A method for preventing or treating osteoporosis, characterized by administering teriparatide or its salt twice a week.

Abstract

To provide a method for treating and / or preventing osteoporosis using teriparatide or its salts that is highly safe and / or effective. [Solution] A method for treating and / or preventing osteoporosis, comprising administering 28.2 μg of teriparatide or its salt as an active ingredient, twice a week.

Description

Technical Field

[0001] The present invention relates to a method for preventing or treating osteoporosis, characterized by administering teriparatide or a salt thereof twice a week.

Background Art

[0002] Osteoporosis is defined as "a skeletal disease characterized by a decrease in bone strength and an increased risk of fractures" (Non-Patent Document 1), and this definition is generally used.

[0003] The main purposes of the prevention and treatment of osteoporosis are said to be to prevent or suppress fractures and maintain life functions and QOL (Quality of life). Since the pain caused by fractures, the decline in physical support functions, and the subsequent life function disorders caused by motor function disorders are serious problems, the clinical significance of the prevention and treatment of osteoporosis, especially with a high risk of fractures, can be said to be high.

[0004] Under such circumstances, as drugs effective for osteoporosis with a high risk of fractures, preparations for daily administration and preparations for once-a-week administration containing teriparatide or a salt thereof as an active ingredient have been developed, and after obtaining sales approval, they are actually used in clinical practice (Non-Patent Documents 4 and 8).

[0005] However, preparations for daily administration and preparations for once-a-week administration containing teriparatide or a salt thereof as an active ingredient are not necessarily sufficiently excellent in terms of safety.

[0006] PTH is known to have a vasorelaxant effect on vascular smooth muscle (Non-Patent Document 21). In a clinical trial using a preparation for daily administration, it has been reported that dizziness is significantly higher compared to the placebo group (Non-Patent Document 9). It is also known that shock, loss of consciousness accompanied by a transient rapid decrease in blood pressure, convulsions, and falls may occur from immediately after administration to several hours after administration of preparations for daily administration and preparations for once-a-week administration (Non-Patent Documents 4 and 8).

[0007] Alternatively, it has been reported that teriparatide acetate administration is associated with a higher incidence of nausea, vomiting, and headache (Non-Patent Literature 9). For example, in a clinical trial in which a once-weekly formulation was administered, the frequency of nausea was significantly higher compared to the placebo group, exceeding 20% ​​of the total in the once-weekly formulation group, and the rate of discontinuation due to adverse events was also high at approximately 20% (Non-Patent Literature 5).

[0008] Furthermore, in clinical trials where the daily-administered formulation was provided, the incidence of moderate hypercalcemia (exceeding 10.6 mg / dl) was reported to be 11% (compared to 2% in the placebo group) (Non-Patent Literature 7).

[0009] In addition, fever has been observed as an adverse event in studies using formulations administered once a week and formulations administered daily (Non-Patent Literature 6, 21).

[0010] Generally, it has been reported that 52.1% of patients drop out of medication within 5 years of starting treatment for osteoporosis. Furthermore, poor adherence to medication is seen as a problem, leading to reduced fracture prevention, increased need for facility use, and stagnation in healthcare cost reduction (Non-Patent Literature 9). Factors associated with poor medication adherence include the presence of pain, side effects, and medication for gastrointestinal disorders (Non-Patent Literature 9).

[0011] On the other hand, preparations containing teriparatide or its salt as the active ingredient have been criticized for their low treatment continuation rate, with a reported 12-month treatment continuation rate of 34.9% (Non-Patent Literature 22). Regarding safety, concerns about decreased medication adherence due to side effects are known, and in a study where a once-weekly formulation was administered, the incidence of adverse events leading to discontinuation of the investigational drug (other than serious events) was reported to be high at 14.1% in the group using this drug (Non-Patent Literature 23).

[0012] Thus, while daily and once-weekly formulations containing teriparatide or its salts as the active ingredient present many safety challenges, they do not necessarily offer sufficient benefits in terms of efficacy.

[0013] For example, in a 72-week clinical trial in which a once-weekly formulation was administered to osteoporosis patients at high risk of fracture, it was reported that lumbar spine bone mineral density increased by approximately 4.9-6.0% at 48 weeks after the start of administration (Patent Document 1 (Table 26), Non-Patent Document 5 (FIG. 3)). In addition, in a 24-month clinical trial in which a once-weekly formulation was administered to osteoporosis patients at high risk of fracture, it was reported that lumbar spine bone mineral density increased by approximately 6.9% at 48 weeks after the start of administration (Non-Patent Document 6).

[0014] Regarding the efficacy of both drugs, not only are their effects on increasing bone density known, but their effects on preventing fractures are also recognized. For example, in a clinical trial in which a daily administration formulation was provided, it was reported that the risk of vertebral fractures was reduced by 65% ​​(Non-Patent Literature 7).

[0015] Furthermore, it has been reported in recent animal studies and clinical trials that daily administration of teriparatide shows a strong bone formation-promoting effect in areas with a high concentration of cancellous bone, such as the vertebral bodies, while increasing voids within cortical bone, such as in limb bones. It has also been suggested that the effects on cortical bone may differ depending on the frequency of intermittent administration of PTH (Non-Patent Literature 14). In addition, it has been reported that CTX, one of the bone resorption markers, tends to increase in a dose-dependent manner 24 weeks after the start of daily administration of teriparatide compared to the start of administration.

[0016] Studies using ovariectomized rats, a commonly used model of osteoporosis, have reported that bone mineral density and bone strength increase in proportion to the weekly dose of teriparatide (Non-Patent Literature 14). [Prior art documents] [Patent Documents]

[0017] [Patent Document 1] International Publication No. 2011 / 030774 [Patent Document 2] Japanese Patent Application Publication No. 8-73376

Patent Document 3

Non-Patent Documents

[0018]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Non-Patent Document 10

Non-Patent Document 11

Non-Patent Document 12

Non-Patent Document 13

[0019] The object of the present invention is to provide a method for treating and / or preventing osteoporosis using teriparatide or a salt thereof that is excellent in safety and / or efficacy, and an agent for treating and / or preventing osteoporosis containing teriparatide or a salt thereof as an active ingredient. [Means for solving the problem]

[0020] One embodiment of the present invention as an agent for the treatment and / or prevention of osteoporosis, and a method for the treatment and / or prevention of osteoporosis, is characterized in that teriparatide or a salt thereof is used as an active ingredient, and 28.2 μg of teriparatide or a salt thereof is administered twice a week.

[0021] These osteoporosis treatments and / or preventive agents, as well as osteoporosis treatment methods and / or preventive methods, demonstrate excellent safety and / or efficacy.

[0022] In other words, the present invention relates to the following inventions, etc. [1] A therapeutic and / or prophylactic agent for osteoporosis containing teriparatide or a salt thereof as an active ingredient, characterized by administering 28.2 μg of teriparatide or a salt thereof twice a week. [2] The osteoporosis treatment and / or prophylactic agent described in [1] above, wherein the two weekly administration intervals (excluding the administration day) are 2 days and 3 days apart. [3] The osteoporosis treatment and / or prophylactic agent described in [1] above, wherein n is the number of weeks during which the agent is administered twice a week, and m is the number of weeks in which the interval between the two administrations within that week is 2 days and 3 days (excluding the administration day), and (m / n) × 100 (%) is 70% or more. [4] A therapeutic and / or prophylactic agent for osteoporosis according to any of [1] to [3] above, which is administered subcutaneously. [5] An osteoporosis treatment and / or prophylactic agent according to any of [1] to [4] above, administered to a person whose lumbar spine bone density is less than 60% of the average value for a young adult. [6] An osteoporosis treatment and / or prophylactic agent according to any of [1] to [4] above, administered to a person with one existing vertebral fracture. [7] An osteoporosis treatment and / or prophylactic agent according to any of [1] to [4] above, administered to persons with a serum osteocalcin concentration of less than 15.2 (ng / mL). [8] An osteoporosis treatment and / or prophylactic agent according to any of [1] to [4] above, administered to persons aged 80 years or older. [9] An osteoporosis treatment and / or prophylactic agent according to any of [1] to [4] above, administered to men.

[10] An osteoporosis treatment and / or prophylactic agent according to any of [1] to [4] above, administered to patients with osteoporosis at high risk of fracture.

[11] An osteoporosis treatment and / or prophylactic agent according to any of [1] to [4] above, administered to patients with osteoporosis who have all fracture risk factors, including aging, pre-existing fractures, and low bone density.

[12] An osteoporosis treatment and / or prophylactic agent described in any of [1] to [4] above, administered to patients with osteoporosis who satisfy the following conditions (1) to (3): (1) The person must be 65 years of age or older; (2) There are one to five existing vertebral fractures; (3) The bone density of the lumbar spine is less than 80% of the average value for young adults. [Effects of the Invention]

[0023] The present invention provides an agent for the treatment and / or prevention of osteoporosis, as well as a method for the treatment and / or prevention of osteoporosis, which contains teriparatide or a salt thereof as an active ingredient and is excellent in safety and / or efficacy. [Brief explanation of the drawing]

