at least 6 months, of at least 7 months, of at least 8 months, of at least 9 months, of at least 10 months, of at least 11 months, of at least, then at a second dose of about 840 mg once every three months for a duration of at least 1 month, of at least 2 months, of at least 3 months, of at least 4 months, of at least 5 months, of at least 6 months, of at least 7 months, of at least 8 months, of at least 9 months, of at least 10 months, of at least 11 months, of at least 12 months, of at least 13 months, of at least 14 months, of at least 15 months, of at least 16 months, of at least 17 months, of at least 18 months, of at least 19 months, of at least 20 months, of at least 21 months, of at least 22 months, of at least 23 months, or of at least 24 months, or of at least 3 years, or of at least 4 years, or of at least 5 years, or of at least 6 years, or of at least 7 years, or of at least 8 years, or of at least 9 years, or of at least 10 years. In some embodiments, the VH-I, VL-I, VH-2, and VL- 2 comprise the amino acid sequences of SEQ ID NO: 13, 14, 15, and 16 respectively. In some embodiments, the bispecific antibody is a full-length antibody comprising an IgG (e.g., IgG4) Fc fragment. In some embodiments, the first, second, third and fourth polypeptides comprise the amino acid sequences of SEQ ID NO: 17, 18, 19, and 20 respectively. In some embodiments, the method treats osteoporosis or reduces the risk of osteoporosis in a human individual. In some embodiments, the method reduces the risk of developing osteoporosis. In some embodiments, the method reduces the severity of existing osteoporosis. In some embodiments, the method treats or prevents diseases or conditions associated with low bone mass. In some embodiments, the method increases bone mineral density in a human individual. In some embodiments, the method reduces the risk of osteoporotic fracture in a human individual. In some embodiments, the method accelerates fracture healing in a human individual. In some embodiments, the method prevents or reduces the risk of fracture nonunion, and / or prevents or reduces the risk of delayed union, and / or prevents the need for reoperation following fracture repair surgery. In some embodiments, the method prevents or reduces the risk of a vertebral fracture, a non-vertebral fracture and / or a hip fracture, or any combination thereof, in a human individual. In some embodiments, the method prevents or reduces the risk of a lumbar spine fracture and / or a femoral neck in a human individual. In some embodiments, the individual is at high risk for fracture. In some embodiments, the individual is at least about 18, 30, 35, 40, 45, 50, 55, or 60 years old. In some embodiments, the individual is a male. In some embodiments, the individual is a female. In some embodiments, the female is a postmenopausal woman. In some embodiments, the method treats osteoporosis in a postmenopausal female individual. In some embodiments, the67MOFO-359878767Attorney Docket No. 21091-20003.40 individual has a history of osteoporotic fracture. In some embodiments, the individual has been subjected to, failed, or is intolerant to an osteoporosis therapy. In some embodiments, the osteoporosis therapy is selected from the group consisting of romosozumab, denosumab, etidronate, pamidronate, risedronate, alendronate, zoledronate, ibandronate, teriparatide, and abaloparatide. In some embodiments, the individual has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90% or 95% probability of fraction in the next five or ten years as determined by a clinician or under Fracture Risk Assessment Tool (FRAX®). In some embodiments, the individual has a history of a cardiovascular disease, optionally the cardiovascular disease is a myocardial infarction or stroke. In some embodiments, the individual has a hip bone mineral density T-score measured by DXA a) that is between -1 and - 2.5; b) that is -2.5 or lower than -2.5; or c) that is -2.5 or lower than -2.5 and at least one fragility fracture. In some embodiments, the individual has a history of fracture (e.g., a vertebral or non-vertebral fracture). In some embodiments, the individual is subject to a supplement (e.g., daily supplement) comprising Vitamin D (e.g., Vitamin D2 or Vitamin D3) and / or calcium. In some embodiments, the individual is subject to calcium at a dose of about 100, 250, 500, 750 or 1000 mg / day or more daily and / or Vitamin D at a dose of about 100, 250, 500, 750 or 1000 lU / day or more.

[0206] In some embodiments, at about one month, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the individual has an increase in serum P1NP level. In some embodiments, the increase in serum P1NP is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% ,100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, or 200% as compared to the baseline.

[0207] In some embodiments, at about one month, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the individual has a decrease in serum CTX-1 level. In some embodiments, the decrease in serum CTX-1 is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% as compared to the baseline.

[0208] In some embodiments, at about one month, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the individual has an increase in serum osteocalcin level. In some embodiments, the increase in serum osteocalcin is at least about 5%, 10%, 15%,68MOFO-359878767Attorney Docket No. 21091-20003.4020%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% as compared to the baseline.

[0209] In some embodiments, at about one month, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the individual has an increase in serum BSAP level. In some embodiments, the increase in serum BSAP is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, or 150% as compared to the baseline.

[0210] In some embodiments, at about one month, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the individual has an increase in serum iPTH level. In some embodiments, the increase is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, or 150% as compared to the baseline.

[0211] In some embodiments, at about one month, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the individual has an increase in lumbar spine BMD by at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, or 15%. In some embodiments, at about one month, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, , the individual has an increase in total hip BMD by at least about 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10%. In some embodiments, at about one month, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the individual has an increase in femoral neck BMD by at least about 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10%.

[0212] In some embodiments, there is provided a method of increasing bone mineral density and / or treating or preventing diseases or conditions associated with low bone mass in an human individual, comprising administering (e.g., subcutaneously or intravenously) a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises a) a first polypeptide comprising a first heavy chain variable region (VH- 1), b) a second polypeptide comprising a first light chain variable region (VL-1), c) a third polypeptide comprising a second heavy chain variable region (VH-2), d) a fourth polypeptide69MOFO-359878767Attorney Docket No. 21091-20003.40 comprising a second variable region (VL-2), wherein: 1) the VH-1 comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3; 2) the VL-1 comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NOs: 6; 3) the VH-2 comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 9; and 4) the VL-2 comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12, wherein the bispecific antibody is administered at a dose of about 70 mg to about 1050 mg (e.g., about 70 mg to about 840mg, e.g., about 210 mg to about 840 mg, e.g., about 280 mg to about 840 mg, e.g., about 420 mg to about 840 mg, e.g., about 560 mg to about 840 mg, e.g., about 70 mg, e.g., about 140 mg e.g., about 210 mg, e.g., about 280 mg, e.g., about 420 mg, e.g., about 560 mg, e.g., about 840 mg), wherein the bispecific antibody is administered about monthly or quarterly. In some embodiments, the bispecific antibody is administered at a dose of about 70 mg to about 1050 mg (e.g., about 70 mg to about 840mg, e.g., about 210 mg to about 840 mg, e.g., about 280 mg to about 840 mg, e.g., about 420 mg to about 840 mg, e.g., about 560 mg to about 840 mg, e.g., about 70 mg, e.g., about 140 mg e.g., about 210 mg, e.g., about 280 mg, e.g., about 420 mg, e.g., about 560 mg, e.g., about 840 mg) every month for at least or more than about one, two, three, four, five, six, nine, twelve, fifteen, eighteen, or twenty -four months. In some embodiments, the bispecific antibody is administered at a dose of about 70 mg to about 1050 mg (e.g., about 70 mg to about 840mg, e.g., about 210 mg to about 840 mg, e.g., about 280 mg to about 840 mg, e.g., about 420 mg to about 840 mg, e.g., about 560 mg to about 840 mg, e.g., about e.g., about 70 mg, e.g., about 140 mg e.g., about 210 mg, e.g., about 280 mg, 420 mg, e.g., about 560 mg, e.g., about 840 mg) quarterly for at least or more than about six, nine, twelve, fifteen, eighteen, or twenty-four months. In some embodiments, the bispecific antibody is administered at a dose of about 70 mg to about 1050 mg (e.g., about 70 mg to about 840mg, e.g., about 210 mg to about 840 mg, e.g., about 280 mg to about 840 mg, e.g., about 420 mg to about 840 mg, e.g., about 560 mg to about 840 mg, e.g., about e.g., about 70 mg, e.g., about 140 mg e.g., about 210 mg, e.g., about 280 mg, 420 mg, e.g., about 560 mg, e.g., about 840 mg) every month for at least or more than about one month, two months, three months, followed by being administered at the same dose quarterly for at least or more than70MOFO-359878767Attorney Docket No. 21091-20003.40 three, six, nine, or twelve months. In some embodiments, the VH-1, VL-1, VH-2, and VL-2 comprise the amino acid sequences of SEQ ID NO: 13, 14, 15, and 16 respectively. In some embodiments, the bispecific antibody is a full-length antibody comprising an IgG (e.g., IgG4) Fc fragment. In some embodiments, the first, second, third and fourth polypeptides comprise the amino acid sequences of SEQ ID NO: 17, 18, 19, and 20 respectively. In some embodiments, the individual is at high risk for fracture. In some embodiments, the individual is at least about 18, 30, 35, 40, 45, 50, 55, or 60 years old. In some embodiments, the individual is a male. In some embodiments, the individual is a female (e.g., a postmenopausal woman). In some embodiments, the individual has a history of osteoporotic fracture. In some embodiments, the individual has been subjected to, failed, or is intolerant to an osteoporosis therapy. In some embodiments, the osteoporosis therapy is selected from the group consisting of romosozumab, denosumab, etidronate, pamidronate, risedronate, alendronate, zoledronate, ibandronate, teriparatide, and abaloparatide. In some embodiments, the individual has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90% or 95% probability of fraction in the next five or ten years as determined by a clinician or under Fracture Risk Assessment Tool (FRAX®). In some embodiments, the individual has a history of a cardiovascular disease, optionally the cardiovascular disease is a myocardial infarction or stroke. In some embodiments, the individual has a hip bone mineral density T-score measured by DXA a) that is between -1 and -2.5; b) that is -2.5 or lower than -2.5; or c) that is -2.5 or lower than -2.5 and at least one fragility fracture. In some embodiments, the individual has a history of fracture (e.g., a vertebral or non-vertebral fracture). In some embodiments, at about one months, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the individual has an increase in serum P1NP level. In some embodiments, the increase in serum P1NP is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% ,100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, or 200% as compared to the baseline. In some embodiments, at about one months, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the individual has a decrease in serum CTX-1 level. In some embodiments, the decrease in serum CTX-1 is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% as compared to the baseline. In some embodiments, at about one months, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the individual has an increase in serum osteocalcin level. In71MOFO-359878767Attorney Docket No. 21091-20003.40 some embodiments, the increase in serum osteocalcin is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% as compared to the baseline. In some embodiments, at about one months, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the individual has an increase in serum BSAP level. In some embodiments, the increase in serum BSAP is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, or 150% as compared to the baseline. In some embodiments, at about one months, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the individual has an increase in serum iPTH level. In some embodiments, the increase is at least %, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, or 150% as compared to the baseline. In some embodiments, at about one months, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, , the individual has an increase in lumbar spine BMD by at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, or 15%. In some embodiments, at about one months, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the individual has an increase in total hip BMD by at least about 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10%. In some embodiments, at about one months, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the individual has an increase in femoral neck BMD by at least about 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10%. In some embodiments, the individual is subject to a supplement (e.g., daily supplement) comprising Vitamin D (e.g., Vitamin D2 or Vitamin D3) and / or calcium. In some embodiments, the individual is subject to calcium at a dose of about 100, 250, 500, 750 or 1000 mg / day or more daily and / or Vitamin D at a dose of about 100, 250, 500, 750 or 1000 lU / day or more.