[0024] [Figure 1] Figure 1 shows an example of an administration plan when the osteoporosis treatment agent of the present invention is administered twice a week for two weeks, with the administration intervals being 1 and 6 days apart (0 and 5 days apart if the administration day is not included), 2 and 5 days apart (1 and 4 days apart if the administration day is not included), or 3 and 4 days apart (2 and 3 days apart if the administration day is not included). [Figure 2] Figure 2 shows an example of an administration plan when the osteoporosis treatment agent of the present invention is administered twice a week for two weeks, with intervals of 3 and 4 days between administrations (2 and 3 days if the administration day is not included). [Figure 3] Figure 3 schematically shows the treatment plan in an embodiment of the present invention. Figures 4 to 28 show the test results of the embodiment, and the details of each figure are explained below. [Figure 4] Figure 4 shows the change in the average percentage change in lumbar spine bone mineral density (2nd to 4th lumbar vertebrae) when the osteoporosis treatment agent of the present invention was administered to osteoporosis patients over 48 weeks. The horizontal axis represents the number of weeks of administration, and the vertical axis represents the average percentage change from the start. "BL" indicates Baseline. "Final" means "at the end of treatment," showing the percentage change in lumbar spine bone mineral density (2nd to 4th lumbar vertebrae) at the end of treatment for each patient, including the percentage change in lumbar spine bone mineral density (2nd to 4th lumbar vertebrae) for patients who discontinued treatment midway through the 48 weeks. The numbers shown in the two rows at the bottom represent the number of patients treated in each week. "**" indicates p<0.01. [Figure 5]Figure 5 shows the change in the median percentage change in serum CTX when the osteoporosis treatment agent of the present invention was administered to osteoporosis patients over 48 weeks. The horizontal axis represents the number of weeks of administration, and the vertical axis represents the median percentage change from the start. "BL" indicates Baseline. The numbers shown in the bottom two rows represent the number of patients who underwent testing in each week. [Figure 6] Figure 6 shows the change in the median percentage change in serum NTX when the osteoporosis treatment agent of the present invention was administered to osteoporosis patients over 48 weeks. The horizontal axis represents the number of weeks of administration, and the vertical axis represents the median percentage change from the start. "BL" indicates Baseline. The numbers shown in the two rows at the bottom represent the number of patients who underwent testing in each week. [Figure 7] Figure 7 shows the change in the median percentage change in urinary NTX when the osteoporosis treatment agent of the present invention was administered to osteoporosis patients over 48 weeks. The horizontal axis represents the number of weeks of administration, and the vertical axis represents the median percentage change from the start. "BL" indicates Baseline. The numbers shown in the bottom two rows represent the number of patients who underwent testing in each week. [Figure 8] Figure 8 shows the change in the median percentage change in serum OC (osteocalcin) when the osteoporosis treatment agent of the present invention was administered to osteoporosis patients for 48 weeks. The horizontal axis represents the number of weeks of administration, and the vertical axis represents the median percentage change from the start. "BL" indicates Baseline. The numbers shown in the bottom two rows represent the number of patients who underwent testing in each week. "*" indicates Wilcoxon rank sum test p<0.05, and "**" indicates Wilcoxon rank sum test p<0.01. [Figure 9]Figure 9 shows the change in the median percentage change in serum P1NP when the osteoporosis treatment agent of the present invention was administered to osteoporosis patients over 48 weeks. The horizontal axis represents the number of weeks of administration, and the vertical axis represents the median percentage change from the start. "BL" indicates Baseline. The numbers shown in the bottom two rows represent the number of patients who underwent testing in each week. "*" indicates Wilcoxon rank sum test p<0.05, and "**" indicates Wilcoxon rank sum test p<0.01. [Figure 10] Figure 10 shows the change in the average percentage change in lumbar spine bone mineral density (2nd to 4th lumbar vertebrae) after administering the osteoporosis treatment agent of the present invention to osteoporosis patients over 48 weeks, classified by administration interval adherence rate of 70% or more and less than 70%. The horizontal axis represents the number of weeks of administration, and the vertical axis represents the average percentage change from the start. The numbers shown in the two rows at the bottom represent the number of patients included in the analysis for each week. [Figure 11] Figure 11 shows the change in the average percentage change in lumbar spine bone mineral density (2nd to 4th lumbar vertebrae) after administering the osteoporosis treatment agent of the present invention to osteoporosis patients over 48 weeks, classified by administration interval adherence rate of 75% or more and less than 75%. The horizontal axis represents the number of weeks of administration, and the vertical axis represents the average percentage change from the start. The numbers shown in the bottom two rows represent the number of patients included in the analysis for each week. [Figure 12] Figure 12 shows the change in the average percentage change in lumbar spine bone mineral density (2nd to 4th lumbar vertebrae) after administering the osteoporosis treatment agent of the present invention to osteoporosis patients over 48 weeks, classified by administration interval adherence rate of 80% or more and less than 80%. The horizontal axis represents the number of weeks of administration, and the vertical axis represents the average percentage change from the start. The numbers shown in the bottom two rows represent the number of patients included in the analysis for each week. [Figure 13]Figure 13 shows the change in the average percentage change in lumbar spine bone mineral density (2nd to 4th lumbar vertebrae) after administering the osteoporosis treatment agent of the present invention to osteoporosis patients over 48 weeks, classified by administration interval adherence rate of 85% or more and less than 85%. The horizontal axis represents the number of weeks of administration, and the vertical axis represents the average percentage change from the start. The numbers shown in the bottom two rows represent the number of patients included in the analysis for each week. [Figure 14] Figure 14 shows the change in the average percentage change in lumbar spine bone mineral density (2nd to 4th lumbar vertebrae) after administering the osteoporosis treatment agent of the present invention to osteoporosis patients over 48 weeks, classified by administration interval adherence rate of 90% or more and less than 90%. The horizontal axis represents the number of weeks of administration, and the vertical axis represents the average percentage change from the start. The numbers shown in the bottom two rows represent the number of patients included in the analysis for each week. [Figure 15] Figure 15 shows the changes in the average percentage change in femoral neck bone mineral density (%) when the osteoporosis treatment agent of the present invention was administered to osteoporosis patients over 48 weeks, classified into those with an adherence rate to the administration interval of 70% or more and those with an adherence rate of less than 70%. The horizontal axis represents the number of weeks of administration, and the vertical axis represents the average percentage change (%) from the start. The numbers shown in the two rows at the bottom represent the number of patients included in the analysis for each week. [Figure 16] Figure 16 shows the changes in the average percentage change in femoral neck bone mineral density (%) when the osteoporosis treatment agent of the present invention was administered to osteoporosis patients over 48 weeks, classified into those with an adherence rate to the administration interval of 75% or more and those with an adherence rate of less than 75%. The horizontal axis represents the number of weeks of administration, and the vertical axis represents the average percentage change (%) from the start. The numbers shown in the two rows at the bottom represent the number of patients included in the analysis for each week. [Figure 17] Figure 17 shows the changes in the average percentage change in femoral neck bone mineral density (%) when the osteoporosis treatment agent of the present invention was administered to osteoporosis patients over 48 weeks, classified into those with an administration interval adherence rate of 80% or more and those with an adherence rate of less than 80%. The horizontal axis represents the number of weeks of administration, and the vertical axis represents the average percentage change (%) from the start. The numbers shown in the two rows at the bottom represent the number of patients included in the analysis for each week. [Figure 18]Figure 18 shows the changes in the average percentage change in femoral neck bone mineral density (%) when the osteoporosis treatment agent of the present invention was administered to osteoporosis patients over 48 weeks, classified by administration interval adherence rate of 85% or more and less than 85%. The horizontal axis represents the number of weeks of administration, and the vertical axis represents the average percentage change (%) from the start. The numbers shown in the bottom two rows represent the number of patients included in the analysis for each week. [Figure 19] Figure 19 shows the changes in the average percentage change in femoral neck bone mineral density (%) when the osteoporosis treatment agent of the present invention was administered to osteoporosis patients over 48 weeks, classified by administration interval adherence rate of 90% or more and less than 90%. The horizontal axis represents the number of weeks of administration, and the vertical axis represents the average percentage change (%) from the start. The numbers shown in the two rows at the bottom represent the number of patients included in the analysis for each week. [Figure 20] Figure 20 shows the change in the average percentage change in total bone mineral density of the proximal femur over 48 weeks when the osteoporosis treatment agent of the present invention was administered to osteoporosis patients, classified into those with an adherence rate to the administration interval of 70% or more and those with an adherence rate of less than 70%. The horizontal axis represents the number of weeks of administration, and the vertical axis represents the average percentage change from the start. The numbers shown in the two rows at the bottom represent the number of patients included in the analysis for each week. [Figure 21] Figure 21 shows the change in the average percentage change in total bone mineral density of the proximal femur after administering the osteoporosis treatment agent of the present invention to osteoporosis patients over 48 weeks, classified by administration interval adherence rate of 75% or more and less than 75%. The horizontal axis represents the number of weeks of administration, and the vertical axis represents the average percentage change from the start. The numbers shown in the bottom two rows represent the number of patients included in the analysis for each week. [Figure 22] Figure 22 shows the change in the average percentage change in total bone mineral density of the proximal femur after administering the osteoporosis treatment agent of the present invention to osteoporosis patients over 48 weeks, classified by administration interval adherence rate of 80% or more and less than 80%. The horizontal axis represents the number of weeks of administration, and the vertical axis represents the average percentage change from the start. The numbers shown in the bottom two rows represent the number of patients included in the analysis for each week. [Figure 23]Figure 23 shows the change in the average percentage change in total bone mineral density of the proximal femur after administering the osteoporosis treatment agent of the present invention to osteoporosis patients over 48 weeks, classified by administration interval adherence rate of 85% or more and less than 85%. The horizontal axis represents the number of weeks of administration, and the vertical axis represents the average percentage change from the start. The numbers shown in the two rows at the bottom represent the number of patients included in the analysis for each week. [Figure 24] Figure 24 shows the change in the average percentage change in total bone mineral density of the proximal femur after administering the osteoporosis treatment agent of the present invention to osteoporosis patients over 48 weeks, classified by administration interval adherence rate of 90% or more and less than 90%. The horizontal axis represents the number of weeks of administration, and the vertical axis represents the average percentage change from the start. The numbers shown in the bottom two rows represent the number of patients included in the analysis for each week. [Figure 25] Figure 25 shows the average percentage change in lumbar spine bone mineral density (2nd to 4th lumbar vertebrae) 48 weeks after the start of administration, observed in osteoporosis patients who demonstrated adherence to specific values ​​(70%, 75%, 80%, 85%, 90%) or higher for each 2-3 day administration interval, when administered the osteoporosis treatment agent of the present invention. [Figure 26] Figure 26 shows the percentage of clinical fractures (%) when the osteoporosis treatment agent of the present invention was administered to osteoporosis patients who demonstrated adherence to each 2-3 day administration interval at or above specific values ​​(70%, 75%, 80%, 85%, 90%). [Figure 27] Figure 27 shows the median percentage change in oral contraceptives (OCs) after 4 weeks of administration to osteoporosis patients who demonstrated adherence to specific values ​​(70%, 75%, 80%, 85%, 90%) or higher for each 2-3 day administration interval. [Figure 28] Figure 28 shows the percentage of nausea (adverse reaction) observed when the osteoporosis treatment agent of the present invention was administered to osteoporosis patients who demonstrated adherence to specific dose intervals of 2-3 days (70%, 75%, 80%, 85%, 90%) or higher. [Figure 29] Figure 29 shows the basic administration schedules for the investigational drug group and the control group. [Modes for carrying out the invention]

[0025] The present invention will be described in detail below with reference to specific embodiments. However, the present invention is not limited to the following embodiments and can be implemented in any form without departing from the spirit of the invention.

[0026] (1) Teriparatide or its salt (hereinafter sometimes referred to as the active ingredient): In the present invention, human PTH(1-34) is a peptide represented by a partial amino acid sequence consisting of the first to 34 amino acid residues viewed from the N-terminus of the amino acid sequence of human parathyroid hormone, human PTH(1-84).

[0027] In this invention, teriparatide refers to the free form of human PTH(1-34). Teriparatide may also be in the form of a salt.

[0028] In the present invention, examples of teriparatide salts include any salt formed by teriparatide and one or more volatile organic acids. Examples of volatile organic acids include trifluoroacetic acid, formic acid, and acetic acid. The ratio of free teriparatide to a volatile organic acid when forming a salt is not particularly limited as long as it forms a salt. Among these, acetic acid is preferred as the volatile organic acid. That is, teriparatide acetate is a preferred example of a teriparatide salt in the present invention.

[0029] Teriparatide or its salts can be produced by methods known to the public (e.g., Patent Documents 1-3).

[0030] (2) Dosage: The single dose of the active ingredient contained in the osteoporosis treatment and / or preventive agent of the present invention, and used in the osteoporosis treatment and / or preventive method of the present invention, is not particularly limited, but preferably the following are examples.

[0031] In other words, the single dose of the active ingredient is more preferably 20 μg or more, 25 μg or more, 27 μg or more, or 28 μg or more. Furthermore, the single dose of the active ingredient contained in the osteoporosis treatment and / or preventive agent of the present invention is preferably 40 μg or less, more preferably 35 μg or less, or more preferably 30 μg or less.

[0032] In particular, the single dose of the active ingredient is preferably 28.2 μg or 29.2 μg as teriparatide. When teriparatide is used in the form of an acetate, the dose can be exemplified by taking into account the amount of acetate. For example, when teriparatide pentaacetate is used, the single dose of the active ingredient is preferably 30.3 μg or 31.3 μg as teriparatide acetate. Therefore, in the present invention, the term "28.2 μg of teriparatide or its salt per dose" means that the single dose of teriparatide salt is the amount that is 28.2 μg as teriparatide, and in the case of teriparatide acetate, it is 30.3 μg.

[0033] (3) Dosage frequency and interval: One of the features of the osteoporosis treatment and / or preventive agent and the osteoporosis treatment and / or preventive method of the present invention is that they are administered at a frequency of twice a week.

[0034] When administering the osteoporosis treatment agent of the present invention at a frequency of twice a week, the interval between administrations within the week can be 1) 1 and 6 days apart (0 and 5 days apart if the administration day is not included), 2) 2 and 5 days apart (1 and 4 days apart if the administration day is not included), or 3) 3 and 4 days apart (2 and 3 days apart if the administration day is not included) (Figure 1).

[0035] While there are no particular limitations on the interval between administrations within a week, the most preferred configuration is an interval of 3 and 4 days (or 2 and 3 days if the administration day is not included).

[0036] To illustrate the configuration where the weekly administration intervals are 3 and 4 days apart (2 and 3 days apart if the administration day is not included), using an example of an administration schedule over two weeks from the first administration, administering the drug on the 4th or 5th day from the first administration day allows for two doses per week during the week of the first administration (week 1). Subsequently, administering the drug on the 8th day and then on the 11th or 12th day allows for two doses per week during week 2 (Figure 2).

[0037] There are no particular restrictions on the time of administration; it may be during the day or at night. If administered during the day, it may be administered in the morning or in the afternoon. However, if other therapeutic drugs or basic medications (such as calcium or vitamin D) are used in combination, it is preferable that the administration times do not overlap.

[0038] If n is the number of weeks during which the osteoporosis treatment agent of the present invention is administered twice a week, and m is the number of weeks during which the interval between the two administrations within a week is 3 and 4 days (2 and 3 days if the administration day is not included), then (m / n) × 100 (%) can be above a certain level, and examples of lower limits for this percentage include 50%, 60%, 70%, 75%, 80%, 85%, 90%, and 95%, with the lower limit of this percentage preferably being 80% or higher, and more preferably 90% or higher.

[0039] For example, if the osteoporosis treatment agent of the present invention is administered twice a week for a period of 34 days, and the number of weeks in which the interval between the two administrations within a week is 3 and 4 days (2 and 3 days if the administration day is not included) is 2, then the above (m / n) × 100 is calculated as 2 ÷ (34 ÷ 7) × 100, which is approximately 41.2 (%).

[0040] (4) Route of administration and site of administration: The administration route of the osteoporosis treatment and / or preventive agent and the osteoporosis treatment and / or preventive method of the present invention is not particularly limited and may be administered intravenously, subcutaneously, or intramuscularly. Among these, subcutaneous administration is a preferred example.

[0041] The administration site of the osteoporosis treatment and / or preventive agent and the osteoporosis treatment and / or preventive method of the present invention is not particularly limited and can be administered to the upper arm, thigh, or abdomen, for example. However, for subsequent administrations, it is preferable to administer to a site at least 3 cm away from the previous administration site. Furthermore, administration can be facilitated by pinching the area around the administration site with your fingers immediately before administration, causing the area around the administration site to rise above the skin surface.

[0042] (5) Duration of administration: The duration of administration of the osteoporosis treatment and / or preventive agent and the osteoporosis treatment and / or preventive method of the present invention is not particularly limited and may be appropriately determined by the attending physician's prescription or other factors according to the patient.

[0043] The lower limit of the administration period is not particularly limited, and preferred examples of administration periods include, for example, 4 weeks or more, 8 weeks or more, 12 weeks or more, 24 weeks or more, 48 weeks or more, or 1 year or more. Similarly, the upper limit of the administration period is not limited, and preferred examples of upper limits of the administration period include, for example, within 5 years, within 4 years, within 3 years, or within 2 years.

[0044] (6) Diseases and patients: (6-1) Diseases: The osteoporosis treatment and / or preventive agent and the osteoporosis treatment and / or preventive method of the present invention are characterized in that they are administered for the purpose of treating and / or preventing osteoporosis.

[0045] In the present invention, osteoporosis refers to "a skeletal disease characterized by decreased bone strength and an increased risk of fracture" (Non-Patent Literature 1; definition at the 2000 NIH consensus meeting), and includes both primary osteoporosis and secondary osteoporosis.

[0046] Examples of primary osteoporosis include degenerative osteoporosis (postmenopausal osteoporosis and senile osteoporosis) and idiopathic osteoporosis (post-pregnancy osteoporosis, juvenile osteoporosis, etc.). Secondary osteoporosis is osteoporosis induced by specific diseases or medications, and causes include certain drugs, rheumatoid arthritis, diabetes, hyperthyroidism, sexual dysfunction, immobility, nutritional deficiencies, and other congenital diseases. Steroids are an example of a specific drug. Diagnostic criteria for primary osteoporosis are well known (Non-patent Literature 10).

[0047] The osteoporosis described in the present invention preferably includes osteoporosis with a high risk of fracture. Osteoporosis with a high risk of fracture may include patients with risk factors such as low bone density, pre-existing fractures, aging, and a family history of femoral neck fractures. (Non-Patent Literature 9)

[0048] As mentioned above, daily and once-weekly formulations containing teriparatide or its salt as the active ingredient have been developed for the treatment of osteoporosis with a high risk of fracture, and have received marketing approval and are actually being used in clinical practice. Furthermore, development of human anti-sclerostin antibodies is also progressing as a treatment for osteoporosis with a high risk of fracture. Given these circumstances, those skilled in the art can easily and clearly recognize osteoporosis with a high risk of fracture.

[0049] FRAX (registered trademark) from the WHO (World Health Organization) is a well-known tool for assessing an individual's absolute risk of fracture, and it can calculate the probability (%) of an individual developing a fracture in the next 10 years. In routine clinical practice, it can be used as a screening tool to identify individuals at high risk of fracture in asymptomatic elderly patients visiting medical institutions.

[0050] (6-2)Patient: The osteoporosis patient according to the present invention may be an osteoporosis patient who has at least one of the aforementioned fracture risk factors. A preferred example of such a patient is an osteoporosis patient who has three fracture risk factors: aging, pre-existing fractures, and low bone density.

[0051] Furthermore, the osteoporosis patient according to the present invention may also be an osteoporosis patient in which at least one of the aforementioned fracture risk factors satisfies specific conditions (e.g., below a specific threshold, above a specific threshold, within a specific numerical range, presence or absence, etc.).

[0052] In particular, the osteoporosis patient according to the present invention is preferably an osteoporosis patient with a high risk of fracture. Examples of such osteoporosis patients with a high risk of fracture include those who satisfy the following three conditions. 1) The person is 65 years of age or older. 2) There is one or more existing fractures. 3) The lumbar spine bone density is less than 80% of the Young Adult Mean (YAM) value.

[0053] Here, existing fractures can preferably be existing vertebral fractures, and the number of existing fractures can be between one and five. Furthermore, existing vertebral fractures can be existing vertebral fractures with mild deformity (grade 1), moderate deformity (grade 2), or severe deformity (grade 3) (Non-Patent Literature 9).

[0054] Examples of Grade 1 fractures include mild fractures where the vertebral body height is reduced by 20-25%, Grade 2 fractures include moderate fractures where the vertebral body height is reduced by 25-40%, and Grade 3 fractures include severe fractures where the vertebral body height is reduced by 40% or more.

[0055] The osteoporosis patient according to the present invention may be an osteoporosis patient who does not satisfy at least one of the following six conditions. 1) Patients considered to be at high risk of developing osteosarcoma. 2) Patients with hypercalcemia. 3) Patients with primary malignant bone tumors or metastatic bone tumors. 4) Patients with metabolic bone diseases other than osteoporosis. 5) Patients with a history of hypersensitivity to the active ingredient of the osteoporosis treatment and / or preventive agent of the present invention or to other teriparatide preparations. 6) Pregnant women or women who may be pregnant.

[0056] Patients considered to be at high risk of developing osteosarcoma include, for example, patients with Paget's disease of bone, patients with elevated alkaline phosphatase levels, children and young adults whose epiphyseal plates have not yet closed, and patients who have previously received radiation therapy that may have affected the bone.

[0057] Furthermore, the osteoporosis patient according to the present invention may be an osteoporosis patient who does not satisfy at least one of the following five conditions. 1) Patients with low blood pressure. 2) Patients with renal impairment. 3) Patients with severe heart disease. 4) Patients with severe liver dysfunction. 5) Patients with urinary tract stones or a history thereof.

[0058] Alternatively, the osteoporosis patient according to the present invention may be an osteoporosis patient with mild or moderate renal impairment. Renal function can be distinguished as normal, impaired, and the degree of impairment based on creatinine clearance. Specifically, a creatinine clearance of 80 mL / min or more can be determined as normal renal function, 50 mL / min or more but less than 80 mL / min as mild renal impairment, and 30 mL / min or more but less than 50 mL / min as moderate renal impairment. An example of a method for calculating creatinine clearance is the Cockcroft-Gault formula (male: (140 - age) × weight / (72 × serum creatinine value), female: 0.85 × (140 - age) × weight / (72 × serum creatinine value)).

[0059] Furthermore, the osteoporosis patient according to the present invention may also be an osteoporosis patient in which at least one of the following 18 factors possessed by the patient satisfies specific conditions (e.g., below a specific threshold, above a specific threshold, within a specific numerical range, of a type, presence or absence, etc.). 1) Gender. 2) Age. 3) Height. 4) Weight. 5) BMI. 6) Number of years since menopause (limited to female patients who have gone through menopause). 7) History of non-vertebral fracture injury after age 50 (limited to patients aged 50 and over). 8) A history of non-vertebral fractures without significant external force after the age of 50 (limited to patients aged 50 and over). 9) A medical history that affects bone metabolism. 10) Smoking. 11) Alcohol consumption. 12) Parents have a history of femoral fractures. 13) Pre-treatment drug for osteoporosis. 14) 25-Hydroxyvitamin D. 15) Number of existing vertebral fractures. 16) Lumbar spine bone mineral density (YAM equivalent) (%). 17) Femoral neck bone mineral density (YAM equivalent) (%). 18) Total bone mineral density of the proximal femur (YAM equivalent) (%).

[0060] For example, the osteoporosis patients according to the present invention may be defined as male or female patients, patients aged 65 or older but under 75, patients aged 75 or older but under 80, patients aged 80 or older, patients with a lumbar spine bone mineral density (YAM equivalent) (%) of less than 60%, 60% or more but under 70%, or 70% or more but under 80%, patients with zero existing vertebral fractures, patients with one existing vertebral fracture, patients with two to three existing vertebral fractures, patients with four to five existing vertebral fractures, patients with six or more existing vertebral fractures, and so on.

[0061] The osteoporosis patient according to the present invention may also be an osteoporosis patient in which at least one of the following 26 clinical test items satisfies specific conditions (e.g., below a specific threshold, above a specific threshold, within a specific numerical range, etc.). 1) Complete blood count (6 items in total) (red blood cell count, hemoglobin, hematocrit, white blood cell count, white blood cell differential, platelet count). 2) Blood biochemistry test items (14 items in total) (AST (GOT), ALT (GPT), alkaline phosphatase, total cholesterol, urea nitrogen, uric acid, creatinine, CPK, calcium, inorganic phosphorus, sodium, potassium, chloride, albumin). 3) Urine test items (6 items in total) (occult blood, protein, sugar, urobilinogen, bilirubin, pH).

[0062] Here, AST (GOT) refers to aspartate aminotransferase (glutamic oxaloacetic transaminase), and ALT (GPT) refers to alanine aminotransferase (glutamic pyruvic transaminase). Here, CPK refers to creatine phosphokinase.

[0063] Furthermore, the osteoporosis patient according to the present invention may also be an osteoporosis patient in which at least one of the vital signs (sitting systolic blood pressure, sitting diastolic blood pressure, pulse rate, etc.) satisfies specific conditions (e.g., below a specific threshold, above a specific threshold, within a specific numerical range, etc.).

[0064] Alternatively, the osteoporosis patient according to the present invention may be an osteoporosis patient who can produce anti-drug antibodies (e.g., antibodies against teriparatide or its salts) or neutralizing antibodies (e.g., antibodies that can reduce or eliminate the activity of teriparatide or its salts) in conjunction with taking the osteoporosis treatment and / or preventive agent of the present invention.

[0065] Furthermore, the osteoporosis patient according to the present invention may also be an osteoporosis patient in which at least one of the following 12 markers satisfies specific conditions (e.g., below a specific threshold, above a specific threshold, within a specific numerical range, etc.). 1) Blood markers (osteocalcin, P1NP, NTX, CTX, calcium, inorganic phosphorus, albumin, 25-hydroxyvitamin D fraction). 2) Urinary markers (NTX, calcium, inorganic phosphorus, creatinine).

[0066] Here, P1NP refers to type I procollagen N-propeptide, NTX refers to crosslinked N-telopeptide of type I collagen, and CTX refers to type I collagen crosslinked C-telopeptide.

[0067] Patients with osteoporosis according to the present invention include those with a blood osteocalcin concentration of less than 15.2 ng / mL, those with a blood osteocalcin concentration of 15.2 ng / mL or more and less than 21.8 ng / mL, and those with a blood osteocalcin concentration of 21.8 ng / mL or more.

[0068] Alternatively, examples of osteoporosis patients according to the present invention include patients with a blood osteocalcin concentration of less than 14.8 ng / mL, patients with a blood osteocalcin concentration of 14.8 ng / mL or more and less than 21.9 ng / mL, and patients with a blood osteocalcin concentration of 21.9 ng / mL or more.