[0213] In some embodiments, there is provided a method of reducing risk of osteoporotic fracture(e.g., reducing risk for developing osteoporosis, and / or reducing severity of existing osteoporosis), and / or accelerating fracture healing, and / or reducing the risk of fracture nonunion, and / or reducing the risk of delayed union, and / or preventing the need for reoperation72MOFO-359878767Attorney Docket No. 21091-20003.40 following fracture repair surgery and / or increasing cortical and trabecular bone in an human individual, comprising administering (e.g., subcutaneously or intravenously) a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises a) a first polypeptide comprising a first heavy chain variable region (VH-I), b) a second polypeptide comprising a first light chain variable region (VL-I), C) a third polypeptide comprising a second heavy chain variable region (VH-2), d) a fourth polypeptide comprising a second variable region (VL-2), wherein: 1) the VH-I comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3; 2) the VL-I comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LC- CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NOs: 6; 3) the VH-2 comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 9; and 4) the VL-2 comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LC- CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12, wherein the bispecific antibody is administered at a dose of about 70 mg to about 1050 mg (e.g., about 70 mg to about 840 mg, e.g., e.g., about 210 mg to about 840 mg, about 280 mg to about 840 mg, about 420 mg to about 840 mg, e.g., about 560 mg to about 840 mg, e.g., about 70 mg, e.g., about 140 mg e.g., about 210 mg, e.g., about 280 mg, e.g., about 420 mg, e.g., about 560 mg, e.g., about 840 mg), wherein the bispecific antibody is administered about monthly or quarterly. In some embodiments, the bispecific antibody is administered at a dose of about 70 mg to about 1050 mg (e.g., about 70 mg to about 840 mg, e.g., about 210 mg to about 840 mg, about 280 mg to about 840 mg, about 420 mg to about 840 mg, e.g., about 560 mg to about 840 mg, e.g., about 70 mg, e.g., about 140 mg e.g., about 210 mg, e.g., about 280 mg, e.g., about 420 mg, e.g., about 560 mg, e.g., about 840 mg) every month for at least or more than about one, two, three, four, five, six, nine, twelve, fifteen, eighteen, or twenty-four months. In some embodiments, the bispecific antibody is administered at a dose of about 70 mg to about 1050 mg (e.g., about 70 mg to about 840 mg, e.g., about 210 mg to about 840 mg, about 280 mg to about 840 mg, about 420 mg to about 840 mg, e.g., about 560 mg to about 840 mg, e.g., about 70 mg, e.g., about 140 mg e.g., about 210 mg, e.g., about 280 mg, e.g., about 420 mg, e.g., about 560 mg, e.g., about 840 mg) quarterly for at least or more than about six, nine, twelve, fifteen, eighteen, or twenty-four months. In some embodiments, the bispecific antibody is administered at a dose of about 7073MOFO-359878767Attorney Docket No. 21091-20003.40 mg to about 1050 mg (e.g., about 70 mg to about 840 mg, e.g., about 210 mg to about 840 mg, about 280 mg to about 840 mg, about 420 mg to about 840 mg, e.g., about 560 mg to about 840 mg, e.g., about 70 mg, e.g., about 140 mg e.g., about 210 mg, e.g., about 280 mg, e.g., about 420 mg, e.g., about 560 mg, e.g., about 840 mg) every month for at least or more than about one month, two months, three months, followed by being administered at the same dose quarterly for at least or more than three, six, nine, or twelve months. In some embodiments, the VH-I, VL-I, VH-2, and VL-2 comprise the amino acid sequences of SEQ ID NO: 13, 14, 15, and 16 respectively. In some embodiments, the bispecific antibody is a full-length antibody comprising an IgG (e.g., IgG4) Fc fragment. In some embodiments, the first, second, third and fourth polypeptides comprise the amino acid sequences of SEQ ID NO: 17, 18, 19, and 20 respectively. In some embodiments, the individual is at high risk for fracture. In some embodiments, the individual is at least about 18, 30, 35, 40, 45, 50, 55, or 60 years old. In some embodiments, the individual is a male. In some embodiments, the individual is a female (e.g., a postmenopausal woman). In some embodiments, the individual has a history of osteoporotic fracture. In some embodiments, the individual has been subjected to, failed, or is intolerant to an osteoporosis therapy. In some embodiments, the osteoporosis therapy is selected from the group consisting of romosozumab, denosumab, etidronate, pamidronate, risedronate, alendronate, zoledronate, ibandronate, teriparatide, and abaloparatide. In some embodiments, the individual has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90% or 95% probability of fraction in the next five or ten years as determined by a clinician or under Fracture Risk Assessment Tool (FRAX®). In some embodiments, the individual has a history of a cardiovascular disease, optionally the cardiovascular disease is a myocardial infarction or stroke. In some embodiments, the individual has a hip bone mineral density T-score measured by DXA a) that is between -1 and -2.5; b) that is -2.5 or lower than - 2.5; or c) that is -2.5 or lower than -2.5 and at least one fragility fracture. In some embodiments, the individual has a history of fracture (e.g., a vertebral or non-vertebral fracture). In some embodiments, at about one month, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the individual has an increase in serum P1NP level. In some embodiments, the increase in serum P1NP is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% ,100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, or 200% as compared to the baseline. In some embodiments, at about one month, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the individual74MOFO-359878767Attorney Docket No. 21091-20003.40 has a decrease in serum CTX-1 level. In some embodiments, the decrease in serum CTX-1 is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% as compared to the baseline. In some embodiments, at about one month, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the individual has an increase in serum osteocalcin level. In some embodiments, the increase in serum osteocalcin is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% as compared to the baseline. In some embodiments, at about one month, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the individual has an increase in serum BSAP level. In some embodiments, the increase in serum BSAP is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, or 150% as compared to the baseline. In some embodiments, at about one month, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the individual has an increase in serum iPTH level. In some embodiments, the increase is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, or 150% as compared to the baseline. In some embodiments, at about one month, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, , the individual has an increase in lumbar spine BMD by at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, or 15%. In some embodiments, at about one month, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, , the individual has an increase in total hip BMD by at least about 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10%. In some embodiments, at about one month, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, , the individual has an increase in femoral neck BMD by at least about 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10%. In some embodiments, the individual is subject to a supplement (e.g., daily supplement) comprising Vitamin D (e.g., Vitamin D2 or Vitamin D3) and / or calcium. In some embodiments, the individual is subjectMOFO-359878767Attorney Docket No. 21091-20003.40 to calcium at a dose of about 100, 250, 500, 750 or 1000 mg / day or more daily and / or Vitamin D at a dose of about 100, 250, 500, 750 or 1000 lU / day or more.

[0214] In some embodiments, there is provided a method of preventing or reducing risk of a) a vertebral fracture, b) a non-vertebral fracture and / or c) a hip fracture in an human individual, comprising administering (e.g., subcutaneously or intravenously) a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises a) a first polypeptide comprising a first heavy chain variable region (VH-I), b) a second polypeptide comprising a first light chain variable region (VL-I), C) a third polypeptide comprising a second heavy chain variable region (VH-2), d) a fourth polypeptide comprising a second variable region (VL-2), wherein: 1) the VH-I comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3; 2) the VL-I comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LC- CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NOs: 6; 3) the VH-2 comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 9; and 4) the VL-2 comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LC- CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12, wherein the bispecific antibody is administered at a dose of about 70 mg to about 1050 mg (e.g., about 70 mg to about 840 mg, e.g., about 210 mg to about 840 mg, about 280 mg to about 840 mg, about 420 mg to about 840 mg, e.g., about 560 mg to about 840 mg, e.g., about 70 mg, e.g., about 140 mg e.g., about 210 mg, e.g., about 280 mg, e.g., about 420 mg, e.g., about 560 mg, e.g., about 840 mg), wherein the bispecific antibody is administered about monthly or quarterly. In some embodiments, the bispecific antibody is administered at a dose of about 70 mg to about 1050 mg (e.g., about 70 mg to about 840 mg, e.g., about 210 mg to about 840 mg, about 280 mg to about 840 mg, about 420 mg to about 840 mg, e.g., about 560 mg to about 840 mg, e.g., about 70 mg, e.g., about 140 mg e.g., about 210 mg, e.g., about 280 mg, e.g., about 420 mg, e.g., about 560 mg, e.g., about 840 mg) every month for at least or more than about one, two, three, four, five, six, nine, twelve, fifteen, eighteen, or twenty-four months. In some embodiments, the bispecific antibody is administered at a dose of about 70 mg to about 1050 mg (e.g., about 70 mg to about 840 mg, e.g., about 210 mg to about 840 mg, about 280 mg to about 840 mg, about 420 mg to about 840 mg, e.g., about 560 mg to about 840 mg, e.g., about 70 mg, e.g., about 140 mg76MOFO-359878767Attorney Docket No. 21091-20003.40 e.g., about 210 mg, e.g., about 280 mg, e.g., about 420 mg, e.g., about 560 mg, e.g., about 840 mg) quarterly for at least or more than about six, nine, twelve, fifteen, eighteen, or twenty-four months. In some embodiments, the bispecific antibody is administered at a dose of about 70 mg to about 1050 mg (e.g., about 70 mg to about 840 mg, e.g., about 210 mg to about 840 mg, about 280 mg to about 840 mg, about 420 mg to about 840 mg, e.g., about 560 mg to about 840 mg, e.g., about 70 mg, e.g., about 140 mg e.g., about 210 mg, e.g., about 280 mg, e.g., about 420 mg, e.g., about 560 mg, e.g., about 840 mg) every month for at least or more than about one month, two months, three months, followed by being administered at the same dose quarterly for at least or more than three, six, nine, or twelve months. In some embodiments, the VH-I, VL-I, VH-2, and VL-2 comprise the amino acid sequences of SEQ ID NO: 13, 14, 15, and 16 respectively. In some embodiments, the bispecific antibody is a full-length antibody comprising an IgG (e.g., IgG4) Fc fragment. In some embodiments, the first, second, third and fourth polypeptides comprise the amino acid sequences of SEQ ID NO: 17, 18, 19, and 20 respectively. In some embodiments, the individual is at high risk for fracture. In some embodiments, the individual is at least about 18, 30, 35, 40, 45, 50, 55, or 60 years old. In some embodiments, the individual is a male. In some embodiments, the individual is a female (e.g., a postmenopausal woman). In some embodiments, the individual has a history of osteoporotic fracture. In some embodiments, the individual has been subjected to, failed, or is intolerant to an osteoporosis therapy. In some embodiments, the osteoporosis therapy is selected from the group consisting of romosozumab, denosumab, etidronate, pamidronate, risedronate, alendronate, zoledronate, ibandronate, teriparatide, and abaloparatide. In some embodiments, the individual has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90% or 95% probability of fraction in the next five or ten years as determined by a clinician or under Fracture Risk Assessment Tool (FRAX®). In some embodiments, the individual has a history of a cardiovascular disease, optionally the cardiovascular disease is a myocardial infarction or stroke. In some embodiments, the individual has a hip bone mineral density T-score measured by DXA a) that is between -1 and -2.5; b) that is -2.5 or lower than - 2.5; or c) that is -2.5 or lower than -2.5 and at least one fragility fracture. In some embodiments, the individual has a history of fracture (e.g., a vertebral or non-vertebral fracture). In some embodiments, at about one month, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the individual has an increase in serum P1NP level. In some embodiments, the increase in serum P1NP is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% ,100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%,77MOFO-359878767Attorney Docket No. 21091-20003.40190%, or 200% as compared to the baseline. In some embodiments, at about one month, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the individual has a decrease in serum CTX-1 level. In some embodiments, the decrease in serum CTX-1 is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% as compared to the baseline. In some embodiments, at about one month, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the individual has an increase in serum osteocalcin level. In some embodiments, the increase in serum osteocalcin is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% as compared to the baseline. In some embodiments, at about one month, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the individual has an increase in serum BSAP level. In some embodiments, the increase in serum BSAP is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, or 150% as compared to the baseline. In some embodiments, at about one month, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the individual has an increase in serum iPTH level. In some embodiments, the increase is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, or 150% as compared to the baseline. In some embodiments, at about one month, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, , the individual has an increase in lumbar spine BMD by at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, or 15%. In some embodiments, at about one month, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, , the individual has an increase in total hip BMD by at least about 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10%. In some embodiments, at about one month, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, , the individual has an increase in femoral neck BMD by at least about 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10%. In some embodiments,78MOFO-359878767Attorney Docket No. 21091-20003.40 the individual is subject to a supplement (e.g., daily supplement) comprising Vitamin D (e.g., Vitamin D2 or Vitamin D3) and / or calcium. In some embodiments, the individual is subject to calcium at a dose of about 100, 250, 500, 750 or 1000 mg / day or more daily and / or Vitamin D at a dose of about 100, 250, 500, 750 or 1000 lU / day or more.