[0069] Furthermore, examples of osteoporosis patients according to the present invention include patients with a blood P1NP concentration of less than 38.0 μg / L, patients with a blood P1NP concentration of 38.0 μg / L or more and less than 58.5 μg / L, and patients with a blood P1NP concentration of 58.5 μg / L or more.

[0070] Alternatively, examples of osteoporosis patients according to the present invention include patients with a blood P1NP concentration of less than 37.4 μg / L, patients with a blood P1NP concentration of 37.4 μg / L or more and less than 57.3 μg / L, and patients with a blood P1NP concentration of 57.3 μg / L or more.

[0071] Patients with osteoporosis according to the present invention may also be patients with a history of prior treatment with therapeutic drugs for osteoporosis. Examples of prior therapeutic drugs for osteoporosis include calcium drugs, female hormone drugs, SERMs (selective estrogen receptor modulators), active vitamin D3 drugs, vitamin K2 drugs, calcitonin drugs, parathyroid hormone drugs, bisphosphonate drugs, and denosumab.

[0072] Here, preferred examples of SERMs include raloxifene and bazedoxifene, preferred examples of active vitamin D3 drugs include eldecalcitol, alfacalcidol, and calcitriol, and preferred examples of vitamin K2 include menatetrenone. Furthermore, examples of bisphosphonate drugs include etidronate, alendronate, risedronate, minodronate, and ibandronate. Examples of calcitonin drugs include salmoncalcitonin and elcatonin. Examples of parathyroid hormone drugs include daily administration formulations and once-weekly administration formulations containing the aforementioned teriparatide or its salt as the active ingredient.

[0073] Furthermore, the osteoporosis patient according to the present invention may also be an osteoporosis patient suffering from another disease, i.e., an osteoporosis patient with complications. Other diseases include diabetes, hypertension, dyslipidemia (hyperlipidemia, etc.), chronic kidney disease (CKD), rheumatoid arthritis, gout, hyperuricemia, dementia, cataracts, age-related hearing loss, urinary dysfunction, cerebrovascular disease, ischemic heart disease, and the like.

[0074] Alternatively, the osteoporosis patient according to the present invention may be an osteoporosis patient who is in need of long-term care.

[0075] (7) Combined use: The osteoporosis treatment and / or preventive agent of the present invention, as well as the osteoporosis treatment and / or preventive method of the present invention, can be used in combination with other agents. Other agents may be administered together with or sequentially (i.e., at different times) the osteoporosis treatment and / or preventive agent of the present invention, via the same or different routes.

[0076] Other drugs could include at least one of the aforementioned prior treatments for osteoporosis. Alternatively, other drugs could include those used to treat and / or prevent the aforementioned complications. Furthermore, other drugs could be basic medications (such as calcium or vitamin D agents).

[0077] Preferred basic drugs include vD3 (vitamin D3) preparations, magnesium preparations, and calcium preparations. These can be used in any combination or as a combination drug. For example, a calcium preparation containing vD3 and magnesium can be preferably used as a basic drug. Such a combination drug is preferably taken once a day after dinner, and each dose contains 400 IU of vD3, 30 mg of magnesium, and 610 mg of calcium.

[0078] When the osteoporosis treatment and / or preventive agent of the present invention is used as an investigational drug in clinical trials, the evaluation can also be carried out while the subjects are taking the aforementioned or equivalent basic drug (Non-Patent Literature 15). However, it can also be considered that the fracture risk reduction effect of the combined use of vD and calcium preparations is unclear (Non-Patent Literature 25), and that if basic drugs are administered to both the investigational drug group and the control drug group, the influence of the basic drug on the differences between the two groups in terms of efficacy and safety will not be substantially observed. For these reasons, when using the osteoporosis treatment and / or preventive agent of the present invention in clinical practice, the use of vD and calcium preparations is not necessarily required.

[0079] (8) Formulations: The osteoporosis treatment and / or preventive agent of the present invention can take various formulation forms. Generally, it is preferable that the agent be an injectable preparation containing pharmaceutically acceptable excipients and additives from the viewpoint of stability and other factors.

[0080] Excipients and additives are not particularly limited, but may include, for example, sugar alcohols (such as mannitol), inorganic salts (such as sodium chloride), sugars (such as sucrose), and amino acids (such as methionine). This product may contain buffering agents, but may not contain them. The pH of this product can be adjusted as appropriate, for example, to 3.5 to 5.5.

[0081] The concentration of the active ingredient in this drug is not particularly limited, but for example, it can be 50 μg / mL or higher, and can also be 100-200 μg / mL.

[0082] If this drug is an injectable preparation, it can be manufactured by dissolving the active ingredient, excipients, and additives in a suitable solvent (sterile water, buffer solution, physiological saline, etc.), filtering and / or sterilizing them using a filter, and then filling and sealing them into a washed and sterilized container.

[0083] Examples of filling containers include ampoules, vials, pre-filled syringes, and bags. The material of the container is not particularly limited, but glass and plastic are examples. Plastic is a preferred example of a container material from the viewpoint of strength, ease of handling, and safety.

[0084] For example, an automated administration formulation may be created by incorporating a pre-filled syringe with a needle, pre-filled with the drug solution, into an auto-injector. Since the osteoporosis treatment agent according to the present invention exhibits sufficient safety, it can also be used as a formulation for home self-administration.

[0085] (9) Effectiveness: The primary objective of the therapeutic and / or preventive agent for osteoporosis and the therapeutic and / or preventive method for osteoporosis according to the present invention is to prevent or suppress fractures.

[0086] (9-1) Prevention or suppression of fractures: The fractures according to the present invention include both pathological fractures caused by osteoporosis, osteogenesis imperfecta, bone tumors, etc., and traumatic fractures caused by traffic accidents, bruises, etc. Preferably, fractures caused by osteoporosis can be mentioned.

[0087] The fractures according to the present invention include both vertebral fractures and non-vertebral fractures. Non-vertebral fractures are not particularly limited and can include, for example, fractures of the proximal femur, distal radius, proximal humerus, tibia, pelvis, ribs, etc. Vertebral fractures (such as new vertebral fractures and aggravated vertebral fractures) are preferably mentioned as fractures according to the present invention.

[0088] Generally, a proximal femoral fracture refers to a hip fracture in elderly individuals and is understood to be a different fracture from fractures of the proximal part of the femur (Non-Patent Literature 9). Examples of fractures included in proximal femoral fractures are subchondral insufficiency fractures of the femoral head, femoral neck fractures, basal neck fractures, trochanteric fractures, and subtrochanteric fractures (Non-Patent Literature 9).

[0089] Furthermore, because subchondral fractures of the femoral head are extremely rare and diagnosing fractures of the femoral neck base is difficult, they can be classified as either femoral neck fractures or intertrochanteric fractures. Since the distinction between intertrochanteric and subtrochanteric fractures is not clear, it is also possible to classify proximal femoral fractures into two main categories: femoral neck fractures and intertrochanteric fractures (Non-Patent Literature 9). The proximal femur is sometimes referred to as the proximal femur total, to emphasize the whole.

[0090] Vertebral fractures are the most common type of osteoporotic fracture and are important indicators for the diagnosis and treatment of osteoporosis, making their prevention or suppression of these fractures of extremely high clinical significance (Non-Patent Literature 9). Furthermore, proximal femoral fractures are known to cause deterioration of daily living function and quality of life, and are also related to life expectancy (Non-Patent Literature 9), so it is preferable to take sufficient preventive and suppressive measures for proximal femoral fractures.

[0091] Vertebral fractures, as morphological fractures, can be determined by the degree of vertebral deformation, regardless of the presence or absence of clinical symptoms (Non-Patent Literature 9). Morphological fractures can be classified into existing fractures and new fractures.

[0092] A new fracture can be a fracture determined to have occurred by comparing X-ray images, etc., at two different points in time, while an existing fracture can be determined by the degree of vertebral deformation at a single point in time before the start of treatment. Among new fractures, those in which a vertebra that was not deformed before the start of treatment becomes deformed after the start of treatment are classified as new vertebral fractures, and those in which the degree of vertebral deformation increases after the start of treatment are classified as worsening fractures. In this specification, new vertebral fractures and worsening vertebral fractures are distinguished and described in this way.

[0093] The vertebral fractures according to the present invention include both new-onset and aggravated vertebral fractures. For example, the degree of deformation can be classified into grades based on the overall morphology of the vertebral body, and is generally classified as Grade 0 (normal), Grade 1 (vertebral body height reduced by approximately 20-25%, and vertebral body area reduced by 10-20%), Grade 2 (vertebral body height reduced by approximately 25-40%, and vertebral body area reduced by 20-40%), and Grade 3 (vertebral body height reduced by approximately 40% or more, and vertebral body area reduced by 40% or more). The distinction between new-onset and aggravated fractures can be made according to the grade increase pattern in accordance with Genant's criteria. Specifically, if a change from Grade 0 to Grade 1, 2, or 3 is observed, it is diagnosed as a new-onset vertebral fracture, and if a change from Grade 1 to Grade 2 or 3, or from Grade 2 to Grade 3 is observed, it can be considered an aggravated fracture.

[0094] Among the fractures according to the present invention, those diagnosed with clinical symptoms such as pain can be called clinical fractures, and clinical fractures can be classified into clinical vertebral fractures and clinical non-vertebral fractures. In this specification, clinical non-vertebral fractures are simply referred to as non-vertebral fractures. Clinical symptoms include, for example, acute pain in the lower back, and can be confirmed by the subject's complaints.

[0095] Fracture evaluation methods using X-ray images and MRI are well known, and for example, quantitative evaluation methods (QM method) and semi-quantitative evaluation methods (SQ method) are known. The SQ method, proposed by Genant et al. in 1993, has been used in many clinical trials both domestically and internationally, and its evidence has been established, making it a preferred method to use (Non-Patent Literature 11). In addition, the methods of Wu et al. and Fukunaga et al. can also be used (Non-Patent Literature 11-13).

[0096] When testing a treatment and / or preventive agent for osteoporosis, it is preferable to evaluate its fracture-inhibiting effect. When evaluating the fracture-inhibiting effect of an investigational drug, it is also possible to evaluate the fracture-inhibiting effect (such as fracture risk reduction) of the investigational drug in the study without providing a placebo control by, for example, using a control drug that has been shown to have fracture-inhibiting effects based on past clinical data, and comparing the fracture incidence rate of the control drug obtained from the study with that of the investigational drug, or by comparing the fracture incidence rate of the investigational drug with that of the untreated subjects in the study, which can be inferred based on past clinical data.

[0097] (9-2) Increase in bone density: Bone strength consists of two factors: bone density and bone quality. Generally, bone density accounts for approximately 70% of bone strength, while bone quality accounts for the remaining 30% (Non-Patent Literature 9). Preparations for daily administration and once-weekly administration containing teriparatide or its salt as the active ingredient are known to have not only fracture-inhibiting effects but also bone density-increasing effects (Non-Patent Literature 4, 5, 8, 9).

[0098] Here, bone mineral density typically refers to the bone mineral content of the lumbar spine. The lumbar spine is rich in cancellous bone, which has a high bone turnover rate, and therefore has high sensitivity in detecting changes in bone mineral density due to drug treatment. In cases where it is difficult to evaluate lumbar spine bone mineral density, the bone mineral content of the radius, second metacarpal bone, femoral neck, and calcaneus can be used to indicate the relevant bone mineral density. The average value for young adults refers to the average bone mineral density of individuals aged 20 to 44 years.

[0099] Bone density can be measured by known methods such as dual-energy X-ray absorptiometry, photodensitometry, photon absorption spectroscopy, quantitative CT, and quantitative ultrasound.