[0215] In some embodiments, there is provided a method of treating osteoporosis in a postmenopausal female individual, comprising administering (e.g., subcutaneously or intravenously) a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises a) a first polypeptide comprising a first heavy chain variable region (VH-I), b) a second polypeptide comprising a first light chain variable region (VL-I), C) a third polypeptide comprising a second heavy chain variable region (VH-2), d) a fourth polypeptide comprising a second variable region (VL-2), wherein: 1) the VH-I comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3; 2) the VL-I comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NOs: 6; 3) the VH-2 comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 9; and 4) the VL-2 comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12, wherein the bispecific antibody is administered at a dose of about 70 mg to about 1050 mg (e.g., about 70 mg to about 840 mg, e.g., about 210 mg to about 840 mg, about 280 mg to about 840 mg, about 420 mg to about 840 mg, e.g., about 560 mg to about 840 mg, e.g., about 70 mg, e.g., about 140 mg e.g., about 210 mg, e.g., about 280 mg, e.g., about 420 mg, e.g., about 560 mg, e.g., about 840 mg), wherein the bispecific antibody is administered about monthly or quarterly. In some embodiments, the bispecific antibody is administered at a dose of about 70 mg to about 1050 mg (e.g., about 70 mg to about 840 mg, e.g., about 210 mg to about 840 mg, about 280 mg to about 840 mg, about 420 mg to about 840 mg, e.g., about 560 mg to about 840 mg, e.g., about 70 mg, e.g., about 140 mg e.g., about 210 mg, e.g., about 280 mg, e.g., about 420 mg, e.g., about 560 mg, e.g., about 840 mg) every month for at least or more than about one, two, three, four, five, six, nine, twelve, fifteen, eighteen, or twenty-four months. In some embodiments, the bispecific antibody is administered at a dose of about 70 mg to about 1050 mg (e.g., about 70 mg to about 840 mg, e.g., about 210 mg to about 840 mg, about 28079MOFO-359878767Attorney Docket No. 21091-20003.40 mg to about 840 mg, about 420 mg to about 840 mg, e.g., about 560 mg to about 840 mg, e.g., about 70 mg, e.g., about 140 mg e.g., about 210 mg, e.g., about 280 mg, e.g., about 420 mg, e.g., about 560 mg, e.g., about 840 mg) quarterly for at least or more than about six, nine, twelve, fifteen, eighteen, or twenty-four months. In some embodiments, the bispecific antibody is administered at a dose of about 70 mg to about 1050 mg (e.g., about 70 mg to about 840 mg, e.g., about 210 mg to about 840 mg, about 280 mg to about 840 mg, about 420 mg to about 840 mg, e.g., about 560 mg to about 840 mg, e.g., about 70 mg, e.g., about 140 mg e.g., about 210 mg, e.g., about 280 mg, e.g., about 420 mg, e.g., about 560 mg, e.g., about 840 mg) every month for at least or more than about one month, two months, three months, followed by being administered at the same dose quarterly for at least or more than three, six, nine, or twelve months. In some embodiments, the individual has a high risk of fracture. In some embodiments, the individual has a history of osteoporotic fracture. In some embodiments, the individual has failed or is intolerant to other osteoporosis therapy. In some embodiments, the individual has multiple (e.g., at least two, three, four, five, six, seven) risk factors for fracture. Exemplary factors include: a) being over 50, b) having a family history of osteoporosis, c) has a low body weight, d) having broken bone, e) weight loss of more than 1 percent per year in the elderly, f) late onset of sexual development, g) unusual cessation of menstrual periods, h) anorexia nervosa (often related to marked weight reduction), i) athletic amenorrhea syndrome (related to intense physical activity), j) being treated with drugs that affect bone metabolism (e.g., glucocorticoids), k) having diseases linked to secondary osteoporosis, 1) high levels of serum calcium or alkaline phosphatase in otherwise healthy patients, m) hyperparathyroidism, hyperthyroidism, or treatment with high doses of thyroid hormone, n) height loss or progressive spinal curvature. In some embodiments, the VH-I, VL-I, VH-2, and VL-2 comprise the amino acid sequences of SEQ ID NO: 13, 14, 15, and 16 respectively. In some embodiments, the bispecific antibody is a full-length antibody comprising an IgG (e.g., IgG4) Fc fragment. In some embodiments, the first, second, third and fourth polypeptides comprise the amino acid sequences of SEQ ID NO: 17, 18, 19, and 20 respectively. In some embodiments, the individual is at high risk for fracture. In some embodiments, the individual is at least about 18, 30, 35, 40, 45, 50, 55, or 60 years old. In some embodiments, the individual is a female (e.g., a postmenopausal woman). In some embodiments, the individual has a history of osteoporotic fracture. In some embodiments, the individual has been subjected to, failed, or is intolerant to an osteoporosis therapy. In some embodiments, the osteoporosis therapy is selected from the group consisting of romosozumab, denosumab, etidronate, pamidronate, risedronate, alendronate, zoledronate, ibandronate, teriparatide, and abaloparatide. In some embodiments,80MOFO-359878767Attorney Docket No. 21091-20003.40 the individual has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90% or 95% probability of fraction in the next five or ten years as determined by a clinician or under Fracture Risk Assessment Tool (FRAX®). In some embodiments, the individual has a history of a cardiovascular disease, optionally the cardiovascular disease is a myocardial infarction or stroke. In some embodiments, the individual has a hip bone mineral density T-score measured by DXA a) that is between -1 and -2.5; b) that is -2.5 or lower than -2.5; or c) that is -2.5 or lower than -2.5 and at least one fragility fracture. In some embodiments, the individual has a history of fracture (e.g., a vertebral or non-vertebral fracture). In some embodiments, at about one month, two months, one month, two months, s, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the individual has an increase in serum P1NP level. In some embodiments, the increase in serum P1NP is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% ,100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, or 200% as compared to the baseline. In some embodiments, at about one month, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the individual has a decrease in serum CTX-1 level. In some embodiments, the decrease in serum CTX-1 is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% as compared to the baseline. In some embodiments, at about one month, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the individual has an increase in serum osteocalcin level. In some embodiments, the increase in serum osteocalcin is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% as compared to the baseline. In some embodiments, at about one month, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the individual has an increase in serum BSAP level. In some embodiments, the increase in serum BSAP is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, or 150% as compared to the baseline. In some embodiments, at about one month, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the individual has an increase in serum iPTH level. In some embodiments, the increase is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, or 150% as compared to the baseline. In some embodiments, at about one month,81MOFO-359878767Attorney Docket No. 21091-20003.40 two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the individual has an increase in lumbar spine BMD by at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, or 15%. In some embodiments, at about one month, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the individual has an increase in total hip BMD by at least about 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10%. In some embodiments, at about one month, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the individual has an increase in femoral neck BMD by at least about 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10%. In some embodiments, the individual is subject to a supplement (e.g., daily supplement) comprising Vitamin D (e.g., Vitamin D2 or Vitamin D3) and / or calcium. In some embodiments, the individual is subject to calcium at a dose of about 100, 250, 500, 750 or 1000 mg / day or more daily and / or Vitamin D at a dose of about 100, 250, 500, 750 or 1000 lU / day or more.

[0216] In some embodiments, there is provided a method of reducing risk of vertebral fracture in a human individual comprising subcutaneously administering a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises a) a first polypeptide comprising a first heavy chain variable region (VH-I), b) a second polypeptide comprising a first light chain variable region (VL-I), C) a third polypeptide comprising a second heavy chain variable region (VH-2), d) a fourth polypeptide comprising a second variable region (VL-2), wherein: 1) the VH-I comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3; 2) the VL-I comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LC- CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NOs: 6; 3) the VH-2 comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 9; and 4) the VL-2 comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LC- CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12, and wherein the bispecific antibody is82MOFO-359878767Attorney Docket No. 21091-20003.40 administered to the individual at a dose of at least about 1 mg / kg. In some embodiments, the method of reducing risk of vertebral fracture in a human individual includes reducing risk of lumbar spine fracture in a human individual. In some embodiments, the bispecific antibody is administered to the individual at a dose of at least about 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg or 12 mg / kg. In some embodiments, the bispecific antibody is administered to the individual at a dose of at least about 70 mg, 140 mg, 210 mg, 280 mg, 350 mg, 420 mg, 490 mg, 560 mg, 630 mg, 700 mg, 770 mg, or 840 mg. In some embodiments, the bispecific antibody is administered to the individual at least 1 mg / kg monthly for three consecutive months. In some embodiments, the bispecific antibody is administered to the individual at least 3 mg / kg monthly for three consecutive months. In some embodiments, the bispecific antibody is administered to the individual at a dose of at least about 10 mg / kg (e.g., at least 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg or 15 mg / kg) as a single administration within a three-months period. In some embodiments, the individual has a high risk of fracture. In some embodiments, the individual has a history of osteoporotic fracture. In some embodiments, the individual has failed or is intolerant to other osteoporosis therapy. In some embodiments, the individual has multiple (e.g., at least two, three, four, five, six, seven) risk factors for fracture. Exemplary factors include: a) being over 50, b) having a family history of osteoporosis, c) has a low body weight, d) having broken bone, e) weight loss of more than 1 percent per year in the elderly, f) late onset of sexual development, g) unusual cessation of menstrual periods, h) anorexia nervosa (often related to marked weight reduction), i) athletic amenorrhea syndrome (related to intense physical activity), j) being treated with drugs that affect bone metabolism (e.g., glucocorticoids), k) having diseases linked to secondary osteoporosis, 1) high levels of serum calcium or alkaline phosphatase in otherwise healthy patients, m) hyperparathyroidism, hyperthyroidism, or treatment with high doses of thyroid hormone, n) height loss or progressive spinal curvature. In some embodiments, the VH- I, VL-I, VH-2, and VL-2 comprise the amino acid sequences of SEQ ID NO: 13, 14, 15, and 16 respectively. In some embodiments, the bispecific antibody is a full-length antibody comprising an IgG (e.g., IgG4) Fc fragment. In some embodiments, the first, second, third and fourth polypeptides comprise the amino acid sequences of SEQ ID NO: 17, 18, 19, and 20 respectively. In some embodiments, the individual is at high risk for fracture. In some embodiments, the individual is at least about 18, 30, 35, 40, 45, 50, 55, or 60 years old. In some embodiments, the individual is a male. In some embodiments, the individual is a female (e.g., a postmenopausal woman). In some embodiments, the individual has a history of osteoporotic fracture. In some embodiments, the individual has been subjected to, failed, or is83MOFO-359878767Attorney Docket No. 21091-20003.40 intolerant to an osteoporosis therapy. In some embodiments, the osteoporosis therapy is selected from the group consisting of romosozumab, denosumab, etidronate, pamidronate, risedronate, alendronate, zoledronate, ibandronate, teriparatide, and abaloparatide. In some embodiments, the individual has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90% or 95% probability of fraction in the next five or ten years as determined by a clinician or under Fracture Risk Assessment Tool (FRAX®). In some embodiments, the individual has a history of a cardiovascular disease, optionally the cardiovascular disease is a myocardial infarction or stroke. In some embodiments, the individual has a hip bone mineral density T-score measured by DXA a) that is between -1 and -2.5; b) that is -2.5 or lower than - 2.5; or c) that is -2.5 or lower than -2.5 and at least one fragility fracture. In some embodiments, the individual has a history of fracture (e.g., a vertebral or non-vertebral fracture).

[0217] In some embodiments, there is provided a method of reducing risk of non-vertebral fracture in a human individual comprising subcutaneously administering a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises a) a first polypeptide comprising a first heavy chain variable region (VH-I), b) a second polypeptide comprising a first light chain variable region (VL-I), C) a third polypeptide comprising a second heavy chain variable region (VH-2), d) a fourth polypeptide comprising a second variable region (VL-2), wherein: 1) the VH-I comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3; 2) the VL-I comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LC- CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NOs: 6; 3) the VH-2 comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 9; and 4) the VL-2 comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LC- CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12, and wherein the bispecific antibody is administered to the individual at a dose of at least about 6 mg / kg. In some embodiments, the bispecific antibody is administered to the individual at a dose of at least about 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg or 12 mg / kg. In some embodiments, the bispecific antibody is administered to the individual at a dose of at least about 420 mg, 490 mg, 560 mg, 630 mg, 700 mg, 770 mg, or 840 mg. In some embodiments, the bispecific antibody is84MOFO-359878767Attorney Docket No. 21091-20003.40 administered to the individual at least 6 mg / kg (e.g., 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg or 12 mg / kg) monthly for three consecutive months. In some embodiments, the bispecific antibody is administered to the individual at least 420 mg (e.g., 420 mg, 490 mg, 560 mg, 630 mg, 700 mg, 770 mg or 840 mg) monthly for three consecutive months. In some embodiments, the individual has a high risk of fracture. In some embodiments, the individual has a history of osteoporotic fracture. In some embodiments, the individual has failed or is intolerant to other osteoporosis therapy. In some embodiments, the individual has multiple (e.g., at least two, three, four, five, six, seven) risk factors for fracture. Exemplary factors include: a) being over 50, b) having a family history of osteoporosis, c) has a low body weight, d) having broken bone, e) weight loss of more than 1 percent per year in the elderly, f) late onset of sexual development, g) unusual cessation of menstrual periods, h) anorexia nervosa (often related to marked weight reduction), i) athletic amenorrhea syndrome (related to intense physical activity), j) being treated with drugs that affect bone metabolism (e.g., glucocorticoids), k) having diseases linked to secondary osteoporosis, 1) high levels of serum calcium or alkaline phosphatase in otherwise healthy patients, m) hyperparathyroidism, hyperthyroidism, or treatment with high doses of thyroid hormone, n) height loss or progressive spinal curvature. In some embodiments, the VH-I, VL-I, VH-2, and VL-2 comprise the amino acid sequences of SEQ ID NO: 13, 14, 15, and 16 respectively. In some embodiments, the bispecific antibody is a full-length antibody comprising an IgG (e.g., IgG4) Fc fragment. In some embodiments, the first, second, third and fourth polypeptides comprise the amino acid sequences of SEQ ID NO: 17, 18, 19, and 20 respectively. In some embodiments, the individual is at high risk for fracture. In some embodiments, the individual is at least about 18, 30, 35, 40, 45, 50, 55, or 60 years old. In some embodiments, the individual is a male. In some embodiments, the individual is a female (e.g., a postmenopausal woman). In some embodiments, the individual has a history of osteoporotic fracture. In some embodiments, the individual has been subjected to, failed, or is intolerant to an osteoporosis therapy. In some embodiments, the osteoporosis therapy is selected from the group consisting of romosozumab, denosumab, etidronate, pamidronate, risedronate, alendronate, zoledronate, ibandronate, teriparatide, and abaloparatide. In some embodiments, the individual has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90% or 95% probability of fraction in the next five or ten years as determined by a clinician or under Fracture Risk Assessment Tool (FRAX®). In some embodiments, the individual has a history of a cardiovascular disease, optionally the cardiovascular disease is a myocardial infarction or stroke. In some embodiments, the individual has a hip bone mineral density T-score measured by DXA a) that85MOFO-359878767Attorney Docket No. 21091-20003.40 is between -1 and -2.5; b) that is -2.5 or lower than -2.5; or c) that is -2.5 or lower than -2.5 and at least one fragility fracture. In some embodiments, the individual has a history of fracture (e.g., a vertebral or non-vertebral fracture).

[0218] In some embodiments, there is provided a method of reducing risk of hip fracture in a human individual comprising subcutaneously administering a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises a) a first polypeptide comprising a first heavy chain variable region (VH-I), b) a second polypeptide comprising a first light chain variable region (VL-I), C) a third polypeptide comprising a second heavy chain variable region (VH-2), d) a fourth polypeptide comprising a second variable region (VL-2), wherein: 1) the VH-I comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3; 2) the VL-I comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LC- CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NOs: 6; 3) the VH-2 comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 9; and 4) the VL-2 comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LC- CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12, and wherein the bispecific antibody is administered to the individual at a dose of at least about 8 mg / kg. In some embodiments, the method of reducing risk of hip fracture in a human individual includes reducing risk of femoral neck fracture in a human individual. In some embodiments, the bispecific antibody is administered to the individual at a dose of at least about 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg or 12 mg / kg. In some embodiments, the bispecific antibody is administered to the individual at a dose of at least about 560 mg, 630 mg, 700 mg, 770 mg, or 840 mg. In some embodiments, the bispecific antibody is administered to the individual at least 8 mg / kg (e.g., 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg or 12 mg / kg) monthly for three consecutive months. In some embodiments, the bispecific antibody is administered to the individual at least 560 mg (e.g., 560 mg, 630 mg, 700 mg, 770 mg or 840 mg) monthly for three consecutive months. In some embodiments, the individual has a high risk of fracture. In some embodiments, the individual has a history of osteoporotic fracture. In some embodiments, the individual has failed or is intolerant to other osteoporosis therapy. In some embodiments, the individual has multiple (e.g., at least two, three, four, five, six, seven) risk factors for fracture. Exemplary86MOFO-359878767Attorney Docket No. 21091-20003.40 factors include: a) being over 50, b) having a family history of osteoporosis, c) has a low body weight, d) having broken bone, e) weight loss of more than 1 percent per year in the elderly, f) late onset of sexual development, g) unusual cessation of menstrual periods, h) anorexia nervosa (often related to marked weight reduction), i) athletic amenorrhea syndrome (related to intense physical activity), j) being treated with drugs that affect bone metabolism (e.g., glucocorticoids), k) having diseases linked to secondary osteoporosis, 1) high levels of serum calcium or alkaline phosphatase in otherwise healthy patients, m) hyperparathyroidism, hyperthyroidism, or treatment with high doses of thyroid hormone, n) height loss or progressive spinal curvature. In some embodiments, the VH-I, VL-I, VH-2, and VL-2 comprise the amino acid sequences of SEQ ID NO: 13, 14, 15, and 16 respectively. In some embodiments, the bispecific antibody is a full-length antibody comprising an IgG (e.g., IgG4) Fc fragment. In some embodiments, the first, second, third and fourth polypeptides comprise the amino acid sequences of SEQ ID NO: 17, 18, 19, and 20 respectively. In some embodiments, the individual is at high risk for fracture. In some embodiments, the individual is at least about 18, 30, 35, 40, 45, 50, 55, or 60 years old. In some embodiments, the individual is a male. In some embodiments, the individual is a female (e.g., a postmenopausal woman). In some embodiments, the individual has a history of osteoporotic fracture. In some embodiments, the individual has been subjected to, failed, or is intolerant to an osteoporosis therapy. In some embodiments, the osteoporosis therapy is selected from the group consisting of romosozumab, denosumab, etidronate, pamidronate, risedronate, alendronate, zoledronate, ibandronate, teriparatide, and abaloparatide. In some embodiments, the individual has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90% or 95% probability of fraction in the next five or ten years as determined by a clinician or under Fracture Risk Assessment Tool (FRAX®). In some embodiments, the individual has a history of a cardiovascular disease, optionally the cardiovascular disease is a myocardial infarction or stroke. In some embodiments, the individual has a hip bone mineral density T-score measured by DXA a) that is between -1 and -2.5; b) that is -2.5 or lower than -2.5; or c) that is -2.5 or lower than -2.5 and at least one fragility fracture. In some embodiments, the individual has a history of fracture (e.g., a vertebral or non-vertebral fracture).

[0219] In some embodiments, the Fc fragment of the bispecific antibody comprises a first Fc domain and a second Fc domain. In some embodiments, one of the first and the second Fc domains comprises a S228P mutation, and T366W mutation, and optionally a S354C mutation, and wherein the other Fc domain comprises a S228P mutation, T366S mutation, a L368A87MOFO-359878767Attorney Docket No. 21091-20003.40 mutation, a Y407V mutation, and optionally a Y349C mutation, and optionally a H435R mutation, and optionally a Y436F mutation, wherein numbering is according to the EU index.

[0220] In some embodiments, the third polypeptide comprises a CHI domain comprising a V173C mutation, and a C131S mutation; and the fourth polypeptide comprises a CL domain comprising a Q160C mutation and a C214S mutation, wherein numbering is according to the EU index.

[0221] In some embodiments, the individual takes daily calcium and / or vitamin D supplementation. In some embodiments, the individual takes at least 100, 250, 500, 750 or 1000 mg / day calcium. In some embodiments, the individual takes at least 100, 250, 500, 750 or 1000 lU / day vitamin D supplementation (e.g., vitamin D3 or vitamin D2). a) Anti-Sclerostin x Anti-DKK-1 bispecific antibodies

[0222] The bispecific antibodies targeting both Sclerostin and DKK-1 described herein comprising a first antibody moiety that specifically recognizes Sclerostin (e.g., human sclerostin) and a second antibody moiety that specifically recognizes DKK-1 (e.g., human DKK-1). i) Anti-Sclerostin antibody moieties

[0223] Sclerostin is a secreted glycoprotein with a C-terminal cysteine knot-like (CTCK) domain and sequence similarity to the DAN (differential screening-selected gene aberrative in neuroblastoma) family of bone morphogenetic protein (BMP) antagonists. Loss-of-function mutations in this gene are associated with an autosomal-recessive disorder, sclerosteosis, which causes progressive bone overgrowth. A deletion downstream of this gene, which causes reduced sclerostin expression, is associated with a milder form of the disorder called van Buchem disease. Sclerostin has already been a target for osteoporotic therapy, for example the drug romosozumab, an anti-sclerostin monoclonal antibody, has been developed for treatment of osteoporosis.

[0224] In some embodiments, the bispecific antibody comprises an anti-Sclerostin antibody moiety comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, ii) an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and / or iii) an HC-CDR3 comprising the amino acid sequence of SEQ ID NOs: 3, and / or the VL comprises i) an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, ii) an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and iii) an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 6. In some embodiments, the heavy chain variable region (VH) comprises the amino acid sequence of SEQ ID NO: 13 or a variant comprising an amino88MOFO-359878767Attorney Docket No. 21091-20003.40 acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the light chain variable region (VL) comprises the amino acid sequence of SEQ ID NO: 14 or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0225] In some embodiments, the bispecific antibody comprises an anti-Sclerostin antibody moiety that binds to the same epitope of Sclerostin as a second anti-Sclerostin antibody moiety comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, ii) an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and / or iii) an HC-CDR3 comprising the amino acid sequence of SEQ ID NOs: 3, and the VL comprises i) an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, ii) an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and iii) an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 6.

[0226] In some embodiments, the bispecific antibody comprises an anti-sclerostin antibody moiety that specifically recognizes Sclerostin, wherein the antibody moiety comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein: a HC-CDR1, a HC- CDR2, and a HC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within the VH having the sequence set forth in SEQ ID NO: 13, and a LC- CDR1, a LC-CDR2, and a LC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within the VL having the sequence set forth in SEQ ID NO: 14. ii) Anti-DKK-1 antibody moieties

[0227] DKK-1 (Dickkopf-related protein 1, or DKK1) is a member of the dickkopf family of proteins. Members of this family are secreted proteins characterized by two cysteine-rich domains that mediate protein-protein interactions. DKK1 binds to the LRP6 co-receptor and inhibits beta-catenin-dependent Wnt signaling. This gene plays a role in embryonic development and may be important in bone formation in adults.