[0100] The rate of change in bone density can be calculated, for example, using the following formula. The percentage change in bone density at a given time point a = {(Bone density at that time point - Bone density at the start of administration) / Bone density at the start of administration} × 100

[0101] Furthermore, in this invention, the degree of bone atrophy refers to the degree of bone loss on X-ray. The degree of bone atrophy is classified into no bone atrophy, degree I bone atrophy, degree II bone atrophy, and degree III bone atrophy. No bone atrophy in this degree of bone atrophy refers to a normal state, specifically a state in which the trabecular structure cannot be recognized because the longitudinal and transverse trabeculae are dense. Degree I bone atrophy means a state in which the longitudinal trabeculae are prominent, and typically means a state in which the longitudinal trabeculae appear thin but are still densely arranged, and the vertebral endplates also become prominent. Degree II bone atrophy in this degree of bone atrophy means a state in which the longitudinal trabeculae become sparse, appear thick, have a sparse arrangement, and the vertebral endplates also become fainter. Degree III bone atrophy in this degree of bone atrophy means that the longitudinal trabeculae also become indistinct, the vertebral shadow as a whole appears blurred, and the difference with the intervertebral disc shadow decreases. The degree of bone atrophy can be determined, for example, from a lateral lumbar spine X-ray.

[0102] (9-3) Changes in bone metabolism markers: Fluctuations in bone metabolism markers are related to the prevention or suppression of fractures and the increase in bone density. Therefore, when evaluating the efficacy of osteoporosis treatments, it is considered useful to measure bone metabolism marker levels in biological samples (blood samples, urine samples, etc.) derived from subjects and to check their fluctuations (e.g., the difference between values ​​before and after administration) (Non-Patent Literature 9).

[0103] For the purpose of evaluating the efficacy of the osteoporosis treatment and / or preventive agent of the present invention, changes in bone metabolism markers, increases in bone density, or suppression of fractures can be observed. However, in the administration method of the present invention, which involves administration twice a week with intervals of 2 and 3 days within that week (excluding the administration day), it is preferable to evaluate the efficacy by directly observing increases in bone density or suppression of fractures.

[0104] Bone metabolism markers are broadly classified into bone formation markers and bone resorption markers. Bone formation markers are substances that can be produced directly or indirectly by osteoblasts at each stage of osteoblast differentiation, and osteocalcin and P1NP are known examples. Bone resorption markers are substances that can be involved in osteoclast activation and bone resorption, and NTX and CTX are known examples.

[0105] Previously, in the treatment of osteoporosis using teriparatide on a daily basis, the discrepancy between bone formation markers and bone resorption markers that shows a rapid increase from the start of administration, particularly in the early stages, was referred to as the "anabolic window" and was considered to be the mechanism of increased bone density from the early stages of administration (Non-Patent Literature 24). In the osteoporosis treatment and / or preventive agent of the present invention, changes in bone metabolism markers, such as the "anabolic window," can also be used as indicators for treatment monitoring, particularly in the early stages of administration (e.g., within a few months of the start of administration).

[0106] However, the twice-weekly administration method according to the present invention, in which the administration interval within that week is 2 or 3 days (excluding the administration day), can be clearly distinguished from conventional teriparatide treatment methods with respect to the relationship between bone metabolism markers and efficacy. Therefore, when evaluating efficacy in this administration method, it is more preferable to directly observe an increase in bone density or suppression of fractures rather than changes in bone metabolism markers.

[0107] Furthermore, studies using ovariectomized rats, which are commonly used as an osteoporosis model (Non-Patent Literature 14-15), have reported that cortical bone voids increase in proportion to the dose when teriparatide is administered frequently (Non-Patent Literature 14).

[0108] Furthermore, it has been reported that teriparatide is used as a treatment for osteoporosis with a high risk of fracture, that the cortical bone voids increase with age and disease condition in patients who are candidates for this treatment, and that a treatment strategy that takes into account the patient's condition and the characteristics of the pharmacological action of teriparatide is necessary to maximize the therapeutic effect of teriparatide (Non-Patent Literature 14).

[0109] Therefore, in the treatment or prevention according to the present invention, it is preferable that bone formation markers related to increased bone density and fracture prevention rates are increased, while the blood or urinary concentrations of bone resorption markers closely related to cortical bone voiding and porosity decrease over time or their increase over time is suppressed. Examples of bone resorption markers closely related to cortical bone voiding and porosity include NTX and CTX. Furthermore, in such an embodiment of the present invention, when repeated administration is performed, an appropriate interval can be left between administrations to the extent that bone resorption is not continuously enhanced. More specifically, for example, a treatment or prevention in which the dose is 28.2 μg in teriparatide equivalent can be exemplified, and among these, a preferred example is an administration method according to the present invention that is administered twice a week (however, the single dose is 28.2 μg in teriparatide equivalent) with administration intervals of 2 and 3 days (excluding the administration day).

[0110] (10) Safety: (10-1) Adverse events and side effects: All undesirable or unintended illnesses or symptoms thereof that occur in a person who has been administered a drug can be referred to as adverse events (AEs).

[0111] Adverse events that cannot be ruled out as having a causal relationship with the drug can be called side effects. Here, "cannot be ruled out as having a causal relationship" includes not only the recognition of a reasonable possibility of a causal relationship, but also the fact that it cannot be evaluated as not having a reasonable possibility of a causal relationship.

[0112] Adverse events can be broadly classified into serious and non-serious adverse events. The following six adverse events can be considered serious adverse events, while all other adverse events can be considered non-serious adverse events. 1) Something that leads to death (death). 2) Something that threatens life (risk of death). 3) Cases requiring hospitalization or extension of hospitalization for treatment (hospitalization or extension of hospitalization). 4) A condition resulting in permanent or significant impairment or dysfunction (disability). 5) Those that result in congenital abnormalities (congenital abnormalities). 6) Other medically significant conditions (risk of disability, serious as described in 1) to 4) above).

[0113] Furthermore, adverse events can be broadly classified not only by their severity and causal relationship, but also by their degree. For example, the following three degrees can be considered. 1) Mild: Transient and easily tolerable. 2) Moderate: To the extent that it interferes with normal activities. 3) Altitude: To the extent that normal activities become impossible.

[0114] Alternatively, adverse events can be classified by their outcome from the perspective of changes over time, for example, as recovered / resolved, recovering / resolving, not recovered / not resolved, recovered but with sequelae, death, or unknown.

[0115] There are no particular restrictions on the methods used to compare the safety of one drug with another. For example, one could focus on a particular adverse event and compare its frequency, severity, causal relationship, outcome, and / or degree. Alternatively, the two drugs could be compared in terms of treatment interruption due to adverse events as a whole or some of them, or to side effects as a whole or some of them.

[0116] Adverse events may include abnormalities in clinical laboratory values ​​or vital signs.

[0117] Adverse events are not particularly limited and can also be classified by system organ class (SOC). Examples of system organ class related to adverse events are as follows: 1) Infections and infestations 2) Gastrointestinal disorders 3) Musculoskeletal and connective tissue disorders 4) Injury, poisioning, and procedural complications 5)General disorders and administration Site conditions (general disorders, systemic disorders, and conditions at the administration site) 6) Skin and subcutaneous tissue disorders 7) Nervous system disorders 8) Respiratory, thoracic, and mediastinal disorders 9) Eye disorders 10) Metabolism and nutrition disorders 11) Investigations (clinical tests) 12) Neoplasms benign, malignant, and unspecified (incl. cysts and polyps) 13) Ear and labyrinth disorders 14) Cardiac disorders 15) Vascular disorders

[0118] Adverse events classified as "infections and parasitic diseases" include nasopharyngitis and influenza. Adverse events classified as "neurological disorders" include headache and dizziness. Adverse events classified as "respiratory, thoracic, and mediastinal disorders" include inflammation of the upper respiratory tract. Adverse events classified as "gastrointestinal disorders" include nausea, vomiting, and constipation. Adverse events classified as "skin and subcutaneous tissue disorders" include eczema. Adverse events classified as "musculoskeletal and connective tissue disorders" include osteoarthritis. Adverse events classified as "general disorders and conditions at the injection site" include malaise, injection site bleeding, and fever. Adverse events classified as "disorders, poisoning, and procedural complications" include contusions.

[0119] As mentioned above, it has been reported that nausea, vomiting, headache, etc. are frequently observed with the administration of teriparatide acetate (Non-Patent Literature 9). Furthermore, in clinical trials in which daily administration formulations containing teriparatide or its salt as the active ingredient were administered, dizziness was reported to be significantly higher in the group compared to the placebo group (Non-Patent Literature 9). In addition, it is known that shock, transient and rapid loss of consciousness accompanied by a drop in blood pressure may occur immediately after administration or within a few hours of administration of daily or once-weekly administration formulations containing teriparatide or its salt as the active ingredient (Non-Patent Literature 4, 8).

[0120] Therefore, in the treatment or prevention according to the present invention, it is preferable to suppress as much as possible the frequency, severity, and / or degree of at least one adverse event or side effect from among adverse events or side effects such as nausea, vomiting, headache, (floating) dizziness, shock, hypotension, and loss of consciousness.

[0121] (10-2) Continue treatment: As mentioned above, in general, it has been reported that 52.1% of patients drop out of medication within 5 years of starting treatment for osteoporosis. Furthermore, poor adherence to medication is also a cause for concern, leading to decreased fracture prevention, increased need for facility use, and stagnation in reducing medical costs (Non-Patent Literature 9). Factors associated with poor adherence to medication include the presence of pain, side effects, and medication for gastrointestinal disorders (Non-Patent Literature 9). On the other hand, it has also been pointed out that preparations containing teriparatide or its salt as the active ingredient have a low treatment continuation rate, with a reported 12-month treatment continuation rate of 34.9% (Non-Patent Literature 22).

[0122] Therefore, providing drug therapy with teriparatide or its salts that results in a higher treatment adherence rate is considered to have high public significance beyond improving the lives of individual patients, including social welfare and healthcare economics.

[0123] For the reasons stated above, an embodiment of the present invention that exhibits a high treatment continuation rate is preferred for treatment or prevention. [Examples]

[0124] The present invention will be described in more detail below with reference to examples. However, the present invention is not limited to the following examples and can be implemented in any form without departing from the spirit of the invention.

[0125] (Example 1)

[0126] 1. Test method: Participants were randomly assigned to either the investigational drug group or the control drug group. As shown in Figure 3, each participant in the investigational drug group received the investigational drug and a placebo, and each participant in the control drug group received the control drug and an investigational drug placebo, subcutaneously over 48 weeks using a double-blind (double-dummy) method. In addition, participants in both groups took two tablets of the standard concomitant medication once daily after dinner.

[0127] A washout was performed if each subject had used osteoporosis medication within 8 weeks prior to obtaining informed consent for the clinical trial. The washout period began on the day following the last dose or injection of the previous osteoporosis medication, and the start date of the investigational drug trial was acceptable as long as it was 8 weeks (56 days) or later after the washout period. However, as a general rule, the period from obtaining informed consent to the start of treatment with the investigational drug should not exceed 12 weeks (84 days).

[0128] The principal investigator or co-investigator may discontinue the clinical trial for a subject if they determine that the subject meets the specified criteria after the initiation of treatment with the investigational drug. The specified criteria included adverse events, lack of efficacy, inability to follow up, judgment of the principal investigator or co-investigator, significant deviation from the clinical trial protocol, poor compliance with the administration of the investigational drug, subject's request, or judgment of the sponsor.

[0129] 1.1. Investigational drug: The test drug was an autoinjector formulation containing 0.2 g of the drug solution per vial. When the entire vial was administered, 28.2 μg of teriparatide (30.3 μg of teriparatide acetate) was delivered. The drug solution was pre-filled in a needle-equipped pre-filled syringe incorporated into the autoinjector. The autoinjector is a device used for subcutaneous injection of the drug solution into the human body.

[0130] 1.2. Investigational drug (placebo): The investigational drug, placebo, is an autoinjector formulation that is indistinguishable from the investigational drug in terms of appearance and is substantially free of teriparatide.

[0131] 1.3. Control drug: The control drug is a vial formulation containing 63.3 μg of teriparatide (67.9 μg of teriparatide acetate) per vial, and is a lyophilized injectable preparation. The control drug is a preparation in which 56.5 μg of teriparatide is administered when dissolved in 1 mL of Japanese Pharmacopoeia physiological saline solution and administered by syringe.

[0132] 1.4. Control drug: Placebo The control drug (placebo) is a lyophilized injectable preparation that is indistinguishable from the control drug in terms of appearance and is substantially free of teriparatide.