[0228] In some embodiments, the bispecific antibody comprises an anti -DKK-1 antibody moiety comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, ii) an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and iii) an HC- CDR3 comprising the amino acid sequence of SEQ ID NOs: 9, and / or the VL comprises i) an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, ii) an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and iii) an LC-CDR3 comprising the89MOFO-359878767Attorney Docket No. 21091-20003.40 amino acid sequence of SEQ ID NO: 12. In some embodiments, the heavy chain variable region (VH) comprises the amino acid sequence of SEQ ID NO: 15 or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the light chain variable region (VL) comprises the amino acid sequence of SEQ ID NO: 16 or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0229] In some embodiments, the bispecific antibody comprises an anti-DKK-1 antibody moiety that binds to the same epitope of DKK-1 as a second anti-DKKl antibody moiety comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, ii) an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and iii) an HC-CDR3 comprising the amino acid sequence of SEQ ID NOs: 9, and the VL comprises i) an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, ii) an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and iii) an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12.

[0230] In some embodiments, there is provided a bispecific antibody comprising an anti- DKK-1 antibody moiety that specifically recognizes DKK-1, wherein the antibody moiety comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein: a HC-CDR1, a HC-CDR2, and a HC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within the VH having the sequence set forth in SEQ ID NO: 15, and a LC-CDR1, a LC-CDR2, and a LC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within the VL having the sequence set forth in SEQ ID NO: 16. iii) Anti-Sclerostin x anti-DKK-1 bispecific antibodies

[0231] In some embodiments, the anti-Scl erostin x anti-DKK-1 bispecific antibody described herein comprises a) an anti-Sclerostin antibody moiety comprising a first heavy chain variable region (VH-I) and a first light chain variable region (VL-I), and b) an anti-DKKl antibody moiety comprising a second heavy chain variable region (VH-2) and a second light chain variable region (VL-2). In some embodiments, the VH-I comprises i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, ii) an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and / or iii) an HC-CDR3 comprising the amino acid sequence of SEQ ID NOs: 3, and / or the VL-I comprises i) an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, ii) an LC-CDR2 comprising the amino acid sequence of SEQ ID90MOFO-359878767Attorney Docket No. 21091-20003.40NO: 5, and iii) an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 6. In some embodiments, the VH-2 comprises i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, ii) an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and iii) an HC-CDR3 comprising the amino acid sequence of SEQ ID NOs: 9, and / or the VL-2 comprises i) an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, ii) an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and iii) an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12. In some embodiments, the heavy chain variable region (VH-I) comprises the amino acid sequence of SEQ ID NO: 13 or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the light chain variable region (VL-I) comprises the amino acid sequence of SEQ ID NO: 14 or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the heavy chain variable region (VH-2) comprises the amino acid sequence of SEQ ID NO: 15 or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the light chain variable region (VL-2) comprises the amino acid sequence of SEQ ID NO: 16 or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0232] In some embodiments, the bispecific antibody is a full-length antibody comprising a Fc fragment. In some embodiments, the bispecific antibody comprises an Fc fragment of an immunoglobulin selected from the group consisting of IgG, IgA, IgD, IgE, IgM, and combinations and hybrids thereof. In some embodiments, the anti-Sclerostin antibody moiety or the full-length antibody described above comprises an Fc fragment of an immunoglobulin selected from the group consisting of IgGl, IgG2, IgG3, IgG4, and combinations and hybrids thereof. In some embodiments, the Fc fragment has a reduced effector function as compared to the corresponding wildtype Fc fragment. In some embodiments, the Fc fragment has an enhanced effector function as compared to the corresponding wildtype Fc fragment.

[0233] In some embodiments, the bispecific antibody comprises an IgG fragment. In some embodiments, the IgG fragment is an IgG4 Fc fragment.

[0234] In some embodiments, the bispecific antibody comprises an Fc fragment formed from a first Fc domain and a second Fc domain. In some embodiments, the first Fc domain and / or second Fc domain comprises one or more mutations. In some embodiments, the one or more mutations improve the function and / or stability of the bispecific antibody.91MOFO-359878767Attorney Docket No. 21091-20003.40

[0235] In some embodiments, the first Fc domain and / or second Fc domain comprises one or more mutations that prevents Fab arm exchange (FAE) of the bispecific antibody. In some cases, FAE is a process that can result in functionally monovalent bispecific antibodies with unknown antigen specificity and, by extension, reduced therapeutic efficacy. In some embodiments, the first Fc domain and / or the second Fc domain comprises an S228P mutation. See, e.g., J Biol Chem. 2015 Feb 27;290(9):5462-9.

[0236] In some embodiments, the first Fc domain and / or second Fc domain comprises one or more mutations that improve heterodimerization of the bispecific antibody. In some embodiments, heterodimerization of the bispecific antibody occurs through a knobs-into-holes model. See e.g., Front Immunol. 2021; 12: 626616. In some cases, the knobs-into-holes model is based on replacing a smaller amino acid with a larger amino acid (e.g., T336Y) in the CH3 region of an antibody chain to form a “knobs” structure, and at the same time substituting a larger amino acid in the other chain with a smaller amino acid to form a “holes” structure (e.g., Y407T), thereby facilitating heterodimerization of antibody heavy chain homodimers. In some embodiments, the first Fc domain or second Fc domain comprises one or more mutations that improve heterodimerization of the bispecific antibody through the knobs-into- hole model. In some embodiments, the one or more mutations that improve heterodimerization of the bispecific antibody through the knobs-into-hole model are selected from the group consisting of T366W, T366S, L368A, Y407V, Y349C, and S354C, or any combination thereof, wherein numbering is according to the EU index. In some embodiments, the first Fc domain and / or second Fc domain comprises a T366W mutation. In some embodiments, the first Fc domain and / or second Fc domain comprises a S354C mutation. See e.g., J Immunol Methods. 2020 Aug:483: l 12811. In some embodiments, the first Fc domain and / or second Fc domain comprises a T366S mutation. In some embodiments, the first Fc domain and / or second Fc domain comprises a L368A mutation. In some embodiments, the first Fc domain and / or second Fc domain comprises a Y407V mutation. In some embodiments, the first Fc domain and / or second Fc domain comprises a Y349C mutation.

[0237] In some embodiments, the first Fc domain and / or second Fc domain comprises one or more mutations that increase the half-life of the bispecific antibody. In some embodiments, the half-life of the antibody is the serum half-life of the antibody.

[0238] In some embodiments, the first Fc domain and / or second Fc domain comprises one or more mutations that improve the purification of the bispecific antibody. In some embodiments, the one or more mutations improve the purification of the bispecific antibody by preventing binding of protein A to the bispecific antibody. Mutations which alter or prevent92MOFO-359878767Attorney Docket No. 21091-20003.40 protein A binding to the bispecific antibody allow differential protein A elution of the bispecific antibody. See e.g., Sci Rep. 2017 Nov 14;7(1): 15521. In some embodiments, the one or more mutations that prevent binding of protein A to the bispecific antibody are selected from the group consisting of H435R, Y436F, T307P, L309Q, and Q311R, or any combination thereof, wherein numbering is according to the EU index. In some embodiments, the first Fc domain and / or second Fc domain comprises an H435R mutation. In some embodiments, the first Fc domain and / or second Fc domain comprises a Y436F mutation. In some embodiments, the first Fc domain and / or second Fc domain comprises a T307P mutation. In some embodiments, the first Fc domain and / or second Fc domain comprises a L309Q mutation. In some embodiments, the first Fc domain and / or second Fc domain comprises a Q3 HR mutation.

[0239] In some embodiments, the first Fc domain comprises a T366W mutation, and optionally a S354C mutation, and the second Fc domain comprises a T366S mutation, a L368A mutation, a Y407V mutation, and optionally a Y349C mutation, wherein numbering is according to the EU index.

[0240] In some embodiments, the first Fc domain comprises a S228P mutation and T366W mutation, and optionally a S354C mutation, and the second Fc domain comprises a S228P mutation, T366S mutation, a L368A mutation, and a Y407V mutation, wherein numbering is according to the EU index. In some further embodiments, the first Fc domain additionally comprises a S354C mutation, and the second Fc domain additionally comprises a Y349C mutation, a H435R mutation, and / or a Y436F mutation, wherein numbering is according to the EU index.

[0241] In some embodiments, the bispecific antibody comprises a CHI domain and a pairing CL domain. In some embodiments, the CHI domain and the pairing CL domain comprise one or more mutation pairs that promote pairing of said domains in the bispecific antibody. In some embodiments, the CHI domain comprises a V173C mutation, and the pairing CL domain comprises Q160C mutation, wherein numbering is according to the EU index. In some embodiments, the CHI domain comprises a C 13 IS mutation, and the pairing CL domain comprises C214S mutation, wherein numbering is according to the EU index. In some embodiments, the CHI domain comprises V173C mutation, and C131S mutation; and the pairing CL domain comprises Q160C mutation and C214S mutation; wherein numbering is according to the EU index. See e.g., J Biol Eng. 2021 Jun 29; 15(1): 18.

[0242] In some embodiments, the bispecific antibody comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 17, a second polypeptide comprising the93MOFO-359878767Attorney Docket No. 21091-20003.40 amino acid sequence of SEQ ID NO: 18, a third polypeptide comprising the amino acid sequence of SEQ ID NO: 19, and a fourth polypeptide comprising the amino acid sequence of SEQ ID NO: 20. iv) Glycosylation variants

[0243] In some embodiments, the anti-Scl erostin x anti-DKK-1 bispecific antibody described herein is altered to increase or decrease the extent to which the construct is glycosylated. Addition or deletion of glycosylation sites to an antibody may be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites is created or removed.

[0244] Where the antibody moiety comprises an Fc region, the carbohydrate attached thereto may be altered. Native antibodies produced by mammalian cells typically comprise a branched, biantennary oligosaccharide that is generally attached by an N-linkage to Asn297 of the CH2 domain of the Fc region. See, e.g., Wright et al. TIBTECH 15:26-32 (1997). The oligosaccharide may include various carbohydrates, e.g., mannose, N-acetyl glucosamine (GlcNAc), galactose, and sialic acid, as well as a fucose attached to a GlcNAc in the “stem” of the biantennary oligosaccharide structure. In some embodiments, modifications of the oligosaccharide in the antibody moiety may be made in order to create antibody variants with certain improved properties.

[0245] In some embodiments, the anti-Scl erostin x anti-DKK-1 bispecific antibody has a carbohydrate structure that lacks fucose attached (directly or indirectly) to an Fc region. For example, the amount of fucose in such antibody may be from 1% to 80%, from 1% to 65%, from 5% to 65% or from 20% to 40%. The amount of fucose is determined by calculating the average amount of fucose within the sugar chain at Asn297, relative to the sum of all glycostructures attached to Asn 297 (e.g., complex, hybrid and high mannose structures) as measured by MALDI-TOF mass spectrometry, as described in WO 2008 / 077546, for example. Asn297 refers to the asparagine residue located at about position 297 in the Fc region (EU numbering of Fc region residues); however, Asn297 may also be located about ± 3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to minor sequence variations in antibodies. Such fucosylation variants may have improved ADCC function. See, e.g., US Patent Publication Nos. US 2003 / 0157108 (Presta, L.); US 2004 / 0093621 (Kyowa Hakko Kogyo Co., Ltd). Examples of publications related to “defucosylated” or “fucose-deficient” antibody variants include: US 2003 / 0157108; WO 2000 / 61739; WO 2001 / 29246; US 2003 / 0115614; US 2002 / 0164328; US 2004 / 0093621; US 2004 / 0132140; US 2004 / 0110704; US 2004 / 0110282; US 2004 / 0109865; WO 2003 / 085119;94MOFO-359878767Attorney Docket No. 21091-20003.40WO 2003 / 084570; WO 2005 / 035586; WO 2005 / 035778; W02005 / 053742; W02002 / 031140; Okazaki et al. J. Mol. Biol. 336: 1239-1249 (2004); Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004). Examples of cell lines capable of producing defucosylated antibodies include Lecl3 CHO cells deficient in protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); US Patent Application No. US 2003 / 0157108 Al, Presta, L; and WO 2004 / 056312 Al, Adams etal., especially at Example 11), and knockout cell lines, such as alpha- 1,6-fucosyl transferase gene, FUT8, knockout CHO cells (see, e.g., Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94(4):680-688 (2006); and W02003 / 085107).

[0246] In some embodiments, the anti-Scl erostin x anti-DKK-1 bispecific antibody has bisected oligosaccharides, e.g., in which a biantennary oligosaccharide attached to the Fc region of the antibody is bisected by GlcNAc. Such antibody variants may have reduced fucosylation and / or improved ADCC function. Examples of such antibody variants are described, e.g., in WO 2003 / 011878 (Jean-Mairet et al.y, US Patent No. 6,602,684 (Umana et al.y, and US 2005 / 0123546 (Umana et al.y Antibody variants with at least one galactose residue in the oligosaccharide attached to the Fc region are also provided. Such antibody variants may have improved CDC function. Such antibody variants are described, e.g., in WO 1997 / 30087 (Patel et al. WO 1998 / 58964 (Raju, S.); and WO 1999 / 22764 (Raju, S.). v) Methods of bispecific antibody preparation

[0247] In some embodiments, there is provided a method of preparing a bispecific antibody (e.g., anti-Sclerostin x anti-DKK-1 bispecific antibody) that specifically binds to Sclerostin and DKK-1, and a composition such as polynucleotide, nucleic acid construct, vector, host cell, or culture medium that is produced during the preparation of the bispecific antibody or antibody moiety. The bispecific antibody or composition described herein may be prepared by a number of processes as generally described below and using any known methods in the art.

[0248] In some embodiments, there is provided a polynucleotide encoding any one of the bispecific antibodies (e.g., anti-Sclerostin x anti-DKK-1 bispecific antibody) described herein. In some embodiments, there is provided a nucleic acid construct comprising one of the polynucleotides described herein. In some embodiments, the nucleic acid construct further comprises a promoter operably linked to the polynucleotide. In some embodiments, there is provided a vector comprising any polynucleotides that encode the heavy chains and / or light chains of any one of the bispecific antibodies described herein (e.g., anti-Sclerostin x anti- DKK-1 bispecific antibody) or nucleic acid construct described herein. The polynucleotide, nucleic acid, and / or vector can be prepared using any known method in the art.95MOFO-359878767Attorney Docket No. 21091-20003.40

[0249] In some embodiments, there is provided a host cell comprising any polypeptide, polynucleotide, nucleic acid construct and / or vector described herein. In some embodiments, there is provided a host cell prepared using any method described herein. Such expression may be carried out, for example, according to procedures known in the art. Exemplary eukaryotic cells that may be used to express polypeptides include, but are not limited to, COS cells, including COS 7 cells; 293 cells, including 293-6E cells; CHO cells, including CHO-S, DG44. Lecl3 CHO cells, and FUT8 CHO cells; PER.C6® cells (Crucell); and NSO cells. In some embodiments, the bispecific antibodies described herein (e.g, anti-Scl erostin x anti- DKK-1 bispecific antibody) may be expressed in yeast. See, e.g., U.S. Publication No. US 2006 / 0270045 Al, which is hereby incorporated by reference in its entirety. Introduction of one or more nucleic acids into a desired host cell may be accomplished by any method, including but not limited to, calcium phosphate transfection, DEAE-dextran mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection, etc. Non-limiting exemplary methods are described, e.g., in Sambrook et al. , Molecular Cloning, A Laboratory Manual, 3rded. Cold Spring Harbor Laboratory Press (2001). In some embodiments, there is provided a culture medium comprising any antibody moiety, polynucleotide, nucleic acid construct, vector, and / or host cell described herein. In some embodiments, there is provided a culture medium prepared using any method described herein. The bispecific antibodies (e.g, anti-Sclerostin x anti-DKK-1 bispecific antibody) may be purified by any suitable method. Such methods include, but are not limited to, the use of affinity matrices or hydrophobic interaction chromatography. Many methods of purifying polypeptides are known in the art. b) Diseases and conditions

[0250] Methods and compositions / formulations described herein can be used to treat or prevent various diseases or conditions described herein include diseases or conditions associated with regulation of bone formation and absorption. In some embodiments, the methods or compositions described herein can be used to treat diseases or conditions associated with low bone mass, increased risk of bone fracture or damage, and / or impaired ability to rebuild bone.

[0251] In some embodiments, the disease or condition is associated with loss of bone mineral density.

[0252] Decreased bone mass (e.g., decreased bone mineral density) such as osteoporosis result in an increased risk of fracture and decreased strength and mobility. Such conditions96MOFO-359878767Attorney Docket No. 21091-20003.40 can have physical consequences such as pain, disability, or even mortality, as well as loss of independence and high healthcare costs.

[0253] In some embodiments, the disease or condition is low bone mass. In some embodiments, the low bone mass is postmenopausal low bone mass. i) Osteoporosis

[0254] In some embodiments, the disease or condition is osteoporosis.

[0255] Current treatments for osteoporosis include anti-resorptive or anti-remodeling agents such as estrogen, bisphosphonates, and selective estrogen receptor modulators (SERMs), along with parathyroid hormone (PTH), nutritional intake of calcium and Vitamin D, and neutralizing antibodies such as Denosumab is an inhibitor of RANKL. See e.g., Int. J. Mol. Sci. 2019, 20(9), 2213 and Bone. 2011 Apr l;48(4):677-92. However, these treatments result in only mild improvements in bone mineral density and have notable side-effects and limited application scope. For example, bisphosphonates have known side effects including gastrointestinal problems, esophageal inflammation, and gastric ulcers. Long-term bisphosphonate usage may even increase the risk of atypical femoral fracture, specifically subtrochanteric and femoral shaft fractures. Treatment with teriparatide (fragment PTH1-34) is associated with osteosarcoma in rats, and therefore is limited to two years of use and cannot be used by patients with prior radiation therapy of the skeleton, bone metastases, hypercalcemia, or a history of skeletal malignancy. SERMs such as Raloxifene do not result in protection against nonvertebral or hip fractures, and are only efficacious in postmenopausal women, while osteoporosis can also affect healthy women and men.

[0256] In some embodiments, osteoporosis is diagnosed under the World Health Organization (WHO) criteria. The WHO diagnostic classification (Table A) is made by bone mineral density (BMD) testing with dual-energy X-ray absorptiometry (DXA) using the T- score, calculated by subtracting the mean BMD (in g / cm2) of a young-adult reference population from the patient’s BMD and dividing by the standard deviation (SD) of the youngadult reference population. The International Society for Clinical Densitometry (ISCD) recommends that BMD be measured at the lumbar spine (ideally L1-L4), total hip, and femoral neck, with the 33% radius (1 / 3 radius) being measured when the lumbar spine and / or hip cannot be measured (e.g., obese patient who exceeds weight limit of table) or is invalid (e.g., patient with lumbar laminectomy or bilateral total hip replacements). In some embodiments, in a patient with a fragility fracture, a clinical diagnosis of osteoporosis may be considered independently of BMD results, assuming that other causes of skeletal fragility (e.g., osteomalacia) are not responsible for the fracture.97MOFO-359878767Attorney Docket No. 21091-20003.40Table A.World Health Organization criteria for classification of patients with bone mineral density measured by dual-energy X-ray absorptiometry (3).

[0257] In some embodiments, osteoporosis is diagnosed based on bone mineral density (BMD) testing. In some embodiments, BMD testing is performed using a T-score determined through dual-energy X-ray absorptiometry (DXA). T-score can be calculated by subtracting the mean BMD (in g / cm2) of a young-adult reference population from an individual’s BMD and dividing by the standard deviation (SD) of a young-adult reference population. In some embodiments, BMD is measured at the lumbar spine. In some embodiments, BMD is measured at L1-L4 of the lumbar spine. In some embodiments, BMD is measured at the total hip. In some embodiments, BMD is measured at the femoral neck. In some embodiments, the BMD is measured with the 33% radius (1 / 3 radius), particularly when the individual being measured is obese. In some embodiments, a T-score of < -2.5 at the lumbar spine and / or total hip indicates osteoporosis, wherein the individual being measured is a man or postmenopausal woman over the age of 50 years.

[0258] In some embodiments, osteoporosis is diagnosed based on the presence of a fragility fracture. In some embodiments, the fragility fracture is not the result of osteomalacia or other distinct diseases or conditions associated with low bone mass aside from osteoporosis. In some embodiments, a low-trauma hip fracture (fragility fracture of the hip) indicates osteoporosis, wherein the individual with the low trauma hip fracture is a man or postmenopausal woman over the age of 50 years.

[0259] In some embodiments, osteoporosis is diagnosed based on the presence of 1) low bone mass (e.g., osteopenia) as indicated by loss of BMD; 2) a low-trauma vertebral, proximal humerus, pelvis, or, in some cases, distal forearm fracture; and 3) fracture risk assessment tool (FRAX) indicates a fracture risk above the country-specific threshold for treatment. In some embodiments, the country of the country-specific threshold for treatment is the United States of America (USA). In some embodiments, the country-specific threshold for treatment in the98MOFO-359878767Attorney Docket No. 21091-20003.40USA is a 10-year probability of major osteoporotic fracture > 20% or 10-year probability of hip fracture > 3%.

[0260] In some embodiments, the osteoporosis comprises or is premenopausal idiopathic osteoporosis, postmenopausal osteoporosis, menopausal osteoporosis, postoophorectomy osteoporosis, osteoporosis of disuse, drug-induced osteoporosis, osteoporosis due to malabsorption, post-surgical malabsorption osteoporosis and / or senile osteoporosis. ii) Osteopenia

[0261] In some embodiments, the disease or condition is osteopenia. Osteopenia describes a decrease in bone mineral density (BMD) below normal reference values, yet not low enough to meet the diagnostic criteria for osteoporosis. BMD is diagnosed via dual-energy x-ray absorptiometry (DXA) bone scans. Osteopenia, as defined by the World Health Organization (WHO), is a t-score between -1 to -2.5, while values less than -2.5 are diagnostic for osteoporosis. In some embodiments, the osteopenia comprises or is premenopausal idiopathic osteopenia, postmenopausal osteopenia, senile osteopenia, drug-induced osteopenia, osteopenia of disuse, neonatal osteopenia and / or spaceflight osteopenia caused by reduced gravity. iii) Low Bone Mass

[0262] In some embodiments, the disease or condition is low bone mass. The term "low bone mass" refers to any decrease or reduction in bone mineral density (BMD) in an individual below the young adult reference mean and includes both osteoporosis and osteopenia as defined in proposals by the World Health Organization (WHO). The WHO has defined normal as a value of BMD within one standard deviation of the young adult reference mean (T-score > -1). The WHO has defined osteopenia as a value of BMD more than 1 standard deviation below the young adult mean, but less than 2.5 standard deviations below this value (T-score < - 1 and > -2.5). The WHO has characterized osteoporosis as a more severe form of osteopenia and has defined it by value of BMD 2.5 standard deviations or more blow the young adult mean (T-score < -2.5). (See, e.g., World Health Organization Technical Report Series.921 (2003), Prevention and Management of Osteoporosis.) iv) Bone fracture

[0263] In some embodiments, the disease or condition is bone fracture. In some embodiments, the bone fracture is a compression fracture, fragility fracture (such as tibia fracture, femur fracture, or humerus bone fracture), pathologic fracture, stress fracture, hip fracture, fracture of femoral neck, atypical hip fracture, femoral intertrochanter fracture, long99MOFO-359878767Attorney Docket No. 21091-20003.40 bone fracture (such as pelvis fracture, proximal femur fracture, or wrist bone fracture), or fracture of bone in neoplastic disease. Bone fractures, such as hip fractures, can result in impaired mobility, reduced self-care abilities, and a 20-35% mortality rate within 12 months specifically for hip fractures. Reducing the risk, frequency, or severity of hip fractures decreases mortality at 1-year and beyond, thereby improving patient outcomes, including reducing pain, improving quality of life, and improving self-care ability.