[0133] 1.5. Standard concomitant medications: The standard concomitant medication is a calcium preparation containing vitamin D3 and magnesium (Shin Calcichu® D3; manufactured and sold by Nitto Pharmaceutical Co., Ltd., and distributed by Takeda Pharmaceutical Company Limited). Each two tablets of the standard concomitant medication contain 1525 mg of precipitated calcium carbonate (610 mg as calcium), 118.4 mg of magnesium carbonate (30 mg as magnesium), 400 IU of cholecalciferol (vitamin D3), and various additives.

[0134] 1.6. Frequency: Twice a week: The administration interval for the twice-weekly doses was, in principle, set at 3-4 days (2-day or 3-day intervals). This principle of a 3-4 day interval means that one of the two consecutive doses is administered on day 1, and the other dose is administered on day 4 or 5. For example, if an dose is administered on Monday of a given week, the next dose would, in principle, be on Thursday or Friday, as follows. (An example of a standard administration interval) Monday, Day 1: Administration Tuesday, Day 2 Wednesday, Day 3 Administered on Thursday, day 4, or Friday, day 5.

[0135] 1.7. Subjects: The subjects were osteoporosis patients who had all three fracture risk factors: "age," "pre-existing fractures," and "low bone density." More specifically, the subjects were primary osteoporosis patients who met all of the following conditions (1) to (6) (meeting the selection criteria) and did not meet any of the following conditions (7) to (25) (meeting the exclusion criteria). Since the subjects were osteoporosis patients who had all three fracture risk factors: "age," "pre-existing fractures," and "low bone density" (meeting the following conditions (2) to (4)), they were osteoporosis patients at high risk of fracture.

[0136] [1] Selection criteria: (1) Patients diagnosed with primary osteoporosis based on the diagnostic criteria for primary osteoporosis (revised in 2012). (2) Men and women who are 65 years of age or older at the time of obtaining consent. (3) Patients with one to five existing fractures in the vertebral bodies Th4-L4 (4th thoracic vertebra to 4th lumbar vertebra). (4) Patients whose lumbar spine (L2-L4) bone density at the time of provisional registration is less than 80% of the average value for young adults. (5) Outpatients who are able to walk independently. (6) Patients who, prior to the first administration of the investigational drug, have learned the self-injection technique and are capable of managing and administering the investigational drug, as determined by the principal investigator or co-investigator.

[0137] [2] Exclusion criteria: (7) Patients diagnosed with secondary osteoporosis. (8) Patients with diseases other than osteoporosis that cause bone loss. (9) Patients with the following X-ray findings that are thought to affect the evaluation of lumbar spine bone density: • A severe vertebral fracture is observed in one of the lumbar vertebrae, L2 to L4. • Severe osteosclerosis is observed in one of the lumbar vertebrae L2 to L4. • Severe scoliosis, lordosis, and kyphosis are observed. • Severe degenerative spondylotic changes are observed. • In addition, the bone evaluation committee determined that the sample was unsuitable due to the presence of foreign objects or other reasons. The "Bone Evaluation Committee" consists of members who make up the "Bone Evaluation Committee," which was established to uniformly evaluate bone mass and fracture levels for all patients. Each member of the evaluation committee is an expert in the imaging diagnosis of osteoporosis.

[0138] (10) Patients who have undergone vertebral surgery. (11) Patients complaining of acute pain suggestive of a vertebral fracture {patients who have developed or experienced an increase in acute lower back pain from 12 weeks (84 days) prior to obtaining consent until the start of treatment, and who require rest and treatment such as anti-inflammatory and analgesic drugs}. (12) Patients whose medical history is deemed unreliable (at least patients with dementia are excluded). (13) Patients with severe kidney disease, liver disease, or heart disease (wherein "severe kidney disease" means that the serum creatinine level is 2 mg / dL or higher in tests prescribed before provisional registration; "severe liver disease" means that the AST (GOT) or ALT (GPT) level is 2.5 times or higher than the upper limit of the normal range or 100 IU / L or higher in tests prescribed before provisional registration; and "severe heart disease" means that the determination was made based on Grade 2 as shown in "Criteria for Classification of Severity of Adverse Drug Reactions (Pharmaceutical Safety and Security Notification No. 80, June 29, 1992)").

[0139] (14) Patients with a predisposition to hypersensitivity reactions such as bronchial asthma or rashes (erythema, wheals, etc.). (15) Patients whose serum calcium level is 11.0 mg / dL or higher in tests performed before provisional registration. (16) Patients whose alkaline phosphatase levels are twice the upper limit of the normal range in tests performed before provisional registration. (17) A patient with Paget's disease of bone. (18) Patients with a history of or with primary malignant bone tumor or metastatic bone tumor. (19) Patients with a history of or with a concomitant malignant bone tumor within the past five years. (20) Patients who have previously received radiation therapy that may have affected their bones. (21) Patients who have previously received teriparatide preparations or anti-RANKL antibody preparations. (22) Patients who received bisphosphonate preparations within 52 weeks (364 days) prior to obtaining consent (however, for drugs for which a fixed interval period is set in the drug usage instructions, the number of days shall be the 52 weeks (364 days) prior to obtaining consent plus that period). (23) Patients who have received other investigational drugs within 26 weeks (182 days) prior to obtaining informed consent.

[0140] (24) Patients who have received any of the following osteoporosis treatment drugs (A) to (G) on the day consent was obtained (however, if a washout of 8 weeks (56 days) or more (meaning a temporary suspension of the drug for the purpose of eliminating the effects of the previous drug) is possible before the start of treatment, they may be selected as subjects). (A) Calcitonin preparations. (B) Active vitamin D3 preparation. (C) Vitamin K preparation. (D) Ipriflavone preparations. (E) Estrogen preparations. (F) SERM preparation. (G) Anabolic hormone preparations. (25) Any other patient whom the principal investigator or co-investigator deems unsuitable for conducting this clinical trial.

[0141] 1.8. Administration to the investigational drug group and the control drug group: Participants were randomly assigned to either the investigational drug group or the control group. As shown in Figure 3, each participant in the investigational drug group received the investigational drug and a placebo, and each participant in the control group received the control drug and an investigational drug placebo, subcutaneously over 48 weeks using a double-blind (double-dummy) method. In addition, participants in both groups took two tablets of the standard concomitant medication once daily after dinner.

[0142] Each patient assigned to the investigational drug group received one vial of the investigational drug twice a week via subcutaneous injection (self-injection into either the upper arm, thigh, or abdomen). The administration interval was generally 3 to 4 days (with a 2-day or 3-day interval in between). In addition, the same patients received a solution of one vial of the control drug (placebo) dissolved in 1 mL of Japanese Pharmacopoeia physiological saline solution once a week via subcutaneous injection (in-hospital injection).

[0143] Each patient assigned to the control group received one placebo vial twice a week via subcutaneous injection (self-injected into either the upper arm, thigh, or abdomen). In addition, these patients received a solution prepared by dissolving one vial of the control drug in 1 mL of Japanese Pharmacopoeia physiological saline solution once a week via subcutaneous injection (in-hospital injection).

[0144] The primary efficacy endpoint of the study was the percentage change in lumbar spine bone mineral density (2nd to 4th lumbar vertebrae).

[0145] The secondary efficacy endpoints of the study were the percentage change in femoral bone mineral density, the percentage change in lumbar spine bone mineral density (lumbar vertebrae 1-4), the incidence of new vertebral fractures, the incidence of exacerbated vertebral fractures, the incidence of (new and exacerbated) vertebral fractures, the incidence of clinical fractures (clinical vertebral fractures and non-vertebral fractures), the incidence of fragility clinical fractures, the incidence of fragility non-vertebral fractures, and bone metabolism markers.

[0146] The safety endpoints of the study were adverse events, vital signs, clinical laboratory tests, and immunogenicity.

[0147] 1.9. Measurement of bone density change rate: The methods for measuring the rate of change in bone density for lumbar spine bone density and femoral bone density are shown in Table 1-1 below.

[0148] [Table 1-1]

[0149] 1.10. Evaluation of vertebral fractures: The evaluation methods for vertebral fractures are shown in Table 1-2 below.

[0150] [Table 1-2]

[0151] 1.11. Evaluation of clinical fractures (clinical vertebral fractures and non-vertebral fractures): A clinical fracture was defined as a fracture if, within 48 weeks from the start of treatment (at the time of discontinuation), the subject complained of (clinically) symptoms and the principal investigator or co-investigator confirmed the fracture by X-ray or MRI. In particular, if the subject complained of acute pain in the lower back, an X-ray was taken to check for the presence or absence of a fracture.

[0152] The evaluation included the date of fracture occurrence (the day the subject developed the clinical symptoms), the fracture site (vertebral body, proximal femur, radius, humerus, etc.), presence or absence of significant external force, basis for the fracture diagnosis (X-ray, MRI, information from other departments / hospitals, etc.), and the date of X-ray / MRI scans.

[0153] 1.12. Testing of bone metabolism markers: The methods for testing bone metabolism markers are shown in Table 1-3 below.

[0154] [Table 1-3]

[0155] 1.13. Investigation of adverse events: The principal investigator or co-investigator investigated adverse events from the date of informed consent for each subject to one week after the last dose administered, through voluntary reports from subjects, interviews, and various tests.

[0156] The items investigated included the name of the adverse event, the date of onset, the administration status of the investigational drug, the date of disappearance, the outcome, the severity classification, the reason for the severity, the degree of severity, the causal relationship with the investigational drug and standard concomitant medications, the site of the adverse event if it occurred at the injection site, and whether or not the clinical trial was discontinued.

[0157] 1.14. Measurement of vital signs: The methods for measuring vital signs are shown in Table 1-4 below. [Table 1-4]

[0158] 1.15. Clinical Laboratory Tests: The methods for clinical testing are shown in Table 1-5 below. [Table 1-5]

[0159] 1.16. Evaluation of immunogenicity: The principal investigator or co-investigator collected and stored samples (blood) before administering the investigational drug on each test day. After sample collection, anti-drug antibodies against the investigational drug were measured. Neutralizing antibodies were measured only in samples that tested positive for anti-drug antibodies.

[0160] 2. Test results: 2.1. Participants in the efficacy analysis: 859 subjects gave their consent to treatment. Of these, 553 were enrolled in the clinical trial and received treatment. 76 discontinued treatment, and 477 completed treatment. Table 2-1 below shows the background characteristics (summary) of the 551 subjects selected for efficacy analysis from the 553 who received treatment. Table 2-1 indicates that there was no significant bias in background characteristics between the investigational drug group and the control group, and that the fracture risk was likely to be approximately the same.

[0161] [Table 2-1]

[0162] 2.2. Average number of doses and average duration of administration: The average number of administrations and average duration of treatment for the 553 patients who received treatment are shown in Tables 2-2 and 2-3 below. Note that, regarding the average number of administrations, subjects who received the investigational drug as the active drug (MN-10-T AI) also received the control drug placebo (MN-10-T Placebo), and subjects who received the control drug as the active drug (MN-10-T) also received the investigational drug placebo (MN-10-T AI Placebo) (Figure 29). Therefore, the average number of administrations for the four drugs—the investigational drug active, the control drug placebo, the investigational drug placebo, and the control drug active—was calculated.

[0163] [Table 2-2]

[0164] [Table 2-3]

[0165] The average number of administrations did not appear to differ significantly when comparing the active investigational drug in the investigational drug group with the placebo in the control group, and also when comparing the placebo in the control group with the active control drug in the control group.

[0166] The average duration of treatment appeared to be similar between the investigational drug group and the control group. Note that the incomplete data (not reaching 48 weeks) includes cases where treatment was discontinued prematurely.

[0167] 2.3. Time intervals for the average rate of bone density change in the lumbar spine, femoral neck, and proximal femur. Progress: Tables 2-4 to 2-7 below show the time course of the average percentage change in bone density for the lumbar spine (2nd to 4th lumbar vertebrae), lumbar spine (1st to 4th lumbar vertebrae), femoral neck, and proximal femur total in the subjects included in the efficacy analysis. The values ​​in the tables represent the average percentage change from the baseline.

[0168] Furthermore, Figure 4 shows the temporal changes in the average rate of change in lumbar spine (2nd to 4th lumbar vertebrae) bone density among the subjects included in the efficacy analysis.

[0169]

Table 2-4

[0170]

Table 2-5

[0171]

Table 2-6

[0172]

Table 2-7

[0173] Treatment with the test drug showed a higher increase rate in lumbar bone mineral density, femoral neck bone mineral density, and total proximal femoral bone mineral density compared to treatment with the control drug. In particular, it was significantly higher in lumbar bone mineral density.

[0174] When comparing treatment with the test drug and treatment with the control drug, the weekly teriparatide dosage is considered to be substantially equivalent. On the other hand, it has been reported that bone mineral density and bone strength increase in accordance with the weekly teriparatide dosage (Non-Patent Document 14). Therefore, this result, which is considered significant when treatment with the test drug is compared to treatment with the control drug, was considered to be clearly distinguishable from previous medical technologies.

[0175] The subjects for efficacy analysis were divided into subgroups using the lumbar (L2-L4) bone mineral density or the number of existing vertebral fractures at the start as indicators, and the results of analyzing the average value of the bone mineral density change rate at the end in the lumbar region (L2-L4) are shown in Tables 2-8 and 2-9 below. The numerical values in the table indicate the average change rate (%) from the start.

[0176]

Table 2-8

[0177] [Table 2-9]

[0178] It has been reported that a 1SD decrease in lumbar spine bone mineral density increases the risk of vertebral fracture by 2.3 times (Non-Patent Literature 9).

[0179] Using initial lumbar spine bone mineral density and the number of pre-existing vertebral fractures as indicators, the analysis of the increase in lumbar spine bone mineral density after administration showed a tendency for the increase in lumbar spine bone mineral density to be greater with decreasing initial lumbar spine bone mineral density, and conversely, a tendency for the increase in lumbar spine bone mineral density to be less with increasing number of pre-existing vertebral fractures.

[0180] The subjects analyzed for efficacy were divided into subgroups based on their baseline serum osteocalcin levels. The results of analyzing the time course of the average percentage change in bone mineral density in the lumbar spine (2nd to 4th lumbar vertebrae) and femoral neck are shown in Tables 2-10 and 2-11 below. The values ​​in the tables represent the average percentage change from baseline.

[0181] [Table 2-10]

[0182] [Table 2-11]

[0183] The subjects analyzed for efficacy were divided into subgroups based on their baseline blood P1NP levels. The results of analyzing the time course of the average percentage change in bone mineral density in the lumbar spine (2nd to 4th lumbar vertebrae) and femoral neck are shown in Tables 2-12 and 2-13 below. The values ​​in the tables represent the average percentage change from baseline.

[0184] [Table 2-12]

[0185] [Table 2-13]

[0186] Based on the data in the above four tables, the value obtained by dividing the average value of the bone density change rate at the end of the subgroup with the lowest starting OC or P1NP concentration (test drug group) by the average value of the bone density change rate at the end of the subgroup with the lowest starting OC or P1NP concentration (control drug group) is shown in Table 2-14 below.

[0187]

Table 2-14

[0188] Treatment with the test drug was considered to be particularly excellent in terms of the effect of increasing femoral neck bone density in patients with a relatively low blood OC concentration (e.g., less than 15.2 (ng / mL)).

[0189] 2.4. Incidence of vertebral fractures: The time-course of the incidence of new vertebral fractures and the incidence of worsening vertebral fractures by the Kaplan-Meier method in the subjects for efficacy analysis are shown in Tables 2-15 and 2-16 below.

[0190]

Table 2-15

[0191]

Table 2-16

[0192] 2.5. Clinical incidence of vertebral fractures: The time-course of the incidence of clinical vertebral fractures by the Kaplan-Meier method in the subjects for efficacy analysis is shown in Table 2-17 below.

[0193]

Table 2-17

[0194] Based on the above data on vertebral fracture incidence, it can be concluded that treatment with the investigational drug is generally superior to treatment with the control drug in terms of suppressing vertebral fractures.

[0195] 2.6. Bone resorption markers: The time course of bone resorption markers in the subjects included in the efficacy analysis is shown in Tables 2-18 to 2-20 below.

[0196] [Table 2-18]

[0197] [Table 2-19]

[0198] [Table 2-20]

[0199] The time course of bone resorption markers associated with treatment with the investigational drug was comparable to or slightly suppressed compared to the time course of bone resorption markers associated with treatment with the control drug (Figures 5-7).

[0200] Non-patent document 17 reports that daily administration of the investigational drug enhances bone resorption markers. Furthermore, non-patent document 27 indicates that eroded surfaces showing bone resorption are observed on the cortical bone voids resulting from daily administration of the investigational drug (see Fig. 7c, etc.), suggesting a strong relationship between cortical bone porosity and enhanced bone resorption. In light of the contents of these documents, the time course of bone resorption markers in the twice-weekly administration treatment in this study suggests that the twice-weekly administration treatment does not enhance bone turnover to increase the cortical bone void ratio compared to the once-weekly administration treatment.

[0201] 2.7. Bone formation markers: The time course of bone formation markers in the subjects included in the efficacy analysis is shown in Tables 2-21 and 2-22 below.

[0202] [Table 2-21]

[0203] [Table 2-22]

[0204] The time course of bone formation markers associated with treatment with the investigational drug was higher than that associated with treatment with the control drug (Figures 8-9). In particular, in the early stages after the start of administration (here, meaning up to about 12 weeks after the start of administration), the rate of change in bone formation markers was significantly higher with twice-weekly administration compared with once-weekly administration. That is, it can be considered that the bone formation enhancement is superior, and it can be thought that twice-weekly administration may show a greater increase in bone density compared with once-weekly administration.

[0205] 2.8. Safety: The subjects included in the safety analysis were defined as those who received at least one dose of the investigational drug or control drug during the treatment period, and the following aggregate analysis was performed. A treatment-emergent adverse event (TEAE) refers to an adverse event that occurred during the treatment period.

[0206] 2.8.1. Incidence rates of adverse events and side effects (summary): [Table 2-23]

[0207] The incidence of side effects with the investigational drug was significantly lower compared to the incidence of side effects with the control drug.

[0208] [Table 2-24]

[0209] The incidence of adverse events was classified into three categories: the incidence of TEAEs, the incidence of serious adverse events, and the incidence of other important adverse events. The results showed that in all categories, the incidence of adverse events associated with the investigational drug was significantly lower than that associated with the control drug. Here, important adverse events were defined as serious or discontinued adverse events. Furthermore, adverse events excluding serious adverse events were defined as "other important adverse events."

[0210] 2.8.2. Incidence rates of relatively common adverse events and side effects (nausea, vomiting, etc.): [Table 2-25]

[0211] The incidence of adverse events and side effects, such as nausea and vomiting, which were relatively common in both groups, tended to be lower in the investigational drug group compared to the control group. Furthermore, the incidence of adverse events and side effects such as headache and fever also tended to be lower in the investigational drug group compared to the control group.

[0212] 2.8.3. Incidence rates of adverse events and side effects by organ (e.g., nervous system disorders): [Table 2-26]

[0213] When adverse events and side effects were aggregated and analyzed by organ system, the incidence of adverse events and side effects tended to be lower in the investigational drug group compared to the control group in all disorders or conditions, including nervous system disorders, gastrointestinal disorders, general and systemic disorders and administration site conditions, cardiac disorders, and vascular disorders.

[0214] 2.8.4. Incidence rates of adverse events and side effects (shock, hypotension, loss of consciousness) and changes in blood pressure over time: [Table 2-27]

[0215] As mentioned above, it is known that shock, loss of consciousness accompanied by a transient, rapid drop in blood pressure, convulsions, and falls may occur immediately after or several hours after administration of daily or once-weekly formulations of PTH (Non-Patent Documents 4, 8).

[0216] In this study, the incidence of adverse events and side effects related to blood pressure reduction tended to be lower in the investigational drug group compared to the control group. Furthermore, regarding events related to shock and loss of consciousness, no adverse events or side effects were observed in the investigational drug group, demonstrating excellent safety.

[0217] [Table 2-28]

[0218] In the investigational drug group, the mean change in systolic blood pressure (post-administration value - pre-administration value) showed a similar downward trend at all examination times (0, 4, 12, 24, and 48 weeks). On the other hand, in the control drug group, the mean change was greater than in the investigational drug group, particularly at 0, 4, and 12 weeks. The degree of blood pressure reduction was -6.3 to -9.4 mmHg in the investigational drug group and -7.4 to -12.2 mmHg in the control drug group, indicating that the blood pressure reduction in the investigational drug group was more gradual than that in the control drug group.

[0219] [Table 2-29]

[0220] In the investigational drug group, the mean change in diastolic blood pressure (post-administration value - pre-administration value) showed a similar downward trend at all examination times (0, 4, 12, 24, and 48 weeks). On the other hand, in the control drug group, the mean change was greater at 0, 4, and 12 weeks. Regarding the degree of blood pressure reduction, it ranged from -4.2 to -6.3 mmHg in the investigational drug group and from -4.3 to -8.0 mmHg in the control drug group, indicating that the blood pressure reduction in the investigational drug group was more gradual than that in the control drug group.

[0221] 2.8.5. Incidence rates of adverse events and side effects by age: [Table 2-30]

[0222] The tendency for the incidence of adverse events to decrease with age was more strongly observed in the group receiving the investigational drug, and in particular, the incidence of adverse events was significantly lower in patients aged 80 years or older in the investigational drug group.

[0223] 2.8.6. Incidence rates of adverse events and side effects by sex: [Table 2-31]

[0224] Compared to the control group, the investigational drug group demonstrated superior safety in both men and women, but the incidence of side effects was particularly significantly reduced in men.

[0225] 2.8.7. Treatment continuity: [Table 2-32]

[0226] Treatment continuity tended to be higher in the investigational drug group compared to the control group.

[0227] [Table 2-33]

[0228] The rate of treatment discontinuation due to adverse events was lower in the investigational drug group compared to the control group. Furthermore, the number of discontinuations due to adverse events within 24 weeks was 25 in the control group compared to 11 in the investigational drug group, indicating that discontinuation due to adverse events, particularly in the early stages of treatment, was less frequent in the investigational drug group.

[0229] [Table 2-34]

[0230] Treatment with the investigational drug group showed improved treatment continuity compared to treatment with the control drug group, by reducing the incidence of adverse events or side effects such as nausea and vomiting.

[0231] 2.9. Analysis of the effect of dosing interval on therapeutic effect: 2.9.1. Analysis method: The study included 242 subjects from the investigational drug group who completed 48 weeks of treatment (hereinafter referred to as the "treatment completion investigational drug group"). For each subject, the percentage (%) of weeks within the 48-week total treatment period in which the dosing interval (excluding the day of administration) was 2 days or 3 days (hereinafter referred to as the 2-3 day dosing interval compliance rate) was calculated. In this study, weeks that met either condition (1) or (2) below were not considered weeks in which the dosing interval (excluding the day of administration) was 2 days or 3 days. (1) The week in which the period between the day on which the control drug placebo was administered and the day on which the next control drug placebo was administered is 6 days or less. [Table 2-35] (2) The week in which the investigational drug was administered with no interval, 1-day interval, 4-day interval, and 5-day interval, when the period between the administration of the control drug placebo and the administration of the next control drug placebo is 7 days or more.

[0232] [Table 2-36]

[0233] [Table 2-37]

[0234] [Table 2-38]

[0235] [Table 2-39]

[0236] Based on the definition of the compliance rate for the 2-3 day dosing interval, the following five aggregate analyses were performed. (1) Comparative analysis of efficacy and safety between the investigational drug group with a treatment completion rate of 70% or higher and the investigational drug group with a treatment completion rate of less than 70%. (2) Comparative analysis of efficacy and safety between the investigational drug group that completed treatment with a 2-3 day dosing interval adherence rate of 75% or higher and the investigational drug group that completed treatment with a 2-3 day dosing interval adherence rate of less than 75%. (3) Comparative analysis of efficacy and safety between the investigational drug group that completed treatment with a 2-3 day dosing interval adherence rate of 80% or higher and the investigational drug group that completed treatment with a 2-3 day dosing interval adherence rate of less than 80%. (4) Comparative analysis of efficacy and safety between the investigational drug group with a treatment completion rate of 85% or higher and the investigational drug group with a treatment completion rate of less than 85%. (5) Comparative analysis of efficacy and safety between the investigational drug group with a treatment completion rate of 90% or higher and the investigational drug group with a treatment completion rate of less than 90%.