[0264] In some embodiments, the disease or condition is delayed or non-union bone fractures. In some embodiments, the delayed or non-union bone fracture is a hip fracture, pseudoarthritis after fusion or arthrodesis, osteolysis, postsurgical osteolysis, or nonunion after spinal arthrodesis, enhancement / acceleration of spinal fusion, chronic pain after arthroplasty.

[0265] In some embodiments, the condition is a high risk of fracture. There is a robust correlation between BMD and fracture risk, with approximately a 2-fold increase in fracture risk for every 1 standard deviation (SD) decrease in BMD. See e.g.,BMJ. 1996;312(7041): 1254- 1259. The presence of clinical risk factors (CRFs) that are independent of BMD, particularly advancing age, prior fracture, and recency of fracture, can identify patients at high risk for fracture by providing information on fracture risk that is complementary to BMD. The National Osteoporosis Foundation (NOF) in the United States has provided an extensive list of CRFs for osteoporosis and fractures. See Table B. See Lewiecki et al., Osteoporosis: Clinical Evaluation.Table BConditions, diseases and medications that cause or contribute to osteoporosis and fractures (7).100MOFO-359878767Attorney Docket No. 21091-20003.40101MOFO-359878767Attorney Docket No. 21091-20003.40 c) Dosages and dosing frequency

[0266] In some embodiments, the provided method comprises treating an individual with a bispecific antibody (e.g., anti-Sclerostin x anti-DKK-1 bispecific antibody) with a particular dosing regimen. The dosing regimen of the bispecific antibody (e.g., anti-Sclerostin x anti- DKK-1 bispecific antibody), such as the specific dosages and frequencies, used for treating a disease, disorder, or condition as described herein administered into the individual may vary with the particular anti-Sclerostin x anti-DKK-1 construct, the mode of administration, and the type of disease or condition being treated.

[0267] In some embodiments, the bispecific antibody is administered to the individual at a dose of about 0.3 mg / kg to about 15 mg / kg bodyweight. In some embodiments, the bispecific antibody is administered to the individual at a dose of at least about or about 0.3, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, or 14.5mg / kg bodyweight. In some embodiments, the bispecific antibody is administered to the individual at a dose of about 15 mg / kg. In some embodiments, the bispecific antibody is administered to the individual at a dose of about 0.3 mg / kg to about 0.5 mg / kg, about 0.5 mg / kg to about 1 mg / kg, about 1 mg / kg to about 2 mg / kg, about 2 mg / kg to about 3 mg / kg, about 3 mg / kg to about 4 mg / kg, about 4 mg / kg to about 5 mg / kg, about 5 mg / kg to about 6 mg / kg, about 6 mg / kg to about 7 mg / kg, about 7 mg / kg to about 8 mg / kg, about 8 mg / kg to about 9 mg / kg, about 9 mg / kg to about 10 mg / kg, about 10 mg / kg to about 11 mg / kg, about 11 mg / kg to about 12 mg / kg, about 12 mg / kg to about 13 mg / kg, about 13 mg / kg to about 14 mg / kg, bout 14 mg / kg to about 15 mg / kg bodyweight. In some embodiments, the bispecific antibody is administered to the individual at a dose of about 0.3-15 mg / kg, 1-15 mg / kg, 3-15 mg / kg, 4-15 mg / kg, 6-15 mg / kg, 8-15 mg / kg, 10-15 mg / kg, 12-15 mg / kg, 0.3-12 mg / kg, 1-12 mg / kg, 3-12 mg / kg, 4-12 mg / kg, 6-12 mg / kg, 8-12 mg / kg, or 10-12 mg / kg body weight. In some embodiments, the bispecific antibody is administered to the individual at a dose of at least about or about 1 mg / kg bodyweight (such as 1 mg / kg bodyweight). In some embodiments, the bispecific antibody is administered to the individual at a dose of at least about or about 3 mg / kg bodyweight (such as 3 mg / kg bodyweight). In some embodiments, the bispecific antibody is administered to the individual at a dose of at least about or about 4 mg / kg bodyweight (such as 4 mg / kg bodyweight). In some embodiments, the bispecific antibody is administered to the individual at a dose of at least about or about 6 mg / kg bodyweight (such as 6 mg / kg bodyweight). In some embodiments, the bispecific antibody is administered to the individual at a dose of at least about or about 8 mg / kg bodyweight (such as102MOFO-359878767Attorney Docket No. 21091-20003.408 mg / kg bodyweight). In some embodiments, the bispecific antibody is administered to the individual at a dose of at least about or about 10 mg / kg body weight (such as 10 mg / kg bodyweight). In some embodiments, the bispecific antibody is administered to the individual at a dose of at least about or about 12 mg / kg bodyweight (such as 12 mg / kg bodyweight). In some embodiments, the bispecific antibody is administered to the individual at a dose of about 3 to about 15 mg / kg bodyweight. In some embodiments, the bispecific antibody is administered to the individual at a dose of about 4 to about 12 mg / kg bodyweight. In some embodiments, the bispecific antibody is administered to the individual at a dose of about 4 to about 8 mg / kg bodyweight. In some embodiments, the bispecific antibody is administered to the individual at a dose of about 6 to about 12 mg / kg body weight. In some embodiments, the bispecific antibody is administered to the individual at a dose of about 8 to about 12 mg / kg bodyweight. In some embodiments, the bispecific antibody is administered to the individual at a dose of about 10 to about 12 mg / kg bodyweight. In some embodiments, the bispecific antibody is administered to the individual at a dose of no more than or less than about lOmg / kg bodyweight.

[0268] In some embodiments, the bispecific antibody is administered to the individual at a dose of about 21 to about 1050 mg. In some embodiments, the bispecific antibody is administered to the individual at a dose of at least about or about 21, 35, 70, 140, 210, 280, 350, 420, 490, 560, 630, 700, 770, 840, 910, or 980mg. In some embodiments, the bispecific antibody is administered to the individual at a dose of about 1050 mg. In some embodiments, the bispecific antibody is administered to the individual at a dose of about 21 mg to about 35 mg, about 35 mg to about 70 mg, about 70 mg to about 140 mg, about 140 mg to about 210 mg, about 210 mg to about 280 mg, about 280 mg to about 350 mg, about 350 mg to about 420 mg, about 420 mg to about 490 mg, about 490 mg to about 560 mg, about 560 mg to about 630 mg, about 630 mg to about 700 mg, about 700 mg to about 770 mg, about 770 mg to about 840 mg, about 840 mg to about 910 mg, about 910 mg to about 980 mg, or about 980 mg to about1050 mg. In some embodiments, the bispecific antibody is administered to the individual at a dose of about 21-1050 mg, 70-1050 mg, 210-1050 mg, 280-1050 mg, 420-1050 mg, 560-1050 mg, 700-1050 mg, 840-1050 mg, 21-840 mg, 70-840 mg, 210-840 mg, 280-840 mg, 420-840 mg, 560-840 mg, or 700-840 mg. In some embodiments, the bispecific antibody is administered to the individual at a dose of at least about or about 70 mg (such as 70 mg). In some embodiments, the bispecific antibody is administered to the individual at a dose of at least about or about 210 mg (such as 210 mg). In some embodiments, the bispecific antibody is administered to the individual at a dose of at least about or about 280 mg (such as 280 mg). In103MOFO-359878767Attorney Docket No. 21091-20003.40 some embodiments, the bispecific antibody is administered to the individual at a dose of at least about or about 420 mg (such as 420 mg). In some embodiments, the bispecific antibody is administered to the individual at a dose of at least about or about 560 mg (such as 560 mg). In some embodiments, the bispecific antibody is administered to the individual at a dose of at least about or about 700...

Claims

Attorney Docket No. 21091-20003.40CLAIMS1. A method of preventing, treating or reducing risk of a bone-related disease, disorder, or condition in a human individual, comprising administering a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises a) a first polypeptide comprising a first heavy chain variable region (VH-1), b) a second polypeptide comprising a first light chain variable region (VL-1), c) a third polypeptide comprising a second heavy chain variable region (VH-2), d) a fourth polypeptide comprising a second variable region (VL-2), wherein:1) the VH-1 comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3;2) the VL-1 comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NOs: 6;3) the VH-2 comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 9; and4) the VL-2 comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12, and wherein the bispecific antibody is administered to the human individual at a dose of at least about 1 mg / kg.

2. The method of claim 1, wherein the bone-related disease, disorder, or condition is a condition associated with low bone mass.

3. The method of claim 1, wherein the bone-related disease, disorder, or condition is osteoporosis.

4. The method of claim 1, wherein the bone-related disease, disorder, or condition is one or both of a vertebral fracture and a non-vertebral fracture, optionally wherein the vertebral fracture is a lumbar spine fracture.160MOFO-359878767Attorney Docket No. 21091-20003.

405. The method of claim 1, wherein the bone-related disease, disorder, or condition is a hip fracture, optionally wherein the hip fracture is femoral neck fracture.

6. A method of increasing bone mineral density in a human individual, comprising administering a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises a) a first polypeptide comprising a first heavy chain variable region (VH-1), b) a second polypeptide comprising a first light chain variable region (VL-1), c) a third polypeptide comprising a second heavy chain variable region (VH-2), d) a fourth polypeptide comprising a second variable region (VL-2), wherein:1) the VH-1 comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3;2) the VL-1 comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NOs: 6;3) the VH-2 comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 9; and4) the VL-2 comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12, and wherein the bispecific antibody is administered to the human individual at a dose of at least about 1 mg / kg.

7. A method of preventing or reducing risk of osteoporotic fracture or accelerating fracture healing in a human individual, comprising administering a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises a) a first polypeptide comprising a first heavy chain variable region (VH-1), b) a second polypeptide comprising a first light chain variable region (VL-1), c) a third polypeptide comprising a second heavy chain variable region (VH-2), d) a fourth polypeptide comprising a second variable region (VL-2), wherein:1) the VH-1 comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3;161MOFO-359878767Attorney Docket No. 21091-20003.402) the VL-1 comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NOs: 6;3) the VH-2 comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 9; and4) the VL-2 comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12, and wherein the bispecific antibody is administered to the human individual at a dose of at least about 1 mg / kg.

8. A method of reducing risk of or treating fracture nonunion, delayed union or the need for reoperation following the fracture repair surgery in a human individual, comprising administering a bispecific antibody that specifically binds to both sclerostin and DKK-1, wherein the bispecific antibody comprises a) a first polypeptide comprising a first heavy chain variable region (VH-1), b) a second polypeptide comprising a first light chain variable region (VL-1), c) a third polypeptide comprising a second heavy chain variable region (VH-2), d) a fourth polypeptide comprising a second variable region (VL-2), wherein:1) the VH-1 comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3;2) the VL-1 comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NOs: 6;3) the VH-2 comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 9; and4) the VL-2 comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12, and wherein the bispecific antibody is administered to the human individual at a dose of at least about 1 mg / kg.162MOFO-359878767Attorney Docket No. 21091-20003.

409. The method of any one of claims 1-8, wherein the bispecific antibody is parenterally administered to the human individual, optionally wherein the bispecific antibody is subcutaneously or intravenously administered to the human individual.

10. The method of any one of claims 1-9, wherein the bispecific antibody is administered to the human individual a) no more frequently than once every week, b) no more frequently than once every two weeks, c) every four weeks or monthly, d) no more frequently than once every two months, or e) once every three months.