[0237] Here, the efficacy evaluation items were the percentage change in lumbar spine bone mineral density (2nd to 4th lumbar vertebrae), the percentage change in femoral neck bone mineral density, the percentage change in bone mineral density of the entire proximal femur (total proximal femur), the clinical fracture incidence rate, and the non-vertebral fracture incidence rate. In addition, the safety evaluation items were the overall adverse event incidence rate and the nausea (adverse event) incidence rate.

[0238] Furthermore, the average number of administrations and the average duration of administration were calculated for each group being compared.

[0239] 2.9.2.Analysis results: 2.9.2.1. Average number of doses and average duration of administration: For the 242 patients in the investigational drug group who completed treatment, the average number of administrations and the average duration of administration were calculated for each percentage of patients who adhered to the administration interval. The results are shown in Table 2-40 below.

[0240] [Table 2-40]

[0241] When comparing the groups with a 2-3 day dosing interval compliance rate of 70% or higher and those with a compliance rate of less than 70%, there was no significant difference in the average number of doses or the average duration of administration; they were comparable. Furthermore, when comparing the values ​​above and below specific thresholds for each of the 2-3 day dosing interval compliance rates of 75%, 80%, 85%, and 90%, the results were similar to those for the group with a 2-3 day dosing interval compliance rate of 70% or higher. Therefore, it was concluded that there was no difference in the average number of doses or the average duration of administration even with different 2-3 day dosing interval compliance rates, and thus no difference in the amount of exposure to the investigational drug.

[0242] 2.9.2.2.Average percentage change in total bone mineral density (%) for the lumbar spine, femoral neck, and proximal femur, when distinguished by whether the percentage of patients adhering to the 2-3 day dosing interval is above / below a specific value: The average percentage change in bone mineral density (%) for the lumbar spine, femoral neck, and proximal femur was calculated when the adherence rate to each 2-3 day administration interval was categorized as above / below a specific value. This is shown in Tables 2-41 to 2-43 below.

[0243] [Table 2-41]

[0244] [Table 2-42]

[0245] [Table 2-43]

[0246] Furthermore, Figures 10-24 show graphs comparing the average percentage change in lumbar spine bone mineral density (2nd to 4th lumbar vertebrae), femoral neck bone mineral density, and proximal femoral total bone mineral density for each percentage of patients adhering to a 2-3 day administration interval, with those above and below a specific value.

[0247] As mentioned above, lumbar spine bone mineral density (2nd to 4th lumbar vertebrae) is the primary efficacy endpoint of this study. Therefore, Figure 25 shows the results of an analysis of the effect of changes in a specific value on the mean percentage change in lumbar spine bone mineral density (2nd to 4th lumbar vertebrae) shown by patients whose adherence to a 2-3 day dosing interval was above a certain value (%) at 48 weeks after the start of administration.

[0248] In groups where the adherence rate to a 2-3 day dosing interval exceeded a specific value, the average percentage change in bone density tended to increase as the adherence rate to the 2-3 day dosing interval increased. Therefore, it was considered that the higher the proportion of weeks in which the dosing interval (excluding the day of administration) was 2 or 3 days, the greater the therapeutic effect. More specifically, the configuration with an adherence rate of 70% or more showed good therapeutic effects, and the configuration with an adherence rate of 90% or more showed even more remarkable therapeutic effects. In addition, considering the strong positive correlation between the adherence rate and therapeutic effect, it was considered that the therapeutic effect would be generally maximized when the adherence rate reached 100%.

[0249] On the other hand, the adherence rate to a 2-3 day administration interval (3-4 day interval including the administration day) was 0%, and there were two cases where the drug was administered twice a week at approximately 1.4 day intervals (2.5 day intervals including the administration day). Analysis of the mean percentage change in lumbar spine bone mineral density (2nd to 4th lumbar vertebrae) in these two cases showed that at 48 weeks after the start of administration, one case showed 5.8% and the other showed 5.9%. The inventors believe that this result also suggests that adhering to a 2-3 day administration interval (3-4 day interval including the administration day) is useful when administering the drug twice a week.

[0250] 2.9.2.3.Average percentage change in bone density in each category when the adherence rate to the 2-3 day dosing interval is divided into 75-85% and 85-100%:

[0251] [Table 2-44]

[0252] 2.9.2.4. Incidence rates of clinical fractures and non-vertebral fractures when distinguished by adherence rate to 2-3 day dosing intervals (above / below a specific value): The incidence rates of clinical fractures and non-vertebral fractures were calculated for each percentage of patients adhering to a 2-3 day dosing interval, categorized as above / below a specific value. The results are shown in Tables 2-45 to 2-46 below.

[0253] [Table 2-45]

[0254] [Table 2-46]

[0255] As mentioned above, clinical fractures are a type of fracture that includes both vertebral and non-vertebral fractures. Therefore, Figure 26 shows the results of an analysis of the effect of changes in a specific value on the fracture incidence rate (%) of clinical fractures in patients whose adherence to a 2-3 day dosing interval is above a certain value (%).

[0256] In groups exceeding a certain value, the fracture incidence rate (%) generally tended to decrease as the percentage of patients adhering to a 2-3 day dosing interval increased. Therefore, it was considered that the higher the percentage of weeks in which the weekly dosing interval (excluding the day of administration) was 2 or 3 days, the greater the therapeutic effect. More specifically, the configuration with a 2-day and 3-day dosing interval showed good therapeutic effects, and the configuration with a 2-day and 3-day interval showed even more remarkable therapeutic effects. Furthermore, considering the strong positive correlation between the 2-day and 3-day intervals and the therapeutic effect, it was considered that the therapeutic effect would be generally maximized when the 2-day and 3-day intervals reached 100%.

[0257] 2.9.2.5. Time course of bone metabolism markers (urinary NTX (u-NTX), serum NTX (s-NTX), CTX, OC, P1NP) when distinguished by adherence rate to dosing intervals based on whether they are above or below a specific value: The temporal changes in bone metabolism markers (urinary NTX (u-NTX), serum NTX (s-NTX), CTX, OC, P1NP) were calculated for each group of patients who adhered to specific dosing intervals, categorized as above / below a certain value. The results are shown in Tables 2-47 to 2-51 below.

[0258] [Table 2-47]

[0259] [Table 2-48]

[0260] [Table 2-49]

[0261] [Table 2-50]

[0262] [Table 2-51]

[0263] Serum osteocalcin (OC) is widely used as a bone metabolism marker to observe the bone formation effects of daily and once-weekly formulations containing teriparatide or its salt as the active ingredient (Non-Patent Document 5, etc.). Furthermore, in administration of the investigational drug according to the present invention, a peak increase in OC is observed approximately 4 weeks after the start of administration (Figure 8). Therefore, Figure 27 shows the results of an analysis of the effect of changes in a specific value on the OC levels shown in patients whose adherence to a 2-3 day dosing interval is above a certain value (%) at 4 weeks after the start of administration.

[0264] Unlike the therapeutic effects mentioned above, in the case of OC, a bone formation marker, no clear correlation was observed between the rate of adherence to a 2-3 day administration interval and the group of patients whose levels exceeded a specific threshold.

[0265] Parathyroid hormone drugs are known to be bone formation promoters (Non-Patent Literature 9), and the discrepancy between bone formation markers and bone resorption markers is recognized as an indicator of efficacy in daily osteoporosis treatment using teriparatide (Non-Patent Literature 24). Therefore, the results of this analysis, which showed different trends between treatment effect and occlusion (OC), a bone formation marker, regarding the correlation with the rate of adherence to the 2-3 day dosing interval, were considered extremely groundbreaking in light of conventional knowledge about teriparatide therapy.

[0266] 2.9.2.6. Number of cases and percentage of cases of all adverse reactions and nausea (adverse reaction) when distinguished by dosing interval adherence rate (above / below a specific value):

[0267] [Table 2-52]

[0268] [Table 2-53]

[0269] As mentioned above (2.8.2), nausea was the most frequently occurring side effect. Therefore, the percentage of patients who experienced nausea (%) in patients whose adherence to the 2-3 day dosing interval was above a certain value (%) was calculated as follows: Figure 28 shows the results of the analysis of the effects of fluctuations in specific values.

[0270] In groups where the adherence rate to the dosing interval exceeded a specific value, the incidence of nausea (adverse reaction) tended to decrease as the adherence rate increased. Therefore, it was considered that the higher the proportion of weeks in which the dosing interval (excluding the day of administration) was 2 or 3 days, the safer the treatment. More specifically, the configuration in which this proportion was 70% or higher showed good safety, and considering the strong positive correlation between this proportion and safety, it was considered that safety would be roughly maximized when this proportion reached 100%.

[0271] (Example 2)

[0272] 1. Test Method Female rabbits aged 6 months were given a standardized weekly dose of teriparatide at 140 μg / kg. Once a week, twice a week, or seven times a week for four weeks, or teriparatide A control drug without teriparatide was administered subcutaneously seven times a week for four weeks to examine its effects on bone metabolism and bone tissue structure (Table 2-54). In addition, tibia bone density and bone strength were measured. The administered teriparatide solution was prepared as needed by dissolving teriparatide acetate in sterile water for injection, filtering, filling vials, and then dissolving the lyophilized formulation in physiological saline solution at the time of use.

[0273] [Table 2-54]

[0274] 2. Test Results (1) Tibial bone density Analysis of tibial bone mineral density in segmented regions revealed that this drug significantly increased bone mineral density in the proximal region (1 / 5 of the region), which has a high concentration of cancellous bone, compared to the control group. In this region, the bone mineral density of the group administered twice a week was higher than that of the group administered once a week. These results are consistent with the results of Example 1 (Table 2-4), which showed that bone mineral density was higher in the group administered twice a week than in the group administered once a week in the lumbar vertebrae (2nd to 4th lumbar vertebrae) (60% of the lumbar vertebrae are cancellous bone, and 80% of the vertebral body is cancellous bone; Non-Patent Literature 26), which also has a high concentration of cancellous bone, similar to the proximal tibia.

[0275] [Table 2-55] (2) Tibial bone strength Measurements of three-point flexion bone strength of the tibia, taken after the completion of administration, showed that maximum load-bearing values ​​were higher in the groups receiving the drug twice a week and seven times a week compared to the control group.

[0276] [Table 2-56] (3) Morphology of bone tissue of the tibial shaft In the group administered seven times a week, cancellous ossification of the cortical endothelial surface, numerous voids (porosity) within the cortical bone, and disruption of the lamellar structure were observed. However, none of these findings were observed in the groups administered once or twice a week. Non-patent document 14 reports that high-frequency administration of teriparatide enhances bone turnover and suggests that the increase in cortical bone voids due to teriparatide is strongly influenced by the administration frequency. In this example, the fact that twice-weekly administration did not result in an increase in bone turnover that would increase cortical bone voids, despite doubling the administration frequency compared to once-weekly administration, was considered a surprising and groundbreaking result in light of Non-patent document 14. Furthermore, Non-Patent Document 17 states that daily administration of the investigational drug enhances bone resorption markers, etc. It has been reported that, in Non-Patent Document 27, an erosion surface indicating bone resorption was observed on the surface of the cortical bone voids caused by daily administration of the test drug (see Fig. 7 c, etc.), It has been suggested that there is a strong relationship between increased porosity and enhanced bone resorption. In Example 1, the time course of bone resorption markers associated with twice-weekly administration was equivalent to or slightly suppressed compared to the time course of bone resorption markers associated with once-weekly administration (Figures 5-7). Through this mechanism, it can be inferred that twice-weekly administration does not increase bone turnover, thereby increasing the cortical bone void ratio, despite doubling the administration frequency compared to once-weekly administration. Therefore, the effect in Example 1 was supported by the results of the rabbit study in Example 2.

Claims

[Claim 1] A method for treating and / or preventing osteoporosis, characterized by administering 28.2 μg of teriparatide or a salt thereof subcutaneously to patients with osteoporosis twice a week.

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