11. The method of any one of claims 1-10, wherein the bispecific antibody is administered to the human individual no more frequently than once in a period of three months, optional wherein the bispecific antibody is administered to the human individual no more frequently than once in a period of six months.

12. The method of any one of claims 1-11, wherein the bispecific antibody is administered to the human individual a) at least three times, or b) more than three times.

13. The method of any one of claims 1-12, wherein the human individual is treated with the bispecific antibody a) for at least one month, b) for at least three months, c) for at least six months, or d) for at least a year, optionally wherein the human individual is treated with the bispecific antibody for at least fifteen months, eighteen months, twenty-one months, or twenty- four months.

14. The method of any one of claims 1-13, wherein the bispecific antibody is administered to the human individual at a dose of any of a) at least about 2 mg / kg, b) at least about 3 mg / kg, c) at least about 4 mg / kg, d) at least about 6 mg / kg, e) at least about 8 mg / kg, f) at least about 10 mg / kg, or g) at least about 12 mg / kg, optionally wherein the bispecific antibody is administered to the human individual at a dose of at least 3 mg / kg.

15. The method of any one of claims 1-14, wherein the bispecific antibody is administered to the human individual at a dose of any of a) about 1 mg / kg to about 15 mg / kg, b) 2 mg / kg to about 15 mg / kg, c) about 3 mg / kg to about 15 mg / kg, d) about 1 mg / kg to about 12 mg / kg, e) 2 mg / kg to about 12 mg / kg, f) about 3 mg / kg to about 12 mg / kg, g) about 4 mg / kg to about 12 mg / kg, h) about 8 mg / kg to about 12 mg / kg, optionally wherein the bispecific antibody is administered to the human individual at a dose of about 3 mg / kg to about 15 mg / kg.163MOFO-359878767Attorney Docket No. 21091-20003.4016. The method of any one of claims 1-15, wherein the bispecific antibody is administered to the human individual at a dose of less than about 10 mg / kg.

17. The method of any one of claims 1-13, wherein the bispecific antibody is administered to the human individual at a dose of any of a) at least about 70 mg, b) at least about 140 mg, c) at least about 210 mg, d) at least about 280 mg, e) at least about 420 mg, f) at least about 560 mg, g) at least about 700 mg, or h) at least about 840 mg, optionally wherein the bispecific antibody is administered to the human individual at a dose of at least about 210 mg..

18. The method of any one of claims 1-13 and 17, wherein the bispecific antibody is administered to the human individual at a dose of any of a) about 70 mg to about 1050 mg, b) about 140 mg to about 1050 mg, c) about 210 mg to about 1050 mg, d) about 70 mg to about 840 mg, e) about 140 mg to about 840 mg, f) about 210 mg to about 840 mg, g) about 280 mg to about 840 mg, or h) about 560 mg to about 840 mg, optionally wherein the bispecific antibody is administered to the human individual at a dose of about 210 mg to about 1050 mg..

19. The method of any one of claims 1-13 and 17-18, wherein the bispecific antibody is administered to the human individual at a dose of less than about 700 mg.

20. The method of any one of claims 1-13, wherein the bispecific antibody is administered to the human individual a) at a dose of about or at least about 70 mg about monthly or every four weeks, b) at a dose of about or at least about 140 mg about monthly or every four weeks, c) at a dose of about or at least about 210 mg about monthly or every four weeks, d) at a dose of about or at least about 280 mg about monthly or every four weeks, e) at a dose of about or at least about 560 mg about monthly or every four weeks, f) at a dose of about or at least about 840 mg about monthly or every four weeks, g) at a dose of about or at least about 70 mg about once every three months, h) at a dose of about or at least about 140 mg about once every three months.

21. The method of any one of claims 1-17, wherein the bispecific antibody is administered to the human individual!) at a dose of about or at least about 210 mg about once every three months, j) at a dose of about or at least about 280 mg about once every three months, k) at a dose of about or at least about 560 mg about once every three months, 1) at a dose of about or at least about 840 mg about once every three months, m) at a dose of about 70 mg to about 840 mg about monthly or every four weeks for at least about one month, and164MOFO-359878767Attorney Docket No. 21091-20003.40 subsequently at a dose of about 70 mg to about 840 mg about every three months, n) at a dose of about 70 mg to about 840 mg about monthly or every four weeks for at least about three months, and subsequently at a dose of about 70 mg to about 840 mg about every three months, o) at a dose of about 140 mg to about 840 mg about monthly or every four weeks for at least about one month, and subsequently at a dose of about 140 mg to about 840 mg about every three months, p) at a dose of about 140 mg to about 840 mg about monthly or every four weeks for at least about three months, and subsequently at a dose of about 140 mg to about 840 mg about every three months, q) at a dose of about 210 mg to about 840 mg about monthly or every four weeks for at least about one month, and subsequently at a dose of about 210 mg to about 840 mg about every three months, r) at a dose of about 210 mg to about 840 mg about monthly or every four weeks for at least about three months, and subsequently at a dose of about 210 mg to about 840 mg about every three months, s) at a dose of about 280 mg to about 840 mg about monthly or every four weeks for at least about one month, and subsequently at a dose of about 280 mg to about 840 mg about every three months, t) at a dose of about 280 mg to about 840 mg about monthly or every four weeks for at least about three months, and subsequently at a dose of about 280 mg to about 840 mg about every three months, u) at a dose of about 560 mg to about 840 mg about monthly or every four weeks for at least about one months, and subsequently at a dose of about 560 mg to about 840 mg about every three months, or v) at a dose of about 560 mg to about 840 mg about monthly or every four weeks for at least about three months, and subsequently at a dose of about 560 mg to about 840 mg about every three months.

22. The method of any one of claims 1-21, wherein the VH-1 comprises the amino acid sequence of SEQ ID NO: 13, or a variant comprising an amino acid sequence having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 13; and / or wherein VL-1 comprises the amino acid sequence of SEQ ID NO: 14, or a variant comprising an amino acid sequence having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 14.

23. The method of any one of claims 1-22, wherein the VH-2 comprises the amino acid sequence of SEQ ID NO: 15, or a variant comprising an amino acid sequence having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 15; and / or wherein VL-2 comprises the amino acid sequence of SEQ ID NO: 16, or a variant comprising165MOFO-359878767Attorney Docket No. 21091-20003.40 an amino acid sequence having at least about 80% sequence identity to the amino acid sequence of SEQ ID NO: 16.

24. The method of any one of claims 1-23, wherein the bispecific antibody is a full- length antibody comprising a Fc fragment comprising a first Fc domain and a second Fc domain.

25. The method of claim 24, wherein the Fc fragment comprises an IgG fragment.

26. The method of claim 25, wherein the IgG fragment is a IgG4 Fc Fragment, optionally wherein one of the first and the second Fc domains comprises a S228P mutation, and T366W mutation, and optionally a S354C mutation, and wherein the other Fc domain comprises a S228P mutation, T366S mutation, a L368A mutation, a Y407V mutation, and optionally a Y349C mutation, and optionally a H435R mutation, and optionally a Y436F mutation, wherein numbering is according to the EU index.

27. The method of any one of claims 1-26, wherein the third polypeptide comprises a CHI domain comprising a V173C mutation, and a C131S mutation; and the fourth polypeptide comprises a CL domain comprising a Q160C mutation and a C214S mutation, wherein numbering is according to the EU index.

28. The method of any one of claims 1-27, wherein the first polypeptide comprises the amino acid sequence of SEQ ID NO: 17, the second polypeptide comprises the amino acid sequence of SEQ ID NO: 18, the third polypeptide comprises the amino acid sequence of SEQ ID NO: 19, and the fourth polypeptide comprises the amino acid sequence of SEQ ID NO: 20.

29. The method of any one of claims 1-28, wherein the human individual is at risk for fracture.

30. The method of any one of claims 1-29, wherein the human individual is at least about 18, 30, 35, 40, 45, 50, 55, or 60 years old.

31. The method of any one of claims 1-30, wherein the human individual is a male.

32. The method of any one of claims 1-30, wherein the human individual is a female33. The method of claim 32, wherein the female is a postmenopausal woman.166MOFO-359878767Attorney Docket No. 21091-20003.4034. The method of any one of claims 1-33, wherein the human individual has a history of osteoporotic fracture.

35. The method of any one of claims 1-34, wherein the human individual has been subjected to, failed, or is intolerant to an osteoporosis therapy.

36. The method of claim 35, wherein the osteoporosis therapy is selected from the group consisting of romosozumab, denosumab, etidronate, pamidronate, risedronate, alendronate, zoledronate, ibandronate, teriparatide, and abaloparatide.

37. The method of any one of claims 1-36, wherein the human individual has a history of a cardiovascular disease, optionally the cardiovascular disease is a myocardial infarction or stroke.

38. The method of any one of claims 1-37, wherein the human individual has a hip or femoral neck or lumbar spine bone mineral density T-score measured by DXA a) that is between -1 and -2.5; b) that is -2.5 or lower than -2.5; or c) that is -2.5 or lower than -2.5 and at least one fragility fracture.

39. The method of any one of claims 1-38, wherein at about one month, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the human individual has a) an increase in serum N-Terminal Propeptide of Type 1 Procollagen (P1NP) level, optionally wherein the increase is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% , 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, or 200% as compared to the baseline; b) a decrease in serum C-terminal telopeptide of type 1 collagen (CTX-1) level, optionally wherein the decrease is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% as compared to the baseline; c) an increase in serum osteocalcin level, optionally wherein the increase is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% as compared to the baseline; d) an increase in serum bone-specific alkaline phosphatase (BSAP) level, optionally wherein the increase is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%,167MOFO-359878767Attorney Docket No. 21091-20003.4070%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, or 150% as compared to the baseline; and / or e) an increase in serum intact human parathyroid hormone 1-84 (iPTH) level, optionally wherein the increase is at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, or 150% as compared to the baseline.

40. The method of any one of claims 1-39, wherein at about one month, two months, three months, four months, five months, six months, nine months, a year, one and a half year, or two years after initiation of the bispecific antibody administration, the human individual has a) an increase in lumbar spine bone mineral density (BMD) by at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 10.5%, 11%, 11.5%, or 12%; b) an increase in total hip BMD by at least about 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, or 5.5%; and / or c) an increase in femoral neck BMD by at least about 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, or 5%.

41. The method of any one of claims 1-40, wherein the administration of the bispecific antibody reduces any one or more of a) the risk of vertebral fracture, b) the risk of lumbar spine fracture, c) the risk of non-vertebral fracture, d) the risk of hip fracture, and e) the risk of femoral neck fracture.

42. A unit dosage form of a bispecific antibody that specifically binds to both sclerostin and DKK-1 comprising a sealed vial containing a quantity of a bispecific antibody suitable for subcutaneous administration to a patient, wherein said quantity is sufficient to deliver a dose of about 70 mg to about 1050 mg, wherein the bispecific antibody comprises a) a first polypeptide comprising a first heavy chain variable region (VH-1), b) a second polypeptide comprising a first variable region (VL-1), c) a third polypeptide comprising a second heavy chain variable region (VH-2), d) a fourth polypeptide comprising a second variable region (VL-2), wherein:1) the VH-1 comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3;168MOFO-359878767Attorney Docket No. 21091-20003.402) the VL-1 comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 6;3) the VH-2 comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 9; and4) the VL-2 comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12.

43. An injection device comprising a quantity of a bispecific antibody suitable for subcutaneous administration, wherein said quantity is sufficient to deliver a dose of about 70 mg to about 1050 mg, wherein the bispecific antibody comprises a) a first polypeptide comprising a first heavy chain variable region (VH-1), b) a second polypeptide comprising a first variable region (VL-1), c) a third polypeptide comprising a second heavy chain variable region (VH-2), d) a fourth polypeptide comprising a second variable region (VL-2), wherein:1) the VH-1 comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3;2) the VL-1 comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 6;3) the VH-2 comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 9; and4) the VL-2 comprises a LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12.169MOFO-359878767

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